Tutorial andUser's Guide

May 22, 2024

Wavefunction, Inc.
18401 Von Karman Avenue, Suite 435 Irvine, CA 92612 U.S.A.
www.wavefun.com
Wavefunction, Inc., Japan Branch Office
3-5-2, Kouji-machi, Suite 608
Chiyoda-ku, Tokyo, Japan 102-0083
japan@wavefun.com • www.wavefun.com/japan

Copyright © 2024 by Wavefunction, Inc.
All rights reserved in all countries. No part of this book may be reproduced in any formor by any electronic or mechanical means including information storage and retrieval
systems without permission in writing from the publisher, except by a reviewer who may
quote brief passages in a review.

Prepared in the United States of America

2Acknowledgements
The Spartan’24 Tutorial and User’s Guide was prepared by Warren Hehreand Sean Ohlinger, who take both credit for its utility and blame for its
limitations and inaccuracies. Several members of Wavefunction contributed
significantly, with Philip Klunzinger, Bernard Deppmeier, Andy Driessen,
Jeffrey Johnson, Connor Ohlinger and Tom Hehre warranting special
mention. As with past manuals, sincere thanks go to Pamela Ohsan foryears of turning a sloppy manuscripts into a (nearly) finished manuals.
Updates and additional revisions to follow.
Notes for initial release: In the interest of expediting release of
Spartan’24 (for several reasons), the initial documentation materials will
receive only a partial update from the previous version documentation. The
initial documentation highlights the use of a number of new machinelearning (neural network) routines included in this release (representing
several man-years of development effort). In particular, a set of tutorials
focused only on new features is included (upfront), subsequent tutorials
remain largely unchanged.
Beyond the new feature tutorials, the following additional sections are
updated from the previous manual: Section II (Operations and Overview),
Chapters 21 (Setup menu) and 27 (Help menu), as well as Appendices A,
B, and H.
A full Spartan’24 Manual update will be provided in a subsequent
maintenance release planned for later this year.

Wavefunction, Inc.
Irvine, CA
May 20243

Scope of this Guide
This guide provides a general working reference for Spartan’24 forWindows, Macintosh and Linux. Following an introduction which presents
Spartan as a tool for exploring organic, bioorganic and medicinal, inorganicand organometallic chemistry by way of molecular mechanics and quantum
chemical calculations, together with an array of graphical models forconveying the results of these calculations, it comprises 27 chapters grouped
into five sections (along with several appendices).
Section I (New Feature Tutorials) provides a set of tutorials featuring useof the new machine learning (neural network) routines and their application
to energy, structure, and multi-step conformational searching and NMR
protocols.
Section II (Operations and Overview; Chapters 1-2) describes theoperation of Spartan’s graphical user interface and presents a “walkthrough” illustrating basic interface components.
Section III (Organic Molecules; Chapters 3-7) comprises a set oftutorials that illustrate Spartan’s building capabilities (both 2D and 3D),
show how information can be retrieved from the Spartan Spectra andProperties Database (SSPD) and how quantum chemical calculations can be
set up, submitted, and the results accessed/interpreted.
Section IV (Advanced Tutorials; Chapters 8-15) provides additionaltutorials that extend coverage to inorganic and organometallic molecules aswell as molecules of interest to medicinal chemists. These tutorials also
address a number of capabilities not covered in the previous section,
including multi-molecule documents and associated spreadsheet andplotting functions and procedures for identifying low-energy conformers
and establishing conformer distributions, for obtaining NMR spectra oforganic molecules with several degrees of conformational freedom, forfinding reaction transition states and assigning reaction regio andstereochemistry based on matching calculated and experimental
NMR spectra and for assessing the “similarity” of molecules, either in termsof structure or of chemical function descriptors (CFDs).
4

Finally, a set of tutorials is provided to illustrate the access/use of theCambridge Structural Database from within Spartan. The tutorials in thissection are much closer to “research grade” than the earlier tutorials
especially with regard to the use of NMR spectroscopy.
Section V (Features and Functions; Chapters 16-27) describes indetail the functions available from the menus incorporated into thegraphical user interface for Spartan. The focus is on graphical input andmanipulation of structure, input of other required information and text,
spectral and graphical output resulting from molecular mechanics andquantum chemical calculations, and on use of databases of previously
calculated structures, energies, properties and spectra accessible from
Spartan. This section is intended as a general reference to Spartan’24.
What this guide does not do is thoroughly document the performance andcost (in computation time) of the different molecular mechanics andquantum chemical models available in Spartan’24, or explicitly recommend
specific models or combinations of models for use on chemical problems.
Nor does it show the utility of graphical models in presenting andinterpreting the results of the calculations. However, the choice of models
used in the tutorials can be taken as implicit recommendation as to what we
feel as suitable both in terms of accuracy and practicality, and limited
information about the relative cost of these models is supplied, specifically.
performance and cost in Appendix A. They are covered in greater depth in
A Guide to Molecular Mechanics and Quantum Chemical Calculations*
included as a PDF under the Help menu. The guide also provides acollection of illustrative examples.
Additional appendices provide an overview of the program’s overallarchitecture as well as its present capabilities and limitations (B), a
directory of functions under its menus (C), a listing of commonlyused options (D), a listing of units (E), the proper journal citation for* This 2003 reference is somewhat dated as some models cited have certainly been overtaken (replaced) bymodern models (particularly in development of new functionals). An updated version is this guide is a workin progress.

5

Spartan’24 and the SSPD (F), instructions for installing the Cambridge
Structural Database (G), directions for making databases
from Spartan calculations (H), examples of pharmacophore input (I), input
of experimental infrared, UV/visible and NMR spectra (J), setting up andaccessing remote Spartan servers (K) and providing chemical shift
standards for NMR calculations with different theoretical models (L).
Additional materials relating to several of these appendices may be found as
PDFs under the Help menu.
An up-to-date version of this Tutorial and User’s Guide is available on
Wavefunction’s website (directly accessible from the Help menu).

6

Table of Contents
INTRODUCTION................................................................................ 24
Section I
Section II

NEW FEATURE TUTORIALS ......................... 31
OPERATIONS AND OVERVIEW ..................... 31

Chapter 1
Operating Spartan................................................ 32
Starting and Quitting Spartan ............................................................... 32
Menus and Icons .................................................................................... 32
File ......................................................................................................... 33
Edit ......................................................................................................... 33
Model ..................................................................................................... 34
Geometry................................................................................................ 34
Build....................................................................................................... 35
Setup ...................................................................................................... 35
Display ................................................................................................... 35
Search ..................................................................................................... 36
Expt. Data ................................................................................................ 36
Options .................................................................................................... 37
Activities ................................................................................................. 37
Help ......................................................................................................... 37
Additional Icons ...................................................................................... 38
Tabs ......................................................................................................... 38
Mouse/Keyboard Operations .................................................................. 38
Selection .................................................................................................. 39
Manipulation ........................................................................................... 40
Keyboard Operations............................................................................... 41
Touch-Pad/Track-Pad Operations ........................................................... 41
Touch-Screen Operations ........................................................................ 42
Selecting Molecules ................................................................................ 42
Stereo Displays........................................................................................ 42
Changing Colors and Setting Preferences ............................................... 43
Monitoring and Terminating Jobs ........................................................... 43
Chapter 2

Walking Through Spartan ................................... 44

Section III

ORGANIC MOLECULES ............................... 64

Chapter 3

Building Organic Molecules in 3D ................... 66
Organic Model Kit ............................................... 66
Acrylonitrile......................................................... 68
Cyclohexanone..................................................... 70
Limonene ............................................................. 71
Nicotine................................................................ 72
Coumarin ............................................................. 73

Chapter 4

Sketching Organic Molecules in 2D ................. 75
Sketch Palette....................................................... 75
Sketching a Molecule........................................... 76
Manipulating a Sketch ......................................... 77
N,N-Dimethylaniline ........................................... 77trans-Stilbene....................................................... 78
Indigo ................................................................... 79
3-Cyano-4-methylcyclohexenyl Radical ............. 80
Androsterone........................................................ 81

Chapter 5 Spectra and Properties of Organic Molecules
84
from SSPD ..........................................................
13
C Spectrum of Limonene................................... 84
Proton Spectrum of Indigo................................... 86
Infrared Spectrum of trans-Stilbene .................... 87
Chapter 6 Graphical Models for Organic Molecules from89
the Spartan Spectra and Properties Database.
Electrostatic Potential Map for Nicotine ............. 89
Local Ionization Potential Map for
N,N-Dimethylaniline ........................................... 92
LUMO Map for Androsterone ............................. 93
Chapter 7 Spectra, Properties and Graphical Models for
Organic Molecules from Quantum Chemical
Calculations ........................................................
95
Acrylonitrile......................................................... 95
Cyclohexanone ................................................................................. 101
3-Cyano-4-methylcyclohexenyl Radical ......................................... 103
Coumarin .......................................................................................... 106

Section IV

ADVANCED TUTORIALS ............................... 108

Chapter 8Groups of Organic Molecules ............................ 109
Dienophiles in Diels-Alder Cycloadditions ...........................................110
Addition vs. Substitution........................................................................116
Hydration of Carbonyl Compounds .......................................................118
Acidities of Carboxylic Acids ............................................................... 121
Pos. Selectivity Substituted Naphthalenes ......................................... 124
Tautomers of Nucleotide Bases............................................................. 127
Chapter 9Spectra of Organic Molecules ........................... 129
Infrared Spectrum of Methyl Formate .................................................. 130
Searching Spartan’s Infrared Spectral Database . 133 Proton NMR
Spectrum of 1-Methylindole ................................................................. 137
13
C NMR Spectrum of Cytisine............................................................. 140
13
C NMR Spectrum ofcis-1,2-Dimethylcyclohexane ................................................................ 142
Stereochemical Assignments from 13C Spectra ..................................... 143
Aaptamine: Protonated or Not?............................................................. 145
Chapter 10
Inorganic and Organometallic Molecules ........ 148
Sulfur Tetrafluoride ............................................................................... 149
Benzene Chromium Tricarbonyl ........................................................... 151
Indenyl Effect ........................................................................................ 154
Chapter 11
Chemical Reactions ............................................ 157
Ene Reaction of 1-Pentene .................................................................... 157
SN2 Reaction of Bromide and Methyl Chloride .................................... 162
Carbene Additions to Alkenes ............................................................... 164
Stereospecific Diels-Alder Reactions.................................................... 168
Ziegler-Natta Polymerization of Ethylene ............................................ 170
Thermodynamic vs. Kinetic Control..................................................... 172
Activation Energies of Diels-Alder Reactions ...................................... 175
Chapter 12
Medicinal Chemistry .......................................... 179
Anticipating Blood-Brain Transport ..................................................... 180
Terfenadine. A Potassium Channel Blocker? ........................................ 183
Morphine. Structure vs. Pharmacophore............................................... 186
Gleevec. Making a Pharmacophore from PDB..................................... 191
Chapter 13
Flexible Molecules............................................... 195

Internal Rotation in Dimethylperoxide ............................................ 196
Ethinamate........................................................................................ 200
Allyl Vinyl Ether .............................................................................. 201
13
C Chemical Shifts Depend on Conformation ................................ 204
Gleevec. Protein Bound vs. Free Conformer ................................... 207
HMBC Spectrum of Cantharidin ..................................................... 211
Linalool: NMR of Flexible Molecules ............................................ 214
Anethole: Boltzmann Averaging 13C Chemical
Shifts................................................................................................. 216
Ambiguine H. Analysis to Assign Stereoisomer .............................. 217
Chapter 14 “Dry Labs”: Using the Spartan Spectra and Properties
Database.............................................................. 220
Reactivity of Silicon-Carbon Double Bonds ................................... 221
Isomeric C5H8 Dienes ....................................................................... 223
Using Infrared Spectroscopy to Identify an Unknown Ethyl Benzoate
Derivative ......................................................................................... 225
Infrared Spectra of Short-Lived Molecules ..................................... 227
Using 13C NMR to Distinguish Structural Isomers.229 Using 13C NMR
Spectra to Distinguish Stereoisomers............................................... 231
Chapter 15
Using the Cambridge Structural Database ...... 233
Stable Tautomers of Phenol.............................................................. 233
Binding to Iron Tetracarbonyl .......................................................... 234
Luminol ............................................................................................ 235
Tetrahedrane and Cyclobutadiene .................................................... 236
Section V

FEATURES AND FUNCTIONS ....................... 238

Chapter 16
The File Menu ..................................................... 239
New Build ........................................................................................ 239
New Sketch ...................................................................................... 239
Build New Molecule ........................................................................ 239
Sketch New Molecule ...................................................................... 240
Delete Molecule ............................................................................... 240
Append Molecule(s) ...............................................................................240
Open .......................................................................................................240
Close.......................................................................................................241

Open Recent Documents ........................................................................242
Save ........................................................................................................242
Save As ...................................................................................................242
Print ........................................................................................................242
Save Image As ........................................................................................243
Access PDB Online ................................................................................243
Extract Ligands ......................................................................................244
Embedded Data ......................................................................................246
Exit .........................................................................................................247
Chapter 17
The Edit Menu .....................................................248
Undo .......................................................................................................248
Cut ..........................................................................................................248
Copy .......................................................................................................248
Paste .......................................................................................................248
Select All ................................................................................................249
Find.........................................................................................................249
Find Next ................................................................................................249
Center .....................................................................................................249
Clear .......................................................................................................249
Chapter 18
The Model Menu .................................................250
Wire ........................................................................................................251
Ball and Wire..........................................................................................252
Tube........................................................................................................252
Ball and Spoke .......................................................................................253
Space Filling...........................................................................................253
Line.........................................................................................................254
Hide ........................................................................................................254
Global Model .........................................................................................254
Coupled ..................................................................................................255
Hydrogens ..............................................................................................255
Labels .....................................................................................................255
Ribbons...................................................................................................256
Ramachandran Plot ................................................................................256
Hydrogen Bonds .............................................................................. 256
R/S Chirality..................................................................................... 256
CFD’s ............................................................................................... 256

Configure.......................................................................................... 259
Configure Labels .............................................................................. 259
Configure Objects............................................................................. 260
Configure Ribbons............................................................................ 260
Configure CFD’s .............................................................................. 261
Chapter 19
The Geometry Menu .......................................... 262
Measure Distance ............................................................................. 262
Measure Angle ................................................................................. 262
Measure Dihedral ............................................................................. 262
Freeze Center ................................................................................... 263
Set Torsions ...................................................................................... 265
Generate Isomers.............................................................................. 266
Generate Tautomers ......................................................................... 269
Constrain Distance ........................................................................... 270
Constrain Angle................................................................................ 270
Constrain Dihedral ........................................................................... 270
Define Point ...................................................................................... 273
Define Ligand Point ......................................................................... 273
Define Plane ..................................................................................... 273
Define NOE ...................................................................................... 274
Define CFD ...................................................................................... 275
Set Similarity Centers ...................................................................... 275
Similarity Based on Structure .......................................................... 275
Similarity Based on CFD’s .............................................................. 276
Similarity Based on a Pharmacophore ............................................. 277
Align ................................................................................................. 277
Align Based on Labels ..................................................................... 278
Align Based on Structure ................................................................. 278
Align Based on CFD’s ..................................................................... 279
Align to a Pharmacophore ................................................................ 279
Chapter 20
The Build Menu .................................................. 281
2D Sketch Palette ............................................................................. 281
Palette Atoms ........................................................................................ 282
More: Element/Functional Group/Ligands
Library ................................................................................................... 282

Common Rings ..................................................................................... 282
Common Carbonyl Groups ................................................................... 282
Stereochemical Markers ........................................................................ 282
Open-site Markers ................................................................................. 282
Charge/Radical Markers........................................................................ 283
Reaction Arrows .................................................................................... 283
Drawing Tools....................................................................................... 284
Proton and 13C Chemical Shifts ............................................................ 285
CH Couplings ........................................................................................ 286
HH Couplings........................................................................................ 287
Making a Sketch.................................................................................... 289
Manipulating a Sketch .......................................................................... 289
Sketch Operations ................................................................................. 290
Add an Atom, Ring, or Carbonyl Group ............................................... 290
Add Multiple Bonds .............................................................................. 290
Fuse Rings ............................................................................................. 290
Replace an Atom with Another ............................................................. 290
Access an Element, Functional Group or
Ligand from the Library ........................................................................ 291
Add Stereochemical Markers (Dashes and Wedges). ........................... 292
Add an Axial or Equatorial Marker ...................................................... 293
Assign Charges and Radical Sites......................................................... 294
Specify “Open Site” Marker(s) ............................................................. 294
Undo the Last Action ............................................................................ 295
Clean Up a Drawing .............................................................................. 295
Remove an Atom or Bond ..................................................................... 295
Remove a Multiple Bond ...................................................................... 295
Remove a Reaction Arrow .................................................................... 295
Remove a Stereochemical Marker ........................................................ 295
Change or Remove an Axial or Equatorial
Label from a Stereochemical Marker ................................................... 295
Remove a Charge or Radical Marker.................................................... 296
Remove an “Open Site” Marker ...................................................... 296
Clear the Screen ............................................................................... 296
Copy/Paste/Delete Selected ............................................................. 296
3D Builders ...................................................................................... 296

Organic Builder ................................................................................ 297
Groups .............................................................................................. 298
Rings ................................................................................................ 299
More ................................................................................................. 299
Clipboard .......................................................................................... 300
Smiles/InChI..................................................................................... 301
Inorganic Builder.............................................................................. 301
Ligands ............................................................................................. 304
Peptide Builder ................................................................................. 304
Specifying Amino Acid Sequence.................................................... 305
Specifying Macroscopic Structure ................................................... 306
Terminate ......................................................................................... 306
Nucleotide Builder ........................................................................... 307
Specifying Base Sequence ............................................................... 308
Specifying Helical Structure ............................................................ 308
Substituent Builder ........................................................................... 309
Library Preparation .......................................................................... 310
Attachment ....................................................................................... 311
List Generation ................................................................................. 312
Accessing ChemDraw (Windows Only) .......................................... 313
General Molecule Building Functionality........................................ 314
Multiple Fragments .......................................................................... 314
Rotate/Stretch Bonds........................................................................ 314
Replace Atom/Fragment................................................................... 315
Invert Chirality ................................................................................. 315
Building/Editing Menu Functions.................................................... 316
View ................................................................................................. 316
Edit Build ......................................................................................... 316
Edit Sketch ....................................................................................... 317
Delete ............................................................................................... 317
Make Bond ....................................................................................... 318
Break Bond....................................................................................... 318
Minimize ............................................................................................... 319
Guess Transition State ........................................................................... 319
Chapter 21
The Setup Menu.................................................. 321
Calculations ........................................................................................... 323

Calculate ................................................................................................ 325
Task ....................................................................................................... 325
Energy ................................................................................................... 325
Equilibrium Geometry .......................................................................... 326
Transition State Geometry .................................................................... 327
Equilibrium Conformer ......................................................................... 327
Conformer Distribution ......................................................................... 327
NMR Spectrum ..................................................................................... 330
Similarity Library .................................................................................. 333
Similarity Analysis ................................................................................ 333
State ....................................................................................................... 337
In Gas/Solvent ....................................................................................... 337
Type of Calculation ............................................................................... 338
Molecular Mechanics ............................................................................ 339
Semi-empirical models ......................................................................... 340
Hartree-Fock models ............................................................................. 340
Correlated models ................................................................................. 342
Wave Function Based models ............................................................... 342
Density Functional models (DFT) ........................................................ 343
Local Density Approximation (LDA) ................................................... 343
Generalized Gradient Approximation (GGA) ................................... 344
Global Hybrid Generalized Gradient Approximation (GHGGA) ........ 344
Range Separated Hybrid Generalized Gradient Approximation (RSHGGA) ..................................................................................................... 344
meta Generalized GradientApproximation (mGGA) ....................................................................... 345
Global Hybrid meta Generalized
Gradient Approximation (GH-mGGA) ................................................. 345
Range Separated Hybrid meta
Generalized Gradient Approximation(RSH-mGGA) .................................................................................. ….345
Double Hybrid meta Generalized Gradient Approximation (DH-RSHmGGA).....…. ................................................................................... 346
Non Local Corrections ..................................................................... 346“Cost” of Density Functional Models .............................................. 347
Thermochemical Recipes ................................................................. 349

Basis Sets.......................................................................................... 352
Dual Basis Sets ................................................................................. 353
Pseudopotentials ............................................................................... 353
Start from. ........................................................................................ 354
Subject to.......................................................................................... 355
Constraints ........................................................................................ 355
Frozen Atoms ................................................................................... 355
Compute ........................................................................................... 356
IR ...................................................................................................... 356
Raman .............................................................................................. 357
NMR ................................................................................................. 357
Coupling Constants (Empirical, Fermi Contact, Calculated) .......... 359
UV/vis .............................................................................................. 359
QSAR ............................................................................................... 359
Intrinsic Reaction Coordinate .......................................................... 360
Total Charge ..................................................................................... 360
Unpaired Electrons ........................................................................... 361
Options ............................................................................................. 361
Global Calculations .......................................................................... 362
Surfaces ............................................................................................ 362
Common Surfaces and Property Maps............................................. 369
Surface.............................................................................................. 369
Property ............................................................................................ 370
Resolution......................................................................................... 371
IsoValue ........................................................................................... 371
Global Surfaces ................................................................................ 372
Submit .............................................................................................. 372
Chapter 22
The Display Menu ...............................................375
Output .....................................................................................................375
Properties................................................................................................377
Molecule Properties: Molecule QSAR Descriptors, Thermodynamics, 2D
Drawing,
NMR, Utilities ........................................................................................378
Molecule .................................................................................................378
QSAR .....................................................................................................379
Thermodynamics ....................................................................................381

2D Drawing ............................................................................................382
NMR .......................................................................................................382
Utilities ...................................................................................................383
Molecule Utilities ...................................................................................384
Atom Properties......................................................................................384
Bond Properties ......................................................................................386
Constraint Properties ..............................................................................386
Point, Ligand Point and Plane Properties...............................................388
Surface Properties ..................................................................................388
Curve and Plot Properties.......................................................................390
Substituent Properties.............................................................................394
CFD Properties .......................................................................................395
Regression Properties .............................................................................396“Selected” Style .....................................................................................396
Orbital Energies .....................................................................................397
Surfaces ..................................................................................................398
Spectra ....................................................................................................398
Simplified Presentation of Spectra .........................................................398
Generalized Presentation of Spectra ......................................................403
IR, Raman ..............................................................................................403
NMR .......................................................................................................408
UV/vis ....................................................................................................412
Formulas .................................................................................................414
Spreadsheet.............................................................................................418
From the Add Dialog..............................................................................421
From Post Buttons…………………………………427
From the Clipboard ................................................................................428
User-Defined Expressions ................................................................ 428
Numerical Data ................................................................................ 429
Plots .................................................................................................. 431
Simplified Presentation of Plots ....................................................... 431
Generalized Presentation of Plots .................................................... 433
XY Plots ........................................................................................... 435
XYZ Plots......................................................................................... 435
Similarities........................................................................................ 437
Reactions .......................................................................................... 439

Chapter 23
The Search Menu ................................................ 441
Structure Query ................................................................................ 441
Reaction Query................................................................................. 442
Databases .......................................................................................... 445
Cambridge Structural Database (CSD) ............................................ 445
Spartan Spectra and Properties Database (SSPD) ...................... 450
Accessing and Processing Data from SSPD .................................... 452
Molecule Replacement ..................................................................... 452
Substructure and Other Modes of Searching SSPD......................... 453
Plotting Data Resulting from an SSPD
Search ............................................................................................... 456
Regression Analysis of Data Resulting froman SSPD Search................................................................................ 458
Relationships Involving Chemical
Reactions .......................................................................................... 459
Retrieving Data from an SSPD Search. ............................................ 462
Spartan Reaction Database (SRD) ................................................... 462
Substructure Searching..................................................................... 463
Retrieving Data from an SRD Search .............................................. 465
Spartan Infrared Database (SIRD) ................................................... 466
Spectra Searching ............................................................................. 466
Filters................................................................................................ 468
Retrieving Data from an SIRD Search............................................. 471
External Infrared Database (XIRD) ................................................. 472
Chapter 24
The Data Menu ....................................................473
1
13
H/ C .....................................................................................................473
JHH ......................................................................................................................................................................................474
JCH.......................................................................................................................................................................................474
Chapter 25
The Options Menu ...............................................475
Preferences .............................................................................................475
Settings Tab ............................................................................................476
Molecule Tab..........................................................................................482
vdW Radii Tab .......................................................................................484
Databases Tab.........................................................................................485
Jobs Tab..................................................................................................486
Miscellaneous Tab..................................................................................488

Icons Tab ................................................................................................491
URLs Tab ...............................................................................................492
Available Servers Tab ............................................................................493
Embedded Server Tab/Service Control ..................................................495
Colors .....................................................................................................498
Fonts/Graphics Fonts..............................................................................498
Monitor ...................................................................................................499
Calculator ...............................................................................................500
Icons .......................................................................................................500
Chapter 26
The Activities Menu .............................................501
Tutorials/Topics......................................................................................501
Lookup in Wikipedia..............................................................................502
Chapter 27
The Help Menu ....................................................503
Spartan’24 Help.....................................................................................503
Spartan’24 Manual ................................................................................503
License Utility ........................................................................................504
About Spartan’24 ..................................................................................504
Appendix A Topics .............................................................................505
Potential Energy Surfaces ......................................................................507
One Dimensional Energy Surfaces ........................................................507
Many Dimensional Energy Surfaces......................................................510
Theoretical Models.................................................................................515
Hartree-Fock Molecular Orbital Models ...............................................516
Basis Sets.......................................................................................... 517
Beyond Hartree-Fock Models .......................................................... 518
Configuration Interaction Models .................................................... 519
Møller-Plesset Models ..................................................................... 519
Density Functional Models .............................................................. 520
Local Density Approximation (LDA) .............................................. 521
Generalized Gradient Approximation (GGA) .............................. 521
Global Hybrid Generalized Gradient Approximation (GHGGA) ... 521
Range Separated Hybrid Generalized Gradient Approximation (RSHGGA) ................................................................................................ 522
meta Generalized GradientApproximation (mGGA) .................................................................. 522

Global Hybrid meta Generalized
Gradient Approximation (GH-mGGA) ............................................ 523
Range Separated Hybrid meta
Generalized Gradient Approximation(RSH-mGGA) .................................................................................. 523
Double Hybrid meta Generalized Gradient Approximation (DH-RSHmGGA)............................................................................................. 523
Non Local Corrections ..................................................................... 523
Numerical Integration ...................................................................... 524“Cost” of Density Functional Models .............................................. 525
Disadvantages of Density Functional Models ........................... 527
Models for Open-Shell Molecules ................................................... 528
Semi-Empirical Molecular Orbital Models ..................................... 529
Molecular Mechanics Models .......................................................... 530
Choosing a Theoretical Model ......................................................... 531
Finding and Verifying Equilibrium andTransition-State Geometries............................................................. 534
Equilibrium Geometries ................................................................... 534
Transition-State Geometries............................................................. 536
Reactions Without Transition States ................................................ 539
Calculations Using Approximate Geometries .................................. 540
Total Energies and Thermodynamic Kinetic Data. 541 Thermochemical
Recipes and Calculating
Accurate Heats of Formation ................................................................ 547
The T1 Thermochemical Recipe ........................................................... 550
Dealing with Conformationally Flexible Molecules ........................ 552
Interpreting Conformational Preferences .............................................. 557
Calculating Infrared Spectra ................................................................. 560
Quality of Calculated Infrared Spectra ................................................. 564
Database of Infrared Spectra ................................................................. 566
Raman Spectra ...................................................................................... 566
Calculating NMR Spectra ..................................................................... 567
Underlying Theory ................................................................................ 568
Correcting 13C Chemical Shifts from B3LYP/ 6-31G*, ωB97X-D/6-31G* andωB97X-V/
6-31G* Density Functional Models ...................................................... 570

Empirically Corrected 13C Chemical Shifts .......................................... 570
Calculating Chemical Shifts forConformationally-Flexible Molecules .................................................. 572
Assigning Stereo and Regioisomers from
Calculated Chemical Shifts ................................................................... 576
Calculating HH and CH Coupling Constants ....................................... 579
Calculating COSY and HMBC Spectra ................................................ 581
Atomic and Molecular Orbitals............................................................. 582
Orbital Surfaces..................................................................................... 582
Atomic Orbitals ..................................................................................... 583
Orbitals and Chemical Bonds ............................................................... 584
Singlet Methylene ................................................................................. 586
Frontier Molecular Orbitals and Chemical Reactivity .......................... 589
The Fukui-Woodward-Hoffmann Rules ............................................... 591
Electron Densities: Sizes and Shapes of Molecules......................... 593
Space-Filling Models ............................................................................ 593
Electron Density Surfaces ..................................................................... 594
Bond Density Surfaces ..................................................................... 596
Electrostatic Potential Maps: Charge
Distributions ..................................................................................... 599
Local Ionization Potential Maps and LUMO Maps: Electrophilic andNucleophilic
Reactivities ....................................................................................... 605
Local Ionization Potential Maps and Electrophilic Reactivity........ 606
LUMO Maps and Nucleophilic Reactivity ...................................... 607
Appendix B Capabilities and Limitations .................................. 610
Molecular Mechanics Models .......................................................... 610
Semi-Empirical Models ................................................................... 610
Hartree-Fock Models ....................................................................... 610
Density Functional Models .............................................................. 611
MP2 Models ..................................................................................... 611
Wave Function Based Correlated Models........................................ 612
Thermochemical Recipes ................................................................. 612
Excited-State Models ....................................................................... 613
Basis Sets and Pseudopotentials ....................................................... 613
Solvent Models................................................................................. 614

Properties and Spectra ...................................................................... 615
Graphical Models ............................................................................. 616
Similarity Analysis ........................................................................... 617
Appendix C Menus ....................................................................... 618
Spartan Screen ................................................................................. 618
Contextual ........................................................................................ 626
Appendix D Commonly-Used Program Options ....................... 629
Conformational Search .................................................................... 630
Similarity Analysis ........................................................................... 630
Geometry Optimization .................................................................... 631
Molecular Mechanics Calculations .................................................. 632
Quantum Chemical Calculations...................................................... 632
Semi-Empirical Calculations ........................................................... 634
Property and Spectra Calculations ................................................... 634
Miscellaneous and Printing .............................................................. 635
Appendix E Units ...............................................................................636
Appendix F

Citation .................................................................639

Appendix G Configuring the Cambridge Structural
Database ................................................................................................640
Appendix H Constructing Custom Databases .................................642
Appendix I

Pharmacophore Input .........................................643

Appendix J

Input of Experimental Spectra...........................644

Appendix K Platform Dependencies .................................................645
Appendix L NMR 13C Chemical Shift Standards............................652
Glossary .................................................................................................654

Introduction
Every few decades chemists are presented with a new tool so powerful thatit changes the very landscape of the subject. NMR spectroscopy is certainly
an excellent example, for it fundamentally altered the way that the structuresof molecules are revealed, largely (but not entirely) replacing difficult andtime-demanding synthesis with a simple spectral measurement. We believethat computational methodology (“molecular modeling” in the vernacular) is
well poised to have an equal or perhaps even greater impact on the way
chemistry is done.
Molecular mechanics and quantum chemical calculations provide
structures, relative stabilities, properties and spectra of isolated molecules.
Because of their inherent simplicity, molecular mechanics calculations havelong been used throughout the chemical community. Quantum chemical
calculations are much more time demanding, and only in the last decade havefast enough computers become widely available to make their application
routine among mainstream chemists.
Quantum chemical calculations may also be called upon to furnish
information about the mechanisms and product distributions of chemical
reactions, either directly by calculations on transition states, or indirectlybased on the Hammond Postulate, by modeling the steric and electronic
demands of the reactants. Quantitative calculations, leading directly to
information about the geometries of transition states, and about reaction
mechanisms in general, are becoming more and more common, while
qualitative models are still needed for systems that are too large or too
complicated to be subjected to the more rigorous treatments. Quantum
chemical calculations are also able to furnish infrared and Raman spectra,
UV/visible spectra and NMR spectra. The use of calculations to support orchallenge structures assigned solely by NMR or to employ NMR todistinguish among regio and stereoisomers that might result from aparticular chemical reaction is of particular value. Finally, quantum chemical
calculations can supply information to complement existing experimental dataor to replace it altogether, for example, atomic charges for QSAR analyses, andintermolecular potentials for molecular mechanics and molecular dynamics
23

calculations. Machine Learning models have joined the ranks of the available“methods” and while currently more restricted in application, are incredibly fastand reliable. There is every reason to believe that for some tasks, the neuralnetwork models will likely become the dominant approach.
Spartan’24 (“Spartan”) has been designed to address the ever increasingrole that calculations play in chemistry and related fields. It represents acontinuing collaboration between Wavefunction, Inc., and Q-Chem, Inc. QChem codes supplement and extend the traditional strengths of Spartan as
an easy to learn and use tool for molecular mechanics and quantum chemical
calculations. Spartan is intended to be utilized by chemists, not only
computational chemists who are already familiar with the capabilities ofmolecular mechanics and quantum chemical calculations, but also
experimental chemists who may have little or no prior experience, but want
to use calculations much in the same way as experimental techniques suchas NMR spectroscopy.
Spartan includes a series of independent modules, tightly connected via ahighly functional, but simple and uncluttered graphical user interface.
Certainly over the last 30+ years, the interface has become a little less “uncluttered”, but
the Spartan philosophy of keeping these as simple as one can is embraced throughout.
It has been designed not only to greatly reduce the drudgery and possibility
for human error associated with the preparation of input, but also to guidethe interpretation of output.

24

Spartan’s interface provides the gateway to a range of modern
computational methods, including molecular mechanics models, semiempirical and Hartree-Fock molecular orbital models, and correlated models
including a wide variety of density functional models, Møller- Plesset models
and a selection of higher-order wave function-based models such as
CCSD(T). Popular thermochemical recipes such as G3(MP2) and G3
intended to closely mimic the results of CCSD(T) and other high-level
correlated models at a small fraction of the cost are also supported. A fullrange of basis sets is supported including the computationally efficient series
from Pople, cc-pVDZ, cc-pVTZ and cc-pVQZ series from Dunning and thedef2 series from Alhrichs and Weigand as well as basis sets customized forindividual properties. None of these models is likely to be ideal for every
application. While the most sophisticated quantum chemical models may
yield excellent results, they will likely be too time consuming for routine
application, and it may be necessary to contend with lesser treatments.
Spartan’s interface facilitates mixing and matching different molecularmechanics and quantum-chemical models. Results from one model may
easily be passed on for further analysis with other (more rigorous) models.
Machine learning (ML) or neural net (NN) technology offers the possibilityof a new class of models that potentially offer both high reliability andquality as well as low cost. Implemented in Spartan for the first time are aseries of neural nets designed to (i) improve conformer energy differences
provided by MMFF molecular mechanics, (ii) accurately estimate ωB97XD/6-31G* equilibrium geometries starting from MMFF geometries, and(iii) accurately estimate total energies from ωB97X-V/6-311+G(2df,2p),
ωB97M-V/6-311+G(2df,2p) and ωB97M(2)/6-311+G(2df,2p) density
functional models starting from ωB97X-D/6-31G* equilibrium geometries
and energies or estimated ωB97X-D/6-31G* equilibrium geometries andωB97X-D/6-31G* energies ( separate neural network).
The most important quantities to come out of calculation are geometry andenergy. While these are unique for a rigid molecule, molecules with one
or more rotatable single bond and/or six or higher-member ring comprise aseries of conformers, each with its own geometry and energy. Spartan
provides automated (single human step) protocols to furnish either the “best”(lowest-energy) conformer or the set of low- energy conformers that make up
the bulk of a sample. Both molecular mechanics and a variety of quantum
25

chemical models may be used.
Spartan provides access to several common spectral quantities, inparticular infrared spectra (molecular mechanics, semi-empirical, HartreeFock, density functional and MP2 models), Raman spectra (Hartree-Fockand density functional models), NMR spectra (Hartree- Fock and density
functional models) and UV/visible spectra (CIS, CIS(D) and time-dependent
density functional models). Experimental IR, NMR and UV/visible spectrafrom freely available on-line databases are easily accessed and superimposedfor comparison with calculated spectra.
Spartan provides tools to quantify both the similarity of molecular
structures and of chemical environments characteristic of these structures.
Also available is the ability to identify molecules that fit into a specificchemical environment (a so-called pharmacophore). Pharmacophores may
be extracted from small molecules bound to proteins and nucleotides fromthe PDB (Protein Databank).
Spartan includes a variety of graphical tools to assist in interpreting theresults of calculations as well as similarity analyses. These include structure
models as well as molecular orbitals, electron and spin densities, local
ionization potentials and electrostatic potentials that can be displayed assurfaces, slices and property maps.
Spartan accesses several different databases of calculated and (whereavailable) experimental information. The SSPD (Spartan Spectra andProperties Database v. 6.1) comprises calculated geometries and NMR
spectra obtained from the ωB97X-D/6-31G* density functional model for>317,000 molecules. Most entries also include energies from three
additional models (these came primarily as the “training set” data for ourenergy neural networks): ωB97X-V/6-311+G(2df,2p), ωB97M-V/6311+G(2df,2p) and the ωB97M(2)/6-311+G(2df,2p) model, allowing moreaccurate reaction energies to be calculated (“on-the-fly”). About 90% of the
SSPD entries have been appended with supplementary IR spectra,
calculated using the EDF2/6-31G* density functional model. This allows
enthalpies, entropies and Gibbs energies to be accessed (“on-the-fly”).
Finally, heats of formation from the T1 thermochemical recipe are available
for about 90% of the SSPD v. 6.1 entries.
SSPD also includes ≈8,000 calculated transition-state geometries obtained
26

from the ωB97X-D/6-31G* model for concerted reactions (primarily DielsAlder, 1,3-dipolar, Cope, Claisen, ene and hydroboration), along withenergies from the ωB97X-V/6-311+G(2df,2p) model.
Spartan’24 also allows the user to construct a database to be used by itself
or in conjunction with the SSPD v. 6.1 collection, the minimum requirement
being an equilibrium or transition-state geometry obtained from theωB97X-D/6-31G* model.
Additionally, Spartan accesses the freely available data collections such as
the PDB of >213,000 protein structures, IR, UV/vis, and thermodynamic
data from NIST, and chemical shift data from the nmr_shift_db. Finally,and by separate license, Spartan’24 can search the latest release(s) of theCambridge Structural Database (the CSD) of more than a million X-ray
crystal structures.
New features in Spartan’24:
Myriad changes and improvements, both large and small, distinguish
Spartan’24 from its predecessor(s). Among the most notable are:Machine Learning (Neural Network) routines: These presently fall into
2 groups, neural networks that provide improved energies and a single
routine that provides structure (equilibrium geometries), a full description
is available in the Topics section of the Activities menu, or from Appendix
A (to this reference).
Neural Networks for Energy
Molecular Mechanics
Spartan’24 includes a neural network termed Corrected MMFF (notintended to as pejorative, as the routine relies on (requires) an MMFF94
structure, and is trained to provide ωB97X-V/6-311+G(2df,2p)//MMFF
energies (essentially for “free”, but in practice at the time scale of less thana second to a few seconds per calculation). While of significant utility alone,
this routine is most useful in the context of conformational searching. In
Spartan’24 we provide new options for utilizing this neural network inplace of MMFF. Available from the Equilibrium Geometry task as wellas the multi-step density functional-based routines: Equilibrium27

Conformer, Conformer Distribution, and the NMR Spectrum task.
Quantum Mechanics
Three additional neural network routines, given input from either:
ωB97X-D/6-31G* geometries or a neural network estimate the ωB97XD/6-31G* geometries, termed:
Est. Density Functional: ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G*
Est. Density Functional: ωB97M-V/6-311+G(2df,2p)//ωB97X-D/6-31G*
Est. Density Functional: ωB97M(2)/6-311+G(2df,2p)//ωB97X-D/6-31G*

This represents a significant time savings, in that the high quality energy
calculations from the ωB97X-V/6-311+G(2df,2p), ωB97M-V/6311+G(2df,2p) and ωB97M(2)/6-311+G(2df,2p) models, lead tosignificantly improved reaction and conformer energies compared to those
provided by the simpler and much less costly ωB97X-D/6-31G* model. As
perhaps expected, these routines are also offered as either stand-alone
calculations, or as options in a number of multi-step protocols accounting
for conformational analysis.
Neural Networks for Structure
Spartan’24 includes an additional neural network routine that, provided an
optimized MMFF structure, will furnish an Est. Density Functional
ωB97X-D/6-31G* structure (Equilibrium Geometry). This is not an
instant (fraction of a second) calculation, like the neural network routinesthat provide energy, as, similar to most MMFF or QM optimization
routines, the neural network performs an optimization of structure withconvergence criteria and training (against a large, 6 million structure,organic training set) sufficient to closely reproduce ωB97X-D/6-31G*
geometries. Note, this routine is not currently trained for energies, nor does
it supply a wave function (necessary for calculation of most graphicalmodels, NMR chemical shift and a host of other properties). As such, thisneural network is often used in conjunction with either: an Energy (single
point energy) calculation at ωB97X-D/6-31G*, or one of the above three
QM energy neural networks (in the context of conformational searching).
Collectively, the 5 neural networks can be applied to several routine
28

Spartan tasks including:
Energy is available from the first four routines.
Equilibrium Geometries are available, ostensibly in two ways, from
Corrected MMFF, and directly from the Est. Density Functional
ωB97X-D/6-31G* routine.
Conformational Searching has been supplemented with optional use ofneural network routines. The Corrected MMFF routine can be used
individually to improve energy results from MMFF optimized structures,
as well as in conjunction with all of the above-mentioned machine learningmodels. The new routines are also optionally available in all tasks that
include conformational searching with quantum chemical models:Equilibrium Conformer, Conformer Distribution, and NMR Spectrum.
A future maintenance release will update the included core QM
functionality from the Q-Chem 5 release to version 6.
Databases
SSPD (Spartan Spectra & Properties Database). SSPD has been
extended to include an additional ≈12,000 organic molecules (primarily
drug/drug candidates, pesticides, and natural products), as well as another≈8,000 transition states for concerted reactions (primarily Diels-Alder,
dipolar cycloadditions, Cope, Claisen and ene reactions). These havestructures from ωB97X-D/6-31G* and energies from ωB97X-V/6311+G(2df,2p)//ωB97X-D/6-31G* calculations. Transition states areaccessed from the transition state guesses in the Spartan user interface.
Natural Products. The collection of natural products included in theprevious SSPD (bundled with Spartan’24) has been extended, andmodified to provide calculated information on only the lowest energy
conformer (based on ωB97X-V/6-311+G(2df,2p)[6-311G*]//ωB97X-D/631G* calculations). This provides both calculated proton and 13C chemical
shifts and experimental 13C shifts for more than 2700 published natural
products.
Custom (user-generated) database formation. New in Spartan’24, a
computational task, a one-step submission for SSPD compatible, which29performs (minimally) an ωB97X-D/6-31G* geometry, and optionally
includes ωB97X-V, ωB97M-V, and ωB97M(2) /6-311+G(2df,2p) energies,
EDF2/6-31G* frequencies and ωB97X-D/6-31G* NMR chemical shifts.
The SSPD Compatible task also applies to transition states (absent thechemical shifts option). User entries can be automatically placed alongside
the distributed SSPD. This new utility represents significant progress in theease of users generating their own database of spectra & properties, it alsooffers a head start in the availability of the current SSPD collection, acurated collection of >317,000 organic and organometallic molecules, witha full range of pre-calculated data available from high quality density
functional models for structure and energy.
Parallel Processing
The easy access to high end computational hardware (via cloud computing)has enabled performance assessment on several configurations of highperformance configurations. Users running the greater than 16 core license
are encouraged to reach out to us via support@wavefun.com for access to(and assistance with) benchmark data.
Graphical Interface
Generate Isomers. The generate isomer tool has been refined withimproved defaults, and provides automatic stereoisomer/regioisomerelaboration.
2D Drawings. Improvements have been made to the 2D Sketch builder.
Note, our 2D building tools are not intended to provide high quality 2D
sketches. The ChemDraw program (and variations), are the most useful
application for producing high quality 2D representations of molecules. All
Spartan versions will also open native ChemDraw files. Spartan’24, as inprevious releases, the Windows version offers the ability to build in
ChemDraw (2D), and import/auto-convert into 3D in Spartan (Note:
ChemDraw interface can be enabled from Options menu > Preferences >Settings tab).
Dual Display. A new display window provides for 2D structure view whenutilizing the 3D user interface, and for 3D display when using the flat 2D
sketch display.
Expt. Data. The Expt. Data menu has been refined, offering a spreadsheet
30

for import/organization of NMR data (proton and 13C chemical shifts, andproton and CH coupling data).
Output Summary. The HTML presentation format has been improved
resulting in an order or magnitude (or more) speed increase as some datatables are calculated on-the-fly upon opening. All data from the Output
Summary is available for export in single or multi-molecule format.
Computational Enhancements
Spartan’24 will (by default) take advantage of up to 16 cores for paralleljobs, with the option to license >16 cores as well (for high performance
multicore systems). In the initial release, computational enhancements arein the form of the new machine learning models available for various tasks,
also included is our implementation of the Q-Chem package. This releaseis the result of continued collaboration (begun with the release of
Spartan’02 in 2002).
Through this collaboration our customers benefit from both GUI andsignificant computational enhancements (the T1thermochemcial recipe, themulti-step protocols for conformational searching in conjunction with
Boltzmann weighted NMR data, and the new machine learning models), as
well as a growing range of computational options and modern QM
development in Q-Chem. A subsequent maintenance update will include an
updated version of the current Q-Chem package.
Spartan users have consistently and diligently reported program bugs via
support@wavefun.com. Many reported issues from the previous release
have been addressed in this update. Wavefunction would like to thank ourcustomers for their continued help in making Spartan a better program.
User feedback is greatly appreciated!

31Section I
New Feature Tutorials
Neural Network Calculations
The following tutorials provide a number of examples utilizing the newneural network (machine learning) routines incorporated in Spartan’24. In
order to reduce calculation time and also to provide for assessment of
results, these tutorials often start from files that contain the results ofprevious QM calculations (geometries, isomer energies and conformer
energies, NMR shifts, etc.). Sections are loosely organized around specificneural network routine tasks, for example, Estimate ωB97X-D/6-31G*
Equilibrium Geometries.
Basic knowledge of Spartan operation is assumed. New Spartan users
should visit the Activities menu and (minimally) review the first threetutorials as well as the seventh tutorial: Groups of Organic Molecules,
before attempting the following tutorials.
A secondary goal is to quantify the computational time savings, whenemploying (one or more) neural network routines in place of the calculation(or step(s) in a calculation) that were previously performed with quantum
chemical models. Throughout, an attempt is made to estimate the total timerequired to perform the steps in the tutorial (including calculations).
Calculation time estimates are based on Spartan’24 running on either: an
8-core Intel i7 Windows 11 machine, or a 16-core AMD Threadripper
Ubuntu machine (only 8 of the 16 cores were utilized at a time). In general,the Linux OS shows superior parallel performance for most calculations,and offers more efficient memory allocation.
Estimate ωB97X-D/6-31G* Equilibrium Geometries
While the ωB97X-D/6-31G* density functional model has provenremarkably successful for calculation of equilibrium geometries(structures), it becomes impractical for routine calculations on rigid or
nearly rigid molecules with molecular weights greater than perhaps 700
amu, and for even smaller molecules with multiple degrees of32

conformational freedom (including hundreds if not thousands of accessible
conformers). Routine usage requires an alternative approach. A good dealof time has been spent exploring post-molecular mechanics options likesemi-empirical models such as PMx (PM3, PM6, etc.). While thesealternatives meet the needs for “faster” and are “applicable to larger andmore flexible systems”, and while they generally provide reasonableequilibrium geometries, it is known that these options are no better thanmolecular mechanics at providing accurate energies or energy differences(needed to establish an accurate Boltzmann distribution).
A new option, available in Spartan’24, is to use a neural network, trained
to reproduce ωB97X-D/6-31G* geometries starting from molecularmechanics (MMFF94). This is available for neutral, closed-shell organic
molecules including H, C, N, O, F, S, Cl, and Br. Examples follow.
Monacustin structure[10-30 minutes]

1. Open the file monacustin from the neural network folder inside theTutorials directory*:monacustin

This file contains the equilibrium geometry for the natural productmonacustin, obtained from the ωB97X-D/6-31G* density functionalmodel, and will serve as the reference to compare results from a neuralnetwork calculation. The provided calculation results required
approximately 6 and a half minutes wall time on an 8 core Intel I7
processor), you can review the Output via the Display menu.
* For Windows, the Tutorials directory is found in Program Files/ Wavefunction/Spartan24. It should
be copied to another location available to the user (we recommend Documents or Desktop) prior to
opening it in Spartan.
For Macintosh, this is located at the top of the Spartan24 disc image. It needs to be copied to anotherlocation available to the user (we recommend Documents or Desktop).
For Linux, the Tutorials directory is found in the install directory. Copy the Tutorials directory to alocation that allows write permission, typically the user’s home directory.

33

The Output tab includes timing data, toward the bottom of text output.
Optional: To test performance on your machine, you can, click the
Minimize entry from the Build menu, open the Calculations dialog, andsubmit an Equilibrium Geometry using the default ωB97X-D/6-31G*
density functional model. Note the anticipated calculation on a modern
quad-core laptop is on the order of 10-15 minutes.
2. From the Spreadsheet (Display menu > Spreadsheet), make a copy ofmonacustin, and paste this into the Label column under the existing entry(right-click and choose Paste and to Paste Molecule(s). Rename thesecond copy monacustin neural net (double-click in the new cell andoverwrite the auto-generated name). With the copy (monacustin neuralnet) selected, estimate the equilibrium geometry calculation:
3. Open the Calculations dialog, select Equilibrium Geometry and Est.
Density Functional to the right of Calculate. At present, ωB97X-D/631G* is the only selection available. Make certain that the Global
Calculations check box at the bottom right of the dialog is not checked.
Submit the job.
4. When completed (a few seconds), return to the spreadsheet, select (clickon) the first molecule, monacustin ωB97X-D/6-31G* (the full calculated
density functional ωB97X-D/6-31G* equilibrium geometry). Select Alignfrom the Geometry menu and, click on the Align by button at the lower
right of the user interface. (Note: we are aligning by Structure).
5. Visually inspect the results. From the Spreadsheet, click inside theboxes to the left of the two monacustin molecules (enables simultaneous
display). From the (default) Ball and Spoke display style, it appears thatthe two structures are nearly identical. Switch to the Space Filling (Modelmenu) which more accurately depicts the actual molecule (but is less to
explore graphically). In the space filling model, visual differences are moredifficult to discern, the two appear identical.
6. Quantify results. From the Spreadsheet, click the Add button near thebottom left. Click the Molecule List tab, and from the bottom center, clickon Alignment Scores. In the alignment assessment, a score* of 1 is aperfect alignment and a score of 0 is a terrible alignment. By this metric,
the molecules are identical.
7. Explore structural detail. Use the Measure feature (Measure Distance,
Angle and Dihedral Angle from the Geometry menu). Click again inside34

the check boxes to the left of the molecule’s names in the spreadsheet, toturn off simultaneous display. With either example selected, use themeasuring options tools to explore distances, angles, and dihedrals. For
example, measure the CO bond lengths in the two carbonyl groups. The
distances appear at the bottom right of the screen and can be posted to the
spreadsheet by clicking on [].
8. Explore additional organic molecules. Repeat the above tutorial
procedure (steps 2 – 7)for two additional natural products: simaroubin A
and bimsic, sample .spartan files can be found in the neural network
folder inside the Tutorials directory.
9. Do results generally agree between the QM and neural network
calculated structures? Results will very closely follow the ωB97X-D/631G* calculations, see Appendix A for assessment, publication in
preparation.
10. When finished, close monacustin, simaroubin A, and bimsic.
NMR from Estimated ωB97X-D/6-31G* Equilibrium Geometries
The neural network routine used to estimate ωB97X-D/6-31G* equilibriumgeometries (Est. Density Functional ωB97X-D/6-31G*) provides anoptimized structure, it does not, however, provide an energy or the wave
function (needed to calculate NMR chemical shifts or to generate graphicalmodels such as molecular orbitals or electrostatic potential maps). In orderto obtain wave function-based data, an energy (a so called “single point
energy”) calculation is needed from ωB97X-D/6-31G*. Use of the neuralnetwork for structure generation saves ≈ an order of magnitude (or more)in wall/CPU time compared to ωB97X-D/6-31G for the full geometry
optimization.

Ethyl 2-methylpropanoate[10-20 minutes]

1. Sketch or build ethyl 2-methylpropanoate:

ethyl 2-methylpropanoate35

2. Open the Spreadsheet and make a copy of the molecule (right-click,choose Copy, right-click cell underneath and choose paste). For the firstmolecule, enter the Calculations dialog, select Equilibrium Geometry to
the right of Calculate. Select Density Functional, ωB97X-D, and 6-31G*
from the three menus below and to the right of with. Check the NMR checkbox. Make sure the Global Calculations box at the bottom right of the
dialog is not checked and click OK.

3. For the second molecule, enter the Calculations dialog, select Energy
to the right of Calculate. Select Density Functional, ωB97X-D, and 631G* from the three menus below and to the right of with. From themenu(s) to the right of Start From:, select Equilibrium Geometry thenusing: Est. Density Functional (the ωB97X-D/6-31G* model will
populate, the only currently available option). Check the NMR check box.
Confirm the Global Calculations box is not checked. Submit the job.

4. When completed (several minutes), compare both the structures and the
NMR chemical shifts. Open the Properties dialog (Display menu), clickon the carbonyl carbon, and from the Atom Properties dialogue, click on
the [ ] next to Chem. Shift, to post the calculated NMR chemical shifts
for this carbon center (for both examples) into the spreadsheet. One after
another, click on the two ethoxy carbons, and post their chemical shifts into
the spreadsheet. How closely do the NMR results match?
36

5. From the Spreadsheet. Confirm the first entry is selected. From theGeometry menu select Align. Confirm that Structure is selected from thedropdown menu at the lower right of the interface, click on the Align by
button.
6. From the spreadsheet, click the Add button near the bottom left. Clickthe Molecule List tab, and from the bottom center of the Add panel, clickon Alignment Scores. Check the box two the left of each entry to turn on
display.
7. From the Model menu turn off the Coupled toggle. Use the centermouse-wheel to zoom out. Hold the right mouse-button down to translate
one of the molecules away from the other so that the 2 can clearly be seen
separately (not overlapping). From the Model menu turn off theHydrogens toggle. Return to the Model menu and click on Configure.
From the Labels tab, click the radio button to the left of Calc. Chem Shiftand click OK. Compare the shift values on all carbon centers. Differences
are very subtle, on the order of tenths of a ppm.
8. Close the ethyl 2-methylpropanoate.
Indiacen B[10-15 minutes]

indiacen b

1. From the neural network folder inside the Tutorials directory, open thefile indiacen b (a slightly larger natural product molecule, this alkaloid isisolated from certain species of myxobacterium or “slime molds”).
Equilibrium Geometry and NMR chemical shifts are furnished from
ωB97X-D/6-31G*.
2. Open the Spreadsheet and make a copy of the molecule indiacen b
DFT, name it indiacen b est DFT.
37

3. With the renamed copy selected, enter the Calculations dialog, andspecify Energy to the right of Calculate. Select Density Functional,
ωB97X-D, and 6-31G* from the three menus immediately below and to theright of with. From the menu(s) to the right of Start From:, selectEquilibrium Geometry and Est. Density Functional. Check the NMR
check box. Confirm the Global Calculations box is not checked. Submit
the job.
4. When the job completes (just a few minutes), compare the NMR shifts
on the carbonyl carbon, the terminal carbon bonded to chlorine, and anyother carbon centers you like. Use the Atom Properties dialogue and post
the calculated shifts (Chem. Shift) into the spreadsheet to compare results.
While the results are not identical, they are very similar (typically within a
few tenths of a ppm). Use of the neural network routine (in this instance)
saves ≈ a factor of 4 in computational time.
5. This example explored a relatively rigid molecule. Time savings forflexible systems is even more significant, where select individual
calculation steps have the option of utilizing neural network routines rather
than QM models.
6. Close indiacen b.
Neural Networks in Multi-step Conformational Protocols I
For the last several Spartan releases, we have included multi-step
workflows combining both molecular mechanics (MMFF94) and quantum
mechanics (a number of models) to obtain, what we believe to be, accurate
Boltzmann distributions of flexible organic molecules. Both as a standalone task (Conformer Distribution) and in combination with NMR
calculations in the NMR Spectra task, these recipes have proven useful in
confirming (and in some cases rejecting) structural assignments in thenatural products space.*
While increasing in importance and utility, the use of calculated NMR (inparticular Boltzmann weighted shifts) has been limited by the significant
computational demands required (several hours, to days for very flexible
systems).

* J. Nat. Prod. 2019, 82, 8, 2299–2306.

38

We believe replacing strategic steps in these workflows with neural network
calculations, we can significantly reduce the required computational
requirements.
Aspochalasin U and Boltzmann Weighted NMR[30 minutes]

aspochalasin u

1. From the neural network folder inside the Tutorials directory, open
the file aspochalasin u. This file contains NMR Spectrum calculation
results for the macrocyclic natural product aspochalasin u, one of several
alkaloid macrocycles isolated from the desert shrub ericameria laricifolia(or commonly, the turpentine bush). Results originate from the default
NMR Spectrum setup, starting from MMFF conformer searching andincluding multiple QM model steps to provide both an equilibrium
conformation and a set of Boltzmann weighted NMR chemical shifts. This
flexible system with more than 100,000 potential conformations, required
some computational time. On 8 (of 16 cores) on a modern Linux machine,
the calculation requires almost 8 hours (without parallelized QM, thiswould be more than 2 days(!) to complete.
2. Make a copy of the molecule named aspochalasin u DFT multi-stepand paste it under the existing molecule. Rename the second molecule
aspochalasin u NN multi-step. With the second molecule selected, enter
the Calculations dialog and specify: NMR Spectrum with Density
Functional, ωB97X-D, and 6-31G*. Next to using choose Est. ωB97XV/6-311+G(2df,2p) energy and Est. ωB97X-D/6-31G* geometry:39Submit the calculation.
3. When the job completes (perhaps 25 minutes on an 16 core i7, 37 min,using 8 (of 16) cores, AMD Threadripper, under Linux, 45 minutes underan 8 core i7 under Windows), explore how well the returned equilibrium
conformer compares with the example from the long QM-based NMR
Spectrum calculation? Align the two molecules. With the first molecule
selected, enter the Geometry menu and click on Align. In the lower rightof the user interface, click on the Align by button (note we are aligning bystructure). From the spreadsheet, click the Add button near the bottom
left. Click the Molecule List tab, and from the bottom center, click on
Alignment Scores. The neural network example should have goodstructural alignment to the standard NMR Spectrum task (from themultistep MM/QM protocol).
4. How well do the calculated (and Boltzmann weighted) NMR shifts
compare? Right-click on a carbon center; from the resulting contextual
menu, choose Properties. From the Atom Properties dialog, click []to post the calculated chemical shift into the spreadsheet (this is the fourth
item down named Chem. Shift). Note, the molecules are numberedidentically and posting the shift value from an atom on one molecule will
also posts the corresponding shift value from the other copy.
5. Post the calculated Chem. Shift values for the remaining unlabeled
carbons and return to the spreadsheet for comparison. How similar are theresulting shifts? In most cases you will find the results quite similar, inmost cases results to vary by only a few tenths to perhaps 1.5 ppm. The
alignment and NMR shift results suggest, the neural network calculations
40

perform similarly to quantum chemical calculations in the context of themulti-step procedure. In this case (with a rather flexible molecule and using
the neural network routine for structure), the calculation run using
available neural network routines saves a factor of 10 in computational
time.
Improve Energy Results
The fact that ωB97X-V/6-311+G(2df,2p), ωB97M-V/6-311+G(2df,2p) andωB97M(2)/6-311+G(2df,2p) models lead to improved reaction andconformer energies compared to those provided by the simpler and muchless costly ωB97X-D/6-31G* model is well known. Spartan’24
incorporates three machine learning routines (neural networks) trained toreproduce the above energies starting from an ωB97X-D/6-31G* geometry.
The better energy calculation is almost instantaneous, although at the timeof the initial release the neural network model leading to the estimatedωB97M(2)/6-311+G(2df,2p) energies is under development and is planned
for subsequent maintenance release.

Structural Isomers of C15H16O3[15-20 minutes]

1. Open C15H16O3 isomers. The document contains eight C15H16O3
isomers (all natural products) and pre-calculated energies and geometries
from ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G* (labeled ref in the
spreadsheet). The isomers are ordered by relative energies (lowest to
highest). The underlying QM calculations required several hours ofcomputer time.
2. Inside the Calculations dialog, select Energy with Est. Density
Functional ωB97X-V/6-311+G(2df,2p) from the right of Calculate withand Equilibrium Geometry using Est. ωB97X-D/6-31G* from the rightof Start From. Make certain that Global Calculations (at the bottom rightof the dialog) is checked and click on Submit.
3. When the job has completed (several minutes, a minute or so perisomer), return to the spreadsheet. Make sure that the first molecule isselected, click on Add at the bottom of the spreadsheet, click on the
Molecule List tab and under click on ΔE (kJ/mol) at the top left of thepanel (under Energy from Molecule). Optionally, rename the ΔE
41

(kJ/mol) column to: est ωB97X-V:est ωB97X-D), double-click in the ΔE(kJ/mol) header, backspace to view the full expression, and at the left ofthe equal sign, rename the previous to: est ωB97X-V:est ωB97X-D.
4. Bring up the Plots dialog and click on + to add a new plot. Select ref
under X Axis, and select both ref and ΔE (kJ/mol) or est ωB97X-V:est
ωB97X-D, if you renamed the column from the optional step above fromthe Y Axes. Click on Create at the bottom right of the panel. How well
does this combination of neural network routines reproduce the results of
the reference calculations?
5. Open the file Plot_Est_V_QM. In this modified plot, the referenceenergies of the 8 isomers are the larger blue dots, the smaller yellow dots
are the energies determined by the neural network. The neural networks
perform quite well on the task of reproducing both the order and theunderlying relative energy results from high-level quantum chemical
models (in tiny fraction of the time it took to obtain the reference data).
6. Close both C15H16O3 isomers and Plot_Est_V_QM.
Conformers of methyl 4-pentenoate[10-15 minutes]

1. Open methyl 4-pentenoate conformers. The file contains elevenconformers of the small organic molecule methyl 4-pentenoate, precalculated from ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G* (labeled
ref in the spreadsheet), and ordered from lowest to highest energy. This
relatively small molecule with relatively few conformers (11) required
only 30 minutes of wall time, perhaps 4 hours CPU time to complete.
2. Inside the Calculations dialog, select Energy with Est. Density
Functional ωB97X-V/6-311+G(2df,2p) to the right of Calculate andEquilibrium Geometry using Est. Density Functional and ωB97X-D/631G* to the right of Start From. Make certain that Global Calculations(at the bottom right of the dialog) is checked and click Submit.
3. Once completed (perhaps 5-6 minutes), open the spreadsheet and ensure
the first molecule in the list is selected. Click on Add at the bottom of the
spreadsheet, click on the Molecule List tab and click on ΔE (kJ/mol) at the
top left of the dialog (under Energy from Molecule). Rename the ΔE(kJ/mol) data column as: est ωB97X-V:est ωB97X-D.
4. Bring up the Plots dialog and click on +. Select ref under X Axis, both
ref and est ωB97X-V:est ωB97X-D under Y Axes and click on Create at42

the bottom right of the panel. How well does this combination of neuralnetwork routines reproduce the results of the reference calculations? Thisis a reasonable representation of performance within a conformer
distribution. Note that while the equilibrium conformer (the global
minimum) remains the same, there is some change in order based on theenergies from the neural network (over this relatively small energy windowof 6-7 kJ/mol).
5. For comparison, return to the Calculations dialog and specify an
Equilibrium Geometry using MMFF, make sure the Global
Calculations box is checked, and click Submit.
6. When the job completes (less than a minute), return to the Spreadsheet.
The ΔE (kJ/mol) column has now updated to reflect MMFF energies. In
comparison, how well does MMFF reproduce the reference energies?
Bring up the Plots dialog and click on +. Select ref under X Axis, andselect all three: ref, est ωB97X-V:est ωB97X-D, and ΔE (kJ/mol) underY Axes, then click on Create at the bottom right of the panel. While theresults of the combined neural network routines do not perfectly match theunderlying QM reference data, unlike MMFF (reported on the new plot as
ΔE (kJ/mol)), the neural network results obtain the same global minimum,and in general, better comport with reference data.
7. Close methyl 2-pentenoate conformers.
Neural Network Correction to MMFF Molecular Mechanics
MMFF molecular mechanics is the simplest and perhaps most widely usedmethod to explore the accessible conformers of organic molecules. While
it provides a reasonable account of conformer energy differences formolecules with only a single degree of conformational freedom (many ofwhich were used to parameterize MMFF), it has not proven to be reliable
for molecules with multiple degrees of conformational freedom. ωB97XV/6-311+G(2df,2p) calculations using MMFF geometries are much better,although they are much more costly (hours as opposed to seconds).
Spartan’24 incorporates a neural network trained to reproduce conformer
energy differences from ωB97X-V/6-311+G(2df,2p)//MMFF density
functional calculations and intended to improve on MMFF results without
greatly adding to its cost.
43

1,10-oxymyrcene hydroxide[10-15 minutes]

1. Open 1,10-oxymyrcene hydroxide. This document contains 40
conformers of the slightly larger and more flexible example (compared tomethyl 2-pentenoate from the previous tutorial), the organic molecule:
1,10-oxymyrcene hydroxide. Conformers are ordered by energy (low tohigh) from the ωB97X-V/6-311+G(2df,2p)//MMFF density functionalmodel (labeled ref in the spreadsheet). The reference calculations took justunder 5 hours wall time and roughly 37 hours CPU time to complete. Two
additional empty columns, one labeled MMFF and the other corr MMFF,
will be utilized following calculations (below).
2. From the Calculations dialog, select Equilibrium Geometry andspecify Molecular Mechanics and MMFF to right of with. Make certainthat Global Calculations (toward the bottom right of the dialog) ischecked and click on Submit.
3. When the job has completed (a few seconds), ensure that the firstmolecule in the list is selected. Click on Add at the bottom of the
spreadsheet, then click on the Molecule List tab and finally from under
Energy from Molecule, click on ΔE (kJ/mol) toward the top left of the
dialog. Copy the results from the 40 entries in the ΔE (kJ/mol) column into
the MMFF column.
4. Bring up the Plots dialog and click on +. Select ref under X Axis, both
ref and MMFF under Y Axes and click on Create at the bottom right ofthe panel. The resulting plot shows that the MMFF model is rather poor at
reproducing the results from ωB97X-V/6-311+G(2df,2p)//MMFF (the refdata).
5. Update the data using the Corrected MMFF model. From the
Calculations dialog, select Equilibrium Geometry with Molecule
Mechanics and Corrected MMFF and click Submit.
6. Once completed (perhaps a minute for all 40 conformers), return to the
spreadsheet. The ΔE (kJ/mol) values have updated. Copy the updated ΔE(kJ/mol) entries into the corr MMFF column. From the Plots dialog clickon +, select ref under X Axis, both ref and corr MMFF under Y Axes andclick on Create at the bottom right of the panel. Compare the two plots bymoving back and for the between view of Plot1 and Plot2 (optionally,
clicking the ◄ arrow at the top of the plots pane moves the selected plot
44

into the 3D interface for simultaneous display. The results visually confirm
the corrected MMFF model does a much better job reproducing the resultsof the reference calculations.
7. Return to the Spreadsheet. Click on Add at the bottom of the
spreadsheet, then click on the Linear Regression tab. Select ref for theFit, and choose MMFF under Using, click Apply. Create a second
regression with ref fit to the corr MMFF data and click Apply. Two new
entries appear at the bottom of the spreadsheet. Right-click on the Fit1 celland choose Properties. The Regression Properties dialog appears. The
R2 value gives an indication of how well the data fit the regression, with 1
being a perfect fit. The fit of MMFF energies is essentially a scatter plot.
The R2 for the corrected MMFF energies is quite good (.94). Almost as
important as the quality of the fit, the computational time savings issignificant, a minute or less compared to several hours.
8. Close 1,10-oxymyrcene hydroxide.
Neural Networks in Multi-step Conformational Protocols II
In a previous example (the flexible macrocycle aspochalasin) we compared
the performance of the neural network routines at the Boltzmann weighted
NMR Spectrum calculation. In the previous example, the NMR results
were calculated from structures determined by the Est. Density Functional
ωB97X-D/6-31G* neural network. Another potentially useful strategy
would be to utilize the multi-step (NMR Spectrum) routines – but toperform structures (equilibrium geometries) from quantum mechanics andobtain energies (for Boltzmann weighting) from neural network energies.
Leucosolenamine and Boltzmann Weighted NMR

leucosolenamine analogue45[no calculations]1. From the Neural Network folder inside the Tutorials directory, open
the file leucosolenamine. This file contains two copies of a proposed
structure for the natural product leucosolenamine a. The first example hascompleted the default NMR Spectrum calculation, using MMFF andmultiple QM models to provide both an equilibrium conformation and aset of Boltzmann weighted NMR chemical shifts. The second molecule has
replaced the Hartree-Fock geometry step and an initial single point energy
ωB97X-D/6-31G* step with a Corrected MMFF neural network, and thefinal energy calculation: ωB97X-V/6-311+G(2df,2p) with an Est. Density
Functional neural network equivalent. Note that in this case, the final
geometry ALSO comes from quantum chemical calculations, as do the
NMR shifts.
2. Open the Spreadsheet and note that the check boxes to the left of themolecules’ names in the far left-hand column are checked, specifying
display of both copies. If your mouse manipulations move both copies ofthe leucosolenamine. Visit the Model menu and toggle off the Coupled
entry. In this decoupled mode, you can move/manipulate the molecules
independently. To switch focus between molecules, just click on themolecule you want to select.
3. With both copies displayed simultaneously, an additional Annotation
box is also displayed. Note, the text applies to the initial position of theexamples (if you move the molecules around, the annotations don’t
follow). To insert an annotation box of your own, copy any text (either
from inside of Spartan, or any other program) to the clipboard and thenclick inside the 3D space in the Spartan UI and paste the text. To edit or
expand, right-click on the annotation and choose Properties.). The initialdisplay should include the calculation completed with quantum mechanics
on the left, and that with the neural network calculation(s) on the right.
Explore the NMR shifts on select carbons.
4. For qualitative results, a few chemical shift labels already have been
displayed. These were not “cherry-picked”. Compare other carbon centers.
Right-click on a carbon center without a displayed chemical shift label.
From the resulting contextual menu, choose Properties. From the Atom
Properties dialog, click [ ] to post the calculated chemical shift into the
spreadsheet (this is the fourth item down named Chem. Shift). Note, themolecules are numbered identically and posting the value from an atom of
one molecule also posts the corresponding shift value from the other copy.
46

5. Post the calculated Chem. Shift values for the remaining unlabeled
carbons and return to the spreadsheet for comparison. How similar are theresulting shifts? In most cases you will find the results identical, or to varyby only a few tenths of a ppm.
6. Align the two molecules. With the first molecule selected, enter theGeometry menu and click on Align. In the lower right of the user interface,click on the Align by button (note we are aligning by structure). From the
spreadsheet, click the Add button near the bottom left. Click the Molecule
List tab, and from the bottom center of the Add panel, click on Alignment
Scores. The alignment and NMR shift results suggest, the neural network
calculations perform similarly to quantum chemical calculations in thecontext of the multi-step procedure. In this case (with relatively few
conformers), the calculation run using available neural network routines
saves a factor of 3 in computational time.
7. The goal (at least one goal), of this tutorial is to demonstrate the optionof utilizing only the energy related neural networks (retaining theequilibrium geometry at density functional ωB97X-D/6-31G*). This
results in NMR shifts that more closely align with those from the standard(MM and QM based) NMR Spectrum task, than utilizing the neural net
Est. Density Functional: ωB97X-D/6-31G* for structure calculation.
There is still considerable time savings in utilizing just the energy-basedneural networks. Close leucosolenamine.

47Section II
Operations and Overview
The two chapters that make up this section are intended to provide an
overview of the components which control access to Spartan’s graphicaluser interface (Operating Spartan) and following that, a guided tour
through some of the most fundamental operations of the interface (Walking
Through Spartan). Together, these offer sufficient information to “getstarted”. Description of the full range of Spartan’s capabilities is deferred
until Section V which is intended to serve as a reference to the current
Spartan’24 feature set.

48

Chapter 1
Operating Spartan
This chapter describes the general operating features of Spartan’24. It
should be perused prior to starting the tutorials.
Starting and Quitting Spartan
To start Spartan under Windows, click on the Windows button, then clickon All Programs and locate and open Spartan’24 (or double click on the
Spartan shortcut icon on the desktop). To start under Macintosh, double
click on the Spartan’24 icon in the Applications list. To open under Linux,
bring up a terminal and type spartan24. To quit Spartan, select Exit fromthe File menu (Windows) or Quit Spartan’24 from the Spartan’24 menu
(Macintosh), or click the Close button () at the top Right of the Spartan
interface, Windows and Linux, (top left for Mac).
Menus and Icons
Program functions may be accessed either from the menu bar or from icons in
the toolbar which is directly underneath the menu bar. The menu bar may
either be accessed as pull-down menus (Classic List), for example, theSetup menu:

or from a list of icons presented in a palette (Button Pad), for example, theDisplay menu:

49Selection is made in the Settings tab of the Preferences dialog(Preferences... under the Options menu; Chapter 25).
Icons for all menu functions (as shown alongside text in both Classic List andButton Pad styles) are available on screen below the menus. There are too
many icons to be simultaneously displayed and the choice (beyond thedefault initially configured) is made in the Icons tab (Preferences... under
the Options menu; Chapter 25). Icon size is also user selectable in the
Settings tab (Preferences... under the Options menu; Chapter 25).
File

Allows you to build or sketch a new molecule, add or delete a moleculefrom an existing Spartan document, read in a molecule that you havepreviously saved, or a file created by another program. It also allows you
to print text and graphics, embed external files (for example, Word andExcel files) into Spartan documents, to access PDB files online and to
extract ligands from these files. New in Spartan’24 is a one stop saveto database (SSPD) operation.
Edit

50

Allows you to transfer information to and from the clipboard, to undo the lastoperation, to find text strings and molecule fragments, to center molecules on screen,
and to clear the active molecule by deleting it.
Model

Provides control of model style of your model, display of (R/S) chirality labels,hydrogen bonds and chemical function descriptors, as well as coupling or decouplingmouse function for molecules in a multi-molecule document. Allows display of
Ramachandran plot for a protein structures brought in from PDB. Enables labels,
including atom labels by atomic charges or experimental or calculated NMR chemical
shifts (or the difference between them) among other quantities (custom label displays
also available).
Geometry51

Allows you to measure and constrain bond lengths, angles and dihedrals, make lists ofstereo and regioisomers and tautomers, define points, ligand points and planes, defineNOEs, specify frozen atoms, alter default settings for conformational degrees of
freedom, select centers for similarity analysis and align molecules.
Build

Allows you to sketch molecules in 2D or build them in 3D, and to edit molecules thatyou have already sketched or built. Provides tools for making and breaking bonds,
deleting atoms or groups of atoms in 3D builder as well as both 2D and 3D
minimization tools (MMFF) for “cleaning up” 2D drawings and preparing 3D
structures for calculation. Allows seamless access to ChemDraw™ (Windows only).
Allows you to define transition states in terms of curved (reaction) arrows attached toreactants (or products) in either 2D or 3D, and to guess a transition-state geometry
based on a library of reactions. Permits experimental proton and 13C chemical shifts
as well as observed HH and CH couplings to be associated with 2D drawings or 3D
structures.
Setup

Allows you to specify and submit calculations and graphical models, either locallyor to a remote resource via Spartan’s submission tools.
Display52

Allows you to display text output, molecular and atomic properties, QSAR descriptors,
thermodynamic quantities, orbital energy diagrams, surfaces and property maps andinfrared, Raman, NMR and UV/visible spectra, as well as to access experimental IR,
NMR and UV/visible spectra from freely available databases on the internet or from local
files. Spartan’24 further enhances the utility of the Summary Output providing a seriesof tabbed tables containing spectroscopic data that may be copied or printed. Allows you
to present data in a spreadsheet and make plots from and perform regression analysis onthese data, to access the results of a similarity analysis and to compute reaction energies
based either on user data or from entries in the SSPD (Spartan Spectra and Properties
Database). New in Spartan’24 is the dual display option providing a manipulable copyof the user’s molecule in 2D (while the UI is in 3D view mode) or 3D (when in the 2D
Sketch mode) to complement the existing visual mode.
SearchAllows database queries, searching and mining of the SSPD for calculated structures,properties and spectra, and searching the SRD for calculated transition-state structures.
Allows you to search the CSD (Cambridge Structural Database)* and to extract ligands
from the PDB (Protein Data Bank). Allows you to match an unknown infrared spectrum
to calculated spectra in the SIRD (Spartan Infrared Database) which is derived from the
EDF2/6-31G* entries in SSPD or to experimental spectra from the XIRD (NIST
database). Allows you to guess a transition-state geometry based on a library of reactions.
Expt. Data

Allows you to attach experimental proton and 13C chemical shifts to a 3D structure, andto specify observed HH and CH couplings.
* Requires CSD to be licensed. Visit https://www.ccdc.cam.ac.uk/solutions/csd-licence/ for info.

53

Options

Allows you to set display standards, specify databases, monitor executing jobs and specify
queues and customize icons and other aspects of the graphical user interface. Allows you
to access external Spartan compute servers or to setup your machine as a compute server.
Activities

Allows you to display tutorials and topics inside of Spartan and to search
Wikipedia.
Help

Provides access to information on Spartan’s general operation, the Spartan’24 Tutorial
and User’s Guide (current version of this document), and a number of computational
FAQ’s. Also provides access to the Spartan license utility (allows for modification to
the license) New in Spartan’24 is a utility allowing users to Check for Updates… This
will compare the user’s version with the current release available, and offer a link to
update if a newer version exists (note: while this alerts of a new version, the user mustchoose to download/update, we do not do this automatically).
A complete listing of menu functions is provided in Appendix C.

54

Additional Icons
A variety of other icons appear in Spartan, both in individual dialogs and in
the message bar at the bottom of the screen.
Post to Spreadsheet/

Search Transition State Library

Lock/Unlock Constraints

Server Shortcut
Play/

Help/Tool Tips
Pause

/

Revert to Fullscreen

Surface clipping planes
Step

Stop

Extend to Fullscreen
Look Up in Wikipedia

Restore Default Settings/

Move Up/Down Dialog

Make List

Add or Remove Tables

Fit

Tabs
Spartan’24 assigns a tab to each open document. These appear in a single
row along the bottom of the screen in the order that the documents werecreated or opened. Backward and forward step keys ( and ) at the far
right provide access to tabs outside of those displayed. At the left of eachtab is a check box. If checked, this indicates that the document will be(permanently) displayed on screen, even if it is not the selected document.
Mouse/Keyboard Operations
The following functions are associated with a standard mouse andkeyboard. Acknowledged, depending on platform there is reasonablevariability in mice and mice configuration. In general we try to both, takeadvantage of the full range of modern mouse features, but accommodate
older mice (or no mice – in the case of touch pad or touch-enabled devices).

55ButtonKeyboard

Center (wheel)

No keys selected

Zooming, scroll up/down

Keyboard

Left

Right

No keys selected

X/Y rotation, atom/fragment
substitutiona, insertiona

X/Y translate

Shift

Range selection, Z rotate

Zooming (Z translate)

Ctrl (view mode)

multiple selection, X/Y rotation

X/Y translation for all

Windows &Linux

for all visible molecules

visible molecules

Command (view mode)
Macintoshmultiple selection

Ctrl (build mode)
Windows & Linux

selected fragment X/Y rotate,chiral center inversiona

selected fragment X/YtranslateCommand (build mode)
Macintoshselected fragment X/Y rotate,chiral center inversiona

scalingb

Ctrl + Shift (view mode)
Windows & LinuxZ rotation for all visible molecules

Command + Shift(view mode) Macintosh

Z rotation for all visible molecules

Ctrl + Shift (build mode)
Windows & Linux

selected fragment Z rotate,
absolute configuration inversiona

Command + Shift (buildmode) Macintosh

selected fragment Z rotate,
absolute configuration inversiona

Alt/Option (view mode)group selectionb

Alt/Option (build mode)bond rotationc

bond stretchingca) Build mode only, requires double clicking (this is the default behavior, but one can revert to single
click by accessing the Settings tab from the Preferences dialog available in the Options menu).
b) With center wheel depressed or both left and right mouse buttons held down, dragging enables a
selection box for supports group selection.
c) For Linux (only) Ctrl + Shift keys replace the Alt/Option key for bond rotation and stretching.

These broadly fall into two categories: selection (picking) and manipulation(translation/rotation/zooming).
Selection. Clicking (left button) selects objects on screen and/or of menu
items. Center wheel or both left and right buttons together are used to define56

a selection box for copying to the clipboard, as well as for group selection.
Together with the Shift key, the left button allows for selection over a range.
Together with the Ctrl (Control) key, the left button allows for multiple
selection. Both range and multiple item selection apply not only to text
items in lists, but to atoms and bonds in molecules as well. Together with the
Alt/Option key), the left button allows for selection of an entire group(detached molecular fragment).
In (3D) Build mode, double clicking (left button) on an atom exchanges itwith the atom or atomic fragment selected in the model kit. Double clicking
on an atom while holding down the Ctrl (Win or Linux) or the Commandkey (Mac) leads to inversion in chirality of the atom and double clicking on
the molecule while holding down both the Ctrl (Win or Linux) /Command key(Mac) and Shift key, will invert the absolute configuration of the molecule.
In (2D) sketch mode, double clicking on an atom with another atom selectedin the sketch pane replaces it with the selected atom. Double clicking on an
atom with charge/radical selected in the sketch pad adds charge or radical
designation to the atom and adjusts hydrogen count. Unless a ring icon is
selected from the sketch palette, double clicking on a bond increases the bondorder by 1 (single to double or double to triple). Double clicking on a triple
bond replaces it by a single bond. Once an initial fragment, group or ringhas been drawn, double clicking on the background in either 2D or 3D mode
will insert the selected item alongside the existing structure.
Manipulation. The left button is used for rotation and the right button isused for translation and scaling in Spartan’s main screen. With no keys
depressed, moving the mouse while holding down the left button gives rise
to rotation about the X and y (screen) axes, while moving the mouse while
holding down the right button gives rise to translation in the x and y(screen) directions. Together with the Shift key, moving the mouse while
holding down the left button gives rise to rotation about the z direction,
while moving the mouse while holding down the right button gives rise toscaling. The center (scroll) wheel on the mouse may also be used for scaling.
In Edit Build mode (only), the default is focus on the full set of fragmentsthat make up the molecule being constructed, and rotations and translations
refer to this set of fragments as a whole. Use of the Ctrl key changes focus
to a single fragment (the selected fragment), and rotations and translations
now refer only to this fragment.
57

In Edit Build mode (only), moving the mouse while holding down the
Alt/Option key and left mouse button rotates about the selected bond. Bondrotation may also be accomplished by moving the mouse up and down inside
the marked area at the left of the screen while holding down the left button.
Additional keys control various Spartan functions.

58

Keyboard Operations
Page Up, Page Down
Home, End

Moves up (Page Up), down (Page Down), to the top (Home)and to the bottom (End) of the set of open molecules. Also,
moves up and down pages in the Output dialog.

Insert(option for Mac)In Edit Build/Edit Sketch fragment mode only, inserts a new
fragment on screen. This is accomplished by selecting thefragment from the model kit, holding down the Insert key andclicking on screen. Insertion may also be accomplished bydouble clicking on the background following selection of afragment.

DeleteDeletes a fragment, free valence, CFD, reaction arrow, thecontents of a selection box, spectrum, curve, or plot. This isaccomplished by holding down the Delete key and clicking on
the fragment, etc.

Enter
(return for Mac)

Required following text or data entry into spreadsheet or dialogs.

Touch-Pad/Track-Pad Operations
Standard Pad
RotateOne-finger press and rotate
TranslateTwo-finger press and translate
Zoom (translate in the Z pane) Two-finger rest (move fingers up and down)
Rotate in the Z plane
Hold Shift key down, One-finger press (move finger up
or down)
Rotate around bondIn New Build or Edit Build, press on a bond to select it.
A red arrow will indicate selected bond. Move the cursor over vertical strip on the left hand side of theinterface and then One-finger press and move the cursor up or down.
Two Button Pad
RotateOne-finger left-press and rotate
TranslateOne-finger right-press and translate
Zoom (translate in the Z pane) Two-finger rest (move fingers up and down)
Rotate in the Z plane
Hold Shift key down, one-finger left press (move finger
up or down)
Rotate around bondIn New Build or Edit Build, left-press on a bond to selectit. Ared arrow will indicate selected bond. Move the cursor over vertical strip on the left hand side of theinterface and then left-press and move the cursor up or down.

59

Touch-Screen Operations
Tapping = clicking and double tapping = double clicking. Range andmultiple selection have not yet been implemented. One finger motions onscreen are equivalent to left button motions. Two finger motions areequivalent to right button motions. Pinching is equivalent to scroll wheel
operations.
Selecting Molecules
While two or more molecules may be simultaneously displayed, only one
molecule may be selected. Only the selected molecule has access to allcapabilities. Molecule selection occurs by clicking on its structure model oron any of its associated graphical surfaces.
Where the molecule belongs to a document with more than a single
molecule, selection from among the different molecules may be madeusing either theandbuttons or the scroll bar at the bottom left ofthe screen. Clicking on
at the bottom left of the screen animates thedisplay of molecules in the document, that is, steps through themsequentially. Animation speed is controlled from the Settings tab(Preferences... under the Options menu; Chapter 25). Clicking on
stops the animation. If the spreadsheet associated with the document is open
(Spreadsheet under the Display menu; Chapter 22), selection can also bemade by clicking on the molecule label at the left of the spreadsheet.
Two or more molecules from the same document may be displayed at once
(although only one may be selected). Molecules are marked for display bychecking the box immediately to the left of the molecule label in the
spreadsheet.
Stereo Displays
Spartan supports red-cyan stereo. Red/blue glasses must be worn. To enter
stereo mode, access the Preferences dialog, Options menu. The Settings tab
contains an On/Off selection for Stereo mode. Does not apply to the 2D
sketcher.

60

Changing Colors and Setting Preferences
Colors and Preferences... under the Options menu (Spartan’24 menu,
Macintosh) allows for changing default background and graphical object
colors, and for setting (and resetting) program preference defaults,
respectively; Chapter 25. Further control of color is available in the various
Style dialogs accessible from Properties under the Display menu; Chapter
22.
Monitoring and Terminating Jobs
The Monitor lists jobs that are either queued or executing on the local
machine or on a remote server (Monitor). Queued jobs may be started andexecuting jobs may be terminated. The current text output and molecular
structure of executing jobs may be examined. The Monitor is accessible
from the Options menu (Chapter 25).

61

Chapter 2
Walking Through Spartan
This chapter, in the form of a tutorial, introduces a number of basic
operations in Spartan required for molecule manipulation, property queryand spectra and graphics display. This chapter is a must for new Spartan users.
It shows how to: i) open molecules, ii) view different model styles andmanipulate molecules on screen, iii) measure bond distances, angles anddihedral angles, iv) display energies, dipole moments, atomic charges andinfrared, NMR and UV/visible spectra, and v) display graphical surfaces andproperty maps, and via the spreadsheet, display multiple molecules fromthe same document. Other spreadsheet operations are not illustrated, nomolecules are sketched or built and no quantum chemical calculations are
performed.* The final example illustrates one of the neural networks
incorporated in Spartan’24.
1. Start Spartan. Click (left mouse button) on File from the menu bar thatappears at the top of Spartan’s main window. Click on Open... from the Filemenu that appears. Alternatively, click on theicon at the top of thescreen. A file browser appears.
Tap onat the top of the screen. If the icon is not available,
tap on File in the menu bar to bring up a palette of icons andthen tap on.

Move to the Tutorials directory** and open Walking Through Spartan (Filemenu Open Walking Through Spartan).

* The results of quantum chemical calculations in this chapter have been obtained using theωB97X-D/6-31G* density functional model.
** For Windows, the Tutorials directory is found in Program Files/Wavefunction/Spartan24. It needs tobe copied to another location available to the user (we recommend Documents or Desktop) prior to
opening it in Spartan.
For Macintosh, this is located at the top of the Spartan24 disc image. It needs to be copied to anotherlocation available to the user (we recommend Documents or Desktop).
For Linux, the Tutorials directory is found in the install directory. Copy the Tutorials
directory to a location that allows write permission, typically the user’s home directory.

62

Tap on Walking Through Spartan and tap on Open (ordouble tap on Walking Through Spartan). Note that click(left mouse button) and tap (one finger) are equivalent as aredouble click and double tap. We shall only indicate click/double
click throughout the text that follows.

A single file containing ethane, acetic acid dimer, propene, ammonia,
hydrogen peroxide, acetic acid, water, cyclohexanone, camphor, 3benzoylaniline, ethylene, benzene, aniline, cyclohexanone, and two copiesof the natural product camalexin (3-(1,3-thiazol-2-yl)-1H-indole) will be
opened. A ball-and- spoke model for the first molecule (ethane) will be
displayed, and its name appears at the bottom right of the screen. The
appearance of the name indicates that the molecule is included in the
Spartan Spectra and Properties Database (SSPD).
2. Practice rotating (move the mouse while holding down the left button)
and translating (move the mouse while holding down the right button). Use
the scroll wheel to zoom in and out, or alternately move the mouse (up or
down) while holding down both the right-mouse button and the Shift key.
To rotate, move one finger across the screen. To translate,move two fingers across the screen. To zoom out, pinch two
fingers together. To zoom in, move two fingers apart.

Click on Model from the menu bar.

63

Wire

Ball-and-Wire

TubeBall-and-Spoke

One after another, select Wire, Ball and Wire, Tube and finally Ball andSpoke from the Model menu. All four models for ethane show essentiallythe same information. The wire model looks the most like a conventionalline formula. It uses color to distinguish different atoms, and one, two andthree lines between atoms to indicate single, double and triple bonds,
respectively.
The ball-and-wire model is identical to the wire model, except that atom
positions are represented by small colored spheres, making it easy toidentify atom locations. The tube model is identical to the wire model, exceptthat bonds are represented by solid cylinders. The tube model is better than
the wire model in conveying three-dimensional shape. The ball-and-spoke
model is a variation on the tube model; atom positions are represented bycolored spheres, making it easy to see atom locations.

64Select Space Filling from the Model menu.

Space-Filling

The space-filling model is different from the other model styles in that bonds
are not shown. Rather, each atom is displayed as a colored sphere that
represents its approximate relative size. The space-filling model provides ameasure of a molecule’s size. While lines between atoms are not drawn, theexistence (or absence) of bonds can be inferred from the extent to which
spheres on neighboring atoms overlap. If two spheres substantiallyoverlap, then the atoms are almost certainly bonded, and conversely, if two
spheres barely overlap, then the atoms are not bonded. Intermediate overlaps
suggest weak bonding, for example, hydrogen bonding.
3. Click once on the right arrow key at the bottom left of the screen. This
will move to the next molecule in the document, acetic acid dimer. Its
name will appear at the bottom of the screen. use the backwardorforward step keys to get to acetic acid dimer in the document. Fromthe space-filling model, look for overlap between the (OH) hydrogen on
one acetic acid molecule and the (carbonyl) oxygen on the other. Return toa ball-and-spoke model. Click on the Model menu and select Hydrogen
Bonds.

Ball-and-Spoke model for acetic acid dimer with hydrogen bonds displayed

The two hydrogen bonds, that are responsible for the pose or orientation of
the most energetically favorable dimer complex, will be drawn.

65

4. Distances, angles, and dihedral angles can easily be measured with
Spartan using Measure Distance, Measure Angle, and Measure
Dihedral, respectively, from the Geometry menu.

a) Measure Distance: This measures the distance between two atoms. Clickonce on ► to move to the next molecule, propene. Click on the Geometry
menu and select Measure Distance (or click on theicon if it appears at
the top of the screen). Click on a bond or on two atoms (the atoms do notneed to be bonded). The distance (in Ångstroms) will be displayed at thebottom of the screen. Repeat the process for different bonds or pairs of
atoms. When you are finished, select View from the Build menu (or click ontheicon at the top of the screen).

b) Measure Angle: This measures the angle around a central atom. Clickonce on ► to move to the next molecule, ammonia. Click on the Geometry
menu and select Measure Angle (or click on theicon if it appears at the
top of the screen). Click first on H, then on N, then on another H.
Alternatively, click on two NH bonds. The HNH angle (in degrees) will be
displayed at the bottom of the screen.

66

Click on
when you are finished.
c) Measure Dihedral: This measures the angle formed by two intersecting
planes, one containing the first three atoms selected and the other containing
the last three atoms selected. Click once on ►to move to the next molecule,hydrogen peroxide. Click on the Geometry menu and select Measure
Dihedral (or click on theicon if it appears at the top of the screen) andthen click in turn on the four atoms (HOOH) that make up hydrogen
peroxide. The HOOH dihedral angle will be displayed at the bottom of thescreen. Click onwhen you are finished.
5. Energies, dipole moments and atomic charges (among other calculated
properties) are available from Properties under the Display menu.

a) Energy: Click once on ►to move to the next molecule, acetic acid. Clickon the Display menu and select Properties (or click on
icon if it appears
at the top of the screen). The Molecule Properties dialog appears. It is
divided into six parts designated by tabs. Molecule provides the energy andother information relating to the isolated molecule, QSAR provides
quantities that may be used as QSAR descriptors, and Thermodynamics
provides the entropy, enthalpy, Gibbs energy, zero-point energy and heat
capacity. ΔHf (298.15) provides heat of formation data from NIST (ifavailable) and the SSPD (if available) from the T1 model, and an estimated
ΔHf from DFT: ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G*, NMR
relates calculated and experimental NMR chemical shifts and Utilities
introduces standard atom labels, resets model and atom colors as wellas conformational degrees of freedom to standard values, fixes bondtyping, changes absolute configuration adds missing hydrogens and adjusts
X-H bond lengths. Note that the last three of these require that calculations
need to be repeated. Make certain that the Molecule tab is selected.

67This provides the energy* for acetic acid in atomic units (Energy in au).
b) Dipole Moment: The magnitude of the dipole moment (Dipole Momentin Debye) is also provided in the Molecule Properties dialog. A large dipole
moment indicates large separation of charge. You can attach the dipole
moment vector,
where the + side refers to the positive end of the dipole,to the model on the screen, by checking the box to the left of Display Dipole
Vector to the right of Dipole Moment.
The vector will not be displayed if the dipole moment is zero. The
dipole moment will not be reported if the molecule is charged
because in this case it depends on the location and orientation of
the molecule in space.

* The calculated energy depends on a number of factors including computational model, basis set (whereapplicable) and environment. For a discussion, see Activities menu Topics: Total Energies andThermodynamic and Kinetic Data.

68c) Atomic Charges: To display the charge on an atom, click on it with theProperties dialog displayed. Atom Properties replaces the currently
displayed Properties dialog.

Three different atomic charges, Electrostatic, Mulliken and Natural, aregiven in units of electrons. A positive charge indicates a deficiency ofelectrons on an atom and a negative charge, an excess of electrons. Repeat
for other atoms. Confirm that the positively-charged atom(s) lie at thepositive end of the dipole moment vector. When you are finished, close thedialog by clicking on
at the top.
The three sets of atomic charges for acetic acid are different,
sometimes markedly so. Note that the charge on an atom in amolecule cannot be uniquely defined, let alone measured. Whilethe nuclear charge is equal to the atomic number, it is not possible
to say how many electrons “belong” to a particular nucleus.
The different calculated charges correspond to different ways ofcounting the number of electrons associated with an atom.

d) Infrared Spectra: Molecules vibrate (stretch, bend, twist) even if they
are cooled to absolute zero. This is the basis of infrared (and Raman)
spectroscopy, where absorption of69

energy occurs when the frequency of a particular molecular motion matches
the frequency of the light. Infrared spectroscopy is important for identifying
molecules as different functional groups vibrate at noticeably different andcharacteristic frequencies.
Click once on ►to move to the next molecule in the document, water. To
animate a vibration, select Spectra from the Display menu (or click on
if it appears at the top of the screen). This leads to an empty spectra pane at
the bottom of the screen.

Click onspectra.

at the top left of the pane and select70

from the available

The calculated IR spectrum of water from 4000 - 500 cm-1 appears in thepane.

An upward and downward triangle server as a probe indicator, allowing for
further inspection of the plot.
There are three lines, one of moderate intensity around 3728 cm-1, one very
weak around 3608 cm-1 and one very strong around 1624 cm-1. In turn, clickon each of these peaks. In response, the molecular model will vibrate. Theline of moderate intensity corresponds to an asymmetric OH stretchingmotion, the very weak line corresponds to a symmetric OH stretchingmotion and the strong line corresponds to the HOH bend.
To translate the plot inside the pane, position the cursor over the spectrum
and move the mouse left or right while holding down the right button. To
expand or contract the scale of the IR plot from its default range, position
the cursor over the spectrum and use the scroll wheel on your mouse (oralternatively move the mouse while holding down both the right button
and Shift key). To reset the spectra plot to the original values, click onin the bar at the top of the spectra pane. To increase (or decrease) the sizeof the plot, you first need to undock it by clicking on ( ) at the upper right.
You can then size it as you would any other window. To redock the plot,
click again on ( ).
To see a complete listing of frequencies and intensities, clickon(Tables) at the left of the spectra pane.

71

Click on each entry in the table to highlight the frequency in the spectrum
and animate the vibration. Click on
to dismiss the table and click on
to remove the spectrum.
Changing the size of the spectrum dialog as well as translating
and altering the visible scale are quite simple with touch
screen operations. To resize the spectrum, position one finger
inside the menu bar at the top of the spectra pane and move up or
down. To translate the scale, move two fingers over the spectrum.
To alter the scale, pinch two fingers over the spectrum.

Click once on ►to move to cyclohexanone, the next molecule in thelist. The spectra pane is still on screen but should be empty. (If it is not onscreen, select Spectra from the Display menu or click on
if it appears
at the top of the screen to restore.) Click onin the bar at the top of thespectra pane and on. The calculated infrared spectrum of
cyclohexanone appears.

The calculations actually provide a list of frequencies and an associated listof intensities (some of which may be zero or very close to zero). The
spectrum that is displayed uses these data but has been broadened (toaccount for finite temperature) and scaled (to account for the fact that theunderlying energy function is assumed to be quadratic as well72

as for limitations of different models). The same broadening parameter(temperature) is applied to all molecules and all levels of calculation. The
same scaling parameter is used for all molecules but it depends on thetheoretical model.
The largest peak appears at 1759 cm-1 and corresponds to a CO stretch. The
fact that the line is both intense and isolated from other features in the
spectrum makes it a very useful indicator of carbonyl functionality. Clickon this peak and examine the “vibrating” model for cyclohexanone on screen
above the spectrum.
Click again on
and this time select. The experimental IR
spectrum (from the freely available NIST database) is superimposed on topof the calculated spectrum.

Note that the two spectra are similar but not perfectly matched.
When you are done, selectfrom the bar at the top of the spectra pane.

e) NMR Spectra: Along with mass spectrometry, NMR spectroscopy is themost powerful tool available with which to assign molecular structure.
Many (but not all) nuclei exhibit NMR spectra, but proton and 13C are by far
the most important.
Click once on to move to the next molecule in the document, camphor.
With the spectra pane on screen, click onin the bar at the top of thespectra pane, click on the NMR tab and select. The calculated
13
C NMR spectrum appears.

73This comprises nine lines, in the range of 150 to 0 ppm (there is a tenth line
corresponding to the carbonyl carbon at 216 ppm). You can zoom out to see
this line by using the scroll wheel on your mouse. More instructive is tozoom in on the range from 60 to 0 ppm to get a better look at the other lines.
Click on one of the probe triangles to select the probe and move the mouse
while holding down the left button over the spectrum. When you come to aline, the chemical shift will appear at the top of the spectrum and the atom
(or atoms) responsible for this line will be highlighted on the model
displayed above the spectrum.

Again, click onin the bar at the top of the spectra pane and select. The experimental 13C spectrum obtained from the freely available
nmrshiftdb database will be superimposed on top of the calculated
spectrum.

74You will see that the overall agreement between calculated andexperimental 13C spectra is quite good. As with infrared spectra (seepreceding discussion of cyclohexanone), the data resulting from thequantum chemical calculations has been empirically corrected.
Click again on
and select. An “idealized” proton spectrum where
three-bond HH coupling constants are set to zero appears.

Spectra manipulations are as before and the hydrogens responsible forselected lines are highlighted in the model. No experimental spectrum isavailable, but the quality of the match would be expected to be similar to that
previously observed with comparison of 13C spectra.
Click again on
and selectfrom the palette. The spectrum thatappears is more complicated and much closer to what would be observed
experimentally. In this example, HH coupling constants have not been
calculated from quantum mechanics, but they have been estimated based on
local environment.

75

Zoom in on specific lines (scroll wheel) to see the detailed splitting patterns.
For example, the two protons at C3 are both split by the proton at C4. The
doublet at 2.36 ppm shows a much larger splitting than the doublet at 1.85
ppm (you need to zoom in considerably to see that this is a doublet). This
reflects the fact that the proton responsible for the line at 2.36 ppm makes
a dihedral angle of 43° with the proton at C4, whereas the proton responsible
for the line at 1.85 ppm makes a dihedral angle of 80°.
Finally, note that you can switch among the three calculated NMR spectra(as well as the experimental 13C spectrum) for camphor by clicking on theassociated button in the bar above the spectra pane. When you are done, remove
all three spectra. Click on
three times in succession to remove the spectra.
f) UV/visible Spectra: Absorption of light in the visible or ultraviolet rangeof the electromagnetic spectrum leads to electronic excitation from theground-state to excited-states and (in the case of absorption in the visible), is
responsible for a molecule’s color. UV/visible spectroscopy not only offers
a “fingerprint” but is also an important screen to identify molecules that
may be damaged by exposure to light.
Click once on ► to move to the next molecule, 3-benzoylaniline. The
spectra pane should still be on screen. Click onand select. No
empirical corrections have been applied to the calculated spectrum thatappears.

76

Click again on
and select the UV/vis tab and click on. Theexperimental UV/ visible spectrum from the freely available NIST database
will be drawn on top of the calculated spectrum.

The two spectra are visually similar at least qualitatively. However,calculated and experimental UV/visible spectra are likely to be sufficiently
different that the theory will not often be able to account for the “color” ofthe molecule. Where the theory is likely to be more successful is in
anticipating changes in color resulting from subtle changes in structure.
Click onwhen you are done. Also, remove the spectra pane either byclicking on
at the top right or by selecting Spectra from the Display
menu or by clicking on
at the top of the screen.
6. Spartan permits display, manipulation and query of a number of importantgraphical quantities resulting from quantum chemical calculations. Most
important are the electron density or simply density as it is commonlyreferred to (that reveals how much space a molecule actually takes up), thebond density (that reveals chemical bonds), and key molecular orbitals (thatprovide insight into both bonding and chemical reactivity). In addition, theelectrostatic potential map, an overlay of the electrostatic

77

potential (the attraction or repulsion of a positive charge for a molecule)on the electron density, is valuable for describing overall molecular charge
distribution as well as anticipating sites of electrophilic addition. Anotherindicator of electrophilic addition is provided by the local ionization
potential map, an overlay of the energy of electron removal (ionization) on
the electron density. Finally, an indicator of nucleophilic addition is provided
by the |LUMO| map, an overlay of the absolute value of the lowestunoccupied molecular orbital (the LUMO) on the electron density.
Click once on
to move to the next molecule in the list, ethylene. Clickon the Display menu and select Orbital Energies (or click
if it appears
at the top of the screen). An orbital energy diagram for ethylene will appear
at the left of the screen. This provides the energies of all six occupied
valence molecular orbitals and the first ten unoccupied molecular orbitals.

Note: Right-clicking on the MO diagram, and choosing Properties from theresulting contextual menu provides access to display of up to the first 10
occupied and unoccupied orbitals. MO’s outside this range can be requested
individually from the Surfaces dialog (Setup and Display menu).
Click on the energy level in the diagram labeled HOMO. In a second, thefamiliar π bond in ethylene will appear. Note that the graphic has “blueand red” regions. These correspond to positive and negative values of the78

orbital (the absolute sign is arbitrary). Examine the other occupied orbitals(by clicking on their respective energy levels in the diagram) as well as thelowest-unoccupied molecular orbital (the LUMO). Note that you can movefrom one level to the next by moving the mouse up or down while holding
down and then releasing the left button. You can also use the up and downarrow keys on your keyboard. Click onwhen you are done.
“Swipe” one finger up or down over the orbital energy
diagram to move to the next higher or lower energy level.

Click once on ►to move to the next molecule in the list, benzene.
Click on the Display menu and select Surfaces from the palette (or clickon
if it appears at the top of the screen). The Surfaces dialog appears.

Select electrostatic potential map inside the Surfaces dialog (check the box
to the left of the name). An electrostatic potential map for benzene willappear.* Click on the map. The Style menu will appear at the bottom rightof the screen. Select Transparent from this menu. This makes the map
transparent and allows you to see the molecular skeleton underneath. Go
back to a Solid display (Style menu) in order to clearly see color
differences. The default color scheme follows the coloring in a rainbow:* Discrete displays are the default. You can change the default to continuous displays by turning off theBands checkbox in the Molecule tab of the Preferences dialog (Preferences... under the Options menu;
Chapter 25).

79

red –› orange –› yellow –› green –› blue, where by convention red indicatesa negative potential (the benzene  system) orattraction to a positive charge
while blue indicates a positive potential (the  system) or repulsion by apositive charge. An alternative scheme with only three colors (red, whiteand blue) may be selected. Click on the Display menu and select Properties(or click on
if it appears at the top of the screen) and click on the surface.

Click once on ►to move to the next molecule in the list, aniline, and selectlocal ionization potential map inside the Surfaces dialog. By convention, redregions on a local ionization potential map indicate areas from which electron
removal (ionization) is relatively easy, meaning that they are subject toelectrophilic attack. These are easily distinguished from regions where
ionization is relatively difficult (by convention, colored blue). Note that theortho and para ring carbons are more red than the meta carbons, consistent
with the known directing ability of the amino substituent.
Click once on ►to move to the next molecule in the list, cyclohexenone,
and check LUMO inside the Surfaces dialog. The resulting graphic portrays
the lowest-energy empty molecular orbital (the LUMO) of cyclohexenone.
This orbital is delocalized onto several atoms and it is difficult to tell whereexactly a pair of electrons (a nucleophile) will attack the molecule.
A clearer portrayal is provided by a LUMO map that displays the (absolute)value of the LUMO on the electron density surface. By convention, thecolor blue is used to represent maximum value of the LUMO and the color
red, minimum value. First, remove the LUMO from your structure (uncheck80

LUMO in the Surfaces dialog) and then turn on the LUMO map (check|LUMO|map in the dialog). Note that there are two blue regions, one directly
over the carbonyl carbon and the other over the  carbon. This is entirely
consistent with known chemistry. Enones may either undergo carbonyl
addition or conjugate (Michael) addition.

7. New in Spartan’24 is class of models that generally fall under theheading of machine learning models (colloquially, throughout the manual,
these are referred to as neural network routines, or more simply neural nets).
Click once more on ► to move to the next model camalexin dft (the full
SSPD identifies this as 3-(1,3-thiazol-2-yl)-1H-indole. This example
includes the results of geometry optimization and NMR chemical shifts
from ωB97X-D/6-31G* density functional calculations. The model display
has been simplified to omit hydrogens, and the molecule is rendered in the
tube display with calculated chemical shift labels turned on for 4 specificcarbon centers.
Click once more on ► to move to the next model camalexin est dft nn.
This molecule is a copy of the previous, and also has available NMR datafrom ωB97X-D/6-31G* density functional calculations, the difference inthis case is that equilibrium geometry was determined by a neural network
routine, rather than quantum mechanics. Move the step keys back and forth
to compare chemical shift results.
From the Display menu, select the Spreadsheet. Spartan’s internal
spreadsheet is useful for data organization, analysis, linear regression, andcustomized functions including multi-molecule display. Resize thespreadsheet so that you can see the bottom two entries. Click inside thecheck box to left of both camalexin dft and camalexin est dft nn. This willturn on display of both molecules. You can manipulate both samples
independently (selection is made by clicking on the molecule you wish to
select). Note, it may be desirable to Couple multiple molecule’s positions,such that movements are applied to multiple molecules. This is achieved by81

toggling the Coupled (on or off as needed). Position both copies so that thechemical shifts are visible for comparison. How well did the neural network
routine perform in comparison to the density functional sample?
8. When you are finished, close the document by selecting Close from theFile menu or alternatively by clicking on theicon at the top of thescreen.

82

Section III
Introductory Tutorials
The first step in performing a molecular mechanics or quantum chemical
calculation typically involves specifying molecular geometry. Spartan offers
four ways to do this: building in 3D, sketching in 2D, accessing a databaseand accessing a variety of coordinate formats from the File menu. See
Chapter 16 for a list of supported file types.
To build molecules in 3D, Spartan provides a palette of common atomic
fragments, menus of common functional groups and rings, access to the
clipboard and tools for making and breaking bonds and for deleting atoms orgroups of atoms. The 3D building paradigm is quite general, and covers not
only organic molecules discussed in chapters which make up this section,
but also inorganic and organometallic molecules, as well as polypeptides
and polynucleotides. Tutorials illustrating the essential features andcapabilities of Spartan’s 3D builder for organic molecules are provided in
Chapter 3.
Building in 3D may feel unfamiliar or uncomfortable for many chemists,
who, after all, have been taught to draw molecules in 2D on paper or on awhiteboard. The advent of tablet computers and touch- screen PC’s makes“on-screen” 2D drawing an attractive alternative to 3D building. Spartan
provides a simple but highly functional 2D sketcher directed primarily (butnot restricted) to organic molecules. Simple inorganic and organometallic
molecules may also be sketched. Common atoms, functional groups andrings are all contained in a single palette. Conversion to 3D structure is
automatic, but requires explicit specification of cation, anion, or radical
centers (in order to add the proper number of hydrogens to the sketch) as
well as designation of stereochemistry. While sketch capability is designed
for touch screen devices (and is modeled after the iSpartan app for iOS
devices), it is fully functional using a mouse and keyboard or a touch pad.
Tutorials illustrating the essential features and capabilities of Spartan’s 2D
sketcher are provided in Chapter 4.

83

Properties relating to geometry, for example, bond lengths and angles, arediscussed in these two chapters and a few simple examples are provided.
The intention is to touch on only the most commonly-used features, leaving
discussion of more advanced functions to tutorials in later chapters.
The tutorials in the remaining chapters in this section may be completed startingfrom either the 2D sketcher or 3D builder whichever is more comfortable
for the user. Tutorials in Chapter 5 illustrate the range of molecularproperties and spectra available from quantum chemical calculations, while
those in Chapter 6 illustrate a variety of common graphical models that canbe displayed. No calculations are actually required for these tutorials. Rather,results are taken from the Spartan Spectra and Properties Database (SSPD)
and correspond to calculations using either the B97X-D/6-31G* or
EDF2/6-31G* models. The first tutorials that actually require the user to doquantum chemical calculations are provided in Chapter 7.
Completing the full set of tutorials in this section will take a few hours of yourtime, and make only a modest demand on computer time for the tutorials in
the last chapter. This will not make you an “expert”, but will leave you
comfortable enough to navigate throughout Spartan. “Advanced” tutorials
grouped under the next section will build upon these skills and introduce you
to a wider range of the program’s features and capabilities.

84

Chapter 3
Building Organic Molecules in 3D
The tutorials in this chapter introduce and illustrate tools to build 3D
molecular structures. These include atomic fragments, functional groups andrings contained in the organic model kit together with tools for making andbreaking bonds, deleting atoms and refining structure.
Organic Model Kit
Click onto bring up the 3D model kit. The organic model kit contains
a selection of atomic fragments corresponding to elements commonly foundin organic molecules. The kit may be scrolled if your display is too small to
display it.*

* Additionally, you can save space by removing the icons at the bottom of the model kit. Uncheck Show
Toolbar from the Miscellaneous tab of the Preferences dialog (Options menu; Chapter 25).
Chapter 385

Different hybridization states are provided for some elements (from left toright and then top to bottom):C(sp3)
C(sp2)C(sp)C(aromatic)
Si(sp3)N(sp3)
N(sp2)N(sp)N(aromatic)N(planar)P(sp3)O(sp3)
O(sp2)
S(sp3)
S(sp2)

H
F
Cl
Br
I

A fragment is chosen by clicking on its icon, which is then displayed in a box at
the top of the model kit. The name of the fragment is displayed in the selection
bar underneath, for example,. Once selected, the fragment
may be used to initiate building, to add alongside of an existing structure orbond onto an existing structure. To initiate building, double click anywhere on
screen.* To add alongside of an existing structure, double click in a blank area
on screen. To bond to an existing structure, click on a free valence (not anatom). (Free valences are colored yellow on
the selected molecule.) Bond type in the caseof atomic fragments with multiple bondtypes, for example, sp2 carbon, depends on
the nature of the free valence selected.
Clicking on the Groups button near thebottom of the model kit changes the focus
from fragments to groups, one of which will
be shown in the box at the top of the model
kit and named in the selection bar directly
underneath. Clicking on the selection bar
brings up a menu of available groups.
Once selected from the menu, a group may
be used to initiate building, to add alongsideof an existing structure on screen, or to add to an existing structure.
* For users of much earlier versions of Spartan that have grown accustomed to (or new users who
prefer) a single-click motion to initiate building, this preference can be set from the Options menu >Preferences dialog > Settings tab, by deselecting the Double-Click Start check box and clicking
the OK button. The choice to move to a double-click start for 3D building was made to maintainconsistency with the behavior of the 2D sketch builder.

Chapter 3

86Clicking on the Rings button near the bottom of
the model kit changes the focus to rings, one ofwhich will be shown in the box at the top of themodel kit and named in the selection bar
underneath. Clicking on the selection bar brings
up a menu of available rings.
Once selected from the menu, a ring may be used
to initiate building, to add alongside of an
existing structure on screen, or to add to an
existing structure.
Note that only hydrocarbon rings are available. Heteroatoms may besubstituted for carbons, for example, substituting an oxygen for one of the
carbons in cyclohexane leading to tetrahydropyran. With cyclohexane onscreen, click on sp3 oxygen () in the model kit and then double clickon one of the cyclohexane carbons.
The amide and carboxylic acid/ester groups and the cyclohexane,
cycloheptane, naphthalene, phenanthrene, indene and fluorene rings havemore than one unique free valence. The free valence that is to be used ismarked with a gold • (in the icon shown in the box at the top of the modelkit). The marked position circulates among the possible positions withrepeated clicking on the icon. Selection of an axial or equatorial freevalence in cyclohexane and cycloheptane is indicated by the label ax or
eq appearing alongside the icon.
Acrylonitrile

1. To bring up the organic model kit, click (left button) on the File menu
and select (click on) New Build. Alternatively, click on
if it appears at*
2
the top of the screen. Click on trigonal planar sp hybridized carbon
from the fragment library.
* Icons are fully customizable from the Options menu > Preferences dialog > Icons tab. So whether or
not a particular icon is displayed is at the discretion of the user.

Chapter 387

A model of the fragment appears at the top of the model kit. Bring the cursor
anywhere on screen and double click (left button). Rotate the carbon
fragment (drag the mouse while holding down the left button) so that you
can clearly see both the double free valence (=) and the two single freevalences (–).
2. sp2 carbon is still selected. Click on the double free valence. The two
fragments are connected by a double bond, leaving you with ethylene,
meaning that ethylene is in the Spartan Spectra and Properties Database(SSPD). The name ethylene will appear at the bottom right of the screen. If
you make a mistake and click instead on the single free valence, select Undo
from the Edit menu (or click on
if it appears at the top of the screen).
You can also start over by selecting Clear from the Edit menu (or click on
if it appears at the top of the screen).
3. Click on the Groups button at the bottom of the model kit, click on theselection bar at the top of the model kit, and select Cyano from the groups
available from the menu. Click on any of the four single free valences on
ethylene (they are equivalent). This bonds the cyano group to ethylene, leaving
you with acrylonitrile. Its name will appear at the bottom right of the screen.
4. Click on
at the bottom of the model kit. (You can also select Minimize
from the Build menu or click on
if the icon appears in the toolbar at the topof the screen.) The molecular mechanics energy (36.2 kJ/mol) and symmetry
point group (Cs) are provided at the bottom right of the screen.
5. Select View from the Build menu (or click on theicon in the toolbar).
The model kit disappears, leaving only a ball-and- spoke model ofacrylonitrile on screen. The name appears at the bottom of the screen as
acrylonitrile is also in the SSPD.

Chapter 3

88ball-and-spoke modelThis model can be rotated, translated and zoomed by using the mouse inconjunction with keyboard functions. To rotate the model, drag the mouse
while holding down the left button; to rotate in the plane of the screen also
hold down the Shift key. To translate the model, drag the mouse with theright button depressed. To zoom the model, use the center mouse wheel(scroll wheel) if available, or hold down the Shift key in addition to the rightbutton while dragging the mouse up (zoom in) or down (zoom out).
Rotate the molecule by moving one finger over the screen.
Rotate the molecule in the plane of the screen by twisting
two fingers. Translate by moving two fingers. Zoom by pinching
two fingers.

6. Close acrylonitrile (Close from the File menu or click on thethe toolbar).

icon in

Cyclohexanone

1. Click on the File menu and select New Build from the palette or click on
at the top of the screen. Click on the Rings button near the bottom of
the model kit, click on the selection bar and choose Cyclohexane from themenu of rings. Double click anywhere on screen.
2. Select sp2 carbon

Chapter 3

from the model kit. Double click on89

any carbon atom (not a free valence). The sp3 hybridized center will be
replaced by an sp2 hybridized carbon.
Fragment replacement is subject both to the usual valence rules
and to the availability of free valences. For example, replacementof an sp3 carbon by an sp2 carbon requires that at least two freevalences are available.

3. Select sp2 oxygenfrom the model kit. Click on
the double free valence on the sp2 carbon. You have made cyclohexanone.
Click onat the bottom of the model kit to produce a structure with Cs
symmetry. Click on. The name cyclohexanone appears at the bottom of
the screen as the molecule is in SSPD.
4. Close cyclohexanone.
Limonene

1. Select New Build from the File menu (or click on theicon in the
toolbar) to bring up the model kit. Click on the Rings button near the bottomof the model kit, click on the selection bar and choose Cyclohexane fromthe menu of rings. Double click anywhere on screen.
2. Click on the Groups button near the bottom of the model kit, click on theselection bar and choose the Alkenyl group. Click on the equatorial freevalence on C4 (see figure above for numbering). You have madevinylcyclohexane.
3. Click on the Make Bond icon ( ) at the bottom of the model kit. One
after another click on the axial free valence on C1 and then the axial freevalence on C2. You have made 4-ethenylcyclohex-1-ene.
4. Select sp3 carbon
from the model kit and one after another clickon the free valence on C1 and on the free valence of the vinylic carbon

Chapter 390attached to the ring. You have made limonene. The name will appear at thebottom of the screen as limonene is in SSPD. Click on
at the bottom of
the model kit to give a refined geometry and finally click on ( ).
5. Close limonene.
Nicotine

1. Select New Build from the File menu ( ). Click on the Rings button in
the model kit. Click on selection bar at the top of the model kit and choose
Benzene. Double click anywhere on screen.
2. Click on the selection bar and choose Cyclopentane. Click on one of
the free valences on benzene. You have made phenylcyclopentane.
3. Click on the sp2 nitrogen in the model kit () and double click on
the appropriate (meta) carbon (not a free valence) in the benzene ring. You
have made 3-cyclopentylpyridine.
4. Click on sp3 nitrogen in the model kit () and double click on theappropriate carbon in the cyclopentyl ring. You have made nornicotine.
5. Click on sp3 carbon in the model kit () and click on the free valenceon the nitrogen in the pyrrolidine ring. You have made nicotine. Click on
at the bottom of the model kit to clean up your structure. The namenicotine will appear at the bottom of the screen as the molecule is in SSPD.
6. Select R/S Chirality from the Model menu ( ). The R/S chirality will
be displayed. The S isomer is the naturally occurring isomer of nicotine. If
you have built the R isomer and wish to invert the chiral center, hold down
the Ctrl key on

Chapter 391

your keyboard and double-click on the chiral center.
7. Close nicotine.
Coumarin

1. Select New Build from the File menu ( ). Click on the Rings button in
the model kit. Click on the selection bar at the top of the model kit andchoose Benzene. Double click anywhere on screen.
2. Click on the Groups button, click on the selection bar and choose
Alkenyl. Click on one of the free valences of benzene to make styrene.
3. Click on the selection bar and choose Carboxylic Acid/Ester. A yellow dot
should mark the free valence on carbon in the group shown in the windowat the top of the model kit. If instead it marks the free valence on oxygen,click inside the window to move it. Click on the free valence on the
methylene end of the vinyl group that is cis to benzene to make cis-cinnamicacid.
4. It may be necessary to rotate around the bond marked A and B marked
below to properly position the molecule for bonding.

In turn, click on bonds A and B. A red arrow will curl around the bond andan iconwill appear at the top of a narrow shaded area at the far left ofthe screen. Click inside this area and move the mouse up and down. Position
the bond such that the OH bond is near the phenyl ring as shown below.
Move one finger up and down inside the area at the far left ofthe screen to rotate about the selected bond.

Chapter 3

92

When you can clearly see the two free valences, click on
at the bottomof the model kit and, one after another, click on the two free valences. You
have made coumarin, its name will appear at the bottom of the screen.
5. Close coumarin.
Spartan is able to fuse rings in 3D. This makes building molecules likecoumarin much easier. To build coumarin using the fused-ring approach,select Benzene from the Rings menu double-click to insert benzene onscreen. Select Cyclohexane from the Rings menu, double-click on oneof the CC bonds in benzene to form benzocyclohexane. Choose sp3
oxygen and double-click to replace C1 by oxygen (see numbering on
previous page). Choose sp2 carbon and double-click on C2. Choose sp2
oxygen and add this to the double-bond on the sp2 carbon. Clickon Make Bond ( ) and click on the open axial valences the sp3 ringcarbons C3 and C4 to complete coumarin.
Note, however, that fusing two rings with both bonds involving sp3-sp3
hybridized centers, for example, two cyclohexane rings, can lead to one
of two different results, in the case of two cyclohexane rings, either cis ortrans-decalin. In this case, it may be necessary to invert the chirality of
one of the resulting ring-fused carbons. This is accomplished by holding
down on the Control (Ctrl) key (Command on Mac), positioning the
cursor over the carbon and double clicking.

Chapter 3

93Chapter 4
Sketching Organic Molecules
in 2D
The tutorials in this chapter introduce and illustrate tools to sketch organic
molecules in 2D and then to convert them into realistic 3D structures.
Not only are 2D sketches (“drawings”) more familiar to most chemists than 3D
structures, they are typically easier to produce especially for complex
molecules that may incorporate fused rings or require stereochemistry to be
defined. The advent of touch-screen computers makes the argument for
sketching as an alternative to building even more compelling. Molecules that
require several minutes to build in 3D can be drawn in seconds. The key is
automatic and reliable conversion from 2D drawings to 3D structures and from
3D structures to 2D drawings.
Sketch Palette
The sketch palette contains tools for making and manipulating 2D drawings,
including tools for adding cues to designate stereochemistry.*

These include atoms that are most commonly found in organic
molecules (H, B, C, N, O, F, Si, P, S, Cl, Br and I), the phenyl,* A row of icons appears immediately above the sketch palette. These are intended to add arrows to designate
reaction transition states and to append experimental NMR chemical shifts and observed HH and CH
couplings to the sketch palette

Chapter 494

cyclohexyl and cyclopentyl rings and the carbonyl, acid/ester and amide
functional groups. The button immediately below H and B atoms allows forentering additional elements, functional groups, and ligands. The palette also
contains stereochemical markers and charge/ radical markers. Complete
details are found in Chapter 20.
Sketching a Molecule
To start a sketch, first select (click on) an atom, group, ring or wildcard icon in
the palette and then double click in the white portion of the screen (thedrawing area). To draw a bond, first click on an atom, group, ring or
wildcard icon in the palette to designate what is at the end of the bond, thenposition the cursor over the atom in the drawing area where you want the bondto start, move the cursor while holding down the left button (“drag” thecursor) to the place in the drawing area where you want the bond to end andrelease the button. Multiple bonds are made by dragging over existing
bonds.*

To make a bond touch the screen where you want it to start, move
one finger to where you want it to end and lift. Replace position bytouch, drag by move and release by lift in the diagram above.

* With Spartan’24, and alternative way of drawing multiple bonds is simply to double click on a single
bond. Double clicking (on a double bond) draws a triple bond and double clicking on a triple bond reverts
to a single bond. The one exception is double clicking on a bond when a ring is selected in the palette as
this signifies ring fusing.
Chapter 495

Manipulating a Sketch
To translate the sketch, move the mouse over the screen while holding down
the right button. To rotate the sketch (in the plane of the screen), move themouse up and down while holding down both the left button and Shift key.
Use the scroll wheel to resize the sketch.
To translate the sketch, move two fingers over the screen. To rotate
the sketch in the plane of the screen, “twist” two fingers on thescreen. To resize the sketch, pinch (or spread) two fingers on the screen.

N,N-Dimethylaniline
N

1. Select New Sketch from the File menu (or click on
at the top of thescreen) to bring up the sketch pad. Click on ( ) in the palette and double
click on screen.
2. Click on ( ) in the palette. Position the cursor over the “top” carbon on
the benzene ring, drag it up and release. You have drawn aniline.
3. Click on ( ) in the palette. Position the cursor over the nitrogen, drag it up
and to the left and release. ( ) is still selected. Again position the cursor overthe nitrogen, drag it up and to the right and release.
4. Click on ( ) in the palette to clean up your drawing and click on ( ) to
produce a 3D structure. The name N,N-dimethylaniline will appear at thebottom of the screen as the molecule is in SSPD.
5. Close N,N-dimethylaniline.

Chapter 496

trans-Stilbene

1. Select New Sketch from the File menu ( ) to bring up the sketch pad.
Click on ( ) in the palette. Position the cursor on the screen, drag it to theright and release. Position the cursor on one end of the line (CC bond) thatyou have just drawn, drag it to the other end and release. You have drawn
ethylene.
2. Click on ( ). Position the cursor over the left end of the double bond, dragit down and to the left and release. You have drawn styrene.

3. ( ) is still selected. Position the cursor over the right end of the doublebond, drag it up and to the right and release. You are done.
4. Click on ( ) to clean up your drawing. Click on ( ) to convert it to a 3D
structure. The name trans-stilbene will appear at the bottom of the screen
as the molecule is in SSPD.
5. Close trans-stilbene.

Chapter 4

97

Indigo
H O
6
5

7a

3'

N
2

3a

3

4'
3a'

5'

2'
1' N

6'
7a'
7'

O H

1. Select New Sketch from the File menu (double click on screen.

). Click on () and

2. ( ) is still selected. Position the cursor over C2 (see numbering in diagram
above), drag it to the right and release. Your sketch should appear as below.

3. Select ( ) from the palette. Position the cursor above C3, drag it awayfrom the ring and release. Again position the cursor above C3, drag it along
the CO bond to the oxygen and release. Alternatively, double click on the
CO bond that you have just made to turn it into a double bond. Repeat for
C3'. You are left with a drawing.

4. Select ( ) from the palette and one after another double clickon C1 and C1'.

5. Select ( ) from the palette. Position the cursor above C2, drag it to C2'
and release. Alternatively, double click on the C2-C2’ bond.
Chapter 498

6. Select ( ) from the palette and double click on the bond connecting C3a
and C7a.* Repeat for C3a' and C7a'.
7. Click on ( ) to clean up your drawing and click on ( ) to turn it into
a 3D structure. The name indigo will appear at the bottom of the screen as
the molecule is in SSPD.
8. Close indigo.
3-Cyano-4-methylcyclohexenyl Radical

This tutorial shows you how to use a wildcard to specify a functional groupand how to designate a radical site.
1. Select New Sketch from the File menu (and double click on screen.

). Click on () in the palette

2. Click on ( ) in the palette. Position the cursor over C4 (see diagram
above for numbering), drag it up and to the right and release. You havedrawn methylcyclohexane.
3. ( ) is still selected. Position the cursor over C1, drag to C2 and release.
Alternatively double click on the C1-C2 bond. You have drawn 4methylcyclohexene.
4. Double-click on the wildcard icon that is located immediately below H
and B in the palette. Click on the Groups tab and click on CN. CN now
appears as the wildcard icon. Position the cursor over C3, and drag it awayfrom the ring and release. You have drawn 3-cyano-4-methylcyclohexene.

* This is the exception referred to earlier regarding double clicking on a bond to change itfrom single to double (or double to triple).

Chapter 499

5. One of the following icons will appear in the palette directly below thesulfur icon. If it is not the radical marker, click to adjust:With the radical markder selected, double-click
6. Click on (3D structure.

) to clean up your drawing and click on () to make a

7. Close 3-cyano-4-methylcyclohexenyl radical.
Androsterone

The steroid androsterone is typical example of a molecule that is difficult
to build (3D) but quite easy to sketch (2D).
1. Select New Sketch from the File menu ( ) to bring up the sketch
pad. Click on ( ) and double click on screen. Cyclohexane is still selected.
Double click on the C5-C10 bond (see diagram above).

2. Cyclohexane is still selected. Double click on the C8-C9 bond.

3. Click on ( ) and double click on the C13-C14 bond. You have now
drawn the complete steroid skeleton.

Chapter 4100

4. It is necessary to explicitly specify hydrogens at C5, C8, C9 and C14 in order
to incorporate the necessary stereochemical cues (up and down “wedges”) in
your drawing. Click on ( ), position the cursor over C5, drag away fromthe ring and release. Repeat for C8, C9 and C14.
5. Click on ( ), position the cursor over C10, drag up and release.
Repeat for C13.
6. Click on ( ). Position the cursor over C3, drag down and to
the left and release.
7. ( ) is still selected. Position the cursor over C17, drag up and to the rightand release. Convert the single (CO) bond at C17 to a double bond. Again
position the cursor over C17, drag along the bond to oxygen and release.
Alternatively, double click on the CO single bond to turn it into a doublebond. Your structure should now look as follows.

8. Click on ( ). Position the cursor over C10, drag along the bond to themethyl group that you drew in step 5 and release. Repeat for C13. Position
the cursor over C8, drag along the CH bond that you drew in step 4 andrelease. Up wedges will appear for all three centers.
9. Click on ( ). Position the cursor over C3, drag along the CO bond thatyou made in step 6 and release. Position the cursor over C5, drag along the
CH bond that you made in step 4 and release. Repeat for the CH bonds at
C9 and C14. Down wedges will appear for all four centers.

Chapter 4

101

Spartan’24 offers an alternative way to specify stereochemistry. Replacesteps 4-6 and 8-9 by steps A-D.
A. Click on ( ) in the sketch palette. Click on ( ) (( ) remains
selected), position the cursor over C8, drag up and release.
B. Click on (). ( ) remains selected. One after the other, position
the cursor over C5, C8, and C14, drag down and release.
C. Click on () and then on ( ). One after the other, position the
cursor over C10, and C13, drag down and release.
D. Click on ( ) and then on ( ). Position the cursor over C3, dragdown and to the left and release.

10.Click on () to clean up your drawing. Click on ( ). The nameandrosterone should appear at the bottom right of the screen as the molecule
is in SSPD. If it does not, you have made an error somewhere. Select Edit
Sketch from the Build menu or click on ( ) if it appears at the top of thescreen to return to the sketch pad.
11.Androsterone incorporates seven chiral centers. To view the R/S
assignment, click on the R/S Chirality entry in the Model menu ( ). R/Slabels will appear next to each of the chiral centers.
12.Close androsterone.

Chapter 4102

Chapter 5
Spectra and Properties ofOrganic Molecules from SSPD
The tutorials in this and the two chapters that follow involve the moleculesthat you built or sketched in the preceding two chapters. The emphasis shifts
from providing input structures, to analyzing the results of quantum
chemical calculations (in this and the following chapter) to actually doing
calculations (in the final chapter in this section).
The Spartan Spectra and Properties Database (SSPD) provides atomic andmolecular properties and NMR spectra for >300,000 molecules, calculatedusing the ωB97X-D/6-31G* density functional model properties, IR and
NMR spectra for the same set using the less accurate and less “costly” EDF2/631G* model. In addition, the ωB97X-D/6-31G* set contains more than
2,000 transition-metal organometallics and organolanthanides. Except for
the trans-stilbene tutorial, you can use either ωB97X-D/6-31G* or
EDF2/6-31G* models to explore what is calculated without having toactually run calculations. We suggest the former. Selection is made fromthe menu at the bottom of the dialog which results from clicking on themolecule name at the bottom of the screen.

13

C Spectrum of Limonene

1. Build limonene ( ), minimize ( ) and exit the builder ( ).
Alternatively, sketch limonene ( ) and exit the sketcher ( ).

Chapter 4103

2. Click on the name limonene at the bottom of the screen. Make sure that
B97X-D/6-31G* is selected from the dialog that appears and click on
Replace. Properties and spectra for limonene are now available.
3. Select Spectra from the Display menu, or click on ( ) at the top of thescreen. Click on
at the top of the spectra pane that results to show a tabbed
dialog with available calculated spectra (in red) and (possibly) available
experimental spectra (in blue).

4. Selectfrom the NMR tab. The calculated 13C NMR spectrum
appears in the spectra pane. There are ten lines corresponding to ten uniquecarbons in limonene. Up and down triangles demark a moveable cursor. Clickon either (or on the dotted line connecting them) to select and with the left
mouse button (or your finger), move horizontally over the spectrum. When
you intersect a NMR resonance, it will be highlighted in the spectrum, thevalue of the chemical shift indicated, and the carbon (or carbons) in the
structure responsible will be highlighted in the structure model (on the main
screen).

Chapter 5104

4. Again, click on
at the top of the spectra pane, but this time, select. The experimental 13C spectrum of limonene will be superimposedon top of the calculated spectrum.* Visual comparison will give you an ideaof the quality you can expect from NMR calculations. To get an even better
idea, shift the range of the scale (initially from 150 to 0 ppm), move thecursor over the spectrum and zoom in with the center mouse wheel. You
can return to the original setting by clicking on () in the bar at the topof the screen
Move one finger over the spectrum to select a line. Move two
fingers over the spectrum to shift the range of the scale andpinch two fingers to zoom in and out.

5. Close limonene.
Proton Spectrum of Indigo

1. Build indigo ( ), minimize ( ) and exit the builder
Alternatively, sketch indigo ( ) and exit the sketcher (.
).

2. Click on the name indigo at the bottom of the screen. B97X-D should still
be selected from the menu in the dialog that results. Click on Replace.
Properties and spectra for indigo are now available. If the name does notappear, then you have made an error. In this case, re-enter either the builder
by selecting Edit Build from the Build menu ( ), or the sketch pad byselecting Edit Sketch from the Build menu ( ) and correct your model.
3. The calculated proton NMR spectrum of indigo can be displayed in two
ways. The simpler “idealized” presentation assumes that
* The experimental spectrum comes from the NMRShiftDB. Requires on-line access, source subject toavailability.

Chapter 5105three-bond HH coupling constants are zero. Select Spectra from the
Display menu ( ) to bring up the spectra pane and click onin the barat the top to show available calculated spectra (in red) and possibly available
experimental spectra (in blue). Selectfrom the palette. The spectrum
that results shows only lines corresponding to the five unique hydrogens. To
see a “familiar” proton spectrum, click again on, but this time select. The same four lines appear, but all are split (as in an experimental
proton spectrum). The lines at 6.72 and7.88 ppm are doublets due to C7 and C4, respectively (and split by C6 and C5,
respectively). The lines centering at 6.89 and 7.44 are quartets (doublet of
doublets), due to C5 and C6, respectively (and split by C4 and C6 and C5 andC7, respectively).
4.

Close indigo.
Infrared Spectrum of trans-Stilbene

We will use the EDF2/6-31G* IR data included in the SSPD for thisexample.
1. Build trans-stilbene ( ), minimize ( ) and exit the builder (Alternatively, sketch trans-stilbene ( ) and exit the sketcher ( ).

).

2. Click on the name trans-stilbene at the bottom of the screen and thenclick on Replace.
3. Select Spectra from the Display menu ( ). Click on in the bar at the
top of the spectra pane and select. The calculated IR spectrum oftrans-stilbene appears in the spectra pane.

Chapter 5106

4. As with NMR spectra, up and down triangles demark a moveable cursor.
Select and move it horizontally over the spectrum. You will see that as you
intersect a line in the spectrum, it will turn yellow and the value of thefrequency will appear at the bottom. In addition, the molecular model“vibrates” to reflect the motion that the molecule undergoes. Examine themotions of one or more lines of moderate intensity in the vicinity of 1500
cm-1 (at 1446, 1494 and 1609 cm-1). You might find it useful to expand thescale (use the scroll wheel) or to shift it (move the mouse horizontally overthe spectrum while holding down the left button). You can return to theoriginal settings by clicking on () in the bar at the top of the pane.
5. Click on from the bar at the top of the spectra pane and then.
The experimental IR spectrum of trans-stilbene obtained from the freelyavailable NIST database will be superimposed onto the calculated
spectrum. You will need to be online. Note that the two spectra are similaralthough the experimental spectrum exhibits a number of (small) lines notfound in the calculated spectrum.
To see lists of the 3N-6 calculated IR frequencies as well as the (≤3N-6) frequencies assigned to the experimental spectrum together
with intensities relative to their respective most intense frequency,
click onat the left of the spectra dialog. Checking individual
lines (in the calculated IR) moves the cursor on the spectrum andanimates the vibrational motion.

6. Close trans-stilbene.

Chapter 5

107

Chapter 6
Graphical Models for Organic
Molecules from the Spartan
Spectra and Properties
Database
The tutorials in this chapter illustrate two of the most commonly-usedgraphical models, the electrostatic potential map for elucidating molecularcharge distributions, and the local ionization potential and LUMO maps
for anticipating electrophilic and nucleophilic reactivity, respectively.
Entries in the Spartan Spectra and Properties Database (SSPD) not only include
the molecular structure, energy, properties and spectra, but also the wave
function. This allows graphical models to be requested and displayed “onthe-fly”. You will use the SSPD entries obtained from the ωB97X-D/631G* model for the examples in this chapter.
Electrostatic Potential Map for Nicotine

Chapter 6108

Note: If you see the name 3-[(2R)-1-methylpyrrolidin-2-yl]pyridine,
instead, go ahead and click replace (you will note in the SSPD preview,next to the model, you also see the word [Enantiomer]. This indicates thatyou have built 3-[(2R)-1-methylpyrrolidin-2-yl]pyridine, but what exists in
the SSPD is this molecule’s enantiomer, replacing will result in access tonicotine.
3. Select Surfaces from the Display menu or click on ( ) if it appears at
the top of the screen. Click on Add (at the bottom of the Surfaces dialog
that results) and select electrostatic potential map from the menu. This
requests an electrostatic potential map (an electron density surface onto which
the value of the electrostatic potential is color mapped). The line electrostatic
potential map appears at the top of the dialog.
The graphics calculation will run automatically following your request.*
When it completes in a few seconds, check the box to the left of electrostatic
potential map in the Surfaces dialog. The surface itself corresponds to theelectron density, and provides a measure of the overall size and shape of
nicotine. The colors indicate values of the electrostatic potential on thissurface.
By convention, colors toward red correspond to negative potential (stabilizing
interaction between the molecule and a positive charge), while colors toward
blue correspond to positive potential. The two nitrogen atoms show thelargest negative potential (red). You will see that the nitrogen in the pyridine
ring is more negative than the nitrogen in the pyrrolidine ring.
4. Quantify your observation. Select Properties from the Display menu or
click on ( ) if it appears at the top of the screen and click anywhere on theelectrostatic potential map to bring up the Surface Properties dialog.

* If they do not complete automatically, check the box to the left of Auto-Gen Graphics under theMiscellaneous section in the Settings tab in the Preferences dialog from the Options menu (Chapter
25)…

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Check the box to the left of Display Legend towards the bottom right of the
dialog to display the property range on screen. To translate the legend, clickon the legend to select, then hold down the right mouse button and move themouse. The legend is useful when making qualitative comparisons ofproperty values. Turn the map such that you can clearly see the pyridine
nitrogen and click on the area that is “most red”. An arrow marks the point on
the surface and the value of the potential is shown to the right of the legend.
Do the same for the pyrrolidine nitrogen.
Tap on the legend to select. Move two fingers to move it
around the screen. Pinch two fingers to make the legend
smaller or larger.

5. Nicotine is relatively small and it is easy to associate regions on the map withthe underlying molecular skeleton. This becomes more difficult withincreasing molecular size. Change the presentation, from the Style menu
located inside the Surface Properties dialog or at the bottom right of thescreen. Select Transparent or Mesh. You now can “see through” the map
to the underlying molecular structure.
6. Close nicotine and any open dialogs.
Chapter 6110

Local Ionization Potential Map for N,N-Dimethylaniline

1. Build or sketch N,N-dimethylaniline and click on.

2. Click on N,N-dimethylaniline at the bottom of the screen. Click on
Replace. Your structure will be replaced by that in SSPD.
3. Select Surfaces from the Display menu ( ). Click on Add at the bottomof the Surfaces dialog that results and select local ionization potential
map from the menu. This requests a map showing the energy required toremove an electron (the “ionization potential”) as a function of its location on
the electron density surface. Calculation will only take a few seconds. Whencompleted, check the box to the left of local ionization potential map in
the Surfaces dialog. The color convention is the same as for theelectrostatic potential map, although the scale is completely different. Local
ionization potentials are always positive. The default scale (5 to 15 eV) can
be changed to highlight the differences. Select Properties from the Display
menu ( ) and click on the local ionization potential map. Change “5” atthe left below Property Range to “10” and close the dialog. Colors toward
red correspond to small ionization potentials (greatest electrophilic
reactivity) and colors toward blue correspond to large ionization potentials.
Note that the red regions on the map are over the ortho and para ring
positions. This is exactly what is experimentally observed.
4. Close N,N-dimethylaniline and any open dialogs.

Chapter 6111

LUMO Map for Androsterone

1. Sketch androsterone () and exit the sketcher ().

2. Click on the name androsterone at the bottom right of the screen. If the (correct)
name is not provided, then you have made a mistake. In this case, re-enter thebuilder by selecting Edit Sketch from the Build menu ( ), and make anynecessary changes. Click on Replace to replace your structure by that in the
SSPD.
3. Select Orbital Energies from the Display menu or click on ( ) if itappears at the top of the screen. An orbital energy diagram will appear at
the left of the screen. To examine the molecular orbital corresponding to aline in the diagram, click on the line. You will see that the LUMO is a π*
orbital localized on the carbonyl group, although it is not at all clear whether
it is more or less concentrated on the face away from the two methyl groups.
This subtle distinction might be important, for it would be expected that
nucleophilic addition would occur from the face on which the LUMO ismore concentrated. A |LUMO| map provides a much clearer picture.
4. Select Surfaces from the Display menu ( ). Click on Add and select|LUMO| map from the menu. The graphics calculation will require only afew seconds. When completed, check the box to the left of |LUMO| map
inside the Surfaces dialog. The largest (absolute) values of the LUMO arecolored blue. Rotate to examine both the faces (with and without the two
methyl groups). From the |LUMO| map you can clearly see that the LUMO
is more concentrated on the face away from the methyl groups.

Chapter 6112

In this example, the LUMO corresponds to the expected π* orbital
primarily localized on the carbonyl bond. This may not always be
the case, and it may be necessary to look at higher-energy
unoccupied molecular orbitals, LUMO-1, LUMO-2, etc. Spartan
allows any orbital to be superimposed on the electron density
surface.

5. Close androsterone and any open dialogs.

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113

Chapter 7
Spectra, Properties andGraphical Models for Organic
Molecules from Quantum
Chemical Calculations
The tutorials in this chapter provide the earliest and simplest examples of
specifying and performing quantum chemical calculations. As in theprevious two chapters, they refer to molecules examined in Chapters 3 and
4. Calculations are performed utilizing the B97X-D/6- 31G* model, andtime estimates are based on this model using a quad-core desktop machine(3 GHz Intel I7 processor, 16 GB RAM, 800 GB solid state drive) running inparallel under Windows 10 Pro. Alternate computational models can beused in place of B97X-D/6-31G*. Completion times will vary accordingly.
5 minAcrylonitrile

We return to acrylonitrile for the first tutorial that actually involves
quantum chemical calculations.
1. Build or sketch acrylonitrile.
2. Select Calculations... from the Setup menu or click on ( ) if it appears
at the top of the screen, and perform the following operations in the
Calculations dialog that appears.

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a. Select Equilibrium Geometry from the top menu to the right ofCalculate. This specifies optimization of equilibrium geometry. At Groundstate in Gas will appear in the menus to the right of Equilibrium Geometry.
b. Select Density Functional, B97X-D and 6-31G* from the three bottom
menus to the right of with. This specifies that the B97X-D/6-31G* density
functional model will be used for this calculation.
c. Click on Submit at the bottom of the dialog. A file browser
appears.

Because the molecule is in SSPD (even though we will not use the data), thename acrylonitrile is presented in the box to the right of File name.

Chapter 7115

Either use it or type in whatever name you like and then click on Save. You
will be notified that the calculation has been submitted (is running).

Click on OK to remove the message from the screen.
After a molecule has been submitted, and until the calculation has
completed, you will not be permitted to modify any dialogs orother information associated with molecules in the document.

3. You will be notified when the calculation has completed.

Click on OK to remove the message from the screen. Select Output fromthe Display menu or click on ( ) if it appears at the top of the screen.
Displayed initially is a brief summary (Summary tab, describing the task
and providing the molecule name and molecular formula together with thetotal charge (if it is not 0) and number of unpaired electrons (if it is not 0),
the calculation model (method and basis set) and the energy.

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116

The summary may be all that you really want (or need) but more detailed
information can be obtained by selecting Output from the menu at the topof the dialog.

You can scan the output from the calculation by using the scroll bar at theright of the window or by clicking (left button) inside the output window andusing the scroll wheel on your mouse. Information at the top of the dialog issimilar to that reported in the summary, although additional details areprovided. Eventually, a series of lines appear, under the heading
Optimization. These tell the history of the optimization process. Each line
Chapter 7117

(or Step) provides results for a particular geometry. Ideally, the energy will
monotonically approach a minimum value for an optimized geometry. If thegeometry was not optimized satisfactorily, an error message, such as:
OPTIMIZATION has exceeded N steps, (or similar) will be displayedfollowing the last optimization cycle. Optimization failure is not common,so if it occurs, check to see if you have correctly built the structure.
Near the end of the output is the final total energy* (-170.76462 atomic units
for acrylonitrile if you used the ωB97X-D/6-31G* model)**, and thecomputation time. Click on
at the top of the output dialog to close it.
You may examine the total energy and dipole moment among othercalculated properties without having to go through the output. SelectProperties from the Display menu to bring up the Molecule Properties
dialog (make certain that the Molecule tab and not the QSAR,
Thermodynamics, 2D Drawing, NMR or Utilities tab is selected).

To see the dipole moment vector (indicating the sign anddirection of the dipole moment), check the box to the left of* See Calculations... (Setup menu; Chapter 21) for a discussion of how total energy relates to heat offormation and strain energy.
** The number you actually get will likely differ in the last decimal place due to machine
precision.

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118

Display Dipole Vector. Wire, ball-and-wire or tube models are best for thisdisplay.

Uncheck the box to remove the dipole moment vector.
Click on an atom. The (Molecule Properties) dialog will be replaced by
the Atom Properties dialog.

Among other things, this provides three different sets of atomic charges:
Electrostatic, Mulliken and Natural.* To obtain the charge on anotheratom, simply click on it. Inspect all the atomic charges on acrylonitrile (byclicking on the appropriate atoms). When you are finished, click on
atthe top of the Atom Properties dialog to close it.
4. Select Surfaces from the Display menu ( ). Click on Add
at the bottom of the Surfaces dialog that results, and select* Atomic charge is not (and cannot be) a measurable property; numerous ways have been formulated to
calculate it. Not surprisingly the different charge models can (and do) lead to markedly different results.

Chapter 7

119electrostatic potential map from the menu. This requests an electrostatic
potential map (an electron density surface onto which the value of theelectrostatic potential is mapped). The graphics calculation will run without
needing to resubmit the job. When it completes in a few seconds, check thebox to the left of electrostatic potential map in the Surfaces dialog. The
surface itself corresponds to the electron density and provides a measure of theoverall size and shape of acrylonitrile. The colors indicate values of theelectrostatic potential on this surface; by convention, colors toward redcorrespond to negative potential (stabilizing interaction between themolecule and a positive charge), while colors toward blue correspond topositive potential. The nitrogen (the most electronegative atom) is red andthe hydrogens (the most electropositive atoms) are blue.
5. Close acrylonitrile and any open dialogs.
5 min

Cyclohexanone

This tutorial offers another example of running quantum chemical calculation
on a very simple molecule. It also provides an opportunity to further
illustrate graphical models for elucidating the stereochemistry of organic
reactions.
1. Build or sketch cyclohexanone.
2. Select Calculations... from the Setup menu ( ). Specify Equilibrium
Geometry, Ground and Gas from the top menus to the right of Calculate,and Density Functional, ωB97X-D and 6-31G* from the menus specifying
computational model. Click on Submit and accept the name cyclohexanone.
Wait until the calculation completes before proceeding to the next step.
3. Cyclohexanone undergoes nucleophilic attack at the carbonyl carbon, and
it is reasonable to expect that the molecule’s lowest-unoccupied molecularorbital (the LUMO) will be localized here. To visualize the LUMO, bring up
the Surfaces dialog (Surfaces from the Display menu or click on). Clickon Add and select LUMO from the menu. Also request an electron density
Chapter 7120

surface onto which the (absolute) value of the LUMO has been mapped incolor (a so-called LUMO map). Click on Add and select |LUMO| mapfrom the menu. The two graphics calculations will run automatically andwill require only a few seconds.
4. Check the box to the left of LUMO in the Surfaces dialog. You will seethat the resulting graphic is a π* orbital primarily localized on the carbonylgroup, consistent with the fact that nucleophiles (electron pairs) add to thecarbonyl carbon. See if you can tell which face of the carbonyl carbon the
LUMO is more concentrated on.
5. Uncheck the box to the left of LUMO in the Surfaces dialog (to turn off
the display of the LUMO). Then check the box to the left of |LUMO|
map to display the electron density surface onto which the (absolute) valueof the LUMO has been mapped. By convention, colors toward red indicate
small (absolute) values of the LUMO (near zero), while colors toward blue
indicate large (absolute) values of the LUMO. We are looking for a “bluespot”. Note that it is directly over the carbonyl carbon. This corresponds tothe maximum value of the LUMO and is where nucleophilic attack will
occur.
6. You will see that the blue spot over the axial face of the carbonyl carbon isbigger (and more blue) than that over the equatorial face. This indicates
preferential attack by nucleophiles onto the axial face. Quantify thedifference by measuring the (absolute) value of the LUMO on these two
faces. Select Properties from the Display menu ( ) and click anywhereon the LUMO map surface to bring up the Surface Properties dialog.

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121

Check the box to the left of Display Legend to display the property range
on screen. The legend is useful when making qualitative comparisons ofproperty values. Turn the map such that you can clearly see the axial faceof the carbonyl carbon, and click on the area of maximum blue. The(absolute) value of the LUMO at the surface point you have selected isprovided in the dialog to the right of Val. Note the value, and then turn themap over such that you can see the equatorial face of the carbonyl carbon,
and click on the region of maximum blue on this face. You will find thatthey support your qualitative conclusions from viewing the image.
7. Close cyclohexanone and any open dialogs.
5 min

3-Cyano-4-methylcyclohexenyl Radical

3-cyano-4-methylcyclohexene radical will be used to introduce
graphical models associated with radicals (molecules with one

Chapter 7

122unpaired electron).
1. Build or sketch 3-cyano-4-methylcyclohexenyl radical.
2. Select Calculations... from the Setup menu ( ). Specify Equilibrium
Geometry at Ground state in Gas from the top menu to the right ofCalculate, Density Functional and B97X-D and 6-31G* and from themenus specifying computational model.
This molecule has one unpaired electron. Change Unpaired Electrons
from 0 to 1. Click on Submit at the bottom of the Calculations dialog.*
Name it 3-cyano-4-methylcyclohexenyl radical. (A name will not beprovided as the radical is not in the SSPD.**) Wait (a few minutes) for the
calculation to complete before proceeding.
3. Select Surfaces from the Display menu ( ). Click on Add and selectspin density from the menu. Click on Add and select spin density map fromthe menu. You have requested two different representations of spin
distribution. The first presents spin density as a surface of constant value,
while the second uses color to map the value of the spin density onto anelectron density surface. Finally, request the singly-occupied molecularorbital. Click on Add one more time and select aHOMO (the highestoccupied molecular orbital of  spin that is, the orbital that contains theunpaired electron) from the menu.
4. The three graphics you requested will run without having to resubmit thejob and will require only a few seconds to complete. When they are done,check the box to the left of spin density in the Surfaces dialog to display thespin density surface. Note that the spin density is delocalized over two of thering carbons and onto the cyano group.

* Spartan checks that the structure and the number of electrons specified from Charge andUnpaired Electrons settings are compatible and if they are not will return an error message.
** With very few exceptions, SSPD contains only neutral closed-shell (paired-electron)
molecules.

Chapter 7123

5. Remove the spin density surface (uncheck the box to the left of spin
density in the Surfaces dialog) and then check the box to the left of spin
density map to display a surface on which the spin density is mapped onto
the electron density. Note that the areas of maximum spin (colored blue)
closely match those where the surface is large in the previous image.
6. Remove the spin density map (uncheck the box to the left of spin densitymap), and then check the box to the left of aHOMO (the molecular orbital
which holds the unpaired electron). Aside from the colors (different signs of
the orbital), note that this graphic is nearly identical to the previouslydisplayed image of the spin.
7. Uncheck the box to the left of aHOMO. Click on More Surfaces... at thebottom of the (Surfaces) dialog, and select Slice from the Surfaces menu
and spin density from the Properties menu. Click on OK. A new line Slice,
spin density appears in the window at the top of the dialog.* Select it bychecking the box at the left. A plane (a slice of spin density) surrounded bya frame appears in the middle of the model on screen. Click inside the frame
to select. The frame will turn gold. Position the cursor outside the frame,then use the scroll wheel to zoom the plane. You can also translate androtate the plane independently of the molecule using the usual mouse
operations. Alternatively, you can move the molecule and plane together by
first clicking on the molecule (the frame will now turn white) and then using
the mouse. For all operations, be certain to keep the cursor positioned
outside of the frame. Size
* You can change the display style from Contours to Solid or Transparent using the Stylemenu at the bottom right of the screen. This will appear only when the slice is selected.

Chapter 7124and orient the slice as you wish.

Tap on the graphic to select the graphic and on the frame toselect the frame. Use one finger to rotate and two fingers totranslate the graphic or frame. Pinch two fingers to zoom thegraphic or frame.

8.

Close 3-cyano-4-methylcyclohexenyl radical and any open dialogs.
5 min

Coumarin

Coumarin illustrates the calculation of a UV/visible spectrum.
1. Build or sketch coumarin.
2. The name coumarin appears at the bottom of the screen. Click on it, makesure that B97X-D/6-31G* is selected from the dialog that appears andclick on Replace.
3. Select Calculations... from the Setup menu ( ). Select Energy fromthe top menu to the right of Calculate. (Density Functional, B97X-D and
6-31G* should already be selected

Chapter 7125

from three menus immediately below.) You already have the equilibrium
structure from SSPD and only need to obtain the energy and wave function
as the basis of a UV/visible spectrum calculation. Check the box to the leftof UV/vis (to the right of Compute). Click on Submit. Accept the namecoumarin.
4. The calculation will take several minutes. While coumarin is relatively
small, calculations on several low-lying excited states in addition to the groundstate are required to produce a UV/visible spectrum. When completed, selectSpectra from the Display menu (). Click on ( ) inside the spectra
pane, and select ( ). The calculated UV/visible spectrum will appear in
the spectra pane.

5. Click again on
and this time select (). The experimental
UV/visible spectrum from the freely available NIST database will besuperimposed onto the calculated spectrum.

6. Close coumarin.

Chapter 7126

Section IV
Advanced Tutorials
The tutorials in the chapters in this section build upon and extend those in theprevious section. Groups of Organic Molecules introduces spreadsheets,
associated statistics, and plot capabilities. Spectra of Organic Molecules
provides “real” examples of calculated IR and NMR Spectra. Inorganic andOrganometallic Molecules illustrates applications to “non-organic”
molecules, in particular, molecules incorporating transition metals.
Organic Reactions describes and illustrates strategies for finding andverifying a reaction transition state. Medicinal Chemistry illustrates
examples of interactions of small molecules (drugs) in biological systems.
Flexible Molecules addresses issues involved in identifying the lowestenergy conformer of a flexible molecule and in establishing the relative
energies of alternative (higher-energy) conformers, the latter being
necessary to “average” properties and spectra. Some of the tutorials in thissection require significant computation time, in particular, those involving
quantum chemical methods applied to flexible molecules. With this in mind,
a number of tutorials have been provided in the last chapter “Dry Labs”.
Using the Spartan Spectra and Properties Database to further illustrate avariety of important features without having to consume computer time (oryour time waiting for the calculations to finish).
Quantum chemical calculations utilize the B97X-D/6-31G* model. Timeestimates are given for completion of the tutorials based on this model using
quad-core desktop machine (3.2 GHz Intel i5 processor, 8 GB RAM, 900 GB
hard drive) running serial on Windows 10. Other computational models canbe used in place of B97X-D/6-31G*. Completion times will vary
accordingly.
Icons are provided for all menu entries as they are requested. Icon displays
may be customized according to user preference (Icons tab underPreferences in the Options menu; Chapter 25).

Chapter 8

109Chapter 8Groups of Organic Molecules
The tutorials in this chapter introduce and illustrate a number of basic
operations involved in processing groups of molecules, as well as theassociated spreadsheet for organizing and fitting data and facilities formaking plots.
Computational investigations, like experimental investigations, are rarely
restricted to a single molecule, but typically involve a series of related
molecules. Here, it may be of interest to compare geometries, energies orother calculated properties, or to compare trends in calculated and measured
properties. Spartan provides facilities for these purposes. In particular, it
allows molecules to be grouped, either manually, or automatically as a result ofa conformational search, from following a particular vibrational motion, orfrom a scan of one or more geometric variables. Once grouped, molecules
may be aligned to make similarities or differences more apparent based
either on their structure, chemical functionality or atom labels. Calculations
may be performed either on individual molecules or, just as simply, on thecomplete group of molecules. On multi-core computers, several molecules
can be run at once. The results of calculations on a group can be examined
and analyzed individually or altogether to seek out trends. In particular,
reaction and activation energies may be obtained and statistical measures,among them the DP4 measure, may be applied to calculated NMR spectra.
Associated with a group of molecules (or an individual molecule) is aspreadsheet. This allows convenient access to virtually any calculated quantitythat can be given a numerical value. Additionally, data may be enteredmanually into the spreadsheet or transferred from another application such as
Excel. Data in the spreadsheet may be manipulated, linear regression analyses
performed and plots displayed. Alternately, the data in a Spartan spreadsheet
may be transferred to Excel (or other applications) for further analysis. An
Excel worksheet can be
stored inside a Spartan document if desired (see Embedded Data
under the File menu; Chapter 16).
Chapter 8

109

The tutorials in this chapter introduce and illustrate a number of the basic
group operations available in Spartan. These include building a group fromscratch and processing groups resulting from both a conformational search
and from systematically varying a torsion angle. Also provided is an exampleof fitting an experimental observable to one or more calculated properties by
way of linear regression. Finally, Reactions dialog is illustrated both as it
operates on molecules in a group and on molecules derived from substitution ofgrouped molecules.
20 mins

Chapter 8129

To test this hypothesis, you will examine whether or not experimental relative
rates of Diels-Alder cycloadditions involving cyclopentadiene and a variety of
cyanoethylenes correlate with dienophile LUMO energies.
1. Build ( ) and minimize ( ) acrylonitrile, H2C=C(H)CN. Select View
from the Build menu ( ). Copy the structure to the clipboard. Either rightclick on the background and choose Copy from the resulting contextual
menu, or select Copy from the Edit menu ( ).
2. Select Build New Molecule (not New Build) from the File menu ( ).
This allows for adding an additional molecule to the current document. The
screen will be cleared and the model kit displayed. Click on Clipboard at thebottom of the model kit and click on screen. Acrylonitrile will appear. Click on
Groups in the model kit, select Cyano and add to the appropriate freevalence on acrylonitrile to make 1,1-dicyanoethylene. Click on.
3. Repeat this procedure (Build New Molecule, followed by Clipboard,
followed by Groups, followed by ) four more times to build cis and trans1,2-dicyanoethylene, tricyanoethylene and tetracyanoethylene. When you
have built all six molecules, click on
The 2D sketcher could be used in place of the 3D builder. Sketch
acrylonitrile, right click on screen and select Copy from the menu
that appears. Select Sketch New Molecule (not New Sketch) fromthe File menu, right click on screen and select Paste from themenu. Add a cyano group to make 1,1-dicyanoethylene. Repeat thesequence to make the remaining molecules and finally click on.
4. The molecules have been grouped together, that is, put into a single
document, allowing calculated properties to be accessed via a spreadsheet.
Select Spreadsheet from the Display menu.

Chapter 8130

To select an individual molecule in the group, click on its label (M0001, ...)
in the left hand column, or use the ◄ and ► keys at the bottom left of thescreen. Left click on the header cell (“Label”) to select the entire group, thenright click and select Rename Selected Using SSPD from the contextual
menu that results.

This results in replacement of the default labels by proper names from theSpartan Spectra and Properties Database.

5. Select Calculations... from the Setup menu ( ) and specify
Equilibrium Geometry at Ground State in Gas using
Chapter 8131the B97X-D/6-31G* model Make certain that Global Calculations at
the bottom of the dialog is checked to ensure that the settings will be applied
to all the molecules in the list.
6. Click on the Submit button at the bottom of the Calculations dialog.
Name it Diels-Alder dienophiles it will take several minutes for thiscalculation to complete. After it completes, enter the following experimental
relative rates into the spreadsheet.
Experimental relative rates forDiels-Alder cycloadditions of cyclopentadiene*log10
dienophile(relative rate)acrylonitrile0
cis-1,2-dicyanoethylene 1.94
tricyanoethylene
5.66

dienophile

log10(relative rate)

1,1-dicyanoethylenetrans-1,2-dicyanoethylene
tetracyanoethylene

4.64
1.89
7.61

* J. Sauer, H. Weist and A. Mielert, Chem. Ber., 97, 3183 (1964).

Double click inside the header cell for a blank column in the spreadsheet,
type Log(rate)= and press the Enter key (return key on Mac). You need topress the Enter (return) key following each entry (or use the key). Sort byrelative rate. Click on the column header Log(rate), and then click on Sort
at the bottom of the spreadsheet.
7. Click inside a header cell for a blank column and click on Add... at thebottom of the spreadsheet (alternatively, right click inside the header cell fora blank column in the spreadsheet, and select Add... from the contextual
menu that results). Click on the E LUMO button under the Molecule tab.

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132

The spreadsheet, which contains both the calculated LUMO energies andexperimental relative rates, has served its purpose. Remove it from thescreen by clicking on
at the top).
8. Select Plots... from the Display menu (pane at the right of the screen. Click onpane.

). This leads to an empty plot
in the toolbar at the top of theSelect Log(rate) from the list of items in the X Axis menu andE LUMO(eV) from the Y Axes* list.

Click on Create.

* The Y axis specification is plural “Axes” as users can generate plots with multiple Y axes displayed.
If more than one Y axis is specified, color is used to distinguish data points and plot lines.

Chapter 8133

9. By default, only data points are displayed. Click onin the toolbar at
the top of the pane. This leads to display of the Edit Plot dialog. Check thebox next to Curve, click on the button to the left of Least Squares and clickon Done to display a least squares fit of the reaction rates to LUMO
energies. The least- squares line will be drawn.

10.

Close Diels-Alder dienophiles and any open dialogs.

Chapter 8134

no calculations

Addition vs. Substitution
Alkenes normally undergo addition reactions whereas aromatic compounds
normally undergo substitution reactions. For example, bromine reacts withcyclohexene to give trans-1,2-dibromocyclohexane (the addition product) not 1bromocyclohexene, whereas it reacts with benzene to give bromobenzene(the substitution product) not trans- 5,6-dibromo-1,3-cyclohexadiene.

In this tutorial you will use results from the Spartan Spectra and Properties
Database (SSPD) as accessed from Spartan’s reaction energy calculator toestablish the preferred product for each reaction. Specifically, energies fromthe B97X-V/6-311+G(2df,2p) density functional model stored in SSPD
will be employed. No calculations are involved.
1. One after another, build or sketch cyclohexene, trans-1,2dibromocyclohexane, 1-bromocyclohexene, benzene, trans- 5,6-dibromo1,3-cyclohexadiene, bromobenzene, bromine (Br2) and hydrogen bromide(eight molecules in total). Put all in the same document. Use New
Build ( ) or New
Sketch ( ) for the first molecule and Build New Molecule( ) or Sketch New Molecule ( ) for each successive molecule.
2. Select Spreadsheet from the Display menu ( ). Left click inside theheader cell for the leftmost column, then right click and select Rename
Selected Using SSPD in the menu that appears. Click on OK in the dialog
that results. The molecules can now be referenced using chemical names.
Close the spreadsheet.

Chapter 8135

3. Select Reactions from the Display menu ().

Choose SSPD Database from the menu to the right of Source andΔE from the menu to the right of Calculate at the bottom of the dialog.
Compute the energy for Br2 addition to cyclohexene: select cyclohexene
and bromine as Reactants and trans-1,2- dibromocyclohexane (leave thesecond product selection at <none>) as Products. Repeat for thecorresponding substitution energy (same reactants but the products are 1bromocyclohexene and hydrogen bromide) and for both addition andsubstitution reactions of benzene (reactants are benzene and bromine andproducts are trans-5,6-dibromo-1-3-cyclohexadiene and <none> foraddition and bromobenzene and hydrogen bromide
for substitution).
Are all reactions thermodynamically favorable (exothermic)? Identify any
reactions that are not and provide a rationale as to why. Why is there a change
in preferred reaction in moving from the alkene to the arene?
You can if you wish also calculate ΔH and ΔG for these reactions. The
first adds zero-point energy and temperature corrections to E and thesecond also adds the entropy. In both cases, EDF2/6-31G* is used tofurnish vibrational contributions.

4. Close the document and any open dialogs.

Chapter 8136

no calculations

Hydration of Carbonyl Compounds
The hydration of carbonyl compounds has been extensively studied
primarily because it serves as a model for a number of important reactions,
nucleophilic addition to carbonyl compounds among them. In this tutorial,
you will use Spartan’s linear regression analysis tool to correlate calculated
properties of carbonyl compounds with measured equilibrium constants fortheir hydration. The molecules are all in SSPD so no calculations areneeded.

1. Build or sketch all the compounds listed in the next page for which
experimental equilibrium constants are available. If you build, start with
New Build from the File menu ( ) for the first molecule and Build New
Molecule from the File menu () for each successive molecule. If you
sketch, start with New Sketch ( ) for the first molecule and Sketch New
Molecule () for each successive molecule, both from the File menu.
2. Click on the name of whichever molecule is selected at the bottom of thescreen. Confirm that the B97X-D/6-31G* model is selected and click on
Replace in the dialog that results and then on All to replace all molecules withentries from the SSPD.
3. Select Spreadsheet from the Display menu ( ) to bring up the
spreadsheet. Double click inside the header cell of an empty column, typeLog(Keq) and press the Enter key (return key on Mac). Then enter theexperimental equilibrium constants from the table below.

Chapter 8137

Experimental Keq for hydration of carbonyl compoundslog(keq/55.5)
PhCOCH3
CH3COCH3PhCHO
t-BuCHOCH3CHO

-6.8
-4.6
-3.8
-2.4
-1.7

log(keq/55.5)
CF3COCH3
PhCOCF3
H2CO
CF3CHO
CF3COCF3

-0.2
0.1
1.6
2.7
4.3

* J.P. Guthrie, Can. J. Chem., 53, 898 (1975); 56, 962 (1978).

You need to press the Enter (return) key following each data entry. Sort
the list according to the value of Log(Keq). Click inside the header cell
LogKeq and then click on Sort at the bottom of the spreadsheet.

4. Select Properties from the Display menu, click the
E HOMO.

icon to the left of

5. Click on the oxygen atom for whatever compound is displayed.
Click onto the left of Electrostatic (under Charges) in the Atom
Properties dialog (that has replaced the Molecule Properties dialog), toplace oxygen charges into the spreadsheet.
6. Click on Add... at the bottom of the spreadsheet, and then click on the Linear
Regression tab at the top of the dialog that results.

Chapter 8138

Select Log(Keq) from the Fit menu and both EHOMO (eV) andElectrostatic (O1)* from the Using list. Click on Apply. A new row (Fit1)
will be added at the bottom of the spreadsheet. Select Properties from the
Display menu ( ), click anywhere on the Fit1 row. The Regression
Properties dialog appears.

This provides information about the fit of Log(Keq) to the charge on oxygen,in particular, the value of R2. The closer to unity, the better the fit.
7. Select Plots from the Display menu ( ). Click onin the bar at the
top of the plots pane. Select Log(Keq) from the X Axis list and FitVals(Fit1)
from the box below YAxes, and click on Add.
8. To see the correlation between measured and fit rates, click on Edit () from the toolbar at the top of the pane. Check the Curve box and click the
Least Squares button. Finally, click the Done button.
9. Close the document and any open dialogs.
* Your numbering may differ as it depends on the order that atoms were introduced during building,but the reference is to the carbonyl oxygen.

Chapter 8139

no calculations

Acidities of Carboxylic Acids
Acid strength is among the most important molecular properties. It isreadily available from calculation, either in terms of absolute deprotonationenergy,AH

A– + H+or, more commonly, as the deprotonation energy relative to that of somestandard acid (ARH).
The energy calculations discussed so far apply strictly to gas-phase
acidities* and likely do not reflect acidities in solution. This prompts a search
for alternative descriptions. One possibility is the value of the electrostatic
potential in the vicinity of the acidic hydrogen in the neutral acid.
Electrostatic potential maps would certainly be expected to reveal gross trends
in acidity, for example, the acidic hydrogen in a strong acid, such as nitricacid, should be more positive than that in a weak acid, such as acetic acid,
which in turn should be more positive than that in a very weak acid, such as
ethanol.

nitric acidacetic acidethanol

In this tutorial, you will use electrostatic potential maps to quantify changes
in acid strength due to subtle variations in structure. You will use the Spartan
Spectra and Properties Database (SSPD) to eliminate the need for quantum
calculations.
* This is not to say that quantum chemical treatments of solvated molecules have not been developedor have not been implemented within Spartan, but rather that in our opinion are not reliable enough toprovide quantitative data.
Chapter 8140

1. One after another, build or sketch trichloroacetic, dichloroacetic,
chloroacetic, formic, benzoic, acetic and pivalic acids. Put all molecules into
the same document. Use New Build () or New Sketch () both from theFile menu for the first molecule and use Build New Molecule () orSketch New Molecule () both from the File menu for each successive
molecule. Click onwhen you are done.
2. All of the molecules that you have built are available in SSPD. Click on
the name of whichever molecule is selected at the bottom of the screen, makesure that B97X-D/6-31G* is selected from the menu in the dialog that
results, click on Replace, and finally on All. Structures obtained from
B97X-D/6-31G* density functional calculations will replace those you
have built. The wave function is also provided with the database entry.
3. Select Spreadsheet from the Display menu ( ). Expand it so that you
can see all seven molecules, and that two data columns are available. Double
click inside the header cell of the first available data column, type pKa andpress the Enter key (return key on Mac). Enter the experimental pKa’s(given in the table below) into the appropriate cells under this column. You
need to press the Enter (return) key following each entry.
acid

pKa

acid

pKa

trichloroacetic (Cl3CCO2H)
dichloroacetic (Cl2CHCO2H)
chloroacetic (ClCH2CO2H)
formic (HCO2H)

0.7
1.48
2.85
3.75

benzoic (C6H5CO2H)
acetic (CH3CO2H)
pivalic ((CH3)3CCO2H)

4.19
4.75
5.03

Experimental data from: E.P. Sargeant and B. Dempsey, Ionization Constants ofOrganic Acids in Aqueous Solution, IUPAC no. 23, Permagon Press, 1979.

4. To display all molecules at once, check the box to the left of the molecule
name (Label column) in the spreadsheet for each entry. To manipulate themolecules independently of one another, click to deselect Coupled from theModel menu ( ). Arrange the seven molecules on screen such that you canclearly see the acidic hydrogen on each.

Chapter 8141

5. Select Surfaces from the Display menu ( ) and then click on Add andselect electrostatic potential map. When the electrostatic potential map
calculations complete (they will be marked “completed”), check the box at
the left of electrostatic potential map in the Surfaces dialog. SelectProperties from the Display menu ( ) and click on the electrostatic
potential map to display the Surface Properties dialog. Click on(the
Post icon) to the left of Max inside the Surface Properties dialog. The
maximum value of the electrostatic potential (corresponding to the acidic
proton) will be posted to the spreadsheet. Leave the dialog on screen.
6. Plot experimental pKa vs. maximum in the electrostatic potential. SelectPlots from the Display menu ( ) and then select pKa under the X Axis
menu and Property Max (Surface) from the Y Axes list. Click on Create.
Click onto edit the plot and check the box next to Curve. Choose theLeast Squares option and click on Done. Does there appear to be a correlation
between pKa and the maximum value of the electrostatic potential?
7. Close the document and any open dialogs.

Chapter 8142

no calculations

Positional Selectivity of Substituted Naphthalenes
Thermochemical stabilities of positional isomers may depend on several
factors, including a tendency to minimize unfavorable non- bonded
intramolecular interactions (sterics) and to minimize overall dipole moment(electrostatics). Naphthalene offers a good example with only two different
positions.
XX

1-substituted naphthalene

2-substituted naphthalene

In this tutorial you will use B97X-V/6-311+G(2df,2p) energies from theSpartan Spectra and Properties Database (SSPD) to establish differences inheats of formation between 1 and 2-substituted naphthalenes. Instead ofbuilding a series of substituted naphthalenes, you will use Spartan’s
substituent model kit to construct one “molecule” marked for substitution
on the 1-position and the other “molecule” for substitution on the 2position. No calculations are involved.
1. One after another build methane, ammonia, water, hydrogen fluoride,hydrogen cyanide and formic acid. Put all in the same list (use New Build() to enter the builder for the first molecule and Build New Molecule () for each successive molecule). Select Spreadsheet from the Display
menu ( ), double click inside the leftmost cell for each molecule and replace
the identifier (M0001, …) by proper functional group names (methyl,amino, hydroxy, fluoro, cyano and carboxylic acid). Put the contents on
the clipboard. Click in the header cell to select all molecules, then right click
and select Copy from the contextual menu that results. Alternatively, selectCopy from the Edit menu ( ). Close the document without saving.
2. Select New Build from the File menu (Chapter 8) and build naphthalene.

143

Then, select Substituent from the menu at the top of the model kit to bringup the substituent builder.

Click on Cust. A near the middle of the model kit, then right click inside
the box near the bottom and select Paste from the contextual menu that
results. Alternatively, left click inside the box and select Paste from the Editmenu ( ). Names of the six functional groups that you built in the previous
step will appear in the box. As you click through the list, ball-and-wire modelsof their structures will appear in the small screen at the top of the model kit.
Note that one of the hydrogens (white balls) for each is highlighted in gold.
This hydrogen will be removed to make a free valence for attachment. The
carboxylic acid group has two different hydrogens, one on carbon (leading
to a carboxylic acid) and one on oxygen (leading to a formate). If thehydrogen on the carbon is not already highlighted, click on it and it will behighlighted. Click on the free valence on naphthalene that will lead to 1substituted naphthalenes. The molecule on screen will now appear with amarker to indicate substitution at the 1-position.

Chapter 8

144

3. Select Build New Molecule from the File menu (). Select Organicfrom the tab at the top of the model kit and again build naphthalene. SelectSubstituent from the menu to bring the substituent model kit. Make certainthat Cust. A is selected (if not, click on it). Click on the free valence on
naphthalene that will lead to 2-substituted naphthalenes. Click on
toremove the model kit.
4. Select Spreadsheet from the Display menu ( ). Double click inside theleftmost cell for the first molecule and replace the default identifier(M0001) with 1-substituted naphthalenes. Double click inside thecorresponding cell for the second molecule and replace the default identifier by
2-substituted naphthalenes.
5. Select Reactions from the Display menu ( ). Choose SSPD Databasefrom the menu to the right of Source and E from the menu to the right ofCalculate. This signifies that energies obtained from the B97X-V/6311+G(2df,2p) model associated with each of the entries in SSPD will be
employed. Select 1-substituted naphthalenes as Reactants and 2substituted naphthalenes as Products, and click on Compute at the bottomof the dialog. Reactions will be written (and reaction energies computed)
for all six substituents. The Boltzmann weights column provides aweighting of positional preferences.
6. Close the document and any open dialogs.

Chapter 8145

30 mins

Tautomers of Nucleotide Bases
Protons bound to heteroatoms in heterocyclic compounds are likely to bevery mobile in solution and, where two or more heteroatoms are present ina structure, different isomers (tautomers) may be in equilibrium. As a casein point, consider the nucleotide base cytosine (where a methyl group has
replaced the sugar-phosphate backbone at the 1-position).

The existence of a low-energy tautomer could have far-reachingconsequences, given that the valence structure of cytosine is key tohydrogen bonding in DNA. In this tutorial, you will examine the possible
tautomers of 1-methylcytosine for evidence of low-energy structures.*
1. Build or sketch 1-methylcytosine or alternatively one of its tautomers.
2. Note that the word Tautomer appears at the bottom right of the screen,
indicating that tautomers exist. Select Generate Tautomers from theGeometry menu ( ). Step through the tautomers using the and keys
that appear at the bottom right of the screen. To put the tautomers in a list,
click on at the bottom right of the screen and click on OK in the on-screen
message “Generate a Tautomer List” that results.

* Note, however, that were the energy of an alternative tautomer only 10 kJ/mol higher than that for thenormal structure, this would translate into a relative abundance of only about 1% at room temperature.
Thus, any alternative tautomers would need to be very close in energy to the lowest-energy tautomer tohave noticeable effect.

Chapter 8146

3. Select Calculations... from the Setup menu ( ) with the list of
tautomers. (To avoid confusion, it is a good idea to close the molecule you
used to get the tautomers.) Specify calculation of Equilibrium Geometry
using the B97X-D/6-31G* density functional model. Submit the job with
the name cytosine tautomers.
4. After the calculations have completed, select Spreadsheet from the
Display menu ( ). Click on the cell corresponding to the original structurefor 1-methylcytosine. Click on Add at the bottom of the spreadsheet andthen click on the Molecule List tab; select rel.E and Boltzmann Weightsfrom the available quantities and kJ/mol from the Relative Energy Unitsmenu. Click on the background to release the dialog. Are either of thealternatives close in energy to the normal form of cytosine?
5. If you find that one of the alternative tautomers is within 10 kJ/ mol of 1methylcytosine, perform B97X-V/6-311+G*(2df,2p) energy calculations on
this tautomer as well as 1-methylcytosine. These may require upwards of anhour of computer time.
6. Close the document and any remaining open dialogs.

Chapter 8147

Chapter 9
Spectra of Organic Molecules
The tutorials in this chapter illustrate applications involving the calculationof IR and also illustrate the use of calculated IR spectra to identify an
experimental unknown. Additionally, calculation of proton and 13C NMR
spectra are demonstrated. DP4 analysis is illustrated to identify which
stereoisomer best fits an experimental 13C NMR spectrum.
In addition to equilibrium geometries, conformations andconformational energy differences, reaction energies, as well as diverse
molecular properties, calculations provide infrared and Raman spectra, NMR
spectra and UV/visible spectra. IR and Raman spectra arise from thetransitions between ground and excited vibrational states, NMR spectrafrom transitions between nuclear spin states and the UV/visible spectra fromtransitions between ground and excited electronic states.
Chemists use spectra, in particular, NMR spectra to provide essential clues
needed to assign the structure of an unknown molecule. That is, features inthe spectrum may be used to support a proposed structure assignment,
whereas their absence suggests that the assignment is likely to be incorrect. On
the other hand, a calculated spectrum starts with a known structure. A highdegree of similarity with a measured spectrum may be taken as evidence thatthe calculated molecule is the same (or at least very similar to) that for which
the spectrum was measured. Lack of similarity suggests that the twomolecules are not the same.
The first two tutorials in this section deal with infrared structure and use the
EDF2/6-31G* model. The first details the steps needed to calculate theinfrared spectrum of methyl formate and to relate the spectrum to theunderlying molecular structure, and the second illustrates use of the Spartan
Infrared Database to identify a molecule based on its infrared spectrum.
The remaining tutorials

Chapter 9148deal with NMR spectroscopy and use the B97X-D/6-31G* model and(optionally) the SSPD database. The first of these details the steps involvedin calculating and displaying a proton spectrum for 1-methylindole, and thesecond, the 13C spectrum of caulophyline, both of which are rigid molecules.
The third considers the 13C NMR of cis-1,2-dimethylcyclohexane, a moleculethat rapidly (relative to the time scale of the NMR experiment) moves
between two equivalent conformers. Discussion of the NMR spectra ofmolecules with multiple degrees of conformational freedom and several
accessible conformers is provided in a later chapter. The final tutorial
examines the dependence of carbon chemical shifts on stereochemistry andillustrates the use of DP4 analysis to decide which best fits the experimental
NMR spectrum.
10 mins

Infrared Spectrum of Methyl Formate
In the harmonic approximation, the frequency at which a diatomic molecule
vibrates is proportional to the square root of the ratio of the force constant(the second derivative of the energy with respect to change in bond length)
and the reduced mass (the product of the masses of the two atoms divided
by their sum). Frequency increases with increasing force constant or
stiffness of the bond and decreases with increasing masses of the atoms
involved in the bond.
frequency force constant
reduced mass

In order to generalize this expression to a polyatomic molecule, it isnecessary to use a coordinate system that leads to a diagonal matrix

Chapter 9149

of second energy derivatives (so-called normal coordinates).* These differ
from internal coordinates (depicting charges in specific bond lengths andangles), and for a polyatomic molecule will typically involve the motionsof several (and likely all) atoms.
The intensity of absorption of infrared radiation by a diatomic molecule is
proportional to the change in the dipole moment with change in bondlength. Since the dipole moment for a homonuclear diatomic molecule does
not change with distance, this means that molecules such as N 2 and O2 aretransparent in the infrared. The intensity of each of the individual lines in
an infrared spectrum of a polyatomic molecule follows from the change in
dipole moment along the associated normal coordinate. Some of the normal
coordinates may not lead to a change in dipole moment, for example, thesymmetric stretch in carbon dioxide where both CO bonds are
simultaneously moving, and infrared absorptions will not be observed.

This tutorial illustrates the steps required to calculate and display an infrared
spectrum and to compare it with an experimental spectrum. You will explore
how the ease or difficulty of molecular motion (the value of the force
constant) and changes in atomic masses affect frequency.
1. Build or sketch methyl formate. Select Calculations... from the* Consider the hypothetical case of a molecule with two coordinates, R 1 and R2. Here the second
derivatives form a matrix.

In order to associate the elements of this matrix with the individual coordinates, it is necessary to choose acoordinate system R' such that the off-diagonal second derivative is zero.

Chapter 9150

Setup menu ( ), and request an equilibrium geometry using the EDF2/631G* density functional model. Check IR to the right of Compute and clickon Submit. Accept the name methyl formate.
The IR spectrum of methyl formate is in SSPD and you could havejust retrieved it instead of having to calculate it.

2. After the calculation has completed (several minutes), select Spectrafrom the Display menu ( ). Click on the in the toolbar at the top of thespectra pane and selectfrom the palette of icons. The experimental
IR spectrum of methyl formate is available in the freely available NIST
database. Click on theagain and selectfrom the icon palette.
Calculated (in red) and experimental (in blue) infrared spectra are now
superimposed.

3. Click on either the up or down triangles that define a cursor and slide themouse while holding down the left button across the spectrum. Position it
over the intense line in the (calculated) spectrum near ≈1774 cm-1. Note thatthe molecular model (on screen above the spectra pane) vibrates. The motion
corresponds to stretching of the CO double bond. Position it over the intenseline near ≈1211 cm-1. This motion corresponds to a combination of stretchingmotions of the two CO single bonds.
4. Select Save As from the File menu () to make a copy of methyl
formate; name it methyl formate d3. Click on
to enter View mode.
Select Properties from the Display menu ( ) and click on one of the threehydrogen atoms on the methyl group to bring up the Atom Properties
dialog. Change Mass Number from 1 to 2 Deuterium. Repeat for the othertwo

Chapter 9151methyl group hydrogen atoms. Resubmit the calculation* (it will require only
a few seconds) by selecting Submit from the Setup menu.
5. Compare the frequencies of the undeuterated and deuterated forms ofmethyl formate, and identify which change the most and which change theleast. To do this open the original methyl formate document and display thecalculated IR spectra. To examine the calculated frequencies, click on the
Tables icon ( ). A table of frequencies and intensities is presented. Examine
the frequencies associated with CH vibrations on the methyl group. Repeat
the procedure examining frequencies associated with CD vibrations on the
methyl group. You can move between the documents by clicking on theappropriate tab at the bottom of the screen.
6. Close all documents and any open dialogs.
2 minsSearching Spartan’s Infrared Spectral Database
Pattern matching (“fingerprinting”) a measured infrared spectrum to acollection of experimental spectra contained in a database is common
practice and is appropriate for identifying molecules that have previously
been characterized. However, NMR has replaced infrared spectroscopy as
the method of choice for structure assignment of “new” (previously
uncharacterized) molecules. Pattern matching to databases of calculated
infrared spectra is not routine. One reason is that the results of calculations(a set of vibrational frequencies and intensities) do not look likeexperimental infrared spectra, at least, spectra obtained at normal
temperatures. However, a fit of the calculated data to a Lorentzian functionin which peak width at half height is treated as a parameter makes the two
spectra visually quite similar, not at all surprising as this loosely corresponds
to temperature. In fact an infrared spectrum measured at low temperaturecomprises* Because force constants (second derivatives) do not depend on mass, the calculation is very simple
and will require only a few seconds.

Chapter 9152

a series of sharp lines (rather than bands).
Practical calculations assume that the frequency of an infrared absorption is
proportional to the square root of the second derivative of the energy at aminimum in the potential surface for a particular vibrational coordinate,that is, to the curvature of the surface. The so-called quadratic
approximation leads to a surface that is too steep, resulting in calculated
frequencies that are larger than measured frequencies. For the most part, theerror is systematic, with calculated frequencies being between 3% and 15%
larger than measured frequencies, depending on the theoretical model.
Hartree- Fock models show an error near the top of the range, while density
functional and MP2 models show an error near the bottom of the range.
Semi-empirical models do not show a consistent error pattern. Such asystematic error can be compensated for, at least in part, by incorporating
a single linear scaling parameter into the fitting function.
Spartan fits calculated infrared spectra to the measured infrared spectrausing a Lorentzian function that incorporates two parameters, a non-linear
parameter accounting for peak width and a linear scaling parameter.
This tutorial illustrates the way in which searches of the Spartan Infrared
Database (SIRD) are setup and carried out and the results examined. SIRD
is an additional access route to the molecules contained in the Spartan
Spectra and Properties Database (SSPD) and derives from EDF2/6-31G*
calculations. You may choose from a small selection of measured infrared
spectra (or supply your own spectra as a .dx file).
1. You need to have a Spartan document open in order to access SIRD.
Select New Build from the File menu ( ), and then select Databases
from the Search menu ( ). Click on the SIRD tab to bring up the Spartan
Infrared Database dialog.

Chapter 9

153Click on Select Spectrum at the bottom right of the dialog. Navigate to thespectra of organic molecules subdirectory under the Tutorials directory.*
Select one of the following files and click on Open.

The experimental infrared spectrum of the selected molecule will appear in thewindow at the top right of the dialog with the name underneath. Immediately
to the left is a scroll box containing the most intense lines in the spectrum(obtained from a fit of the experimental spectrum to a Lorentzian function).

* For Windows, this directory is found in Program Files/Wavefunction/Spartan24. For security reasons,the program file directory is protected. Copy the folder to your desktop or to another location available tothe user prior to opening it in Spartan. For Linux, this is found in the directory where Spartan was
installed. For Macintosh, this is located at the top level on the Spartan24 disc image.

Chapter 9154

2. Click on Filters at the bottom right of the dialog to bring up the
Search Filters dialog.

This provides for substructure and formula filters as well as functional groupfilters. You can, if you wish, check an appropriate entry. For example, if you
have selected chromone-3-carbonitrile as the “unknown”, checking nitrile
from among the Functional Group Filters would limit the search tomolecules with nitrile functionality. Click on OK to exit the dialog.
3. Click on Search at the bottom of the (Spartan Infrared Database)dialog. The search may require a minute or two. When
Chapter 9155

it has completed, scan the list of hits at the bottom of the dialog for the nameof your query. It will be at or near the top of the list.* Click on the name.
The calculated infrared spectrum (red) will be superimposed onto the fit of
the experimental spectrum (blue) in the window at the top right of the
dialog.
4. Close all documents and any open dialogs.
10 mins

Proton NMR Spectrum of 1-Methylindole
Proton NMR spectroscopy was the first tool available to chemists that allowed
definitive assignment of the molecular structures of complex organic
molecules. By the 1970’s, it had largely replaced infrared spectroscopy andto a large extent chemical proofs of structure. 13C NMR is now more
dominant, but proton NMR remains an essential tool in the chemist’s
arsenal.
An NMR spectrum follows from the fact that nuclei possess spins that caneither align parallel or antiparallel to an applied magnetic field, giving rise
to different nuclear spin states. The relative energy of these states (ΔE)
depends on the nucleus and on the strength of the applied magnetic field,
by way of a simple relationship:∆E = ℏB0

 is the gyromagnetic ratio (a constant for a given type of nucleus), ℏ is
Planck’s constant divided by 2π and B0 is the strength of the magnetic fieldat the nucleus. While the two nuclear spin states are normally inequilibrium, this equilibrium can be upset by applying a second magnetic
field. The absorption of energy as a function of field strength (a resonance)
between the states can then be detected.
The key to the utility of the magnetic resonance experiment is that theenergy at which a nucleus resonates depends on its location in the molecule,and is measurably different for each (chemically) distinct* This will not always be the case. Errors inherent to the calculations as well as the absence of detail may
result in better matches to “incorrect” but closely related molecules. Of course, a query may also not be in
the database, so it is possible to find only related molecules.
Chapter 9156

nucleus. The reason is that the applied magnetic field is weakened byelectrons around the nucleus. Nuclei that are well shielded by the electron
cloud will feel a lesser magnetic field than those that are poorly shielded,
and will show a smaller energy splitting. The difference, given relative to a
standard, is termed a chemical shift. By convention, both proton and 13C
chemical shifts (treated later in this chapter) are reported relative totetramethylsilane (TMS) as a standard.
While each unique proton in a molecule gives rise to a single line
(resonance) in the spectrum, the spins on nearby protons add or subtract tothe external magnetic field. This leads to a splitting of lines, the splitting
pattern depends on the number of neighboring protons and their geometry.
In practice, only two-bond ( ) and three-bond ( ) interactions or coupling
are important. Discounting splitting, the intensity of the lines isapproximately proportional to the number of equivalent protons that
contribute.* For example, the proton NMR spectrum of 1-methylindole
would be expected to show seven lines, six with unit intensity
corresponding to the protons on the indole ring and one line with three times
the intensity corresponding to the three equivalent methyl group protons.

In this tutorial, you will use the B97X-D/6-31G* model to calculate theproton NMR spectrum of 1-methylindole and compare it with theexperimental proton spectrum in the absence of three-bond HH coupling.
1. Build or sketch 1-methylindole. Select Calculations... from the Setup
menu ( ). Specify calculation of equilibrium geometry using the B97XD/6-31G* density functional model. Check NMR to the right of Computeand click on Submit. Accept the name 1-methylindole. The calculation will
require several* More generally, the relative intensity of the sum of the lines corresponding to a proton that has been
split is approximately proportional to the number of chemically equivalent protons.

Chapter 9157

minutes.*
2. When the calculation has completed (or after you have retrieved resultsfrom SSPD), select Spectra from the Display menu ( ). Click onin the bar at the top of the spectra pane and select(proton NMR
spectrum in which there is no HH coupling).

Move the mouse while holding down the left button over the spectrum.
When you intersect a line, a numerical value for the chemical shift appears
at the top of the spectrum and the proton is highlighted in the structure
model.
3. Click again on
and this time select(experimental proton
NMR spectrum with HH coupling constants set to 0). The experimental
spectrum will be retrieved from the freely available NMRShiftDB database**and displayed with the calculated spectrum. You will need to be online.

The comparison gives you an idea of the level of agreement that can be
expected between calculated and experimental proton spectra.

* 1-methylindole is in the Spartan Spectra and Properties Database (SSPD). You can, if you like, avoid doing
any calculations and simply retrieve it. In this case, click on the name at the bottom of the screen, makesure the B97X-D model is selected and click on Replace in the dialog that results.
** The NMRShiftDB is primarily a collection of 13C spectra, although some proton spectra including that for
1-methylindole are available.

Chapter 9158

4. Click again on
and select(calculated proton NMR spectrum).
The calculated proton spectrum that now appears accounts for three-bond
HH coupling.

You can focus in on details by a combination of zooming the spectrum(scroll wheel) and shifting the displayed range (move the mouse while
holding down the right button). You will see that lines due to protons at C2, C3,
C4 and C7 are doublets, while those due to protons at C5 and C6 are quartets(doublet of doublets).
5. Close 1-methylindole and any open dialogs.
20 mins13

C NMR Spectrum of Cytisine

There are several reasons why NMR spectroscopy, in particular, 13C NMR,
is one of the most important routine analytical techniques available forcharacterizing organic molecules. The analysis is straightforward, can be
carried out quickly requiring relatively small samples and is nondestructive. The resulting spectrum is quite simple, comprising but a single
line for each and every unique carbon.* However, assigning 13C spectra is by
no means trivial, even for seemingly simple molecules. The problem is thatthe positions of the lines in the spectrum (the chemical shifts) are very
sensitive to the environment in which the carbons find themselves.
Experiments exist to separate 13C resonances based on the number of attachedhydrogens, however, where two or more carbons in a molecule reside in“similar environments”, it may be very difficult to distinguish them. This isparticularly problematic for quaternary carbons.
*

CH coupling does split carbon resonances but is almost always eliminated by what is termed proton
decoupling.

Chapter 9

159

This tutorial uses the alkaloid cytisine to illustrate the use of calculated 13C
spectra to assist in assigning the measured spectrum of the molecule.
NH

1. Either build or sketch cytisine. This can pose a challenge, if you end up
NOT seeing the name cytisine appear in the lower right of the interface(upon completing your drawing/sketch), you can also build via InChI
string. From the New Build or Edit Build mode, in the Organic tab of theModel Kit, click on the InChI button. In the resulting dialog, you can paste
the following string: InChI=1/C11H14N2O/c14-11-3-1-2-10-9-4-8(5-126-9)7-13(10)11/h1-3,8-9,12H,4-7H2/t8-,9+/m0/s1 and then click OK. At
the top of the Model Kit, a 3-D image of the molecule cytisine will appear.
Double-click to insert this on screen. Select Calculations... from the Setup
menu ( ) and specify calculation of equilibrium geometry with the ωB97XD/6-31G* density functional model. Check NMR to the right of Compute andleave the NMR setting at Current Model. Click on Submit and accept thename cytisine. The job will require a number minutes to complete (≈ 5-10).
2. When the calculation is done (or after you have retrieved the moleculefrom SSPD), select Spectra from the Display menu ( ). Click onin13
the bar at the top of the spectra pane and select(experimental C
13spectrum). The experimental C spectrum is drawn.

3. Use the calculated spectrum to associate the individual lines in theexperimental 13C spectrum with specific carbons in the structure of cytisine.
Click onand this time select(calculated 13C spectrum). The
calculated spectrum (in red) will be superimposed on top of the experimental
spectrum (in blue). This both gives an impression of the performance of thequantum chemical calculations, and also allows you to assign the lines in the
Chapter 9160experimental spectrum to specific carbons. Click on one of the triangles thatdesignate the cursor and move the mouse while holding down the left button
over the spectrum. A “hit” on a line will display the value of the chemical
shift and will highlight the carbons responsible for this line in the structure
model.
Optional
4. Open the Spreadsheet and right-click on the entry (under the Label)column. Click on Rename Selected Molecule(s) Using SSPD. Again rightclick, this time on the name cytisine and choose Replicate Selected
Molecule(s) in New Document. This will create a new document, enter the
Calculations dialog, and specify Energy using the ωB97X-D/6-31G* density
functional model. To the right of Start from, select Equilibrium Geometry using
Est. Density Functional ωB97X-D/6-31G*. Check the NMR to the right ofCompute, and change the NMR setting to Energy Model. This specifies
determination of structure (Equilibrium Geometry) using one of the NN (neuralnetwork) models, followed by a subsequent Energy (single point energy) calculation
using the quantum chemical ωB97X-D/6-31G* Density Functional model, andfinally an NMR calculation will be performed based on the quantum chemicalenergy. Click on Submit and provide the name cytisineNN. The job will
require less time to complete (perhaps 2-3 minutes).
5. Compare NMR Shift results. From the original cytisine document, rightclick on the carbonyl carbon and choose Properties from the resulting
contextual menu. From the Atom Properties dialog, note the value of thereported Chem. Shift. Click on the tab at the bottom of the GUI next to yourcytisineNN document. Repeat the procedure above, how similar are thechemical shifts on the carbonyl carbon in the document where geometry
was determined by the neural network (Est. Density Functional > ωB97XD/6-31G* model)? Repeat the procedure on other centers. Are the shifts generally
in good accord between the two calculations (bearing in mind one took 3-4 times
longer than the other)?
6. Close both cytisine and cytisineNN any open dialogs.

Chapter 9161

10 mins
13

C NMR Spectrum of cis-1,2-Dimethylcyclohexane

At normal temperatures, the NMR spectrum of a conformationally- flexible
molecule represents an average (Boltzmann-weighted average) of the NMR
spectra of all accessible conformers. Only when the temperature is lowered
will the spectrum reveal its conformational components. The molecule cis1,2-dimethylcyclohexane is a special case where the (two) conformers are
actually the same (identical).

The room temperature 13C NMR spectrum comprises only four lines at 34.9,
31.9, 24.2 and 16.4 ppm relative to TMS, corresponding to an equal
weighting of C1 and C2, C3 and C6, and C4 and C5 and the two methylcarbons, respectively. When the sample is cooled the spectrum reveal eight
distinct lines.
1. Either build or sketch cis-1,2-dimethylcyclohexane. SelectCalculations... from the Setup menu ( ) and specify calculation ofequilibrium geometry with the B97X-D/ 6-31G* density functionalmodel. Check NMR to the right of Compute and leave the NMR setting at
Current Model. Click on Submit and accept the name cis-1,2dimethylcyclohexane. The calculation will take less than 10 minutes.
2. When the calculation is done, select Spectra from the Display menu ( ),click onin the bar at the top of the spectra pane and from the NMR tab
select(calculated 13C spectrum). There should be only four lines,
the positions of which should correlate fairly well with what is observed
experimentally at room temperature (within 1.5 - 2 ppm)*. Spartan has
recognized that there are two equivalent structures and has calculated theaverage.
*

13

C chemical shifts from B97X-D/6-31G* calculations have been empirically corrected.

Chapter 9162

3. Close cis-1,2-dimethylcyclohexane and any open dialogs.

10 minutes

Stereochemical Assignments from 13C Spectra
NMR spectroscopy, in particular 13C spectroscopy, is without doubt themethod of choice to establish the three-dimensional structure of organic
molecules. Only X-ray diffraction provides more definitive results, although
the requirement of a crystalline sample often limits its application. It is now
practical to routinely calculate the NMR spectra of moderate size (MW on
the order of 500 amu) organic molecules. Accurate calculations provide a“virtual NMR spectrometer” offering organic chemists an entirely newparadigm for structure determination, that is direct comparison of a measured
spectrum with calculated spectra for one or more chemically reasonablecandidates.
In this tutorial, you will first obtain 13C chemical shifts for endo and exo
stereoisomers of 2-methylnorbornane using the B97X-D density functionalmodel, then enter the experimental shifts for one of the two isomers and use
the DP4 metric to decide which provides the better match. Note that isomers
MUST be labeled identically in order to make meaningful comparisons.
1. Sketch 2-methylnorbornane. Start with a six-member ring, draw a one-carbon
bridge between two carbons, add “up” stereochemical markers. Finally, add acarbon to the 2 position.

Chapter 9163

You need to add a stereochemical marker to distinguish between endo and exo
stereoisomers, but before you do so, copy the sketch to the clipboard. Rightclick on screen and select Copy from the menu. Add themarker to givethe endo stereoisomer. Select Sketch New Molecule (not New Sketch)from the File menu, right click on screen and select Paste from the menu.
Add themarker to give the exo stereoisomer. Click on
to give 3D*
structures for both isomers.

2. Bring up the spreadsheet, left click on the Label cell to select all molecules,
then right-click and choose Rename Selected Using SSPD. Specify
calculation of equilibrium geometry using theωB97X-D/6-31G* density functional model and check the NMR box. Make sure
Global Calculations is checked and submit the job. The job (twomolecules) will require a few minutes to complete.
3. When the calculations are completed, select the first molecule, bring up
the Properties dialog and one after the other click on the individualcarbons. Click on the Edit drop down menu to the right of Expt Chem
Shift: and use the number pad to enter the experimental shift values givenin the table below:
Experimental 13C NMR Data
C1
C2
C3
C4
*

42.2
34.6
40.7
38.2

C5
C6
C7
CH3

30.6
22.4
38.9
17.4

Building the structures in this way assures that the atom labels will be consistent between the twostereoisomers. This is a requirement to obtain proper DP4 results.

Chapter 9164

4. Click on
to revert the Atom Properties dialog to the Molecular
Properties dialog. Click on the NMR tab (in the Properties dialog). Clickon
to the left of DP4 in the dialog. Bring up the spreadsheet to see theDP4 score for the two stereoisomers. The scale is from 0 to 100 with thelarger numbers corresponding to better fits. (You can also examine DP4scores from the Properties dialog if you flip between the stereoisomers.)
5. Close the document and any open dialogs.
Aaptamine: Protonated or Not?
NMR spectra for aaptamine* and closely-related natural productmethylenedioxyaaptamine** have been reported. The 13C chemical shifts
noted below are nearly identical despite the fact that aaptamine is shown as
protonated, whereas its methylenedioxy analogue is not.***Are one of the assignments for aaptamine or methylenedioxy- aaptamine
incorrect insofar as the state of protonation? Could aaptamine not be
protonated in water (the solvent the NMR was taken in) or could
methylenedioxyaaptamine be protonated in methanol (the solvent its NMR
was taken)? To find out, perform NMR calculations on both molecules inboth protonated and non-protonated forms.
* H. Nakamura, J. Kobayashi, and Y. Ohizumi, Tetrahedron. Lett, 23, 5535 (1982).
** T. Hamada, Y. Matsumoto, C.-S. Pham, T. Kamada, S. Onitsuka, H. Okasura, T. Iwagawa,N. Arima, F. Tani and C.S. Vairappan, Nat. Prod. Commun., 14, 1 (2019).
*** We have reversed the experimental assignment for C6 and C7 in aaptamine and for C8 and C9 formethylenedioxyaaptamine.

Chapter 9165

1. Build or sketch aaptamine. Select Expt. Chem. Shifts from the Expt
Data menu, click on each chemically unique carbon, click on Edit to theright of Expt. Chem. Shifts at the bottom right of the screen, type in thechemical shift in the number pad and click on Enter. When you are done,right click on the background and select Copy from the menu that appears
to make a copy of both the structure and its chemical shifts. You may or
may not need this copy.
2. Select Calculations from the Setup menu. Select NMR Spectrum,(Density Functional), B97X-D and (6-31G*) from the top four menus to
the right of Calculate and B97X-D/
B97X-D/6-31G* Energy and HF/3-21G from the bottom two menus. Make
certain that Total Charge is set to Cation. Click on Submit at the bottomof the dialog.
3. The job will require several tens of minutes as it involves a sequence of
calculations involving the possible conformers. When it has completed,bring up the Properties dialog (Display menu) and click on the NMR tab.
Check on the Best Fit (not Boltzmann Average) tab at the center of the
dialog. The RMS, Max Absolute and Mean Absolute statistics are thosefor the conformer that best fits the experimental data. RMS is probably thebest of these measures and a value of <2 ppm is generally considered a goodfit. Do you agree with the author’s assignment of aaptamine as protonatedunder the conditions of the NMR experiment?
4. If you do agree, skip to step 5. If not, select New Build from the File menu,
right click on screen and select Paste from the menu that appears. The copythat you made of aaptamine appears on screen. Select Delete from the Buildmenu ( ) and click on the hydrogen attached to nitrogen at position 4 (seediagram on the previous page). You also need to delete the free valence asotherwise it will turn into hydrogen. Repeat the calculation being certainthat Total Charge is now set to Neutral. Does the deprotonated form ofaaptamine provide an acceptable fit?
5. Build or sketch methylenedioxyaaptamine as the deprotonatedChapter 9166form (as depicted in the paper). Enter the 13C chemical shifts in the same
way as before. Again, make a copy by right clicking on the background andselecting Copy from the menu.
6. This molecule is rigid so you can replace the multi-step procedure needed
for aaptamine by a simple (and less costly) structure optimization. Inside
the Calculations dialog (Setup menu) select Energy, Ground and Gas
from the three top menus to the right of Calculate and Density
Functional, ωB97X-D and 6-31G* from the three bottom menus. SelectEquilibrium Geometry from the menu to the right of Start From: andHartree-Fock and 3-21G from the two menus that then appear. Click inside
the NMR box to the right of Compute near the bottom of the dialog. You
have requested an NMR calculation using the ωB97X-D/6-31G* density
functional model but with a geometry obtained from the HF/3-21G model.
After you make certain that Total Charge is set to Neutral, click on
Submit.
7. This job will require only a few minutes. When it has completed, bring up
the Properties dialog (Display menu) and click on the NMR tab. Based on
the RMS statistic, are the calculations for the non-protonated form of
methylenedioxyaaptamine in accord with the experimental NMR? If they
are, you are done. If not, go to the next step.
8. Select New Build from the File menu. Right click on the background andselect Paste from the menu. Inside the organic model kit, select -H from thelist of atomic hybrids and double click on screen nearby to the (nonprotonated) nitrogen (N4). Click on
at the bottom of the model kit, clickon the free valence on the hydrogen and double click on the nitrogen. Clickonat the bottom of the model kit. Setup the Calculations dialog as
before (step 6) to Cation. Submit and after the job completes, bring up the
NMR properties dialog. Is the calculated spectrum now in good accord withthe experimental data?
9. Close all open Spartan documents and dialogs.

Chapter 9167

Chapter 10
Inorganic andOrganometallic Molecules
This chapter illustrates applications to inorganic and organometallic
molecules constructed using the inorganic builder in Spartan’s model kit.
Organic molecules typically comprise only a relatively few elements andobey conventional valence rules. The geometry about individual atoms is“tetrahedral” (sp3), “trigonal planar” (sp2) or “linear” (sp). As such they areeasily constructed using the organic model kit. On the other hand,construction of many inorganic and organometallic compounds in particular
those involving transition metals may require the enhanced flexibility
provided by the inorganic builder.
Transition-metal inorganic and organometallic compounds may also requiredifferent quantum chemical methods from those that have proven to besatisfactory for organic molecules. While there are a large number ofexperimental structures, almost entirely from X-ray diffraction, accurate
experimental thermochemical data on molecules incorporating transition
metals is virtually non-existent making assessment of the various models
problematic.
The PM3 and PM6 semi-empirical models have been explicitly
parameterized for most transition metals and generally (but not always)
provide a reasonable account of geometries. However, they would not be
expected to properly account for reaction energies as they generally perform
poorly for reactions involving molecules without metals.* Hartree-Fock andMP2 models are known to produce poor geometries where transition metals
are involved and cannot be*

It should be noted that experimental thermochemical data for inorganic molecule especially for thoseincorporating transition metals is far less common (and likely less reliable) than that for organic
molecules.

Chapter 9168

recommended.* On the other hand, density functional models appear to bequite successful for calculation of geometries of molecules incorporating
both transition metals and lanthanides (although their performance forenergy comparisons remains to be clarified).
1 min

Sulfur Tetrafluoride

Sulfur tetrafluoride cannot be constructed using Spartan’s organic builder.
This is because sulfur is not in its normal bent dicoordinate geometry, butrather in a trigonal bipyramid geometry with one of the equatorial positions
vacant. However, the molecule can easily be made using the inorganic
builder.
1. Bring up the inorganic builder by clicking on
and thenclicking on the Inorganic tab at the top of the model kit.

*

The poor performance of MP2 is likely a result of its dependence on a Hartree-Fock wave function.
Chapter 10

169

The inorganic builder comprises an atom bar (clicking on this brings up the
Periodic Table*) followed by a selection of atomic hybrids. Buttons accessmenus of groups, rings and ligands, additional libraries (More) and the
clipboard. Finally, a selection of bond types is provided at the bottom of
the model kit.
2. Click on the atom bar to bring up the Periodic Table.

Select (click on) S in the Periodic Table and the five coordinate trigonal
bipyramid structurefrom the list of atomic hybrids. Double click onscreen. A trigonal bipyramid sulfur will appear at the top of the model kit.
3. Again, click on the atom bar, select F in the Periodic Table and the onecoordinate entry
from the list of atomic hybrids. Alternatively switch tothe organic builder (click on the Organic tab) and selecticon. One after
another, click on both axial free valences of sulfur, and two of the threeequatorial free valences.
4. It is necessary to delete the remaining free valence (on an equatorial position);otherwise it will become a hydrogen. Click on
and then click on theremaining equatorial free valence.
5. Click on. Click on.

6. Select Calculations... from the Setup menu (). Specify* Not all methods are available for all elements listed. Elements for which a specific method (selected in the
Calculations dialog) are available will be highlighted following selection of a theoretical model or basis
set from the Model menu that appears in the center of the Periodic Table. Note the availability of someheavier elements (>Kr) assumes use of the LANL2DZ basis set which Spartan will employ automaticallywhen required.

Chapter 10170calculation of equilibrium geometry* using the B97X-D/ 6-31G*
density functional model and click on OK.
7. Select Surfaces from the Setup menu, click on Add and select HOMO
from the menus the at results and click on OK.
8. Submit the job. Accept the name sulfur tetrafluoride. Whencompleted, select Properties from the Display menu ( ) and click on
an atom, for example, sulfur. Three different atomic charges will appear inthe (Atom Properties) dialog (corresponding to different methods forestablishing atomic charge). Of these, the procedure based on fitting theelectrostatic potential is generally considered to be the best. Are the electrostatic
charges consistent with covalent or ionic bonding?
9. Check the box to the left of HOMO inside the Surfaces dialog. The
HOMO is largely concentrated along the axial direction which lacks afluorine, consistent with the notion that sulfur is surrounded by six electron
pairs (five involved in SF bonds and one a “lone pair”.
10.Close sulfur tetrafluoride and any open dialogs.
no calculations

Benzene Chromium Tricarbonyl

Comparison of electrostatic potential maps for benzene chromium
tricarbonyl and free benzene will allow you to classify Cr(CO)3 as anelectron-donor or an electron-acceptor substituent.
* It should be noted that were an incorrect geometry specified at the outset, optimization would lead to thecorrect structure, as long as the starting geometry possessed no symmetry (C1 point group). Thus, squareplanar SF4 in D4h symmetry would remain square planar, while an “almost” square planar structure(distorted only slightly from D4h symmetry to C1 symmetry) would collapse to the proper structure upongeometry optimization.

Chapter 10171

1. Select New Build from the File menu ( ) and click on the Inorganic
tab at the top of the model kit. Click on the atom bar and select Cr from the
Periodic Table. Select the four-coordinate tetrahedral structurefrom thelist of atomic hybrids. Double click anywhere on screen.
2. Click on Ligands in the model kit and select Benzene from the menu ofavailable ligands.

Click on one of the free valences on the four-coordinate chromium center.
3. Select Carbon Monoxide from the Ligands menu, and click on theremaining (three) free valences on chromium. Click on
to produce arefined structure.
Benzene chromium tricarbonyl among many organometallics may
easily be constructed using the 2D sketcher. Inside the sketch pad,double click on the wild card icon, select the Periodic Table tab
and click on Cr. Double click inside the sketch. Double click asecond time on the wild card icon (which will now read Cr), selectthe Ligands tab and click on benzene ligand. Draw a line upwardfrom Cr. Double click on the wild card icon a third time (which
will now display benzene ligand), select the Ligands tab and clickon carbon monoxide ligand. Draw three lines down from Cr. Clean
up the sketch ( ) and click on ( ).

Chapter 10172

4. Select Build New Molecule from the File menu (). Click on Rings,
select Benzene and click on the screen. Click on
and then on. The
document now contains both benzene chromium tricarbonyl and benzene.
5. Both benzene and benzene chromium tricarbonyl are available in the
Spartan Spectra and Properties Database (SSPD). Click on the name ofwhichever molecule is selected at the bottom of the screen, make certain that
ωB97X-D/6-31G* is selected and click on Replace. Click on All in the
dialog that results.
6. Select Surfaces from the Display menu ( ). Click on Add and choose
electrostatic potential map from the menu. Make certain that Global
Surfaces is checked. Do not close the Surfaces dialog.
7. You don’t need to submit, as graphics calculations will be performed“on-the-fly”. When completed select Spreadsheet from the Display menu (), and check the box to the left of the label for both entries. This allows both
molecules to be displayed simultaneously on screen. By default, the motionsof the two molecules are coupled. To uncouple their motions allowing thetwo molecules to be moved independently, select (turn off) Coupled from
the Model menu. Orient each molecule so that you can clearly see thebenzene face (exposed face in the case of the organometallic).
8. Check electrostatic potential map in the Surfaces dialog. Compare
electrostatic potential maps for both free and complexed benzene, withattention to the exposed benzene face.* Does the Cr(CO)3 group donate orwithdraw electrons from the ring? Would you expect the aromatic ring inbenzene chromium tricarbonyl to be more or less susceptible toelectrophilic attack than free benzene? More or less susceptible tonucleophilic attack?
9. Close all documents and any open dialogs.

* Electrostatic potential maps (as well as other maps) for molecules in a single Spartan document will be put
onto the same (color) scale. This allows comparisons to be made among different members.

Chapter 10173

20 mins

Indenyl Effect
Substitution of one of the carbonyl ligands in cyclopentadienyl manganesetricarbonyl by another two-electron donor ligand may either proceed via an
associative or dissociative mechanism. At first glance both mechanisms
would seem to be unfavorable, the dissociative pathway because it involves
a 16-electron intermediate and the associative pathway because it passes
through a 20-electron intermediate. However, the associative mechanism
may not be as bad as it first appears as it might be possible to reduce thecoordination of the cyclopentadienyl ring from 5 to 3 giving rise to an 18electron association intermediate.

Such a possibility is supported by the observation that substitution of
cyclopentadienyl by an indenyl ligand leads to increased association rates.
The indenyl effect as it is known, is attributed to the possibility of enhanced
aromaticity of 3 coordinated indenyl relative to 5 indenyl.

In this tutorial, you will use the PM3 model to calculate geometries for thereactants, intermediates and products for associative ligand exchange bytrimethyl phosphine of cyclopentadienyl and indenyl manganesetricarbonyl complexes, and then the B97X-D/6-31G* model to calculateenergies.

Chapter 10174

1. Build all eight molecules (the two reactant complexes, the twointermediates and the two product complexes as well as trimethyl phosphineand carbon monoxide), and put into a single Spartan document. Assume 5
coordination of cyclopentadienyl and indenyl ligands in reactants and productsand 3 coordination for the two intermediates. 5 cyclopentadienyl isavailable from the Ligands menu, and 5 indenyl is in the ligands document
accessed by clicking on ( ) to the right of More. 3cyclopentadienyl and 3
indenyl ligands are not available from menus and need to be built. To build
3 cyclopentadienyl, first complex an (3) allyl ligand to manganese, move tothe organic builder, add sp2 carbons () to both inward pointing allyl
free valences, click on Make Bond ( ) and then on the double
free valences on the two fragments that you have just added. To build the 3indenyl complex, start with the 3 cyclopentadienyl complex, select Benzene
from the Rings menu (in the Organic builder) and double click on the “doublebond” in the allyl ligand. Make certain that you minimize the energy of eachof the eight structures before proceeding to the next step.
2. Select Calculations from the Setup menu and specify calculation ofequilibrium geometry using the semi-empirical PM3 model. Make certain
the Global Calculations at the bottom of the dialog is checked. Submit thejob with the name indenyl effect.
3. When completed (a few minutes at most), compare the structure of the tworeactants (or products) with those of the corresponding intermediates. Verify
that the cyclopentadienyl and indenyl ligands have shifted from 5 to 3
coordination.
4. Reenter the Calculations dialog (Calculations under the Setup menu),
and specify calculation of energy using the B97X-D/ 6-31G* density
functional model. Resubmit the job. The eight calculations will require
several minutes to complete.**
You could do the geometry and energy calculations in a single step. Inside the Calculations dialog,
specify energy with the B97X-D/6-31G* density functional model and set the menus to the right of Start
From to Equilibrium Geometry, Semi-Empirical, and PM3. Of course, this does not allow you to
examine the geometries before doing the density functional calculations.

Chapter 10

1755. Use the reaction energy calculator (Reactions from the Display menu)
to calculate the energy of ligand substitution in both complexes. Is trimethyl
phosphine a “better” or “worse” ligand than carbon monoxide? Is thedifference diminished or exaggerated in the indenyl complex relative to thatin the cyclopentadienyl complex? Next calculate the energy of the twointermediates. Relative to reactants, which is more stable, trimethyl
phosphine cyclopentadienyl manganese tricarbonyl or trimethyl phosphine
indenyl manganese tricarbonyl?
6. Close indenyl effect and any open dialogs.

Chapter 10176

Chapter 11
Chemical Reactions
This chapter outlines and illustrates strategies for locating and verifying
transition states for reactions as well as exploring changes in productdistributions as a function of substituents and reactant stereochemistry.
The treatment of chemical reactions adds an entirely new dimension to theapplication of quantum chemical models. While unique valence structures
may generally be written for most molecules and, based on these structures,
reasonable guesses at bond lengths and angles may be made, it is often difficult
to designate appropriate valence structures for transition states, let alone
specify detailed geometries. There is a complete absence of experimental
data for the structures of transition states. However, transition-state geometries
may be calculated. To aid in guessing starting geometries, Spartan provides
both a small library of calculated transition-state structures for common
reactions and a facility for automatically matching an entry in this librarywith the reaction at hand.* The Spartan Reaction Database (SRD) as the libraryis called, also can be searched by substructure to yield all available
transition states of reactions related to the one of interest.
Spartan also provides a procedure for driving user-defined coordinates. Asidefrom conformational analysis (see discussion in Chapter 12), the major
application of this is to force reactions, thereby permitting identification oftransition states.
The tutorials in this chapter illustrate Spartan’s automatic procedure forguessing transition-state geometries based on SRD. They also illustrate theuse of vibrational analysis (infrared spectroscopy) to verify that a particular
structure indeed corresponds to a transition state and to show the motion
leading it to reactants and products.

* Where a reaction is unknown to Spartan’s library, a fallback technique which averages reactant and productgeometries (similar to the so-called linear synchronous transit method) is invoked.
Chapter 11

177

The first four tutorials examine simple organic reactions, while the fifthtutorial provides an example of a transition state calculation for an
organometallic reaction. The sixth tutorial illustrates how a reaction may be
driven through a transition state. This tutorial, along with the fourth tutorial,
draw the connection between relative activation energies and kinetic
product distributions. The last tutorial in this chapter illustrates howtransition states may be extracted from the Spartan Reaction Database.
10 mins

Ene Reaction of 1-Pentene

The proposed mechanism of the ene reaction involves simultaneous transfer
of a hydrogen atom and CC bond cleavage. In this tutorial, you will obtain thetransition state for the ene reaction of 1-pentene from an HF/3-21G calculation,and examine the reaction coordinate for evidence of concerted motion. While
the HF/3-21G model is a less rigorous model than many available in
Spartan, it is certainly good enough to illustrate the steps involved in obtaining
and verifying a transition state.
1. Build 1-pentene in a conformation in which one of the terminal hydrogens
on the ethyl group is poised to transfer to the terminal methylene group. To
rotate about a (single) bond, first click on it to select (the bond will be encircled
by a red arrow), and drag the mouse up or down in the area below
at theleft of the screen. Alternatively, hold down the left button and Alt key (option
key on Mac) and drag the mouse up and down. Click on.
2. Select Transition State from the Build menu (). Click on bond a in
the figure on the following page and then click on bondb. A curved arrow from double bond a to single bond b will be drawn.

Chapter 11

178

Next, click on bond c and then on bond d. A second curved arrow from bonds
c to d will be drawn. Finally, click on bond e and then, click on the (methyl)hydrogen to be transferred and on the terminal (methylene) carbon to receive
this hydrogen. A third curved arrow from bond e to the center of a dottedline that has been drawn between the hydrogen and oxygen will appear.

If you make a mistake, you can remove an arrow by selecting Delete fromthe Build menu ( ) and then clicking on the arrow. Alternatively, holddown the Delete key as you click on an arrow. Selectto continue. With
all three arrows in place, click on
at the bottom right of the screen. Your
structure will be replaced by a guess at the ene transition state. If the resulting
structure is unreasonable, then you have probably made an error in theplacement of the arrows. Select Undo from the Edit menu ( ) to return tothe model with the arrows and modify (if needed).
Undo is reserved for moving back from the transition-state
structure (rather than from undoing reaction arrow placements).
You could also have used the 2D sketcher to provide the guess tothe ene transition-state. Enter the sketcher and draw 1-pentene.
2D sketches, do not include hydrogens and you need to draw a CH
bond from the terminal sp3 carbon (C5).

Click onin the icon bar above the sketch pane. Click on the
CH bond and then on both H and the terminal sp2 carbon (C1). An
arrow will be drawn. Click on the C1C2 bond and then on the C2C3
bond. A second arrow will be drawn. Click on the C3C4 bond andthen on the C4C5 bond giving the third and final arrow.

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Click on
to give the transition state guess and move to themain screen.

3. Select Calculations... from the Setup menu ( ), and specify
calculation of transition-state geometry using the HF/3-21G model. SelectTransition State Geometry from the top menu immediately to the right ofCalculate, and choose Hartree-Fock and 3-21G from the two bottom menus.
Finally, check IR to the right of Compute. This will allow you to confirm
that you have found a structure that corresponds to a transition state, and thatit smoothly connects reactant and product. Click on Submit and name it ene
reaction 1-pentene.
4. When the job completes, animate the motion of atoms along the reaction
coordinate. Select Spectra from the Display menu ( ), click on in the barat the top of the spectra pane and click onin the palette that results.
Click on(Tables) at the left of the spectra pane to bring up a table offrequencies and intensities.

Click the top entry in the list. It corresponds to an imaginary frequency,
and will be designated with an i in front of the number.
Within the harmonic approximation, a vibrational frequency is
proportional to the square root of the ratio of the force constant(reflecting the curvature of the potential surface along a particular
coordinate) divided by a combination of the masses of atoms
involved in motion along that coordinate. At a transition state (aChapter 11180

maximum in the reaction coordinate), the curvature is negative.
Since the mass term is positive, the quantity inside the square root
is negative and the frequency is an imaginary number.

Is the vibrational motion consistent with an ene reaction of interest and notwith some other process?
5. Click on(Make List) at the left of the spectra pane. Controls in the
dialog that result allow for changing both the amplitude of vibration (Amp)and the number of steps that make up the motion (Steps). The default numberof steps (11) is fine but change the default amplitude. Click inside the box tothe right of Amp: and enter 0.3 using the number pad that appears. Next, clickon Make List at the bottom of the dialog. This will give rise to a group of 11
structures that follow the reaction coordinate down from the transition state(structure 6) both toward reactant and product. You are done with ene
reaction 1-pentene, so close it.
6. Click on the list document, select Calculations... from the Setup menu () and specify calculation of Energy using the HF/3-21G model (thesame level of calculation used to obtain the transition state and calculate thefrequencies). Make certain that Global Calculations is checked and clickon OK. Select Surfaces from the Setup menu ( ) and specify evaluationof a bond density surface. Click on More Surfaces..., select density (bond)for Surface and none for Property. Before you click on OK, make certainthat Global Surfaces is checked.
7. Submit the calculation*. Name it ene reaction 1-pentene sequence. Oncethe job has completed, enter the Surfaces dialog, check the box to the left ofdensity and examine the surface that you have calculated. Step through thesequence of structures ( and ) keys at the bottom of the screen) or animate
the reaction ( ). Note, in particular, the changes in bonding revealed by thebond density surface.
8. Close ene reaction 1-pentene sequence and any open dialogs.
* In this example, you have requested graphical surfaces prior to submitting the calculation.
You could also have requested them to be done “on-the-fly” following the calculation.

Chapter 11181

5 mins

SN2 Reaction of Bromide and Methyl Chloride
The SN2 reaction passes through a transition state in which carbon is in a
trigonal bipyramid geometry and the entering and leaving groups arecolinear. In this tutorial, we will identify it as the “top” of a pathway leadingsmoothly from reactants to products, employing a semi-empirical molecularorbital model in order to minimize calculation time.

1. Bring up the inorganic builder by selecting New Build from the File menu( ), and clicking on the Inorganic tab click on the atom bar, select C fromthe Periodic Table and the five-coordinate trigonal bipyramid ( ) from the listof atomic hybrids and click on screen. Move to the organic builder (click on
the Organic tab). Select Cl and click on one of the axial free valences. SelectBr and click on the other axial free valence.
2. Select Measure Distance from the Geometry menu ( ) and then clickon the CBr bond. Click inside the box to the right of Length at the bottom
right of the screen and enter 3.8 (3.8Å) using the number pad that appears.
You have made a complex representing the reactant.
3. Select Constrain Distance from the Geometry menu ( ). Click on the
CBr bond, and then click on
at the bottom right of the screen. The icon
will change toindicating a constraint is to be applied to this distance.
Check the box to the left of Profile at the bottom of right of the screen. This
will result in two additional text boxes.

Leave the value 3.8 (3.8Å) in the leftmost box alone, but change the numberin the box to the right of to, to 1.9 (1.9Å). Click inside

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the box and use the number pad. In the same way, change the number in thebox to the right of Steps from 10 (the default) to 20. 20 Calculations with CBrbond lengths constrained from 3.8Å (the starting point) to 1.9Å (the ending
point) will be performed. The transition state should have a CBr distance inbetween these values. Click on.
4. Select Calculations... from the Setup menu ( ), and select Energy
Profile, Semi-Empirical and AM1 from the appropriate menus to the right ofCalculate in the dialog that results. Make sure to change Total Charge toAnion.
5. Submit the job. Name it bromide+methyl chloride. When completed, it
will give rise to a sequence of calculations placed in bromide+methyl
chloride.Prof.M0001. You will be prompted as to whether you want to open
this file. Click on YES. You can close the first document bromide+methyl
chloride.
6. Align the molecules that make up the sequence. Click on(Geometry menu), select Structure from the menu at the bottom right ofthe screen and, one after the other, click on the chlorine, the carbon and oneof the hydrogens. Finally click the Align by button at the bottom right of thescreen. Click on. Use the and keys at the bottom left of the screen
to step through the reaction sequence.
7. Select Spreadsheet from the Display menu ( ). Click on Add....
Select E(kJ/mol) from among the quantities listed in the Molecule tab. Next,
enter the (constrained) CBr distances and bromine charges in the
spreadsheet. Select Constrain Distance from the Geometry menu (),
click on the constraint marker in the model and click on
at the bottom
right of the screen. Click on. Select Properties from the Display menu
to bring up a Properties dialog. Click on bromine and click on
to the leftof Electrostatic under Charges in the Atom Properties dialog. Close theAtom Properties dialog. Close the spreadsheet.
8. Select Plots from the Display menu ( ) to bring up the Plots dialog andclick on in the bar at the top of the dialog. SelectChapter 11

183Constraint (Con1) (the distance at which the CBr bond has been constrained)from the X Axis menu, and both E (kJ/mol) and Electrostatic (Br1) fromthe YAxes list in the dialog that results. Click on Create. By default, only thedata points are displayed. Click onin the bar at the top of the plots plane,select Point- to-Point and then click the down arrow to the right of the y-axis
field and again, choose Point-to-Point, then click on Done.
One plot gives the energy as the reaction proceeds and the other gives charge
on bromine. Are the two related? Explain.

9. Close all documents and any open dialogs.
5 minsCarbene Additions to Alkenes

Singlet carbenes add to alkenes to yield cyclopropanes. A singlet carbene
possesses both a high-energy occupied molecular orbital in the plane of themolecule, and a low-energy, out-of-plane unoccupied molecular orbital, andthe reaction presents an interesting dilemma. It is clearly moreadvantageous for the low-lying vacant orbital on

Chapter 11184the carbene, and not the high-lying filled orbital, to interact with the olefin system during its approach.

However, this leads to a product with an incorrect geometry, suggesting that thecarbene needs to twist by 90° during the course of reaction.

In this tutorial, you will use the Hartree-Fock 3-21G model to obtain thetransition state for addition of singlet difluorocarbene, CF2, to ethylene andthen analyze the motion of the fragments.
1. Build ethylene using the organic model kit.
2. Selectfrom the model kit. Hold down the Insert key (option key
on Mac) and then click anywhere on screen. Alternatively, double click on
a blank area of the screen. Next, selectfrom the model kit and click3
on two of the free valences on the sp carbon. Next, click onand click3
on one of the remaining two free valences on the sp carbon. Click onand click on the remaining free valence. You are left with two fragments,
ethylene and difluorocarbene. Orient the two as to be poised for reaction.** Proper orientation of the two fragments is not crucial in this case, but is primarily to allow you
to associate the arrows with the intended reaction. Proper orientation is, however, essential where
different stereochemical outcomes are possible.
Chapter 11185

Translations and rotations normally refer to the complete set offragments, but if you click on a fragment (not on a free valence)
to select it, and then hold down the Ctrl key they will refer to anindividual fragment.

3. Select Guess Transition State from the Build menu ( ). Click on the
carbon on the CF2 fragment and then click on the closer of the carbons on
the ethylene fragment and finally click on the CF2 carbon again. A dotted line
is drawn between the two carbons that are to be bonded along with an arrowfrom the CF2 carbon to the center of this line.

Click on the CC double bond and then click on the other ethylene carbon andon the CF2 carbon. A second dotted line and arrow will be drawn.

Click onat the bottom right of the screen. Your structure will be replaced
by a guess at the transition state.
4. Select Calculations... from the Setup menu ( ), and request calculationof a Transition State Geometry using the HF/3-21G model. Check IR to theright of Compute, and click on Submit. Name the job
difluorocarbene+ethylene.
5. When the job is complete, examine the geometry of the transition state. In
light of the previous discussion, would you describe your

Chapter 11186

structure as corresponding to an early or late transition state? Animate thevibration corresponding to the reaction coordinate. Select Spectra from the
Display menu ( ). Click on thein the bar at the top of the spectra paneand selectfrom the resulting palette of choices. The “infrared
spectrum” calculated for the transition state appears. Click on
at the farleft of the spectra pane. This brings up a table of calculated frequencies andinfrared intensities. The frequency at the top of the list should be preceded by
an “i” designating it as imaginary. It corresponds to the reaction coordinate.
Note the value of this frequency as well as that of the largest frequency.
Click in the check box corresponding to this frequency. Does the animation
show that the carbene reorients as it approaches the double bond? Turn the
animation off by again clicking in the imaginary frequency box. Close theSpectra pane and click on ( ).
6. Select Properties from the Display menu ( ) and, in turn, click on eachof the four hydrogens in the transition state. Change the value in the Mass
Number menu in the Atom Properties dialog (Properties under the
Display menu) from 1 to 2 Deuterium. Resubmit the job. (No additional
quantum chemical calculations are involved, but the vibrational analysis
needs to be repeated.) When complete, examine the new set of vibrationalfrequencies, in particular, the imaginary frequency associated with thereaction coordinate. For comparison, examine the largest frequencies whichcorresponds to one combination of CH stretching motions. You will see thatthe value of the former has barely changed as hydrogen motions are notsignificantly involved in the addition reaction, whereas the latter has beenmarkedly reduced.
7. Close difluorocarbene+ethylene and any open dialogs.

Chapter 11187

15 mins

Stereospecific Diels-Alder Reactions

Diels-Alder cycloaddition of 5-substituted cyclopentadienes withacrylonitrile can lead to four stereoproducts, in which the substituent, X, at the
5 position is syn or anti to the dienophile, and the nitrile is endo or exo. Antiproducts are preferred when X is alkyl while syn products are favored when
X is halogen or alkoxy. In general, endo adducts are kinetically favored
over exo adducts (see following tutorial).
In this tutorial, you will use HF/3-21G molecular orbital calculations to
obtain both syn and anti endo and exo transition states for Diels- Alder
cycloaddition of 5-fluorocyclopentadiene and acrylonitrile, and then use
97X-D/6-31G* calculations to estimate relative activation energies. We will
use the stereoisomer generation tool first introduced in Spartan’20 tosimplify your work.
1. Build or sketch the substituted norbornene shown below (the product ofendo addition of cyclopentadiene and acrylonitrile). Click on.

2. Select Transition State from the Build menu ( ). Click on bond a (seefigure above) and then on bond b. A curved arrow will be drawn from a tob. Next, click on bond c and then on bond d; a second curved arrow from c
to d be drawn. Finally, click on bond e and then on bond f, leading to a third
curved arrow. The model on screen should now appear as follows.

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Click onat the bottom right to produce a guess at the transition state.

3. Select Generate Isomers from the Geometry menu and click on C2 and C7
in the transition state structure (which will be marked as chiral centers). They
will be identified with green circles.
C7

C2

Click on Generate List to the right of Isomers at the bottom right of the screen,
select New Document in the dialog that appears and click on OK. A list of
the four stereoisomers will appear in a new document.
4. Select Calculations from the Setup menu. Specify Energy at Groundstate in Gas from the three top menus to the right of Calculate and with
Density Functional, B97X-D and 6-31G* from the three bottom menus.
Select Transition State Geometry using Hartree-Fock and 3-21G from thethree menus to the right of Start From. You have requested that transition
state geometries for the four stereoisomers be calculated with the HF/321G model and following that energies calculated using the B97X-D/631G* density functional model. Make certain that Global Calculations at
the bottom of the dialog is checked and click on Submit. Name the job DielsAlder stereochemistry.
5. After the calculations have completed (a few minutes) selectSpreadsheet from the Display menu. You can if you like replace the default
labels (M0001, ...) by proper identifiers (syn endo, syn exo, anti endo, anti

Chapter 11189exo), to fit the stereoisomers. Click on Add at the bottom of the spreadsheet,and then on Energy (au) in the dialog that results. Identify the isomer withthe lowest (most negative) energy and click on its label to select it. Again
click on Add and then the Molecule List tab at the top of the dialog that
results and finally click on Relative Energy (kJ/mol) in the dialog that
results.
6. Close all documents and any open dialogs.
30 mins

Ziegler-Natta Polymerization of Ethylene
Ziegler-Natta polymerization involves a metallocene. This complexes
an olefin, which then inserts into the metal-alkyl bond.

In this tutorial, you will use the semi-empirical PM3 model to obtain atransition state for insertion of ethylene into Cp2ZrCH3+ and, estimate theactivation energy using the ωB97X-D/6-31G* density functional model.
1. Select New Build from the File menu ( ) and then Inorganic from themenu at the top of the model kit. Click on the atom bar and select Zr fromthe Periodic Table. Selectfrom the list of hybrids and double click onscreen. Select Cyclopentadienyl from the Ligands menu and click on two of
the free valences on zirconium.
2. Select Organic from the menu at the top of the model kit to move to theorganic model kit. Select sp3 carbon
and click on the remaining freevalence on zirconium. Select Alkenyl from the Groups menu, hold down
the Insert key (option key on Mac) and click anywhere on screen or double
click in a blank area on screen.

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3. Orient the two fragments (Cp2ZrCH3 and ethylene) as shown below:(To move the fragments independently, hold down the Ctrl key and use themouse while in the Edit Build mode.)
4. Select Guess Transition State from the Build menu ( ). Click on theZrC (methyl) bond and one after another, click on the methyl carbon and on
one of the ethylene carbons. Next, click on the ethylene double bond and,one after another, click on the other ethylene carbon and on zirconium. Clickonat the bottom right of the screen. In a few seconds, a guess at thetransition state appears.
5. Select Calculations... from the Setup menu ( ). Specify a transition
state geometry calculation using the PM3 semi- empirical model. Change
Total Charge to Cation and check IR to the right of Compute. Click on
Submit and name the job Cp2ZrMe cation + ethylene.
6. When the job has completed, select Spectra from the Display menu (). Click on the in the bar at the top of the spectra pane and select.
The “infrared spectrum” calculated for the transition state appears. Click on
at the far left of the spectra pane. This brings up a list of calculated
frequencies and infrared intensities. The frequency value at the top of thelist should be preceded by an “i”, designating it as imaginary. Click on thisfrequency and examine the vibrational motion.
7. Perform density functional energy calculations using PM3 geometries toobtain a better estimate for the energy barrier for ethylene insertion. SelectSave As from the File menu () to make a copy of Cp2ZrMe
cation+ethylene; name it Cp2ZrMe cation+ethylene density functional.
Select Calculations... from the Setup menu ( ) and specify calculation ofenergy using the ωB97X-D/6-31G* density functional model. Spartan
will

Chapter 11191

automatically make use of a pseudopotential for Zr instead of the allelectron 6-31G* basis set. Remove the checkmark on IR (to the right ofCompute). Total Charge should still be set to Cation. Click on Submit.
8. While you are waiting for the energy calculation to complete, build both
ethylene and Cp2ZrCH3+ (name them ethylene density functional and
Cp2ZrMe cation, respectively). For Cp2ZrCH +, start with three-coordinate
trigonal Zr, and then
add two cyclopentadienyl ligands and a four-coordinate3
tetrahedral carbon. For each, select Calculations... from the Setup menu (), and specify calculation of energy using the B97X-D/ 6-31G* density
functional model. Select Equilibrium Geometry, Semi-Empirical and PM3from the three menus to the right of Start From to designate use of a PM3
geometry. For Cp2ZrMe cation density functional (only), set Total
Charge to Cation. Make certain that Global Calculations at the bottom of
the Calculations dialog is not checked.
9. Submit both jobs. When they have completed, calculate an activationenergy for the insertion reaction (subtract the sum of the energies of ethylene
and Cp2ZrMe cation from the energy of the calculated transition state).
10.

Close all documents and any open dialogs.
15 mins

Thermodynamic vs. Kinetic Control
Chemical reactions may yield different products depending on theconditions under which they are carried out. High temperatures and longreaction times favor the most stable (thermodynamic) products, whereas low
temperatures and short reaction times favor the most readily formed(kinetic) products. For example, the kinetic product in Diels-Alder
cycloaddition of cyclopentadiene and maleic anhydride is the endo adduct,
whereas it seems likely that the less-crowded exo adduct is thethermodynamic product.
Here you will first obtain pathways for reactions leading to both endo andexo adducts using the PM3 semi-empirical model and then follow these by
B97X-D/6-31G* energy calculations to get a better estimate of thedifference in activation energies.
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1.

Build or sketch the endo Diels-Alder adduct of cyclopentadiene andmaleic anhydride.

2.

Select Constrain Distance from the Geometry menu ( ), and clickon bond a in the figure above. Click on the icon at the bottom rightof the screen (it will then turn to). Check the box to the left ofProfile in the middle of the screen. This will give rise to three
additional check boxes. Change the value in the leftmost box to 1.5Å byclicking inside the box and entering 1.5 using the number pad. In thesame way, enter 2.7 (2.7Å) and 13 (13 steps) into the boxes to the rightof to and Steps, respectively. You have specified that bond a will be
constrained first to 1.5Å, then to 1.6Å, then to 1.7Å, etc. and finally to
2.7Å. Click on . Make certain that Global Steps to the right of Profile
is checked. This means that the two bonds will move in concert.

3.

Repeat the process for bond b. When you are done, both bonds a andb will be constrained from 1.5Å to 2.7Å in 13 equal steps. Click on

4.

Select Calculations... from the Setup menu ( ) and select Energy
Profile from the top menu to the right of Calculate, and SemiEmpirical and PM3 from the two bottom menus in the dialog that
results. Click on Submit at the bottom of the dialog. Name it
cyclopentadiene+ maleic anhydride endo.

5.

When completed, the job will give rise to a new document
cyclopentadiene+maleic anhydride endo.Prof.M0001. This

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contains 13 calculations corresponding to the 13 steps that make up theenergy profile. You will be prompted as to whether you want to open thisfile. Click on Yes.*
6. Select Spreadsheet from the Display menu ( ), and click on Add... at
the bottom of the spreadsheet. Select rel. E (kJ/mol) from among the entries
in the Molecule List tab and click on the spreadsheet to release the Add
menu. Next, click on Constrain Distance from the Geometry menu
andclick on one of the two CC bonds varied in the energy profile. Click on at
the bottom right of the screen. Close the spreadsheet by again selecting it
or clicking on
or by clicking on
at the top right. Click on. Select
Plots from the Display menu ( ) and click on
to bring up the Add Plots**
dialog. Select Constraint (BondX) from among the items in the X Axis
menu and E (kJ/ mol) from the Y Axes list and click on Create. By default,
only the data points are displayed. Click onin the bar at the top of theplots plane, select Point-to-Point in the resulting Edit Plot dialog and thenclick on Done.

Identify both the reactant and transition state from the plot and estimate theactivation energy for the cycloaddition reaction.
7. Repeat steps 1 to 6 for the exo adduct. Compare the activation* To avoid confusion, it is a good idea to close the original file cyclopentadiene+maleic anhydrideendo.
** Bonds are numbered in the order they were formed upon initial construction of the molecule.

Chapter 11194energy for exo addition to that for endo addition (above). What is the kinetic
product?
8. Open cyclopentadiene+maleic anhydride endo.Prof.M0001 () andmake a copy (). Name it cyclopentadiene +maleic anhydride endo DFT.
Select Calculations from the Setup menu ( ) and specify an energy
calculation with the B97X-D/ 6-31G* model in the dialog that results.
Make sure that Global Calculations at the bottom of the dialog is checked.
Click on Submit. When completed, perform the same spreadsheet and plot
operations you did for the PM3 calculations.
9. Repeat the above procedure for the exo adduct and compare the two
activation energies. What is the kinetic product?
10.

Close all documents and any open dialogs.
1 min

Activation Energies of Diels Alder Reactions
In an earlier tutorial, Dienophiles in Diels-Alder Reactions (Chapter 8), you
looked for a correlation between LUMO energies for a series of related
dienophiles and relative rates of Diels-Alder cycloadditions involving
cyclopentadiene. In this tutorial, you will compare calculated activationenergies for this same set of reactions with the experimental rates. You will use
the previous set dienophiles and obtain transition states from the Spartan
Reaction Database (SRD). The only quantum chemical calculation that isrequired is for cyclopentadiene.
1. Build or sketch cyclopentadiene. Select Append Molecule(s)... from theFile menu, locate the file Diels-Alder dienophiles (from Chapter 8) and click
on Open. If you have not yet completed this tutorial, you can find this file in
the organic reactions folder inside the Tutorials* directory.
* For Windows, this directory is found in Program Files/Wavefunction/Spartan24. For security reasons,the program file directory is protected. Copy the folder to your desktop or to another location available tothe user prior to opening it in Spartan. For Linux, this is found in the directory where Spartan was
installed. For Macintosh, this is located at the top level on the Spartan24 disc image.

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2. Open the Spreadsheet from the Display menu ( ). Click on the Labelheader cell and then right click and choose Rename Selected Using SSPD
from the contextual menu that results. Close the Spreadsheet whenfinished.
3. Select Calculations... from the Setup menu ( ). Specify an
Equilibrium Geometry calculation using the Hartree-Fock 3-21G model.
Make sure the Global Calculations box is checked. Submit the job with thename Diels-Alder reactants.*
4. Select New Build from the File menu ( ). Build cyclopentadiene, selectAlkenyl from the Groups menu, hold down the Insert key (option key onMac) and click on screen (or double click in a blank area on screen).
Cyclopentadiene and ethylene will both appear on screen, although they will
not be connected. Select Cyano from the Groups menu and click on one of
the free valences on ethylene. Both cyclopentadiene and acrylonitrile willappear on screen.
5. Orient the two molecules such that they are poised for a Diels- Alderreaction leading to an endo product.
NC
d a
ef

Select Reaction Query from the Search menu ( ).** Click on the bondmarked a in the above figure and then click on the two carbons that whenconnected will lead to the bond marked b. A dotted line will be drawn
between these carbons and a curly arrow drawn from the center of bond ato the center of bond b. Next, click on bond c and then on bond d. A second
arrow will be drawn. Finally, click on bond e and, click on the two carbons
that when connected will lead to the bond marked f. A second dotted line
and a third arrow will be drawn.
* Spartan identifies calculations that have already been done, in this case, the set of
dienophiles. The only calculation remaining is that for cyclopentadiene.
** Reaction Query is equivalent to Transition State for the purpose of defining curly arrows.
It lacks the ability to automatically guess a transition state.

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6. Select Structure Query from the Search menu ( ). Click on all three
free valences on the acrylonitrile fragment. They will be replaced by orange
cones, meaning that anything (including hydrogen) may be attached to these
positions.
7. Select Databases from the Search menu ( ) and click on the SRD tabat the top of the dialog that results. This leads to the Spartan Reaction
Database (SRD) dialog.

Before you begin the search, click on to the right the Search button at thebottom of the dialog. This brings up the Search Options dialog.

Check 3-21G under Method Filters and click on OK. Click on the Searchbutton to search the Spartan Reaction Database for Diels-Alder transition
states between cyclopentadiene and substituted acrylonitriles.
8. When the search completes, a listing of hits appears at the right of the
dialog.

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This should contain four Diels-Alder transition states for endo additions of
cyclopentadiene and trans-1,2-dicyanoethylene, cis- 1,2-dicyanoethylene,
tricyanoethylene and tetracyanoethylene. All need to be retrieved into asingle document. Click on
to the right of the Retrieve button at thebottom of the dialog to bring up the Retrieve Options dialog. Make surethat New Document is selected in this dialog and click on OK. Hold down the
Ctrl key, select (click on) all four Diels-Alder transition states and click on
Retrieve at the bottom of the dialog. A new (unnamed) document will becreated. Close the file and save it as Diels-Alder transition states.
9. As soon as Diels-Alder reactants completes, select Append
Molecule(s)... from the File menu, navigate to Diels-Alder transition states
and click on Open.
10.
Select Reactions from the Display menu ( ). One after the other,calculate activation energies for the six Diels-Alder reactions. Use
cyclopentadiene and one of the dienophiles for Reactants and theappropriate transition state and none for Products. Select Current
Document under Source at the bottom of the dialog, E under Calculate andclick on Compute. Is the ordering calculated activation energies consistent
with the experimental relative rates (available in the tutorial Diels-Alderdienophiles in Chapter 8)?
11.

Close all documents and any open dialogs.

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Chapter 12
Medicinal ChemistryThis chapter illustrates applications of Spartan to problems of relevance tomedicinal chemists.
Medicinal chemistry is a diverse field, the common thread being its
concerns with the design, properties and behavior of molecules that areimportant in biological systems. The tutorials in this chapter illustrate someof the roles that calculations might play.
The first addresses simple models to estimate the rate at which molecules
are transported between blood (hydrophilic media) and the tissue in thebrain (hydrophobic media); this is not something that can be directly
calculated, and instead we will rely first on the so-called polar surface
area (PSA) and later refine this using electrostatic potential maps.
The second and third tutorials use similarity analysis to identify “new”
molecules (drugs) that are structurally or functionally similar to moleculeswith known drug action. In the second, involving the antihistamine
terfenadine, similarity analysis is not carried out between molecules but
between a molecule and an environment. In the third, similarity analysis isused to suggest compounds that “look like” morphine and hence might
exhibit similar analgesic action.
The last tutorial accesses the on-line Protein Data Bank (PDB). While
calculations on biopolymers (proteins and RNA/DNA strands) are limited
to molecular mechanics models, quantum chemical calculations can beroutinely applied to molecules bound to biopolymers. The focus is not themolecule itself, but rather the binding environment. This is turned into a socalled pharmacophore (a simplified representation of the environment); a
search for other molecules that may also be consistent with thisenvironment is illustrated.

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no calculations

Anticipating Blood-Brain Transport
To be effective, a drug must be capable of transportation to its target. For
orally administered drugs, this includes transfer through cell membranes in
the intestine. In the case of most neural drugs, this also involves traversing
the blood-brain barrier. In this tutorial, you will first examine how well thepolar surface area (the area of space- filling model due to nitrogen andoxygen atoms together with any attached hydrogens) correlates with log(Cbrain/Cblood)*.
1. Open blood brain transport from the medicinal chemistry sub- directory(Tutorials directory).** This comprises a list of drugs/ drug candidates forwhich experimental data relating to the ratio of concentrations in the brain
and in the blood (Cbrain/Cblood) are available. These span a range of nearly 5
log units.
2. Select Spreadsheet from the Display menu ( ) and size the spreadsheet
to show all compounds, several extra rows and three columns, in addition
to the column of experimental data log(brain/blood) that is alreadydisplayed. Select Properties from the Display menu ( ) and click on the
QSAR tab in the dialog that results. Click on(Post) to the left of PSA.
Polar surface area values will fill one column in the spreadsheet.
3. Click on the Add button at the bottom of the spreadsheet and select (clickon) the Linear Regression tab at the top of the dialog that appears. Selectlog(brain/blood) from the Fit menu and click on PSA in the box under
Using. Click on Apply. Select Properties from the Display menu ( ) andthen click on the cell labeled Fit1 at the bottom of the spreadsheet under the
Label column. This brings up the Regression Properties dialog in which
RMSD and R2 values are reported. The smaller* J. Kelder et al, Pharmaceutical Res., 16, 1514 (1999). All 19 named compounds considered in this paper
have been included.
** For Windows, this directory is found in Program Files/Wavefunction/Spartan24. It must be copied
to another location available to the user prior to opening it in Spartan. For Linux, this is found in the
directory where Spartan was installed. For Macintosh, this is located at the top level of the Spartan'24
disc image.

Chapter 12200

RMSD and the closer to unity R2, the better the fit. Close theRegression Properties dialog.
4. Make a plot of log(brain/blood) vs. the regression fit. Select Plots fromthe Display menu ( ). Click onin the bar at the top of the plots pane
to bring up the Plots dialog. Select log (brain/blood) from the X Axis menu,
Fit Vals (Fit 1) from the Y Axes list and click on Create. Click on
andcheck the box to the left of Curve and the radio button next to Least Squares
and finally the Done button.
A least-squares line is drawn through the points.

Next, you will consider an alternative definition of polar surface area basedon electrostatic potential maps.
5. Select Surfaces from the Display menu ( ) and select electrostatic
potential map in the dialog that results. An electrostatic potential map forthe selected drug appears (maps for the remaining drugs may be seen by
stepping through the list using the step buttons in the bottom left of thescreen). The overall size and shape is that of the electron density andcorresponds roughly to a conventional space-filling model. The colors
indicate the value of the electrostatic potential. Colors toward red designate
areas of negative potential (where a positive charge is most likely to be
attracted), while colors toward blue designate areas of positive potential(where a positive charge is least likely to be attracted). To see the molecularskeleton underneath the electrostatic potential map,

Chapter 12201change to a transparent or mesh display. Click on the map to select it andselect Transparent or Mesh from the Style menu that appears at the bottom
right of the screen.
6. Select Properties from the Display menu ( ). Click on the map. Clickon the button to the left of P-Area the Surfaces Properties dialog that
results. Polar areas, defined as the area for which the absolute value of theelectrostatic potential is > 100 kJ/mol*, will be added to the spreadsheet.
7. Click on the Add button at the bottom of the spreadsheet and click on the
Linear Regression tab at the top of the dialog that results. Selectlog(brain/blood) from the Fit menu and click on Polar Area from thequantities in the box under Using. Click on Apply. Bring up the Regression
Properties dialog by clicking on the cell labeled Fit2 under Label in the
spreadsheet. Note that the R2 value is better (closer to unity) for this fit thanfor the previous fit (to PSA defined in the usual manner). Make a plot oflog (brain/blood) vs. the new regression fit. Select Plots from the Display
menu ( ) and click onin the bar at the top of the plots pane. Chooselog (brain/blood) from the X-Axis menu and FitVals (Fit 2) from the Y
Axes list and click on Create. Click on
and again specify Least Squares
for the Curve in the Edit Plot dialog and click Done. Which property
provides better correlation with transport across the blood/brain barrier,
PSA or polar area?

* This value may be changed in the Settings Preferences dialog (Preferences under the
Options menu; Chapter 25).

Chapter 12202

8. Close blood brain transport and any open dialogs.
5 minsTerfenadine. A Potassium Channel Blocker?
Cardiovascular toxicity due to blocking of potassium ion channels iscommonly screened early in the drug development process. One way this isdone is to compare drug candidates to a pharmacophore deduced from 3D
QSAR studies. This tutorial uses a published pharmacophore* to see whether
the antihistamine, terfenadine should be considered a potential channel
blocker.

1. Open terfenadine similarity library from the medicinal chemistry subdirectory(Tutorials directory).** This file contains the coordinates for adiverse selection of several hundred conformers of terfenadine (the actual
number is reported in the Molecule Properties dialog) obtained from asimilarity library calculation. It has been supplied in order to save computer
time. Close terfenadine similarity library.
2. Open potassium channel blocker pharmacophore from the medicinal
chemistry sub-directory (Tutorials directory). This is a five-point
pharmacophore comprising four aromatic hydrophobe centers (purple
spheres) and one positive ionizable center (red sphere).
* S. Ekins et al, J. Pharmacology and Experimental Therapeutics, 301, 427 (2002).
** For Windows, this directory is found in Program Files/Wavefunction/Spartan24. It needs to be copied
to another location available to the user prior to opening it in Spartan. For Linux, this is found in the
directory where Spartan was installed. For Macintosh, this is located at the top level of the Spartan’24
disc image.

Chapter 12203

3. Select Set Similarity Centers from the Geometry menu ( ) and thenselect CFD from the menu at the bottom right of the screen next toSimilarity by:. In turn, click on each of the (five) pharmacophore elements.
In response, each will be surrounded by a violet circle indicating that it is to
be used in the similarity analysis calculation.
4. Select Calculations... from the Setup menu ( ). Select Similarity
Analysis from the top left menu to the right of Calculate inside theCalculations dialog. This leads to a new configuration of the Calculations
dialog.

Click on Add Library to bring up a file browser. Locate terfenadinesimilarity library in the medicinal chemistry sub- directory (Tutorials
directory) and click on Open. This indicates that the library of terfenadine
conformers will be searched for a match to the pharmacophore. Click on
Submit.
5. When the analysis has completed, select Similarities... fromthe Display menu ( ) to bring up the Similarities dialog.

Chapter 12204

Multiple hits will appear at the right of the dialog, together with a similarity
score (limiting on 1.0 which means a perfect match). Click on the hit withthe highest score. A composite graphic of terfenadine and thepharmacophore will appear in a window at the left of the dialog. You canmanipulate the two (as a single object) in the usual way (you need toposition the cursor inside the window). Note that the positive ionizable
center is positioned above nitrogen, while the four aromatic hydrophobes
are above phenyl rings and the tert-butyl group.
The scoring algorithm not only accounts for position but also fordirection of any nitrogen or oxygen centers that overlap with (nonhydrophobe) pharmacophore elements.

6. You can, retrieve a selected hit (without retrieving the pharmacophore),by clicking on the Retrieve button at the bottom left of the Similarities
dialog. This can be used for further analysis.
7. Close all open documents and dialogs.

Chapter 12205

15 mins

Morphine. Structure vs. Pharmacophore
H

O

D

H

NMe

HO
morphine

Three “chemical aspects” of morphine appear to be required in order for themolecule to act as an analgesic. These are: i) the nitrogen center (assumed
to be protonated in the protein-bound complex),ii) the aromatic ring and iii) the hydroxyl group attached to the aromaticring. The loss of any of these results in significant reduction of activity. Thisknowledge may either be used directly to identify other likely analgesics
based on structure, or indirectly to construct a simple 3-point
pharmacophore that in turn may be employed to find compounds withpotentially comparable analgesic activity.
This tutorial comprises three parts. In the first part, you will identify
molecules in the Spartan Spectra and Properties Database (SSPD) thatincorporate the three required elements. In practice, you will look formolecules that incorporate a nitrogen center substituted by a methyl groupand two other (sp3) carbons and a substituted phenol. You will then select asingle hit and generate a conformer library for similarity analysis simply inorder to save computer time. This is a superficial investigation. To becomprehensive, one would need to use several (or all) hits.
1. Select New Build from the File menu ( ) and bring up the organic
model kit. Select Benzene from the Rings menu and double click anywhereon screen. Select sp3 oxygen () and click on one of the free valencesof benzene. You have made phenol. Select sp3 nitrogen (), double
3
click on a blank region on screen to insert a non-bonded sp nitrogen.
Two

Chapter 12206molecules (phenol and ammonia) appear on screen. Click on sp3 carbon () and click on all three free valences on the nitrogen. Phenol andtrimethylamine now appear on screen. Click on.
2. Select Structure Query from the Search menu ( ). Click on all five
free valences on the carbons in the phenol fragment and on all three freevalences on two of the three methyl groups and on one free valence for theremaining methyl group in the trimethylamine fragment. Orange cones willappear at all (twelve) selected positions.

This defines a search in which anything can be “grown” from the selected
positions (including hydrogen) but a hit must contain phenol and a nitrogenbonded to three sp3 carbon centers.
3. Select Databases from the Search menu ( ). Click on the SSPD tab in
the dialog that results. Click on Search at the bottom of the SSPD dialog.
4. To sort in alphabetical order, click on Name at the top of the list inside in
the scroll box at the right of the SSPD dialog. Find and click on cephaeline.** The search above was done on the full ≈315,000 molecule SSPD. The smaller subset bundled with theSpartan’24 install will find significantly fewer “hits”.

Chapter 12207

Its structure will be displayed in the window at the left of the dialog. You
can manipulate the model in the usual way by positioning the cursor inside
this window. Click on to the right of the Retrieve button at the bottom of
the SSPD dialog to bring up the Retrieve Options dialog. Check New
Document under Retrieve Options and click on OK. Finally, click on the
Retrieve button. Dismiss the SSPD dialog either by again selecting
Databases from the Search menu ( ) or by clicking on at the top righthand corner of the SSPD dialog.
Save the molecule you retrieved under the name cephaeline. Close the fileused for the search (phenol and trimethylamine) without saving.
5. For similarity library generation, it is advised to use a more restrictive
conformational analysis routine. For this example, the molecule retrieved
from the database has been set to do so. To confirm this, select Set Torsions
from the Geometry menu ( ). Your molecule should be augmented withthree yellow cylinders (only). If this is not the case, select Preferences fromthe Options menu. In the Settings tab, switch the Conformer Rules toskeletal, and click OK. You will still be in the Set Torsions mode, in thelower right of the interface, click on the Reset button to apply the changes
to your molecule.
6. Select Calculations... from the Setup menu ( ). Select Similarity
Library from the top left menu to the right of Calculate. No further
information is required. Click on Submit at the bottom of the dialog. Nameit cephaeline library. You can continue with the tutorial while you arewaiting for the job to complete. Note, however, that you need to close
cephaeline library before it is used in Step 9.
In the second part of this tutorial, you will specify the key structuralcomponents in morphine and perform a similarity analysis based on
structure using the conformer library for cephaeline.
7. You can either sketch morphine (much easier than building it in 3D) or
to save time, open it: morphine from the medicinal

Chapter 12208chemistry sub-directory (Tutorials directory).* If you sketch it, click onwhen you are done. The name should appear at the bottom of the screen as
morphine is in SSPD. If it does not, you have made a mistake.
8. Select Set Similarity Centers from the Geometry menu ( ) and selectstructure from the menu at the bottom right of the screen. Click on theeleven *’ed atoms in the figure below. These atom centers define the phenol
and the primary amine discussed earlier. A violet circle will be drawn
around each. If you accidentally select the wrong atom, click on the“offending” circle to deselect it.

9. Select Calculations... from the Setup menu ( ). Select Similarity
Analysis from the top left menu to the right of Calculate inside theCalculations dialog. Click on Add Library to bring up a file browser, locateand select cephaeline library, and click on Open. Make certain that
Structure is selected from the Use menu at the lower right of the dialog.
You have requested that the library of cephaeline conformers be searched
for a match to the key structural elements of morphine. Click on Submit.
Supply the name morphine.
10.The similarity analysis will require a few seconds. When it completes,
select Similarities... from the Display menu ( ).

* For Windows, this directory is found in Program Files/Wavefunction/Spartan24. It must be copied toanother location available to the user prior to opening it in Spartan. For Linux, this is found in the directory
where Spartan was installed. For Macintosh, this is located at the top level of the Spartan’24 disc image.

Chapter 12209

11.Hits appear in the box at the right of the dialog together with a score.
Sort according to score (best on top) by clicking on Score at the top of thebox. Select (click on) one of the best matches. A composite graphic
consisting of morphine and the matching cephaeline conformer from thelibrary will appear in a window at the left. You can manipulate the two
structures (as a single object) in the usual way.
Repeat the similarity analysis using CFD’s rather than structure.
12.Select Set Similarity Centers from the Geometry menu ( ), but thistime select CFD from the menu at the bottom right of the screen. CFD’s
will augment the morphine structure.

13.Designate three of the CFD’s as similarity centers. Select (click on) the
CFD over the phenolic oxygen. A violet circle will surround this center
indicating that it is to be used in the similarity analysis. (If you accidentally
select the wrong CFD,

Chapter 12210

click on the circle and it will disappear.) Select (click on) the CFD at the
middle of the phenol ring and the CFD at nitrogen.
14.Select Calculations... from the Setup menu ( ). This should alreadydesignate Similarity Analysis and the appropriate library (cephaeline).
Change the entry in the Use menu to CFD. Click on Submit.
15.When the analysis is complete, select Similarities... from the Display
menu ( ). One or more hits should appear in the box at the right of the
dialog. Select a hit to get a composite graphic (CFD and structure from thelibrary). You can easily see the extent to which the two are matched.
16.Close any open documents and dialogs.
5 minsGleevec. Making a Pharmacophore from PDB

In this tutorial, you will start with a protein structure from the PDB in which
the so-called protein kinase inhibitor, gleevec, is found*. Instead of
abstracting the molecular structure of gleevec, you will abstract its “binding
environment”, that is, the locations from which gleevec interacts with theprotein host in terms of hydrogen-bond or charge-charge interactions (nonsteric contacts). This information,* B. Nager et. al., Cell, 112, 859 (2003): PDB identification 1opj.

Chapter 12211together with knowledge of either the steric requirements of the guest or the
space occupied by the protein (excluded volumes), constitutes a structuralpharmacophore, that is, a “skeleton” into which other possible “guests”
might be accommodated. You will then use a subset of the non-steric contacts
together with excluded volume elements to see to what extent thispharmacophore fits another protein kinase inhibitor, flavopiridol.
1. Select Access PDB Online from the File menu ( ) to obtain the PDB
file 1opj from the PDB or open 1opj from the medicinal chemistry subdirectory (tutorials directory)*. Select Extract Ligands from the File menu( ), click on the model for gleevec (it will be designated as Ligand STI 3
or 4) inside the protein structure (displayed as a set of transparent spheres
similar to a space-filling model) to select it, and click on the Exact Ligands
button at the lower right of the screen. Inside the Extract Ligands dialog,
check both HBA/HBD and +/- Centers and Excluded Volume Centers. If
any other items are selected, make certain to deselect them before you clickon OK.
2. You are finished with 1opj and may close it. Also, simplify the displayof the extracted information by removing the excluded volume elementsfrom view. Select Configure... from the Model menu ( ) and click on the
CFDs tab. Uncheck Excluded Volumes and click on Apply (this will hide
the excluded volumes and leave the Configure dialog on screen).
3. The model that now appears comprises five purple spheres representing
non-steric contacts between gleevec and its protein host. Turn on labels. In
the Configure dialog, click on the Labels tab, check CFD Labels and clickon OK.

* For Windows, this directory is found in Program Files/Wavefunction/Spartan24. It must be copied
to another location available to the user prior to opening it in Spartan. For Linux, this is found in the
directory where Spartan was installed. For Macintosh, this is located at the top level of the Spartan’24
disc image.

Chapter 12

212

These have been assigned based on the observation that each is within apredefined distance of (one or more) complementary groups from residues
in the protein host. Because hydrogen positions are not assigned in theexperimental X-ray structure it may not be possible to say whether aparticular site on the guest is acting as a hydrogen-bond donor or acceptor. It
may not even be possible to say whether a particular site is protonated or
deprotonated (although pH may often dictate this). To be “safe”, all nonsteric contacts have initially been given four CFD definitions: hydrogen-bondacceptor (HBA), hydrogen-bond donor (HBD), positive ionizable (+) andnegative ionizable (–). Examination of the structure of gleevec suggests
more focused assignments: 1 (HBA, +), 2 (HBA), 3 (HBD), 4 (HBA) and5 (HBA). (See previous figure for numbering.)
4. You will use only three elements of this pharmacophore (together with theexcluded volume elements) to assess whether or not flavopiridol is likely to
fit into the same host environment as gleevec. Select Properties from the
Display menu ( ). Click on CFD1, remove the checks next to HBD and-Ionizable (leaving HBA and +Ionizable). Repeat the process, designating
CFD3 as HBD only, and CFD5 as HBD only. Next, select Set Similarity
Centers from the Geometry menu ( ). Ensure that the CFD (notStructure) is selected in the lower right corner of the screen. Click CFDs 1,
3, and 5. A violet circle will appear on each, indicating that it is to be usedin the similarity analysis calculation. Click on.
5. Select Calculations... from the Setup menu ( ) and then Similarity
Analysis from the top left menu to the right of Calculate. Click on Add
Library... and then locate and selectChapter 12213

flavopiridol in the medicinal chemistry sub-directory (Tutorials directory)
and click on Open. Make certain that CFD is selected next to Use: in thelower right of the Calculations dialog. Click on Submit. Name thedocument flavopiridol fit to gleevec pharmacophore.
6. When the similarity analysis has completed, select Similarities... from the
Display menu ( ). Sort the hits according to similarity score (click on Score
at the top of the dialog). One after the other, click on the top scoring entries
in the box to the right of the dialog and examine the fits in the window at
the left.
7. Close any open documents and dialogs.

Chapter 12

214Chapter 13
Flexible Molecules
This chapter describes procedures available for calculations on
flexible molecules.
Up to this point, we have not paid much attention to the different
conformers that molecules might adopt. Many of the molecules dealt withso far are rigid or dominated by a single conformer and, where they are not,we have chosen to downplay the importance of conformation. In fact, thevast majority of molecules are not rigid and knowing the “right” conformer
or conformers can be important to properly describing molecular spectra
and properties and overall chemical behavior.
The five tutorials in this chapter illustrate a variety of approaches for dealing
with flexible molecules. The first tutorial presents a molecule with only asingle degree of (conformational) freedom. Here the focus is not only on
identifying the “best” conformer, but also on rationalizing why it is the best.
The second tutorial explores a molecule with two degrees of freedom. The
focus here is on identifying all “reasonable” conformers and comparing theordering of energies for these conformers with different theoretical models.
The third tutorial involves a molecule with several degrees of conformational
freedom and hundreds of conformers. Its goal is simply to find the lowestenergy conformer using practical methodology. The last two tutorials havemore of a chemical focus. The first of these asks a question about the “price”
that needs to be paid in order for a molecule to be properly oriented for an
intramolecular reaction. The second asks a similar question, but this timewith regard to a proper conformation for binding to a protein.

195

Chapter 13

25 mins

Internal Rotation in Dimethylperoxide

Quantum chemical calculations may be called on to furnish data toparameterize empirical energy functions for use in molecular mechanics
and/or molecular dynamics calculations. Perhaps most important are data
relating to torsional motions where small changes torsional angles may leadto large changes in overall shape, as well as significant changes inmolecular spectra and properties.
Any function chosen to represent the energy of rotation about a single bondneeds to reflect the inherent periodicity, that is, it must repeat itself in 360°.
The most common choice is a truncated Fourier series.
Etorsion () = ktorsion1 (1 - cos( - eq)) + ktorsion2 (1 - cos2( - eq))+ ktorsion3 (1 - cos3( - eq))

Here, eq is the ideal dihedral angle and ktorsion1, ktorsion2 and ktorsion3 areparameters. The first (one-fold) term accounts for the difference in energy
between syn and anti conformers, the second (two-fold) term for thedifference in energy between planar and perpendicular conformers, and thethird (three-fold) term for the difference in energy between eclipsed andstaggered conformers.
In this tutorial, you will examine the energy for rotation about the oxygenoxygen bond in dimethylperoxide, first using B97X-D/6- 31G* density
functional calculations to establish geometry and then using B97X-V/6311+G (2df,2p)[6-311G*]calculations to get a more accurate account. Both
B97X-D and B97X-V functionals account for long-range dispersiveinteractions, the former by an empirical correction and the latter more
properly by explicit calculation. The 6-311+G(2df,2p) basis set is much
more flexible than 6-31G*, but the calculation can be simplified using theso-called dual-basis set approximation where convergence is first reachedwith the smaller 6-311G* basis set. You will fit your data to truncatedFourier series.
Chapter 13

216

1. Build dimethylperoxide. If the molecule is not already in an anti
conformation, select Measure Dihedral from the Geometry menu ( ),click on COOC atoms in order, click inside the box to the right of Dihedral...
and enter 180 (180°) using the number pad that appears. Do not minimize.
2. Select Constrain Dihedral from the Geometry menu ( ). Select the
COOC torsion (click on COOC atoms in order), and then click on at thebottom right of the screen. The icon will change toindicating that adihedral constraint is to be applied.
3. Check the box to the left of Profile at the bottom right of the screen. This
will result in two additional text boxes.

Leave 180° in the original (leftmost) box alone, but change the value in thebox to the right of to to 0°. Click inside the box and enter 0 using the number
pad. Steps should be 10. If it is not, click inside the box and enter 10 using
the number pad. What you have specified is that the dihedral angle will be
constrained first to 180°, then to 160°*, etc. and finally to 0°. Click on.
4. Select Calculations... from the Setup menu ( ) and specify Energy
Profile from the top menu to the right of Calculate, and DensityFunctional, B97X-D and 6-31G* from the three bottom menus. Click on
Submit and accept the name dimethylperoxide.
5. When the calculations have completed (several minutes), they will go
into a file named dimethylperoxide.Prof.M0001. A prompt will ask you if
you want to open this file. Click on OK. Align the conformers. Select Alignfrom the Geometry menu ( ), select Structure from the Align by menu
at the bottom right of the screen and, one after the other, click on both oxygens
and on one of the carbons. Then click on the Align by button at the bottom
right of the screen. Select Spreadsheet from the* The difference between constraint values is given by: (final-initial)/(steps-1).

Chapter 13

217

Display menu ( ), and enter both the energies relative to the 180°
conformer, and the COOC dihedral angles. First click on the label(M0001) for the top entry in the spreadsheet (the 180° conformer), thenclick on the header cell for the leftmost blank column, and finally, click on
Add... at the bottom of the spreadsheet. Select rel. E (kJ/mol) from thequantities in the Molecule List tab, and click on the spreadsheet to release
the dialog. To enter the dihedral angle constraints, select Constrain Dihedral
from the Geometry menu ( ), click on the constraint marker attached todimethylperoxide and click on
at the bottom of the screen (to the rightof the value of the dihedral angle). Click on.
6. Select Plots from the Display menu ( ). Click on
at the topof the (empty) plot pane and select Constraint(Con1) from the X Axis menu
and rel. E(kJ/mol) from the Y Axes list and then click Create.

To fit the points to a Fourier series, click on
at the top of the plot pane,select Fourier to the right of Curve in the resulting dialog and click on
Done.

Chapter 13

218

7. To get a better account of the energy profile for rotation about the OO
bond in dimethylperoxide, perform calculations with the B97X-V/6311+G (2df,2p)[6-311G*] density functional model* (using the equilibriumgeometries that you obtained from the B97X-D/6-31G* model). First,
make a copy of dimethylperoxide.Prof.M0001. Name it dimethylperoxide
B97X-V. Select Calculations... from the Setup menu ( ) and specify
calculation of energy using the B97X-V/6-311+G (2df,2p)[6-311G*]
density functional model. Make certain that Global Calculations (at thebottom of the dialog) is checked to signify that energy calculations areto be performed on all conformers. Click on Submit.
8. Energy calculations for all ten conformers will require several minutes tocomplete. When they are done, draw a new energy plot and compare it to
the energy plot produced earlier.
9. Close all documents and dialogs.

*

This is different from the model provided in SSPD in that it employs the dual basis set approximation
where 6-311G* is the supporting small basis set. Use of the dual basis set approximation leads to anorder of magnitude reduction in cost with little noticeable difference in relative conformer energies.

Chapter 13219

30 mins

Ethinamate

NH2

Ethinamate is a prescription drug previously used for the treatment of
insomnia. It involves two degrees of conformational freedom, rotation of
the single bond to the carbonate group (two unique arrangements) andinversion of the six-member ring (two unique chair conformers).
1. Build or sketch ethinamate. Click on. Select Calculations... from the
Setup menu () and request a Conformer Distribution with theB97X-V/6-311+G (2df,2p)[6-311G*] density functional model using
B97X-D/6-31G* geometries. This actually invokes a multistep recipe
starting from a systematic conformer search using MMFF molecularmechanics and proceeding through several immediate steps to gradually
reduce the number of conformers for the final energy calculation. Click on
Submit, and accept the name ethinamate.
2. The calculation will require several tens of minutes. When it completes,
ethinamate will display the lowest-energy conformer but the total energy,
dipole moment and Mulliken atomic charges* will refer to a Boltzmann
weighted average over all accessible conformers. A Spartan document
containing these conformers (ethinamate_1) has been returned. Open thelatter document, enter the total energies into the spreadsheet. You will seethat the total energy of the best conformer is in fact lower than that of the
Boltzmann averaged value (found in ethinamate).**3. Close any open documents and dialogs.

* Natural charges are available only for the 6-311+G(2df,2p) basis sets. Electrostatic charges are too
costly to calculate for molecules with large numbers of accessible conformers and are deliberately
excluded.
** This may be surprising but is necessarily the case as the Boltzmann average while dominatedby the lowest-energy conformer includes contributions from higher energy conformers.

Chapter 13220

5 mins

Allyl Vinyl EtherThe Equilibrium Conformer and Conformer Distribution selections
under Calculations in the Setup menu directly access the MMFF molecularmechanics model and either the B97X-V or B97M-V density functionalmodels with the 6-311+G(2df,2p) [6-311G*] basis sets. They represent theextremes in terms of cost computation and are intended to be used in two
situations with entirely different expectations. There are numerous models andcombinations of models in between and the purpose of this tutorial is to
explore one of them. Here we seek a semi-quantitative account of the energy
required to go from the “best” conformer of a molecule to a conformer poisedfor chemical reaction. This is different than the expectation of the following
tutorial which is to accurately account for the NMR spectrum of a flexible
molecule.
Allyl vinyl ether undergoes Claisen rearrangement, the mechanism
presumes a chair arrangement of the reactant.
‡

Is this the lowest-energy conformer (global minimum) or is additional energy
required to properly orient the molecule for reaction? To find out, you needto locate all the conformers of allyl vinyl ether, identify the best chairstructure and evaluate its energy relative to that of the actual global minimum.
You will first carry out a conformational search using the MMFF molecularmechanics model, and then refine relative conformer energies using singlepoint B97X-D/6-31G* density functional calculations based on 3-21G
Hartree-Fock equilibrium geometries. The results are not expected to be as
good as those that might be obtained from better geometry and especiallyenergy calculations, but they should be sufficient for the objective at hand.

Chapter 13

2211. Either build

or sketch

allyl vinyl ether.

2. Select Calculations... from the Setup menu ( ) and specify Conformer
Distribution from the top menu to the right of Calculate and Molecular
Mechanics and MMFF from the two bottom menus. Click on Submit andaccept the name allyl vinyl ether.
3. When completed, it will give rise to a series of low-energy conformers*
placed in a new file allyl vinyl ether.Conf.M0001.** A prompt will ask you if
you want to open this file. Click on OK.*** Select Spreadsheet from the
Display menu ( ). Size the spreadsheet such that all rows (corresponding
to different conformers) are visible at one time. Click on Add... at the bottomof the spreadsheet. Click on the E (kJ/mol) button from the Molecule tab
and click on the spreadsheet to remove the Add dialog. Energies for eachof the different conformers will be added to the spreadsheet. Examine thelowest-energy conformer (the top entry). Is it in a chair conformation suitablefor Claisen rearrangement? If not, identify the lowest-energy conformer thatis suitable. You can keep two or more conformers on screen at the sametime by checking the boxes immediately to the left of the molecule labels(the leftmost column) in the spreadsheet. To get a clearer idea of structuralsimilarities and differences, align the conformers. Select Align from theGeometry menu ( ) and select Structure from the Align by menu at thebottom right of the screen. A message will appear at the bottom left of thescreen.
Click on oxygen and on the two carbons of the vinyl group bonded tooxygen to designate them as alignment centers. Each will be marked by a
red circle. If you make a mistake, click on the circle and it will disappear.
When you are done, click on the Align by button at the bottom right of thescreen. Click on.

* By default, only conformers within 40 kJ/mol of the global minimum will be kept. This can bechanged (see Conformational Search in Appendix D).
** M0001 is the default label of the molecule you built. You can change it by altering the Labels field in
the Molecule Properties dialog (Properties under the Display menu; Chapter 22).
*** To avoid confusion, it is a good idea to close the original file allyl vinyl ether.
Chapter 13222

4. To obtain a better estimate of the energy required to twist allyl vinyl ether
into a conformer suitable for Claisen rearrangement, perform B97X-D/631G* energy calculations using 3-21G geometries. Select Save As from theFile menu ( ) to make a copy of allyl vinyl ether.M0001. Name it allyl vinyl
ether density functional. Using the copy, delete all conformers except the
global minimum and the lowest-energy conformer that appears to be mostclosely poised for Claisen rearrangement. Select each conformer to bediscarded, and then select Delete Molecule from the File menu ( ).
Alternatively, click on the cell in the spreadsheet containing the label for themolecule to be deleted, and then click on Delete at the bottom of the
spreadsheet. When you are done, the spreadsheet should contain only two
entries.
5. Select Calculations... from the Setup menu ( ) and specify an Energy
calculation and B97X-D Density Functional method with the 6-31G*
basis set. Also, specify Hartree-Fock and 3-21G from the Start frommenu. Make certain that Global Calculations at the bottom of the dialog ischecked to specify that the dialog settings apply to both conformers. Click on
Submit.
6. When completed, examine the conformer energies. Select Spreadsheet
from the Display menu. Click on the Add button at the bottom of the
spreadsheet and click on the rel.E (kJ/mol) button from the Molecule List
tab. Click on the spreadsheet to release the Add dialog. What is the energy
needed to go from the global minimum to a conformer poised to undergo
Claisen rearrangement?
7. Close all open documents and dialogs.

Chapter 13223

2 hours
13

C Chemical Shifts Depend on Conformation

At normal temperatures, the time for nuclear spin relaxation is very long
relative to time required for equilibration among conformers. This meansthat for each of the carbon chemical shifts in the NMR spectrum of a flexible
molecule, 13C, will be a weighted average of the shifts NMR of theindividual conformers,13Ci.
C = Σi ωi13Ci

13

The weight, ωi, is given by the Boltzmann equation, and depends on its
energy, εi (relative to that of the lowest-energy conformer, ε0) and on
temperature, T. Summation is over all conformers (including the lowestenergy conformer), gi is the number of times that conformer i appears in theoverall distribution and k is the Boltzmann constant.
ωi = gi exp - [εi - ε0/kT]/Σj {exp - [εj - ε0/kT]}In practice, conformers that are 10 kJ/mol or more above the lowest- energy
conformer make a negligible contribution to the total (at room temperature).
However, in order to actually know which conformers are important and toconstruct a proper Boltzmann average, it is necessary to examine all ofthem.
In this tutorial, you will use the protocol first introduced with Spartan’18
to calculate the 13C NMR spectrum of limonene. This comprises two parts,
the first a multi-step protocol starting from MMFF molecular mechanics
and ending with a series of large basis set density functional calculations to
obtain “accurate” Boltzmann weights, and the second a set of small basis
set density functional calculations to obtain 13C chemical shifts. The twoparts are then combined to produce a Boltzmann averaged 13C spectrum.
1. Build or sketch limonene.

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2. Enter experimental 13C chemical shifts (shown above) either on thesketch or 3D model. If you choose to add to the sketch, select Edit Sketch( ) from the Build menu and then click on (1H/13C) from the row of icons
above the sketch pad. Click in turn on each carbon, click inside the box thatappears to its right, use the number pad that comes up to type in the chemical
shift and click on Enter. If you choose instead to add to the 3D model, selectExpt. Chem. Shifts [1H/13C] from the Expt. Data menu. As with the sketch,click in turn on each carbon, click inside the box that appears to its right, use
the number pad to type in the chemical shift and click on Enter.
3. Select Calculations... from the Setup menu, NMR Spectrum (Density
Functional)*, B97X-D and (6-31G*)* from the top three menus to theright of Calculate and B97X-V/ 6-311+G(2df,2p)[6-311G*] Weighted
Average and B97X-D/ 6-31G* from the bottom two menus. Click on
Submit.
4. The calculation may require an hour or more.** When completed, bring up
the Properties dialog (Display menu) and click on the NMR tab. Statistics
related to the fit between calculated and experimental 13C shifts are provided
on the left at the center of the dialog that results, specifically RMS, Max
Absolute and Mean Absolute errors. If the Boltzmann Average tab ischecked, these correspond to a Boltzmann weighted average overconformers. If the Best Fit tab is checked, they instead correspond to theconformer which best fits measured values. You will see that

* Pre-selected menu items cannot be altered.
** If you don't want to wait, a pre-calculated file is available. For Windows, this directory is found in
Program Files/Wavefunction/Spartan24. It must be copied to another location available to the userprior to opening it in Spartan. For Linux, this is found in the directory where Spartan was installed. For
Macintosh, this is located at the top level of the Spartan’24 disc image.

Chapter 13225

both measures provide good concurrence between calculated andmeasured 13C chemical shifts.
Spartan provides two different ways to assess the fit between
calculated and measured 13C chemical shifts. The first and clearly themore rigorous measure involves constructing a proper Boltzmannweighted average. This requires accurate conformer energies andassociated Boltzmann weights which in turn functionals that takeproper account of long-range interactions such as the B97X-V
functional and large basis sets such as 6-311+G(2df,2p). While
such an approach can be applied to medium-size organic moleculeswith moderate conformational flexibility, it can involve many hours
of computer time. The second approach only requires that a set of“good” conformers be identified, and from among these selects theconformer 13C chemical shifts for which best fit measured values.
Lacking the need for accurate Boltzmann weights, it can rely on
simpler functionals such as B97X-D where long range
interactions are dealt with empirically and smaller basis sets suchas 6-31G*, and as a result, is an order of magnitude faster.

5. The structure that has been returned corresponds to that with the lowest
B97X-V/6-311+G(2df,2p)[6-311G*] energy (the leading contributor in
the Boltzmann average). A secondary file, limonene_Conf, has beencreated (but not opened). This contains NMR chemical shift calculations
for all conformers.
6. Close any open documents and dialogs.

Chapter 13226

2 mins

Gleevec. Protein Bound vs. Free Conformer

Gleevec (Glivec, Imatinib) is a protein kinase inhibitor used in anticancer
therapy. It specifically targets a protein kinase coded for in the rogue gene bcrabl. Several crystal structures for gleevec docked in protein kinases areavailable in the PDB. In this tutorial, you will examine one of them* toestablish whether or not the conformation of gleevec in the protein is identical(or similar) to that of the free (gas- phase) molecule, and if not, what energy
penalty is to be paid to adopt the protein-bound conformation. The next
tutorial will return to this same structure and extract a pharmacophore(gleevec’s footprint).
1. Retrieve a protein structure from the PDB. Select Access PDB Online...
from the File menu ( ). Type 1opj into the box to the right of PDB ID andclick on Open.
If you are not online, you may skip this step as the structure isavailable as 1opj in the medicinal chemistry sub-directory(tutorials directory).**The protein will be represented by a ribbon model. Red sections correspondto parts of the chain that are  helices, while blue
* B. Nager et al, Cell, 112, 859 (2003): PDB identification 1opj.
** For Windows, this directory is found in Program Files/Wavefunction/Spartan24. It must be copied toanother location available to the user prior to opening it in Spartan. For Linux, this is found in the directory
where Spartan was installed. For Macintosh, this is located at the top level of the Spartan’24 disc image.

Chapter 13227

regions correspond to parts that are  sheets (the remaining regions are green).
A Ramachandran plot (the  and  torsional angles connecting the individual
amino acids) allows you to see the clustering of  helices and  sheets. To
display, select Ramachandran Plot from the Model menu ( ). The
colors of the dots in the resulting plot map one-to-one with the colors of theribbon model. When you are done, click on to remove the plot.
The colors on the ribbon display may be modified, by selecting
Configure... from the Model menu ( ) and clicking on the
Ribbons tab. Coloring By Residue will give each amino acid its
own unique color.

The protein you have brought in from PDB incorporates two sets of boundmolecules, depicted in the model as two sets of translucent spheres. Gleevec
is the larger of the two incorporated molecules and is designated by its PDB
HET code STI.
2. Select Extract Ligands from theFile menu ( ). Select (click on) one of
the gleevec molecules inside the protein
structure and click on the Extract
Ligands button at the bottom right of thescreen. This leads to the Extract
Ligands dialog.
Check Ligand Structures under Include and Grow Hydrogens under
Extraction Filters inside the dialog (if other options are selected, removethem) and click on OK.
3. A ball-and-spoke model for gleevec will appear on screen. (You no longer
need the protein; select and close it.) Put a copy of gleevec on the clipboard.
With the molecule selected, choose Copy from the Edit menu or right clickon the background and select Copy from the menu that appears.
4. Select Build New Molecule (not New Build) from the File

Chapter 13

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menu (). Select Clipboard from the organic model kit and click
anywhere on screen. Click on. You now have two copies of gleevec in asingle document. You can step between them using the step buttons at thebottom left of the screen.
5. Select the first copy; select Calculations... from the Setup menu ( ).
Equilibrium Geometry from the top left menu to the right of Calculate andMolecular Mechanics and MMFF from the two bottom menus. The
conformation will not be altered, but bond lengths and angles will be
optimized.
Structure optimization is necessary in order to establish the energy
difference between protein-bound and free conformations ofgleevec. The resolution of protein X-ray crystallography is notadequate to establish bond lengths and angles to chemical
accuracy.

Remove the checkmark from Global Calculations at the bottom of the
dialog to signify that your choice (geometry optimization) only applies tothis copy of gleevec. Click on OK (not on Submit).
6. You will use the second copy of gleevec as a starting point for a
conformational search. First, remove some degrees of conformational
freedom in order to shorten the computer time for the conformational search.
With the second copy, select Set Torsions from the Geometry menu ( ).
Your model will be augmented with yellow cylinders and circles to designate
flexible bonds and rings, respectively. Remove the markers (circles) on thepiperazine ring by double clicking on each in turn. The conformation of thepiperazine ring will not change during the search. The model should now
appear as below.

Chapter 13229

7. Select Calculations... from the Setup menu ( ). Select Equilibrium
Conformer from the top left menu to the right of Calculate and (as before)
Molecular Mechanics and MMFF from the two bottom menus. Click on
Submit, and provide the name gleevec protein bound vs. free conformer.
8. When the calculations have completed (perhaps minutes), selectSpreadsheet from the Display menu ( ). Click inside leftmost the cell forthe second molecule (the one on which a conformational search was
performed) then click inside the header cell for a blank data column. Click on
Add at the bottom of the dialog and select Rel. E from the scroll box in the dialog
that appears and kJ/mol from the Energy menu. The relative energy of theprotein bound conformer is provided in the spreadsheet. Is it close to zeromeaning that the protein-bound conformer will be present in significant
amount in a sample of free gleevec?
9. Close gleevec protein bound vs. free conformer and any open dialogs.

Chapter 13230

15 mins

HMBC Spectrum of Cantharidin
Cantharidin provides a very simple example for the way in which an HMBC
spectrum is set up and displayed and the results compared with assigned
experimental CH couplings. The molecule is rigid eliminating concerns
about conformation and its structure has been confirmed by X-ray
crystallography.
1. Build or sketch cantharidin. Enter both experimental proton and 13C
chemical shifts as shown below (the 1.24 in parenthesis following the 13C
shift of 12.7 for the C10 and C11 are the associated proton shifts).*

2. In 3D mode, select Expt. Chem. Shifts from the Expt Data menu or
click on each chemically unique carbon and hydrogen, click on Edit to theright of Expt. Chem. Shifts at the bottom right of the screen, type in thechemical shift in the number pad and click on Enter.
3. Observed 2 and 3-bond CH couplings are as follows (seenumbering above):
H6
H6
H7
H10
*

C4, C5, C7, C9
C5, C6, C7
C5, C6, C7
C2, C4, C9

Experimental data from: D. Sicker, K-P. Zeller, H-U Siehl and S. Berger, Natural Products, Isolation,
Structure Elucidation and History, Wiley -VCH, Wenheim, Germany, 2018.

Chapter 13

231

In 3D mode, select CH Couplings from the Expt. Data menu or click on[JCH]. Clicking on one of the four hydrogens noted on the previous page, forexample H6 will result in all carbons where 2 or 3-bond CH coupling might
be observed being highlighted. Click on one of these, C4, C5, C7 or C9, in
this example, will draw an arrow from hydrogen to carbon. Click again on
the same hydrogen to specify the couplings for the other carbons. Repeat
for the remaining hydrogens. Your 3D model (tube representation) shouldlook as follows.

4. Cantharidin is rigid, so the multi-step procedure involving different
possible conformers is not necessary. Select Calculations from the Setup
menu and specify calculation of equilibrium geometry using the ωB97XD/6-31G* model. Check NMR to the right of Compute and selectCalculated (Fermi Contact) from the menu to the right of Coupling
Constants. You have requested both chemical shifts and coupling constants
to be calculated, the latter using the so-called Fermi contact approximation.
This is nearly as accurate and significantly faster than the full coupling
constant calculation. Click on Submit.
5. When the job completes (a few minutes), select Spectra from the
Display menu (or click on), click on
at the top left of the spectra
display that occupies the lower half of the screen and select. Click
again onand select. Calculated and experimental HMBC
spectra will be superimposed and appear at the center of the spectra display
area. Click on to bring them onto the main screen and then click on
atthe top right of the spectra display area to dismiss it.

Chapter 132326. Expand the spectra on the main screen by first clicking on either the left
vertical axis (13C) or the bottom horizontal axis (1H) and then using thescroll wheel. Alternatively, on touch screen devices, pinch your fingers
together after selecting an axis. The scale of the 13C axis (0 - 200 ppm) is OK,
but change the proton axis to range from 0 - 5 ppm. Click on the axis toselect and enter 5 to replace the default value of 10 ppm and press Enter.
The HMBC plot should appear as follows.

The crosses represent experimental couplings and the open circles
calculated couplings. Orange circles designate 3 bond couplings andmagenta circles designate 4-bond couplings. You can see details (proton and13
C chemical shifts in ppm and, in the case of calculated values, coupling
constants in H3) by clicking inside the circles or at the center of the crosses.
7. Close all open files and dialogs.

Chapter 13233

5 hours

Linalool: Calculating the NMR Spectrum of a Flexible Molecule
Spartan provides two different pathways, each supported by an automatedmulti-step protocol, for calculating proton and 13C spectra as well as 2D
COSY and HMBC spectra of flexible molecules. The more rigorous andmore costly in terms of required computation involves construction of aproper Boltzmann-weighted average, in practice, calculation of accurate
Boltzmann weights for all accessible conformers followed by calculation ofchemical shifts and (optionally) coupling constants for each of theconformers. Boltzmann weight calculation is the limiting step as it requires
density functional models that account explicitly for long-range van der
Waals or dispersive interactions coupled with large basis sets. Calculationsof moderate size (MW in the range of 500 amu) with 100 or more
conformers can easily consume many hours on present generation personal
computers.
The second less costly and less rigorous approach replaces the need for
accurate Boltzmann weights with the less demanding task of identifying the
low-energy conformers and then choosing from among these conformers
the one that best fits the experimental NMR data. Of course, this requiresthat the experimental data exist! Simpler density functional models withmuch smaller basis sets are suitable.
In this tutorial, you will calculate 13C chemical shifts for the natural productlinalool using the simpler procedure and compare results both toexperimental values as well as those obtained from Boltzmann averaging.
1. Build or sketch linalool. Enter the 13C shifts (see figure below). SelectExpt. Chem. Shifts from the Expt. Data menu, click on each chemicallyunique carbon, click on Edit to the right of Expt. Chem. Shifts at thebottom right of the screen, type in a chemical shift using the number padand click on Enter. When you are done, click on .

Chapter 13234

2. Open the Calculations dialog (Calculations from the Setup menu)
and select NMR Spectrum (Density Functional), ωB97X-D and (631G*) from the four top menus to the right of Calculate and ωB97X-D/631G* and 3-21G from the two bottom menus. This specifies calculationof energies and chemical shifts from the ωB97X-D/6-31G* density
functional model using Hartree-Fock 3-21G equilibrium geometries. Clickon Submit.
3. The job will take several hours. When completed, bring up the NMR
properties dialog (Properties from the Display menu and click on NMR).
Click on the Best Fit tab at the center left of the dialog to see how well the
calculated shifts fit the experimental data. RMS is perhaps the best measure
where values less than or close to 2 ppm indicating a good match.
4. The calculation you performed selects the conformer that best fits theexperimental NMR data rather than constructing a proper Boltzmannweighted average. You can do the latter if you wish (it will requiresignificantly more computer time) by changing the entries in the two bottom
menus to the right of Calculate in the Calculations dialog to B97X-V/6311+G(2df,2p) [6-311G*] Weighted Average and B97X-D/6-31G*.
When this job completes, you need to select the Boltzmann Average tab in
the NMR properties dialog instead of the Best Fit tab. The errors should be
identical or similar to:
RMS 1.88
Max Absolute 3.36
Mean Absolute 1.60
Both procedures provide a good description in this case.
5. Close any Spartan documents and open dialogs.

Chapter 13235

1 hour

Anethole: Boltzmann Averaging 13C Chemical Shifts
The natural product anethole provides a very simple illustration of obtaining
13
C chemical shifts as a Boltzmann-weighted average over different
conformers.

The molecule is small and there are only two conformers, so the task can becompleted using only a few minutes of computer time.
1. Build or sketch anethole. Enter 13C experimental chemical shifts (provided
in the drawing above). Select Expt. Chem. Shift from the Expt. Data menu
and in turn click on each unique carbon*, click on Edit to the right of Expt.
Chem. Shift at the bottom right of the screen, use the number pad to enterthe value of the shift and click on Enter.
2. Inside the Calculations dialog (Calculations from the Setupmenu), select NMR Spectrum, (Density Functional),
B97X-D and (6-31G*) from the four top menus to the right of Calculate
and B97X-V/6-311+G(2df,2p)[6-311G*] Weighted Average andB97X-D/6-31G* from the two bottom menus. You have requested that
Boltzmann weights be obtained in a multi-step procedure for the (two)conformers of anethole using the B97X-V/6-311+G(2df,2p)[6311G*]//B97X-D/ 6-31G* density functional model, and following this,chemical shifts for the conformers be calculated with the empiricallycorrected B97X-D/6-31G* density functional model, allowing that the
Boltzmann average to be obtained. Click on Submit at the bottom of the
dialog.
* Spartan detects identical atoms (in this example the two carbons ortho and the two carbonsmeta) to the methoxy group. You only need to enter experimental data for unique atoms.

Chapter 13236

3. When completed (probably 10-20 minutes), bring up the NMR properties
dialog (Properties under the Display menu and click on the NMR tab. Make
sure that Boltzmann Average tab (not Best Fit) tab is selected. The
reported error statistics indicate an excellent fit of calculated toexperimental 13C shifts.
4. Close any open Spartan documents and dialogs.
several hours

Ambiguine H. DP4 Analysis to Assign Stereoisomer
The structure assigned to the natural product ambiguine H is shown below.
It contains four stereocenters, two of which designated R dictate thedisposition of substituents attached to the incorporated trans-decalin
bicyclic.

In this tutorial, you will use the DP4 metric to confirm or refute theexperimentally assigned stereochemistry about these two centers. This
involves chemical shift calculations on the four distinct structures each ofwhich is conformationally flexible.
1. Build or sketch ambiguine H. To enter the experimental 13C chemical
shifts, select Expt. Chem. Shift from the Expt. Data menu. Click on eachcarbon in turn, click on Edit to the right of Expt. Chem. Shift at the bottom
right of the screen, use the number pad to type in a value and click on Enter.

Chapter 13237

2. Rotatable bonds should be properly marked, but it is a good idea to check.
Select Set Torsions from the Geometry menu. The three bonds shown in
the figure below should be marked (encircled with yellow cylinders). If any
are not, double click on the bond to select. If on the other hand, any otherbonds are selected, double click to deselect.

3. Make a list of the four stereoisomers. Select Generate Isomers from theGeometry menu. In turn, click on each of the two stereocenters bearing
substituents. They will be encircled in green (see figure below). Click on
Generate list to the right of Isomers at the bottom right of the screen. SelectNew Document from the dialog that appears and click on OK. The four
isomers (including the RR stereoisomer that you started with) will be placedin a new Spartan document. Click on Save (File menu) and name it
ambiguine H isomers. It’s a good time to close the original document.

Chapter 13

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4. Bring up the Calculations dialog (Calculations from the Setup menu)
and select NMR Spectrum, (Density Functional), B97X-D and 631G* from the four top menus to the right of Calculate and B97X-D/631G* and HF/3-21G from the two bottom menus. What you have requested
is done “under the hood” in two steps. First, NMR spectra for all conformers
for each of the four stereoisomers are calculated, allowing the conformer
for each isomer that best fits the experimental 13C chemical shifts based on
its DP4 score to be identified. Second DP4 scores for this set of “best” areevaluated. Make certain that Global Calculations at the bottom of the dialog
is checked before you click on Submit.
5. The job will take several hours to complete. It involves calculations on as
many as 108 molecules (up to 27 conformers on each of the 4stereoisomers). When it is done, bring up the NMR properties dialog(Properties under the Display menu and click on the NMR tab). Step
through the four isomers and identify the one with the highest DP4 score. Is
this the one that has been assigned based on its NMR spectrum? Are anyother isomers competitive?
6. Close all open Spartan documents and dialogs.

Chapter 13239

Chapter 14“Dry Labs”:
Using the Spartan Spectra andProperties Database
The tutorials in this chapter comprise examples where structures, energies,
spectra and other properties can be extracted from the Spartan Spectra andProperties Database doing away with the need for new quantum chemical
calculations.
The Spartan Spectra and Properties Database (SSPD) is a collection ofmolecular structures, spectra and diverse properties initially available from asingle density functional model (EDF2/6-31G*). With the release of
Spartan’16 the computational model has shifted to a new standard (ωB97XD/6-31G*), which provides superior quality data (although is also morecomputationally costly). Both models are available. The ωB97X-D/6-31G*
will be the default model, but users are able to change to EDF2/6-31G* if
desired.
SSPD comprises over 300,000 molecules, each of which includes a wide
range of molecular properties including a selection of QSAR descriptors(EDF2/6-31G* only), IR Spectra (EDF2/6-31G* only), NMR spectra, andthe wave function, allowing “on-the-fly” generation of molecular orbitals,
electron densities and other graphical surfaces as well as the electrostatic
potential map and other property maps. In short, SSPD provides a rich sourceof diverse information for a large selection of molecules.
The emphasis of SSPD on only two theoretical models (with theωB97X-D/6-31G* model being favored) is a deliberate attempt to turnattention away from the characteristics of a particular model (and thequestion “which model is best”) and to focus on the chemistry at hand.
While the choice of the new standard, theChapter 13

240

B97X-D/6-31G* model, may be seen as a continued compromise between
accuracy and practicality, in fact, B97X-D/6-31G* provides high quality
results for a variety of properties that can be accurately measured, including
molecular geometry and NMR spectra. Further, both the T1 heat offormation and the B97X-V/6-311+G(2df,2p) energy are included in the
SSPD entry as a property. We believe that over the wide variety of molecules
considered, T1 provides as reliable an indicator of H 298 as the G3(MP2)recipe (which in turn is within measurable experimental error).
Collections such as the Spartan Spectra and Properties Database may be
used to eliminate the need to perform calculations that have already been
done. Taking this to the extreme, a database might serve as an exclusive
source of information, doing away altogether with the need for quantum
chemical calculations. From the instructional perspective (teaching aboutmolecular models and molecular modeling) this allows use of more
complex examples than might otherwise be practical due to time
constraints. The tutorials in this chapter fall into this category, and can bethought as the ultimate in molecular modeling “dry labs”.
To complete the tutorials in this chapter, SSPD needs to be available. Either
the sample version installed with all copies of Spartan and which comprises≈6,000 molecules or the full version which comprises >300,000 molecules
which needs to be separately downloaded.
Reactivity of Silicon-Carbon Double Bonds
With the exception of so-called phosphorous ylides, compounds
incorporating a double bond between carbon and a second-row element arequite rare. Most curious perhaps is the absence of stable compounds
incorporating a carbon-silicon double bond. This can be rationalized byusing local ionization potential and LUMO maps to compare the reactivitiesof olefins and silaolefins.
1. Build both 2,3-dimethyl-2-butene and tetramethylsilaethylene and put
into the same document. Start the second molecule with Build New
Molecule or Sketch New

Chapter 14

241

Molecule from the File menu instead of New Build or New Sketch.

2. Both molecules are in SSPD. Click on the name of whichever molecule
is selected at the bottom of the screen, confirm that the ωB97X-D/6-31G*
model is selected and click on the Replace button and then click on All.
3. Select Surfaces from the Setup menu ( ). First request a local
ionization potential map. Click on Add and select local ionization potential
map from the menu. Then request a LUMO map. Click on Add and select|LUMO|map from the menu. Surface generation is automatic and will takeonly a few seconds to complete.
4. Select Spreadsheet from the Display menu ( ) and check the box at the
far left for each entry in the spreadsheet. This allows simultaneous display ofboth molecules. Deselect Coupled from the Model menu ( ) to uncouple
the motions of the molecules. Position the two molecules side by side on
screen. Close the spreadsheet.
5. Inside the Surfaces dialog, select local ionization potential map.
Compare local ionization potential maps for the olefin and silaolefin,
recognizing that the more red the color, the lower the ionization potential andthe more susceptible toward electrophilic attack. Which molecule do you
conclude is likely to be more reactive toward an electrophile? Turn the local
ionization potential maps off by again selecting it. Select |LUMO|map toturn the LUMO maps on. Here, the more blue the color, the greater theconcentration of the LUMO and the more susceptible toward nucleophilic
attack. Which molecule do you conclude is likely to be more reactive toward
a nucleophile? Speculate why molecules which incorporate a silicon-carbon
double bond are chemically problematic.

Chapter 14242

6. Close all documents and any open dialogs.
Isomeric C5H8 Dienes
In addition to 2-methyl-1,3-butadiene, cis and trans-1,3-pentadiene(conjugated dienes) and 1,4-pentadiene (a non-conjugated diene), there arethree other dienes with the same formula: 3-methyl-1,2- butadiene, 2,3pentadiene, and 1,2-pentadiene.

1. Build or sketch all seven C5H8 dienes (place in a single document). Clickon the name of whichever diene is selected at the bottom of the screen. Make
certain that B97X-D/6-31G* is selected, click on Replace and finally clickon All from the dialog that results. This will substitute entries in SSPD for
all seven C5H8 dienes. Select Spreadsheet from the Display menu ( ) andexpand the spreadsheet to see all seven dienes. Select Properties from the
Display menu ( ) and make sure that the Molecule tab in the resulting
dialog is selected. Click on the
buttons to the left of both Expt. Heatand T1 Heat in the Molecule Properties dialog. This enters theexperimental heat of formation (from the NIST database) as well as the value
obtained from the T1 thermochemical recipe into the spreadsheet. The T1 heatof formation will generally provide a more accurate account of relative
stability than available from the B97X-D/ 6-31G* model itself.

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The T1 model is presently defined only for uncharged, closed-shellmolecules comprising H, C, N, O, F, Si, P, S, Cl and Br only. T1heats of formation are not available for the other molecules in SSPD(~2% of the total).

2. First verify that the T1 model correctly reproduces the ordering ofexperimental heats. Then use the T1 heats to answer the following
questions:
What is the difference in stability (heat) between the best of the three
conjugated dienes and 1,4-pentadiene? What is the approximate energy gain
due to conjugation? What is the difference in stabilities between the best of
the substituted allenes and the best of the conjugated dienes?
3. There are several other C5H8 isomers in addition to the dienes discussed
above, a number of which will be in SSPD (many more in the full version
than in the sample set). Use any one of the seven dienes as a query. SelectDatabases from the Search menu ( ) and click on the SSPD tab in the
dialog that results. Click on to the right of the Search button in the SSPD
dialog and select Isomer under Search By in the Search Options menu that
results. Click on the Search button. Select several (or all) of the non-dieneisomers, by clicking on them in the list at the right of the dialog while holding
down the Ctrl key. Click on to the right of the Retrieve button, then clickon Current Document in the dialog that results. Close the Databases
window. Bring up the spreadsheet (Spreadsheet from the Display
menu ( ). Note that not all the experimental heats of formation areavailable. In the NIST database, experimental heats of formation exist for
only 2,000-3,000 molecules. According to the T1 model, are any of the nondiene isomers more stable than the best diene?
4. Close all documents and open dialogs.

Chapter 14

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244

Using Infrared Spectroscopy to Identify an Unknown Ethyl Benzoate
Derivative
Unlike NMR spectra (at least 13C spectra) infrared (IR) spectra are richin detail. Some chemists would view this as a negative, in that thecomplexity of an infrared spectrum masks its connection with the threedimensional molecular structure. Others might see complexity as a positive,
providing a detailed pattern or fingerprint with which to identify a molecule.
This reflects the different ways that chemists actually use NMR and infrared
spectroscopy. NMR is most commonly employed to assign structures of newmolecules whereas IR is most commonly used to identify previously
characterized (known) molecules.
Extensive databases of experimental infrared spectra exist, andsophisticated programs have been developed to search these databases formatches to unknown spectra. Spartan is able to search the public NIST
database of experimental infrared spectra. Infrared spectra calculated fromdensity functional models and adjusted to account for known systematic
errors in frequencies and for finite temperature, generally closely match
experimental spectra. This suggests that they might be used in lieu ofexperimental spectra to identify unknowns. This tutorial illustrates thepoint, attempting to identify which of a series of meta-substituted ethyl
benzoates contained in the Spartan Infrared Database (SIRD) best matches
the infrared spectrum of an unknown molecule.
SIRD uses the infrared spectra contained in the Spartan Spectra andProperties Database (SSPD) that have been obtained using the EDF2/ 631G* model. Infrared spectra from the ωB97X-D/6-31G* model are notpresently available in SSPD. The fact that there are two different tabs
simply reflects the different search paradigms (spectra matching for SIRD
vs. substructure matching for SSPD).

1. Build or sketch ethyl benzoate. Select Structure Query from the Searchmenu ( ) and click on one of the free valences on the phenyl ring that ismeta to the ester group.

2. Select Databases from the Search menu ( ) and click on the SIRD tabat the top of the dialog that results. Size the dialog to occupy the greater partof the screen. Click on Select Spectrum, move to the using SSPD
subdirectory under the tutorials directory*, click on unknown ethyl
benzoate and click Open. In a few seconds, the experimental infrared
spectrum of the unknown will appear at the top right of the dialog. A list of
the frequencies for all peaks may be found under Unknown: immediately
to the left is the spectrum. This has been obtained by fitting the experimental
spectrum to a Lorentzian function. You can obtain the frequency of a line in
the spectrum using the yellow measurement bar. Position the cursor on topof the bar, hold the left button and move the mouse left or right until the bar
is over the peak.
3. You can carry out your search with nothing other than the unknown
spectrum (see the optional part of this tutorial), or you can restrict it using
structural or other information that you have. Assume that you know that theunknown is a meta-substituted ethyl benzoate. Click on the Filters button
and then click on Copy Current Molecule at the top left of the Search
Filters dialog that results. Click on OK to exit the dialog. You haverestricted the search to meta-substituted ethyl benzoates, that is, examine
only molecules that contain this particular substructure (ethyl benzoate
substituted in the meta position). Click on the Search button and wait for the
search to complete. Hits resulting from the search appear at the bottom of
the SIRD dialog, in* For Windows, this directory is found in Program Files/Wavefunction/Spartan24. It must be copied
to another location available to the user prior to opening it in Spartan. For Linux, this is found in the
directory where Spartan was installed. For Macintosh, this is located at the top level of the Spartan’24
disc image.

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numerical order starting from the best (lowest Score). As you click on each,the corresponding calculated infrared spectrum will be superimposed onto
the experimental spectrum (of the unknown) at the top left of the display.
Propose a structure for the unknown.
4. Remove the substructure filter and repeat the search. Click on the Filters
button, click on the Clear button at the top left of the Search Filters dialog
and click on OK. Click on the Search button. Unlike searches ofexperimental databases where spectra are directly compared, each of thecalculated spectra in the database are adjusted for frequency scale and peakwidth as it is compared to the unknown. Removing the substructure filter
greatly increases the number of spectra that need to be examined. Does themeta substituted ethyl benzoate that came in at the top in the previous
search, also come in at or very near the top in the full search?
Be patient. A search of the full database will require significantly
more computer time than the search of the 6,000 molecule sample
database supplied with Spartan, simply because it contains many
more molecules.

5. Close all documents and any open dialogs.
Infrared Spectra of Short-Lived Molecules
While infrared spectroscopy is by no means as formidable a tool as NMR
for elucidating the structures of molecules, it does offer significant
advantages which can make it the method of choice in some instances. It is
more sensitive, meaning that it can be used to detect transient species, forexample, molecules trapped in an inert matrix at very low temperature. On
the practical side, an infrared spectrometer is inherently simpler (morerobust) and can be put into a much smaller package than an NMR
spectrometer. This means that the spectrometer can be brought to thesample rather than the other way around. Imagine, putting an NMR
spectrometer on the Mars rover! The problem is that IR spectroscopy unlike
NMR typically does not provide an unambiguous structure. However, aChapter 14247

close match to a calculated spectrum may offer convincing evidence for theveracity of a particular structure (or a mismatch convincing evidence that a
structure is incorrect).
The infrared spectrum of an unknown C4H4 isomer shows strong
absorptions at 854, 1608, 2994 and 3080 cm-1. Possible structures include
but-1-yne-3-ene, butatriene, cyclobutadiene, methylenecyclopropene andtetrahedrane.

1. Build or sketch any one of these molecules. Select Databases from the
Search menu ( ) and click on the SSPD tab. Click on to the right of the
Search button, ensure that EDF2/6-31G* (only) is selected under Model
Filter and select Isomer under Search By: inside the Search Options
dialog and click on OK. Click on the Search button. Structures for all C4H4
isomers will appear in a list at the right of the Databases dialog. Retrieve
all of them to a new document. Click on to the left of the Retrieve button,
select New Document and click on OK. Click on each in turn while holding
down the Ctrl key. Click on the Retrieve button. Close the Databases
dialog.
2. Select Spectra from the Display menu ( ) and click on
at the top of
the resulting dialog. Click on(calculated IR spectrum). Movethrough the list to bring up the spectra for the other isomers. Which, if any,
calculated infrared spectrum of the C4H4 isomers best fits the unknown
infrared spectrum (with peaks at 854,1608, 2994 and 3080 cm-1)?
3. Close all documents and any open dialogs.

Chapter 14248

Using 13C NMR to Distinguish Structural Isomers
NMR spectroscopy, in particular 13C NMR spectroscopy, is arguably thesingle most important tool available to an organic chemist to establish
molecular structure. Obtaining an NMR spectrum is straightforward and thespectrum itself is very simple, comprising but a single line for each uniquecarbon the molecule. Because a mass spectrum is normally also available,
the molecular formula will be known, and assignment of the NMR supports
deciding among possible isomers. Chemical evidence (how the molecule
was made) can usually be counted on to eliminate some choices and tostrengthen the case for others. Still, pinning an NMR spectrum to aparticular molecule can be difficult and fraught with error.
NMR assignment problems can be reduced but not altogether eliminated byrequiring that both proton and 13C NMR spectra are consistent with aparticular structure. This is routine practice. In principal, ambiguity can beeliminated by cross-correlating the results of the 13C NMR with those of proton
NMR with an HMBC spectrum.
The fact that NMR spectra for reasonable size organic molecules may now
be routinely calculated in a few minutes to a few hours on a personal
computer costing $1000 or less raises the possibility for another tool toassist with spectral assignments. Whether this becomes common practiceultimately depends on the ability of calculations to obtain NMR spectra thatare sufficiently accurate to distinguish among the different isomers.
In this tutorial you will first compare calculated and experimental 13C
spectra of morphine. You will then examine calculated spectra for two
isomers, norcodeine and hydromorphone. The objective is to provide youwith an impression of the ability of the calculations to reproduce a 13C
spectrum for a known compound and more importantly, to challenge
structure assignments based on NMR spectroscopy.
1. Sketch morphine. Click on its name at the bottom of the screen and click
on Replace. If the name fails to appear, then you have made a mistake. In thiscase, select Edit Sketch from the Build menu ( ) and correct your sketch.

Chapter 14249

2. Select Spectra from the Display menu ( ) and click onin the bar at
the top of the plots pane. Selectfrom the palette. Click again on
and this time selectfrom the palette. Calculated and13experimental C spectra are now superimposed. Focus your attention on thefour “most isolated” resonances, specifically those with calculated chemical
shifts of 20.3 ppm, 59.7 ppm, 66.2 ppm and 95.2 ppm.
3. Sketch norcodeine and hydromorphone and retrieve both molecules fromSSPD.

4. Select Spectra from the Display menu ( ) and click onand selectfrom the palette. You only need to do this once if you put
norcodeine and hydromorphine in the same document. Does either
spectrum fit the experimental 13C for morphine (again focus on the four
isolated lines)?
5. Close all documents and any open dialogs.

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Using 13C NMR Spectra to Distinguish Stereoisomers
As mentioned in the previous tutorial, the combination of 1D and 2D NMR
spectra is almost always able to provide unambiguous assignment ofmolecular structure, including assignment of stereochemistry. However, as
noted, practical considerations (time on an expensive instrument) often
make 2D experiments (in particular HMBC) the exception rather than therule. Without the additional experiments, distinguishing stereoisomers
based on their 13C NMR spectra may be difficult experimentally, simply
because the alternatives are likely to be structurally very similar. For thesame reason, it is likely to be an ideal case for calculations, as comparisons
between molecules with similar structures should benefit from cancellationof errors. The bottom-line question is whether or not calculated 13C NMR
spectra are good enough to be able to clearly distinguish between
stereoisomers. This tutorial provides an illustration.
The hydroxyl CO bond in tibolone, shown below on the left, is gauche to themethyl group at C17 (the alkyne is anti), whereas it is anti (and the alkyne isgauche) in the stereoisomer shown on the right. You will use just three lines
from the experimental 13C spectrum to see if the calculations support orrefute its assignment as tibolone.

1. Sketch both stereoisomers and put into the same document. Click on thename of whichever molecule is selected at the bottom of the screen, click on
Replace in the dialog that results and click on All. NMR spectra for both
molecules are now available.
2. Focus on tibolone and Expt. Chem. Shifts [H/C] from the Expt. Data
menu. One after the other, enter the experimental chemical shifts for the
methyl group at C13 (12.7 ppm) and for

Chapter 14251the internal and external alkyne carbons (88.9 and 74.8 ppm, respectively).
2. Select Properties from the Display menu ( ), and click on the NMR
tab. Which isomer provides the better agreement in terms of both RMS,
mean and maximum absolute error scores as well as the DP4 score? Do thecalculations support or refute the experimental assignment, or are they
ambiguous?
4. Close the document and any open dialogs.

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Chapter 15
Using the Cambridge Structural
Database
The Cambridge Structural Database (CSD) is a well-organized and easilyaccessible depository of over 1 million experimental structures, almost
entirely from X-ray crystallography. It is available on a yearly subscription
basis, and when installed and licensed may be seamlessly accessed from
Spartan. Searches may be carried out based on substructure (as in SMD
and SSPD databases) as well as using molecule names. The tutorials in thischapter are intended to illustrate the interface and more importantly thetypes of questions to which the database may be used in conjunction withquantum chemical calculations. This requires access to the CSD.
Stable Tautomers of Phenol

1. Build or sketch 2,5-cyclohexadienone. You need to put an explicit
hydrogen on one of the free valences at C4. Select Structure Query ( )from the Search menu and click on all open free valences. Select Databases( ) from the Search menu and click on the CSD tab. Click on ( ) to theright of the Search button, select Organics under Filters and Structure
under Search By and in the Search Options dialog that results and click on
OK. Click on the Search button. Molecules that incorporate the 2,5cyclohexadienone substructure will appear at the right of the dialog. As you
select (click on) each of the entries its structure will appear at the left. The
simplest molecule among the “hits” is 3,5-di-tert-butyl-2,4-dichloro-

253

2,5-cyclohexadienone, identified as DOBHEH. Click on ( ) to theright of the Retrieve button, select New Document under Retrieve To andall entries under Retrieval Filters in the Retrieve Options dialog that results
and click on OK. Click on the entry (DOBHEH) and click on the Retrieve
button. The molecule will appear on screen in a separate document.
2. Bonds to hydrogen in X-ray crystal structures are almost always too short,typically by ≈0.1Ä, and should be adjusted before using as a start forquantum chemical calculations. To do so without affecting heavy-atom
positions, select Minimize from the Build menu ( ).
3. Build the enol tautomer (3,5-di-tert-butyl-2,4-dichlorophenol), placing itin the same document as the cyclohexadienone derivative. Select Build
New Molecule ( ) or Sketch New Molecule ( ) instead of New Buildor New Sketch. You now have structures for both tautomers in a single
document.
4. Select Calculations from the Setup menu ( ). Specify Equilibrium
Geometry using the ωB97X-D/6-31G* density functional model. Submit
the job. Which tautomer is favored? Are their energies close enough toallow both to be seen in an equilibrium mixture?
Binding to Iron Tetracarbonyl
An olefin bonded to iron tetracarbonyl may occupy either an equatorial oraxial position. Search CSD to see if one of the two if seen more frequently
than the other.

1. Build ethylene iron tetracarbonyl. For the purpose of the CSD search itdoes not make a difference whether the ethylene ligand is equatorial or axial.
Select Structure Query ( ) from the Search menu and click on all thefour free valence on ethylene.

254

Select Databases ( ) from the Search menu and click on the CSD tab. Clickon ( ) to the right of the Search button, select Inorganics* under Filters
and Structure under Search By and in the Search Options dialog that
results and click on OK. Click on the Search button. Molecules with four
carbonyl and one olefin ligand in CSD will be listed at the right of the dialog.
Does there appear to be a clear preference for equatorial over axial olefinbinding or vice versa?
2. Build the other conformer and put in the same document as the one thatyou used to query the CSD. Select Calculations from the Setup menu () and specify calculation of equilibrium geometry with the ωB97X-D/631G* density functional model. Make sure that Global Calculations ischecked. Submit the job. Execution will take several minutes. Whichconformer is favored and by how much? Is your result consistent with what
you found (or didn't find) in the CSD search?
Luminol
Several reasonable tautomers may be drawn for the luminol, four of which
are shown below.

Which is the most stable tautomer? Which if any are represented by crystal
structures in CSD?
1. In turn, draw or build each of the four tautomers. Provide explicit
hydrogens (replacing free valences) for atoms that are involved in thetautomerization. Select Structure Query ( ) from the Search menu andclick on all free valences. Select Databases ( ) from the Search menu
and click on the CSD*

This limits the search to about half of CSD with a corresponding reduction in search time.

255tab. Click on ( ) to the right of the Search button, select Organics under
Filters and Structure under Search By and in the Search Options dialog
that results and click on OK. Click on the Search button. For which
tautomer(s) do you find crystal structures? Is luminol itself among them?
2. Obtain equilibrium geometries for each of the four tautomers using theωB97X-D/6-31G* model and follow these with energy calculations with theωB97X-V/6-311+G(2df,2p) model. You can do this in a single step. SelectCalculations from the Setup menu. Select Energy, Density Functional,
ωB97X-V and 6-311+G(2df,2p) from the menus to the right of Calculate
and Density Functional, ωB97X-D and 6-31G* from the menus to the rightof Start From. Submit the job (geometry calculations followed by “better”
energy calculations on four molecules). It will take several minutes tocomplete. What is the lowest energy tautomer? Is it the same as found in the
crystal? Are any other tautomers low enough in energy to contributesignificantly to the properties of luminol?
Tetrahedrane and Cyclobutadiene
The C4H4 isomers, tetrahedrane and cyclobutadiene, are among the mostunlikely of hydrocarbons. It is hard to imagine a molecule that is morestrained than the former while the latter is the prototypical antiaromatic
molecule. Use the CSD to see if derivatives have actually beencharacterized.

1. Build cyclobutadiene. Select Structure Query ( ) from the Searchmenu and click on all open free valences. Select Databases ( ) from the
Search menu and click on the CSD tab. Click on ( ) to the right of the
Search button, select Organics under Filters and Structure under Search
By and in the Search Options dialog that results and click on OK. Click on
the Search button.

256

2. Repeat the process for tetrahedron.
3. Identify the simplest system that is common to both cyclobutadiene andtetrahedrane, that is, one where the substituents are the same. Build the twomolecules (or extract the two from the “hits” on CSD. Calculate equilibriumgeometries for the two using the ωB97X-D/6-31G* model. SelectCalculations from the Setup menu and inside the dialog select Density
Functional, ωB97X-D and 6-31G* from the menus to the right ofCalculate. Submit the job (two molecule). It will require several minutes tocomplete. Which molecule is more stable?

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Section V
Features and Functions
This section describes the functions available under the menus incorporated
into Spartan’24, and is intended to serve as a general reference to theprogram. The coverage follows the order of the menus presented in Spartan’suser interface: File, Edit, Model, Geometry, Build, Setup, Display, Search,Data, Options, Activities and Help. The functions and usage of each of themenu entries is described. Entries under the File, Model, Geometry and
Build menus deal primarily with the input and construction of both 2D
drawings and 3D structures and with their display and query. Entries under
the Setup menu specify molecular mechanics or quantum chemical models
as well as similarity analysis tools, designate what properties and spectra areto be obtained, request one or more graphical models and submit jobs forcalculation in the background. Entries under the Display menu accesscalculated quantities including calculated spectra, under the Expt. Datamenu - input of experimental IR/Raman, NMR (chemical shifts andobserved HH and CH couplings) and UV/visible data is available, and the
Search menu accesses databases of calculated information. Entries under the
Options menu set program defaults and user preferences, designate paths todatabases of calculated and experimental information, control job queues,
designate available servers for remote calculation and control access to
Spartan as a computational server.
The chapters in this section provide only limited commentary about theperformance and requirements of different computational methods and theutility of different graphical models. Additional information is provided
under Topics accessed from the Activities menu and in A Guide to
Molecular Mechanics and Quantum Chemical Calculations*, available asa PDF under the Help menu.
*

This reference was written in 2003, and as such it does not include a full assessment or descriptionof many of the newer computational features included in Spartan’24. In particular many functionals andbasis sets are not covered. An updated version is in the works.

258

Chapter 16
The File Menu
Operations under the File menu access a 2D sketch pad, model kits to build,edit and substitute molecules in 3D, the file system to read and write both
native and non-native files and the online PDB database of protein andmacromolecular structures. They allow text and on-screen graphics to beprinted and text and other files to be embedded into Spartan documents.

New Build ()

Brings up a model kit and clears the screen. Model kits are discussed in
Chapter 20.
New Sketch ()

Brings up the 2D sketch pane and clears the screen. The 2D sketch pane isdiscussed in Chapter 20.
Build New Molecule ()

Brings up a model kit and clears the screen. Build New Molecule259

differs from New Build, in that the resulting molecule is appended to theend of the document associated with the molecule (or sketch) that ispresently selected.
Sketch New Molecule ()

Brings up the 2D sketch pane and clears the screen. The menu bar is still
accessible, but only the View ( ) and Sketch New Molecule ( ) icons
are available. Sketch New Molecule differs from New Sketch in that theresulting sketch is appended to the end of the document associated with themolecule (or sketch) that is presently selected.
Delete Molecule ()

Deletes the selected molecule(s) from a document. Deleting the lastmolecule leads to an empty document.
Append Molecule(s)... ()

Appends one or more documents onto the end of the document that contains
the selected molecule. Append Molecule(s)... leads to a file browser fromwhich one or more documents need to be selected.*
Open... ()

Opens a file that contains all information associated with a particularmolecule or pharmacophore (or list of molecules and/or pharmacophores).
In addition to native (.spartan) files (documents)* Alternatively, molecules may be appended onto an existing document either by copy/paste operations using
the clipboard or by dragging from an external window. Both require that the spreadsheet associated withthe destination document be open on screen.
To copy a molecule open on screen onto the clipboard, first select (click on) it, and then select Copy fromthe Edit menu. Alternatively, click on its label in its spreadsheet (in the leftmost column), and then selectCopy from the Edit menu. The latter permits several molecules to be selected (and copied) at once using
the Shift and Ctrl keys in the usual manner. Once on the clipboard, the molecule or molecules may be
moved to the destination list by clicking on an empty row header in the spreadsheet (for the destination
document), and then selecting Paste from the Edit menu.
To copy a document from an external window, drag it onto the open spreadsheet (associated with thedestination document) inside of Spartan. Several documents can be dragged at once using the Shift andCtrl (Command key for Macs) keys in the usual manner.

260

including 2D sketch files, supported are files containing 2D drawings:
CambridgeSoft (ChemDraw) CDX (.cdx), and MDL SDF (.sdf)*, SKC(.skc), and TGF (.tgf), files containing 3D structures: MacroModel (.mac),
SYBYL Mol (.mol), SYBYL Mol2 (.mol2), and PDB (.pdb), crystallographic
Information (.cif), and files containing 1D “strings”: SMILES (.smi) andInChi (.inchi). Finally, infrared, Raman, NMR and UV/visible spectra may
be input (discussion of file formats is provided in Appendix J).
Experimental spectral data may also be brought into Spartan from the Datamenu (Chapter 24).
We use the word “file” to refer to any information contained in the “filesystem” (the disk on your computer) and the word “document” to referto files that are native to Spartan. Thus, an MDL SDF file may be read
into Spartan and then written as a document. Documents may contain
information on a single molecule or single pharmacophore or on acollection of molecules and/or pharmacophores. This collection isloosely referred to as a “list” or as a “spreadsheet” (in the context that itis presented in a spreadsheet).

Cartesian coordinates from any of these files (except spectra files which do
not necessarily contain coordinates) may be replaced by coordinates
generated based on atomic connectivity using Replace Coords. in the
Molecule Utilities dialog (accessible from Properties under the Display
menu; Chapter 22). Additionally, hydrogen atoms that are missing in the
input structure may be provided using Add Hydrogens from the Utilities
tab in the Molecule Properties dialog. Non-native files are normallyhidden from view, but may be seen by selecting All Files from the Files oftype menu at the bottom of the dialog.
Close ()

Closes the document containing the selected molecule, as well as any
document specific dialogs. If the document has not previously been saved,
a name is requested. If a previously-saved document has been altered,verification that the changes are to be saved is requested.

261

Open Recent Documents ()

Brings up a list of (at most) the ten recent documents. Clicking on one opens
the document.
Save () Save As... ()

Saves the document containing the selected molecule exactly as it appears
on screen. Opening the document will bring it on screen exactly as it waslast saved. If the document has not previously been named, Save behaves as
Save As.... Documents may be either be saved in native format or in one of
the formats listed under Open. In addition, bitmap (.bmp), JPEG (.jpg) andPNG (.png) graphics file formats are supported as is the Spartan Database(.spentry) format for creating custom databases (see Appendix H).
Selection is made under the Save as type menu in the Save As dialog.

Print ()

Selection leads to a dialog in order to designate a printer, specify
print layout and number of copies. It also allows printing to a file.

262

The contents of the spreadsheet (Spreadsheet under the Display menu;
Chapter 22) may be printed using Print from the contextual menu. The
results of a reaction energy calculation (Reactions... under the Display
menu; Chapter 22), may be printed using Print from the contextual menu.
Save Image As... ()

Saves your current molecule system, surface (etc.) as a high resolution PNG(.png), JPEG (.jpg) or bitmap (.bmp) file. Upon save, a new dialog willprompt for dimensions, allowing users to specify height and width (inpixels), PNG format allows saving with a transparent background.
Access PDB Online... ()

Provides access to the online Protein Data Bank (PDB)* comprising morethan 170,000 protein and nucleotide structures. Selection results in a dialog.

*

The PDB web address is https://www.pdb.org.

263

To access a PDB structure, enter the four character identification code in
the box to the right of PDB ID and click on Open. If the PDB entry contains
more than one structure (typical with protein structures obtained from NMR
spectroscopy) and/or the PDB ID yields more than one entry, all structures
will be returned in a single document. The literature reference as it appears
in PDB is available from Molecule Reference (Output under the Display
menu; Chapter 22).
A ribbon model of the PDB file will appear on screen.* A Ramachandranplot associated with a protein structure may either be drawn upon initial
retrieval of the PDB file by checking the box to the left of Draw
Ramachandran Plot or later from Ramachandran Plot under the Modelmenu (Chapter 18).
Extract Ligands ()

This allows “ligands” to be extracted from PDB files ** either as molecular
structures or as footprints (pharmacophores) that these structures leavebehind. The latter is separated into three parts, the first two of which
follow from the molecular structure of the ligand and the third which
follows from the immediate (protein or nucleotide) environment:(i) hydrogen-bond donor/acceptor sites and positive/negative ionizable sites(ii) hydrophobes(iii)excluded volumes

A pharmacophore can be constructed by requiring (i) to account forhydrogen-bonded and electrostatic interactions and (optionally) either (ii)or (iii) to account for steric interactions. Selection of (ii) leads to apharmacophore that is visually simpler, but selection of (iii) may provide
a more realistic picture.
Selection of Extract Ligands leads to a message at the bottom of thescreen.
* If the PDB file does not contain a macromodel structure suitable for rendering in ribbon
display, choose an alternate Model style from the Model menu.
** This capability is not restricted to files in PDB, but extends to files written in PDB format.

264

Ligands in PDB files are represented asa transparent space-filling model.
Clicking on a ligand selects it anddisplays the PDB HET name* atthe bottom of the screen (if a HETname is available). Multiple ligands
may be selected if desired by holding
down on the Ctrl key.
All ligands may be selected by clicking on the Select All Ligands button at
the bottom right of the screen. After one or more ligands have been selected,
clicking on the Extract Ligands button at the bottom right of the screen
brings up the Extract Ligands dialog. This allows selection of whether
Ligand Structures or one or more pharmacophore elements (HBA/HBD
and +/- Centers, Hydrophobe Centers including aromatic centers,
Excluded Volume Centers) or both structure and one or more
pharmacophore elements are to be abstracted from the PDB file, andwhether amino acid and/or nucleotide residues in close hydrogen-bondingor charge-charge contact with the ligand (Environmental Structures) areto be identified. It also allows the Protein/Nucleotide Structure (minus all
ligands) to be extracted.
In the case of extraction of Ligand Structures, the Extract Ligands
dialog also provides a set of utilities:(i)Grow Hydrogens
If checked, adds hydrogens wherever they appear to be missing, based on theactual geometry and on normal valence rules. This function is also available
under Grow Hydrogens in the Molecule Utilities dialog (Properties under
the Display menu; Chapter 22).

* This is the code given to small molecules that are associated with proteins/nucleotides in
PDB files.

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(ii)
Repair Bonds
If checked, attempts to fix bonding errors based on the actual
geometry in the PDB entry and on normal valence rules.
Clicking on OK at the bottom of the Extract Ligands dialog extracts theligand(s) or pharmacophore(s), placing them in a single new (unnamed)
document. Clicking on Cancel dismisses the dialog without ligand(pharmacophore) extraction.
Embedded Data ()

This allows non-native files, for example, Word, Excel or PowerPoint files, tobe embedded in a Spartan document. These may be associated either with anindividual molecule or with all the molecules (or both). Selection results inthe Embedded Data dialog, the upper half of which relates to document
level files and the lower half of which relates to molecule level files.

A file may be imported (at the document or molecule level) by clicking on theappropriate Import button. This leads to a file browser from which a file
may be selected. Once embedded in a Spartan document, a non-native file
may be exported by first selecting (clicking on) it and then clicking on
Export Selected. It may be deleted by first selecting it and then clicking on266

Delete Selected.
Note that applications cannot be launched from the Embedded Datadialog. They need to be copied outside prior to launching.
Exit ()

Exits Spartan, that is, clears the screen and closes all open documents. A
prompt is provided for each document that has not previously been saved.

267

Chapter 17
The Edit Menu
Operations under the Edit menu provide for undoing commands, copying
items to and from the clipboard, finding text and graphics, centering
molecules on screen and clearing the selected molecule.

Undo ()

Undoes the last operation from the Build and Edit menus and from the
Molecule Utilities dialog. Undoes transition-state formation and retrieval
from Spartan’s databases.
Cut (), Copy (), Paste ()

Cut moves the selected item to the clipboard and removes it from the
document. Copy copies the item to the clipboard. The item is unaffected.
Paste transfers the contents of the clipboard to the selected location. The
contents of the clipboard are unaffected. Among the important uses of the
clipboard within Spartan are:(i)Transferring on-screen graphics into other applications such as Microsoft
Word® and PowerPoint®.
(ii)
Temporary storage of a molecular structure for use in moleculebuilding.
(iii)
Transferring data between Spartan spreadsheets and between a
Spartan spreadsheet and other applications such as Microsoft Excel®.

268

(iv)
Making multi-molecule documents and/or transferring
molecules between documents.
Cut operations for (i) and (ii) require drawing a selection box. Position the
cursor slightly above and slightly to the left of the item to be transferred,hold down both left and right mouse buttons and drag the mouse to a locationslightly below and slightly to the right of the item to be transferred and release
both buttons. Copy operations for (i) and (ii) also refer to the contents of a
selection box if one has been drawn, or to the selected molecule if a box has
not been drawn. Copy operations from a Spartan spreadsheet refer to all
information associated with a molecule if selection is made on the header
cell of the leftmost column, but only to the selected (text) information if
selection is made on any other column. Further discussion relating to use of
the clipboard in molecule building is provided in Chapter 20 and formoving data in and out of the spreadsheet is provided in Chapter 22.
Select All ()

Selects all atoms in the selected molecule.
Find...(), Find Next ()

Find locates a text string defined in the Find dialog if an output window ora spreadsheet is selected, or a structure sequence defined on the clipboard if
an on-screen model is selected. Find Next locates the next occurrence of atext string or a structure sequence.
Center ()

Centers on screen all molecules in the document for which the selected
molecule is a member (only the selected molecule is displayed).
Clear ()

Clears (deletes) the structure and other information for the selected
molecule, and brings up a model kit. No information is actually removed
from the file system until the document is saved.

269

Chapter 18
The Model Menu
Structure styles available under the Model menu include: Line, Wire, Balland-Wire, Tube, Ball-and-Spoke, and Space-Filling (CPK) models. A
number of additional items can be toggled on or off, including display ofhydrogens, hydrogen bonding, R/S chirality labels, chemical functionaldescriptors (CFD’s), ribbon displays for biopolymers, and Ramachandranplots for proteins from the Protein Data Bank (PDB). Additional options areavailable for display of Labels (atom and residue), Objects (such as
constraint markers, frozen atoms, and user defined planes), Ribbons(custom color and style options) and CFD’s. Global Model toggles settings in
the Model menu between being applied to individual or to all molecules ina document, and Coupled toggles between manipulations applied toindividual molecules or to all molecules in a document. Configure sets default
labels for atoms, ribbons, CFD’s and a variety of other objects.

Only one model style Wire, Ball and Wire, Tube, Ball and Spoke, Space
Filling, Line or Hide) may be selected. The selected model270

is designated by being highlighted in the Model menu. Global Model,
Coupled, Hydrogens, Labels, Ribbons, Hydrogen Bonds, Chirality, andCFD’s operate as toggle switches.
All structure models, and graphics may be displayed either in orthogonal or
perspective projections. The latter may be valuable in helping to visualize
large molecules. Selection is done in the Settings tab (Preferences...
under the Options menu; Chapter 25). Both structure models andgraphics may be presented in 3D stereo. This may be controlled fromthe Settings tab or by toggling the 3 key on the keyboard. Stereographic
displays require perspective projections.

Wire ()

This represents the molecule as a wire model where the vertices represent
the atoms.

Wire Model

The bonds are drawn in two colors, one for each of the atoms making up thebond. Default atom colors are given in terms of Periodic Table in Figure 181. These are different than the defaults used in previous versions of Spartan.
You can return to the old scheme from the Miscellaneous tab (Preferences...
under the Options menu; Chapter 25). Select Classic under Atom Color
Set.
Atom colors apply globally (to all atoms of given type), and may be changed
using the Set Colors dialog (Colors under the Options menu; Chapter 25).
Colors of individually selected atoms may be set using the Atom Style dialog(Properties under the Display menu; Chapter 22). All models use the samecolor scheme for atoms, and provide for the same mechanism of changing
colors globally or individually.

271

Figure 18-1:Default Atom Colors

Ball and Wire ()

This represents atoms by small balls and bonds by wires.

Ball-and-Wire Model

The balls are color coded according to atom type, and the wires representing
bonds are drawn in two colors (as in wire models).
Tube ()

This is similar to the wire model, except that tubes instead of wires are used
to represent bonds. As with wire models, bonds are drawn in two colors.

Tube Model

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Ball and Spoke ()

This represents atoms by balls (the size and color of which depend on atomtype), and bonds by spokes.

Ball-and-Spoke Model

Bond (spoke) color is gray by default but it may be changed using the Set Colors
dialog (Colors under the Options menu; Chapter 25). Colors of individually
selected bonds may be set using the Bond Style dialog (accessible from
Properties under the Display menu; Chapter 22).
Space Filling ()

This represents the molecule as a composite of spheres, the radii of whichhave been chosen to approximate van der Waals contact distances. * Also
known as CPK models, space-filling models are intended to portray overallmolecular size and shape.

Space-Filling Model

Volume, surface area and polar surface area (PSA)** displayed under the
QSAR tab in the Molecule Properties dialog (accessible from Properties
under the Display menu; Chapter 22) correspond to a space-filling model.
* Default values for van der Waals radii may be changed from the VDW Radii dialog accessible from
Preferences under the Options menu (Chapter 25). Settings apply to all atoms of given atomic number.
** By default, polar surface area is defined as the area due to nitrogen and oxygen and any hydrogens
attached to nitrogen and oxygen. Other combinations of atoms may be employed to define a polar surface
area. See Formulas under the Display menu (Chapter 22).

273

Line ()

A line model is a 2D representation (similar to that provided from drawing
programs such as ChemDraw, MarvinSketch or Biovia Draw). It designates
carbons as the termini or the intersection of lines and non-carbons by theirelemental symbols without use of color.

Line Model

H

H
H H

Line models include stereochemical cues ( and ) if these have been
provided in the 2D drawing or if they are specified from the Bond
Properties dialog (accessible from Properties under the Display menu;
Chapter 22).
Hide ()

This removes the molecular structure model from the screen. This may bedesirable where its display may lead to unnecessary crowding, for example,
in proteins where ribbon displays are more appropriate. A structure model
may be restored by selecting it from the Model menu.
Different parts of a molecule may be rendered in terms of different modelstyles and colors. This allows focus on specific regions of a molecule.
Regions may be individual atoms and/or bonds or any collection of atoms
and/or bonds, contiguous or not. They are selected either by clicking on
an individual atom or bond or, with the aid of the Ctrl (select multiple)
or command key (Macintosh), Shift (select over a range), and Alt (selectall bonded) or option key (Macintosh), by clicking on a set of atoms
and/or bonds, or by defining a selection box. Discussion provided in
Chapter 1. Style and color of selected model components is by way of
the “Selected” Style dialog accessible from Properties under the Display
menu (Chapter 22).

Global Model ()

If highlighted (turned on), this signifies that all molecules in a document
will share attributes. These include presentation of hydrogens, atom274

and other labels, hydrogen bonds, CFD’s and ribbon displays. Global modelstyle is controlled from the Molecule tab (Preferences... under the Options
menu; Chapter 25). Global Model acts in a toggle manner, switching
between global and local display. Global Model is on by default.
Coupled ()

If highlighted (turned on), this signifies that all molecules in a document
selected for simultaneous display will move together. Coupled is turned onfollowing molecule alignment (see Align under the Geometry menu;
Chapter 19). Coupled acts in a toggle manner, that is, repeated selection
couples or decouples.
Hydrogens ()

If highlighted, this signifies that hydrogens are to be included in the model.
Note that 2D SD files, CIF files, as well as structures retrieved from theCambridge Structural Database or the Protein Data Bank may lack hydrogens.
These need to be added to the model before CFD’s (Chemical Function
Descriptors) can be assigned (see discussion later in this chapter) and before
calculations may be performed. This may be done either upon retrieval (seeDatabases and Extract Ligands under the Search menu; Chapter 23) orusing Grow Hydrogens in the Molecule Utilities dialog (accessible from
Properties under the Display menu; Chapter 22). Hydrogens acts in a toggle
manner, that is, repeated selection turns the display of hydrogens on and off.
Labels ()

If highlighted, this signifies that labels associated with atoms, ribbons andbonds as well as with other attributes specified in Configure... (seediscussion later in this chapter) are to be displayed in the model. Labels acts
in a toggle manner, that is, repeated selection turns display of labels on andoff. Labels is automatically turned on following selection of Apply or OK
in the Configure dialog.

275

Ribbons ()

If highlighted, this signifies that ribbons are to be displayed along with theselected model. (If only ribbons are desired, select Hide for the model style.)
Ribbons acts in a toggle manner, that is, repeated selection turns display ofribbons on and off.
Ramachandran Plot ()

If highlighted, this draws a Ramachandran plot for a protein input from theProtein Data Bank (see Access PDB Online under the File menu; Chapter
16). Ramachandran Plot acts in a toggle manner, that is, repeated selection
turns the plot on and off. Note that coloring of the points on the plot (red for-helices, blue for -sheets, green otherwise) is not based on the actual 3D
geometry but rather on assignments in the PDB file. The plot may beremoved by again selecting Ramachandran Plot.
Hydrogen Bonds ()

If selected, this signifies that hydrogen bonds are to be drawn as part of themodel. Hydrogen bonds are defined as non-bonded contacts between anitrogen or oxygen and a hydrogen attached to nitrogen or oxygen separated
by a distance ranging from 1.6 to 2.1Å and making an X–H--Y (X,Y = N, O)
angle of >120°. Note that hydrogen bonds are not used in either molecularmechanics or quantum chemical calculations. Hydrogen Bonds acts in a
toggle manner, that is, repeated selection turns display of hydrogen bonds
on and off.
R/S Chirality ()

If selected, this adds R/S chirality labels to the model. R/S Chirality acts ina toggle manner, that is, repeated selections turns R/S labels on and off.
CFD’s ()

If checked, this signifies that Chemical Function Descriptors (CFD’s) are to
be displayed along with the structure model. CFD’s are descriptors given toa molecule in order to characterize or anticipate276

its chemical behavior or to identify commonality among molecules withdifferent structures. They parallel terms in a chemist’s vocabulary such as lonepair (to suggest the role of a hydrogen-bond acceptor) and sterically crowded(to suggest that getting close may be difficult).
Spartan uses seven different kinds of CFD, the first six of which may
be thought of as attributes of a molecule.

1.
2.
3.
4.
5.
6.

CFD

chemical languagehydrophobearomatichydrogen-bond donorhydrogen-bond acceptor
positive ionizable sitenegative ionizable sitesterically-crowded region
aromatic π systemacidic hydrogenlone pairbasic site
acidic site

Default CFD assignments follow from atomic connectivity and rules
covering common organic functional groups. They may be modified on acase-by-case basis using the CFD Properties dialog (accessible from
Properties under the Display menu; Chapter 22). CFD’s (represented by*’s in the figures below) may either be atom centered, or they may becentered in between atoms. For example, a hydrogen-bond acceptor CFD isplaced on an ether oxygen, while an aromatic CFD is placed at the center ofa benzene ring.

CFD’s may also be associated with a number of common functional groups.
For example, a single CFD is provided for the carboxylic acid group, sited inplane and equidistant from the carbon and two oxygens.
The CFD’s for this and other functional groups may depend on pH. At
neutral (or basic) pH this CFD should be designated both as a hydrogenbond donor and a hydrogen-bond acceptor, whereas at acidic pH it should
be designated as a negative ionizable site.
277

Finally, note that default assignments for hydrogen-bond donors andacceptors depend not only on atomic type (N, O, . . . ) and (in the case ofhydrogen-bond donors) on the availability of hydrogens, but also on known(or presumed) chemical behavior. For example, because an amide nitrogen
would generally not be considered to be a hydrogen- bond acceptor, no(hydrogen-bond acceptor) CFD is provided. It is assigned to be a hydrogenbond donor (if hydrogens are available) and the amide oxygen is assigned
as a hydrogen-bond acceptor.
Note that hydrogen-bond acceptor and donor CFD’s may be related to theelectrostatic potential obtained from quantum chemical calculations. For
example, a negative potential associated with an oxygen center suggeststhat it might serve as a hydrogen-bond acceptor, while a positive potential
associated with a hydrogen attached to such a center suggests its role as ahydrogen-bond donor. While a chemist would reach the same conclusions
simply by looking at the molecule, the calculations may be able to saywhich acceptor or donor sites are likely to be strong and which are likely
to be weak.
Calculated electrostatic potentials may offer significant advantage over
CFD’s and other qualitative descriptions when there are no heteroatoms
and hydrogen bonding is not possible. The π system of benzene and otheraromatics provide the most common examples. The same conditions thatmake the ring susceptible to electrophilic aromatic substitution mean thatit repels other electron-rich regions (and attracts electron-poor regions).

A seventh CFD type, excluded volume, derives from knowledge of amolecule incorporated into a host. Excluded volumes may be obtained forligands extracted from PDB files using the Ligands dialog (Extract
Ligands under the File menu; Chapter 16).
278

Configure... ()

This selects the types of labels attached to atoms and other molecule
attributes.
LabelsUnder Atom, labels may be selected from among the following: Labels, a
unique element/number combination that may be changed from the Atom
Properties dialog (accessible from Properties under the Display menu;
Chapter 22), Element, Mass Number, Mulliken Charge, Electrostatic
Charge, Natural Charge, Strand: Res\Label (polypeptides andpolynucleotides), and Exposed Area (of an atom in a space-filling model),Chem Shift, Expt Chem Shift and Calc-Expt Chem Shift. Selection ofCustom leads to a text box into which a formula defining an atomic label may
be entered. Details are provided in Formulas under the Display menu
(Chapter 22). Under Bond, either Label a unique number prefaced by theword “Bond” that may be changed from the Bond Properties dialog(accessible from Properties under the Display menu; Chapter 22) orCustom entered in a text box. Under Other, Hydrogen Labels, PointLabels, Plane Labels, Constraint Labels, Residue Labels, Reaction
Labels, Coupling (coupling constant) and/or CFD Labels may be provided.
Default settings (for a new molecule) are made in the Molecule tab(Preferences under the Options menu; Chapter 25).

279

Objects
Clicking on the Objects tab leads to the Configure Objects dialog:

If checked, Constraint and Frozen markers, Points and Planes, Reaction
arrows and CFD’s attach to the model. If not checked, these are shown onlyin the respective modes, for example, Frozen markers are shown only if
Freeze Center is selected. Images and Annotations refer to images and text,
respectively, associated with the molecule display. An image or text string
may be associated by first putting it on the clipboard and then pasting it on
screen. Either may be positioned on screen and sized. HH and CH refer toexperimentally assigned HH and CH couplings.
Ribbons
Clicking on the Ribbons tab leads to the Configure Ribbons dialog:

280

Ribbon coloring may be selected in a menu from among the following:
Monochrome, By Secondary Structure, By Strand or By Residue. Ribbon
style may be selected in a menu from among the following: Ribbons,
Extended Ribbons, Beads or Lines.
CFD’s
Clicking on the CFD’s tab leads to the Configure CFDs dialog:

This allows for turning CFD descriptors excluded volumes on or off.
The Configure dialog is removed from the screen with all changes
maintained by clicking on OK. Clicking on Cancel or on removes the
dialog but changes are lost. Clicking on Apply maintains the changes but
leaves the Configure dialog on screen. Note, that Labels (from the Modelmenu) will be turned on following either clicking on OK or Apply.

281

Chapter 19
The Geometry Menu
Functions available under the Geometry menu allow querying andchanging bond lengths, angles and dihedral angles, defining points andligand points, planes and chemical function descriptor (CFD) locations,setting geometrical constraints (distances, angles and dihedral angles) or
ranges of constraints, freezing atomic centers, altering default bond andring conformer assignments, introducing NOE’s (maximum intramoleculardistances) in conformational searching, selecting atoms or CFD’s for
similarity analysis and aligning molecules. Generation of tautomer list has
been moved from the Search menu and the ability to generate a list of stereo
and/or regioisomers.

Measure Distance () Angle () Dihedral ()

Measure Distance displays the distance (in Ångstroms) between any two
atoms. Selection results in a message at the bottom left of the screen:
Clicking on two atoms displays the distance at the bottom right of thescreen:282

Alternatively, clicking on a bond displays its length:

Measure Distance may also be used to alter the distance between atoms byclicking inside the box to the right of Distance (A,B) = or Length (A)=, andeither typing or using the number pad. New from Spartan’20 is the ability
to alter bond distances inside rings. This is accomplished by temporarily
imposing distance constraints followed by molecular mechanization andthen removing the constants.
The distance (length) may be entered into the spreadsheet by clicking onto the right of its display (see Spreadsheet under the Display menu;
Chapter 22). Alternatively, the label “Distance (A,B)=” or “Length (A)=”may be dragged into the spreadsheet, the formula editor (see Formulas
under the Display menu; Chapter 22) or into any of the dialogs associatedwith the Spartan Spectra and Properties Database (see Databases under the
Search menu; Chapter 23).
Angle and dihedral angle queries and charges are handled in a similar manner.
Angles require that three atoms or two bonds be identified in the properorder while dihedral angles require that four atoms or three bonds be
identified in the proper order.
Freeze Center ()

This allows one or more atoms to be held in place during minimization (in the
3D builder) or (optionally) during equilibrium or transition- state geometry
optimization, conformational searching, or energy profile generation using
molecular mechanics or quantum chemical methods. In the latter case, useof frozen atoms needs to be explicitly indicated in the Calculations dialog(Chapter 21).
Atom freezing may be useful in a number of situations, among themguessing a transition-state geometry for a reaction that is closely related to
one for which a transition state is available. For example, a good guess at thetransition state for pyrolysis of cyclohexyl formate will be obtained bymodifying the transition state for pyrolysis of ethyl formate, freezing all but
the modified sections (designated in bold in the following figure) and thenminimizing.
283

Selection of Freeze Center leads to a message at the bottom left of thescreen:Clicking on an atom freezes it, clicking again thaws it. Buttons at the bottom
right of the screen allow for freezing all atoms (Freeze All), freezing all nonhydrogen atoms (Freeze Heavy) and for thawing all atoms (Thaw All).
Another important use of frozen atoms is to adjust XH bond lengths in
structures resulting from a search of the Cambridge Structural Database(see Databases under the Search menu; Chapter 23). Hydrogen
positions are more often than not poorly located in small molecule X-ray
structures, and XH bond lengths are commonly shorter than they should
be. Structures incorporating such bond lengths are inappropriate forenergy and property calculations and may also be problematic as starting
geometries in quantum chemical calculations. Protein crystal structuresoften lack hydrogens, and hydrogen positions of bound ligands extracted
from PDB files may be poorly defined. A reasonable solution to bothproblems is to freeze all heavy (non-hydrogen) atoms (Freeze Heavy)
and then to carry out molecular mechanics optimization using either
Minimize from the Build menu (see discussion in Chapter 20) or from
Calculations... under the Setup menu (see discussion in Chapter 21).

Frozen atoms are indicated by magenta colored markers ( ). Whether or
not these are included with the model (outside of Freeze Center mode) is
controlled from the Molecule Preferences dialog under Preferences... in
the Options menu (Chapter 25).

284

Set Torsions ()

Spartan automatically identifies bonds and rings for conformational
searching and specifies default step sizes.
Three different rule sets have been provided. Normal is appropriate todetermine lowest-energy conformation or to establish a distribution of
low-energy conformers, Skeletal is used to build conformer libraries foruse in similarity analyses and removes conformers that only involvehydrogen positions. Normal and Skeletal rule sets consider only chairconformers for saturated six-membered rings, for example, cyclohexane.
Thorough considers twist-boat conformers in addition to chairconformers. (Different modes of conformational analysis are discussed
in Chapter 21.) Selection of rule set is made in the Settings Preferences
dialog (Preferences... under the Options menu; Chapter 25).

Set Torsions allows these defaults to be altered. Selection results inrotatable bonds being marked by a gold cylinder and flexible rings being
marked by a gold circle around one or more atoms, and a message at thebottom left of the screen:
Clicking on a bond or an atom contained in a ring selects it for rotation. In thecase of a ring, rotation means that the atom is to be puckered up and down
(restricted rotation). The default rotation is provided in a box to the right ofFold at the bottom right of the screen. With Normal rules, this is typically
2 or 3 for a single bond (step size of 180° and 120°, respectively) and 3 for a
flexible ring. A value of either 0 or 1 indicates that the bond (ring) is not to
be rotated (rotation by 360°). Other integer values may be entered into thebox using the number pad that appears immediately above. The original
settings may be retrieved by clicking on Defaults at the bottom right of thescreen. Double clicking on a marked bond or ring atom removes the marker
and eliminates the conformational degree of freedom.
While conformational degrees of freedom in acyclic molecules are“easy” to define (and default selections usually appropriate), dealing
with medium to large rings can be problematic. Experience suggests thattorsions applied to ring bonds are likely to be more effective in “catching”

285

the multitude of possible conformers than puckering motions applied to
atoms. Experimentation may be necessary.

and buttons at the bottom right of the screen are available to step throughthe possible single-bond conformers* (ring conformers are not provided).
Geometries have not been optimized and some conformers may be severely
crowded. Any conformer can be selected in lieu of the initial structure. The
full set of single-bond conformers may be placed in an unnamed document
by clicking on (to the right of the step buttons), and then clicking OK in
the dialog that results. Note, that duplicate conformers are not removed.
The total number of conformers (excluding ring conformers) that will be
examined in a systematic search (see discussion in Chapter 21) is indicatedat the bottom right of the screen Conformers = xx. This is an upper boundto the number of conformers that will actually be kept as duplicates andhigh-energy conformers are eliminated. This can be dragged into the
spreadsheet (see discussion in Chapter 22), into the Formulas dialog (seediscussion in Chapter 23), or into any of the dialogs associated with theSpartan Spectra and Properties Database (see discussion in Chapter 23). The
number of conformers is also available under the Molecule tab in the
Molecule Properties dialog (Properties under the Display menu; Chapter
22). This can be dragged or posted to the spreadsheet.
In practice, an efficient systematic search scheme is employed formolecules that incorporate both flexible rings and acyclic free rotors.
This divides the search into two parts, the first involving only rings andconcluding with the few lowest-energy conformers and the second startingfrom these conformers to explore the conformations of the acyclic rotors.

Generate Isomers ()

This generates a list of regio and/or stereoisomers starting from a single
structure. It’s use may simply be a convenient way to examine* A maximum of 1000 conformers is enforced when exploring conformation in the set torsions mode.

286

the relative energies of possible isomeric products of a chemical reaction
or to see which of these products best fits on observed NMR spectrum. We
first illustrate the more common task of stereoisomer generation. Startingfrom endo-chlorobicyclo[2.2.1]hept-5-ene-2-carbonitrile*, selection ofGenerate Isomers leads to a structure decorated by R/S labels.

Inversion of C2 and C7 leads to four possible stereoisomers. To select, clickon them in turn, following which they will be encircled in green.

Clicking on Generate List to the right of Isomers at the bottom right of thescreen lead to a dialog requesting if the list is to be placed in a new document
or added to the current document. The four isomers are shown below.

Regioisomer generation is signaled by clicking in order on three bonds, forexample, in a C1-C2, C2-C3 and C3-C4 in 1-methyl-7- chlorobicyclo[2.2.1]
hept-2-ene-2-carbonitrile.
* More precisely this is the syn (chloro), endo (cyano) stereoisomer.

287

Clicking on Generate List gives rise to a pair of regioisomers.

Markers for regio and stereoisomers may be applied together.
Set Isomers can also be used to generate a list of transition states (thatwould lead to stereoisomeric products) starting from a single transition
state. We use the Diels-Alder transition state leading to the four stereoisomersof 7-chlorobicyclo[2.2.1]hept-5-ene-2-carbonitrile. The procedure is thesame. Starting from a transition state for one of the isomers, select Set
Isomers and click on C2 and C7.

Clicking on Generate List then provides the four transition states which
will lead to the four stereoisomeric products.

288

Generate Tautomers ()

This allows tautomers, that is, isomers arising from rapid transfer ofhydrogens among heteroatoms, to be identified based only on the structure.
Tautomer identification is especially important in dealing with heterocyclic
compounds where two or more different tautomers may exist in equilibrium,
and the identity of the dominant species may not be obvious. For example,
while 2-hydroxypyridine is an aromatic molecule and would be expected to
be unusually stable, the non- aromatic 2-pyridone molecule is actually
thermodynamically favored.

This, of course, has consequences in trying to locate a particular moleculein a database where it may be represented by a different tautomer.
In contrast, Spartan almost always recognizes different ways to draw
the same structure. For example, benzene can be represented as oneof two structures with alternating double and single bonds or a single
delocalized structure in which all bonds are the same and intermediatein length between single and double bonds.
oror

All of these translate into the same molecule.

The procedure incorporated into Spartan is limited to tautomers involving
nitrogen, oxygen, phosphorous and sulfur. Tautomers involving carbon
have intentionally been excluded. There are too many of them, and inclusion
would swamp the more likely heteroatom tautomers. Also excluded arezwitterion tautomers, for example, H3N+CH2CO2– as a tautomer of glycine.
In the gas-phase, these are likely to be much less stable than “neutral” forms.
Within these limits, all possible tautomers will be identified.

289

The existence of (heteroatom) tautomers is signaled by the word
Tautomer displayed at the bottom right of the screen. If tautomers
exist, individual structures may be examined or a complete list of structuresgenerated by selecting Tautomers from the Search menu (or clicking on theicon on the top of the screen). Following this, clicking on the step buttons
at the bottom right of the screen moves through the list of tautomers. Any
one of these may be used in place of the original. The full list of tautomers
may be generated by clicking on (at the bottom right of the screen). This
leads to a dialog.
Clicking on OK dismisses the dialog and leads to a new document
containing the full list of tautomers. (The original document is unaffected.)
Clicking on either Cancel ordismisses the dialog without generating atautomer list.
Tautomers are generated without consideration of steric crowding,and should be minimized with molecular mechanics (Minimize underthe Build menu; Chapter 20) prior to using them for quantum chemical
calculations. It may also be important to perform a molecular mechanics
search to obtain a guess at the lowest-energy conformer (seeCalculations... under the Setup menu; Chapter 21).

Constrain Distance () Angle () Dihedral ()

These introduce one or more geometrical constraints during structure
minimization (in build mode), and (if requested) during equilibrium ortransition-state geometry optimization or conformational searching using
methods specified in the Calculations dialog (Calculations... from the
Setup menu; Chapter 21). They also allow for setting a range of constraints
needed for generation of energy profiles. Constraints may be useful in a
number of situations, among them:(i)Constructing conformational energy profiles where one or more dihedral
angles need to be fixed while other geometrical variables are optimized.

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(ii)
Optimizing molecular structures where the values of certain key
parameters are known, for example, optimizing the geometry of a moleculewith an intramolecular hydrogen bond or a disulfide linkage.
(iii)
Building molecules with unusual geometries, for example,
molecules with very long bonds, as might be required in the construction oftransition states and intermolecular complexes.
Selecting Constrain Distance results in a message at the bottom left of thescreen:Clicking on two atoms, or a bond results in a message at the bottom right ofthe screen:
Clicking onchanges it toand shows the current distance:

This (constraint) distance can then be changed by clicking inside the box
and either typing or using the number pad that appears immediately above.
Alternatively, the existing distance may be used as the constraint distance. If
the selected distance had previously been constrained, the icon would havebeen initially displayed. In this case, clicking on
turns the constraint off
and returns the icon to . Finally, the value of the constraint (that may bedifferent from the value of the current distance*) may be entered into the
spreadsheet by clicking on to its right. Alternatively, the label Constraint(A,B)= may be dragged into the spreadsheet, the formula editor (seeFormulas under the Display menu; Chapter 22) or into any of the dialogs
associated with the Spartan Spectra and Properties Database (see Databases
under the Search menu; Chapter 23).
This sequence of operations (bond identification followed by turning theconstraint on and off) may be repeated as many times as necessary. Any bonds
or non-bonded distances on which constraints are to be* Note, however, that it may be problematic to carry out a constrained geometry optimization startingfrom a structure that is very different from that satisfying one or more constraints.

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imposed are indicated by magenta colored markers. Any constraints
introduced are automatically enforced only upon energy minimization in Edit
Build mode ( ), but need to be requested for methods specified in the
Calculations dialog (Calculations... from the Setup menu; Chapter 21).
Angle and dihedral angle constraints are handled in a similar manner. Notethat points and planes may not be used to define constraints.
Locking in a constraint leads to two additional text boxes at the bottom rightof the screen. This allows a sequence of constraints to be defined (fromsome initial value to some final value in a given number of steps) for the
purpose of constructing an energy profile along a predefined set ofcoordinates (see Calculations... under the Setup menu; Chapter 21):

The leftmost box specifies the initial value of the constraint, the middle box
to the right of to the final value, and the rightmost box to the right of Steps:
the number of steps. Values are specified by clicking inside the appropriate
box and using the number pad. For example, were the initial value set to 0°,
the final value to 180° and the number of steps to 10, then a series of ten
constraints (0°, 20°, 40°,... 180°) would be specified. This can also be
accomplished using the Constraint Properties dialog, and the value of theconstraint posted to the spreadsheet.
Whether or not constraint markers are included as part of the model (outsideof constrain distance, constrain angle or constrain dihedral mode) is
controlled from the Molecule Preferences dialog (Preferences... under the
Options menu; Chapter 25).
Define Point ()

This defines a point as the geometric (unweighted) center of selected atoms(or points) previously defined. Selection results in display of a message atthe bottom left of the screen:292

Clicking on atoms (or points) in any order, and clicking a second time on
any one of the atoms (or points) defines a point (depicted as a small sphere).
As many points as desired can be defined and these are treated in the same
way as an atom in defining distances, angles, etc. Points move with themolecule as its geometry is altered.
Define Ligand Point ()

This defines a point of attachment directed perpendicular to the geometriccenter of the plane defined by three atoms (or best plane in the case of fouror more atoms). Clicking on atoms (or points) in any order, and clicking asecond time on any one of the atoms (or points) defines a ligand point(depicted as a small sphere). As many ligand points as desired can be
defined. A ligand point shares all the characteristics of a normal point, but
may also be used to bond to atomic fragments, functional groups, etc. See
Make Bond under the Build menu (Chapter 20) for a discussion. Ligand
points move with the molecule as geometry is altered.
Delete from the Build menu (remove a point or ligand point.

) or the Delete key may be used toWhether or not points and ligand points are shown as part of the model iscontrolled from the Molecule Preferences dialog (Preferences... under the
Options menu; Chapter 25).
Define Plane ()

This defines and displays a reference plane. Selection results in displayof a message at the bottom left of the screen:

Clicking on three atoms or points defines a plane. As many planes as desired
may be defined, and these may be used in defining distances, angles, etc.
Planes move with the molecule as its geometry changes.
Delete from the Build menu (remove a plane.

) or the Delete key may be used to293Whether or not planes are included as part of the model for an is controlledfrom the Molecule Preferences dialog (Preferences... under the Options
menu; Chapter 25).
Define NOE ()

Define NOE is used to specify non-bonded distances that need to be kept below a
threshold value. These follow from NOE (Nuclear Overhauser Effect)measurements and may be referred to as NOE conditions or simply NOEs.
NOEs are specified by clicking on two (non-bonded) atoms. In response, amessage appears at the bottom of the screen:

Clicking onchanges it toand enters the default value for the NOE
threshold into the box. This value can be changed. A line is drawn between
atoms that are to be kept within the threshold value.

Once set, NOEs are used in conformational searching (conformer
distribution only; see discussion under Calculations... under the Setup
menu; Chapter 21) without further user intervention. They act as a postprocessor filter to eliminate conformers that do not satisfy the constraints
and do not affect the speed of the search.
Define CFD ()

This defines the position of a new CFD. The CFD Properties dialog(accessible from Properties under the Display menu; Chapter 22) allows
CFD size and type to be specified. Selection results in display of a message
at the bottom left of the screen:294

Clicking on atoms (or points) in any order, and clicking a second time on
any one of the atoms (or points) defines the position of a CFD (depicted asa transparent sphere labeled Null). Clicking twice on only one atom locates
the CFD on the atom. As many CFD’s as desired can be defined. These movewith the molecule as its geometry is altered.
Whether or not CFD’s are included as part of the model is controlled from
the Molecule Preferences dialog (Preferences under the Options menu;
Chapter 25).
Set Similarity Centers ()

This specifies the set of atomic centers, or Chemical Function Descriptors(CFD’s) or pharmacophore elements that are to be used in similarity analysis.
Choice of whether the similarity analysis is to be based on structure or CFD’s(pharmacophore elements) is made from a menu that appears at the bottom rightof the screen following selection of Set Similarity Centers. This menu isalso accessible from the Similarity Analysis task in the Calculations dialog(Calculations... under the Setup menu; Chapter 21).
Similarity Based on Structure
Selection of structure from the Similarity by menu at the bottom right of thescreen results in a message at the bottom left of the screen:
Clicking on an atom designates it as an alignment center and it marks it witha violet circle. Clicking on the circle removes the designation (and thecircle). Hydrogens are not used in similarity analysis and may not be
selected.
The computer time required for similarity analysis based on structure
depends on the number of molecules in the query, the number of moleculesin the library to which comparisons are being made and the choice ofsimilarity centers. Single atoms should never be selected as similarity
centers unless they are unique. Rather, contiguous groups of atoms thatare likely to be unique should be chosen. For example, analysis carried

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out on morphine based on selection of its phenol and trialkylaminecomponents (left) will be much faster and more informative than thatbased on selection of the phenol oxygen, two carbons on benzene andthe nitrogen (right).
HO*

*
*

O

HO*

*
*
*

*

*
H

*

*

O

H

* *

*

*
HO

HO
good

bad

This is because there will be many fewer occurrences of phenol andtrialkylamine substructures in the library entries than there will bearomatic carbons and nitrogen atoms and fewer permutations that need
to be examined and fewer false positive results.

Similarity Based on CFD’s
Similarity analysis may also be based on CFD’s. These indicate whether aparticular center is likely to act as a hydrogen-bond donor or hydrogen-bondacceptor, is likely to take on positive or negative charge or is a hydrophobe.
This is accomplished by selecting CFD from the Similarity by menu at thebottom right of the screen. In response, the selected molecule is augmented
with CFD’s, and a message appears at the bottom left of the screen:

Clicking on a CFD designates it as a similarity center and marks it with a violet
circle. Clicking on the circle removes the designation (and the circle).
The computer time required for similarity analysis based on CFD’s
depends on the number of molecules and/or pharmacophores in the query,the number of molecules and/or pharmacophores in the library and thenature of the selected CFD’s in the query. For each query/library pair,where the query is represented by i CFD’s of type A, j CFD’s of type B,
k CFD’s of type C, etc., the number of different alignment combinations
that need to be considered is given by:296

i!j!k! . . .
(! is the factorial symbol.) This rapidly becomes unmanageable. For
example, if there are 6 CFD’s of type A, 3 of type B and 2 of type C, thenumber of combinations is 6!3!2! or 8640. Considerable savings can beachieved by limiting the number of CFD’s of a given type in the overall
representation.

Similarity Based on a Pharmacophore
Finally, it is possible to base similarity on a pharmacophore. This is set up in
exactly the same way as similarity based on CFD’s insofar as the elementsof a pharmacophore are CFD’s (see previous section).
Align ()

This aligns the selected molecule to all other molecules in the same
document based either on atom labels, on structure, or on CFD’s. If the selected
molecule is a pharmacophore, this aligns the pharmacophore to all moleculesin the same document (based on CFD’s). Choice of whether alignment isbased on labels, structure or CFD’s is made from the Align by menu thatappears at the bottom right of the screen.
The terms “alignment” and “similarity analysis” have subtly different
meanings inside of Spartan. Alignment refers to the operation in which
the molecules in a document are reoriented to best coincide with theselected molecule (or pharmacophore). Where a molecule is selected,alignment may either be based on a set of atoms or on a set of CFD’s.
Where a pharmacophore is selected, alignment is based on a set of CFD’s.
A single reorientation is provided for each molecule in the document thatcan be aligned to the selected molecule (pharmacophore).
Similarity analysis refers to the operation in which all molecules in a userspecified library comprising one or more documents are compared oneon-one to all molecules and/or pharmacophores in the selected document(in the graphical user interface). As with alignment, either structuralelements or CFD’s may be employed. The result is a similarity scorefrom 0 to 1 (1 is perfect) and a manipulable model of the two molecules(or molecule and pharmacophore). It is likely that most comparisons
will not be successful, and also that some comparisons may lead to297

more than one score (corresponding to different orientations of the twocomponents). Similarity analysis both by structure and CFD as well as
to a pharmacophore is discussed further in Chapter 21.
In short, the role of alignment is to orient molecules and/or pharmacophores
in order to highlight their common features, while the role of similarity
analysis is to rank pairs of molecules or molecule/pharmacophore pairs
according to the extent of their common features.

Align Based on Labels/Align Based on Structure
Selection of either Labels or Structure from the Align by menu results in a
message at the bottom left of the screen:
Clicking on an atom designates it as an alignment center, and marks it with a red
circle. Clicking on the circle removes the designation (and the circle).
Following selection of alignment centers, clicking on the Align by button at
the bottom right of the screen aligns the molecules. If no atoms are selectedprior to clicking on Align by, then alignment is based on all (non-hydrogen)atoms.
Following alignment, two or more molecules may be displayed at once
using spreadsheet functions (see Spreadsheet under the Display menu;
Chapter 22). Their motions (coordinates) will be coupled followingalignment, but may be uncoupled allowing the aligned molecules to moveindependently (see Coupled under the Model menu; Chapter 18). Note thatalignment center selections are kept and molecules can be realigned by again
selecting Align from the Geometry menu (or clicking on) followed byclicking on the Align by button.
Align Based on CFD’s
It is also possible to base molecule alignment on CFD’s. These indicate
whether a particular center is likely to act as a hydrogen- bond donor or
acceptor, is likely to take on positive or negative charge or is a hydrophobe.
This is accomplished by choosing CFD from the Align by menu at the bottom
right of the screen followed298

by clicking on the Align by button. In response, the selected molecule isaugmented with CFD’s, and a message appears at the bottom left of thescreen:Clicking on a CFD designates it as an alignment center and marks it with a
red circle. Clicking on the circle removes the designation (and the circle).
The CFD Properties dialog (accessible from Properties under the Display
menu; Chapter 22) allows definitions of the individual CFD’s to be altered.
Following selection of CFD’s, clicking on the Align by button at the bottom
right of the screen aligns the molecules. If no CFD’s are selected prior toclicking on Align by, then alignment is based on all CFD’s.
Following alignment, one or more molecules may be displayed at once
using spreadsheet functions (see Spreadsheet under the Display menu;
Chapter 22). Their motions (coordinates) will be coupled followingalignment, but may be uncoupled allowing the aligned molecules to moveindependently (see Coupled under the Model menu; Chapter 18). Note thatalignment center selections are kept and molecules can be realigned by again
selecting Align from the Geometry menu (or clicking on) followed byclicking
on the Align by button.
Align to a Pharmacophore
Finally, it is possible to align molecules to a pharmacophore contained in
the same list. This is set up in exactly the same way as alignment based on
CFD’s insofar as a pharmacophore element is a CFD (see previous section).
For both structure and CFD alignment (and for alignment to apharmacophore), an alignment score from 0 to 1 (perfect alignment), isavailable in the spreadsheet. This is accessed by clicking on the Add button
at the bottom of the spreadsheet, and299

selecting Alignment Score from the Molecule List tab of available properties(see Spreadsheet under the Display menu; Chapter 22). A score of 0 is
assigned to molecules that cannot be aligned to the selected molecule.

300

Chapter 20
The Build Menu
The Build menu provides access to a sketch palette for drawing organic andorganometallic molecules in 2D, model kits and associated tools for building
and editing organic, inorganic and organometallic molecules as well as
polypeptides and polynucleotides in 3D, for guessing transition-state
structures and a facility for generating lists of substituted molecules. The
Windows version provides a seamless access to ChemDraw. 2D to 3D
conversion and 3D structure refinement is by way of molecular mechanics.
With Spartan’24, the Build menu gives the ability to attach experimental
proton and 13C NMR chemical shifts as well as observed HH and CH
couplings to either 2D drawings or 3D models.
Specification of 3D molecular structure is a necessary first step to any
molecular mechanics or quantum chemical calculation. Spartan provides avariety of tools. Organic and organometallic molecules can either be rendered
as 2D sketches and later brought into 3D, or directly constructed from 3D
fragments. Polypeptides and polynucleotides need to be built in 3D.
2D Sketch Palette
The 2D sketch palette contains tools for making and manipulating drawings.
There are also tools for specifying charges and radical sites, for adding cues todesignate stereochemistry and for setting limits for a substructure search.
Directly above the palette are icons that place curved arrows on 2D
drawings thereby defining chemical reactions as well as for attachingexperimental proton and 13C chemical shifts and observed HH and CH
couplings to 2D drawings.

301

Palette Atoms. H, B, C, N, O, F, Si, P, Cl, Br and I only.
More: Element/Functional Group/Ligands Library. Selection ofMore icon that appears below H and B, leads to a dialog that allows any
atom to be specified from a Periodic Table (Periodic Table tab), a varietyof common functional groups (Groups tab) and a number of common
ligands (Ligands tab). Clicking on an element, group or ligand dismisses
the dialog and results in whatever was selected being placed in the icon
and available for use.
Common Rings. Three icons facilitate the rapid addition of common rings.
The upper icon is for benzene ( ), the middle icon is for cyclohexane,
both as a “flat” drawing ( ) and as a chair ( ), and the lower icon is for
cyclopropane ( ), cyclobutane ( ), cyclopentane ( ) andcycloheptane ( ). In the latter two ring icons, double-tap/ double click
exposes the additional selection options.
Common Carbonyl Groups. Three icons facilitate the rapid addition ofcarbonyl ( ), carboxylic acid/ester ( ) and amide ( ) groups to
drawings. In the latter two icons double-tap/double click exposes
alternate attachment options.
Stereochemical Markers. Wedges and dashes, represented byand, can be used to designate in-out stereochemistry. Immediately to the rightis a single-bond (unwedged) marker.Once a stereochemical marker
has been added to a drawing, it is possible to designate the orientation ofhydrogen atoms and/or substituents bonded to six- member rings asax(ial) or eq(uatorial) (ax and eq labels appear only on the drawing, notin the palette).

302

Open-site Markers.
designates an “open-site” in a drawing. Searchinga database will return all structures with any atoms (including hydrogen) orgroups in open sites.
Charge/Radical Markers. Conventional bonding rules (neutral C makes 4bonds, neutral N makes 3 bonds, and so on) are enforced when 2D
perspective drawings are converted into 3D models. This is accomplished byadding hydrogen atoms to the drawing. For example, a single carbon on screen
will give methane, a single line, ethane, and a double line, ethylene.
(Hydrogen atoms are added to nitrogen, oxygen, phosphorous and sulfur inthe 2D drawings.) When another outcome is desired, for example, for an ion
or free radical, charge or radical markers must be added to the drawing.
Two icons,
and, are used to label atoms that bear formal charges.
is used to label atoms that are neutral, open-shell radicals. Each of thesemarkers affects the number of electrons and the number of hydrogen atoms
added to the 3D model. For example, O will produce a 3D model of water,
H2O. However, adding the appropriate marker will result in 3D models of
H3O+ ( ), HO– ( ), or HO radical ( ), respectively. Only one
charge/radical marker can be assigned to an atom (radical cations and radical
anions cannot be specified in this way) but as many atoms as desired may beprovided charge or radical designations. The sum of charges and radicalsites will be used to determine overall molecular charge and number of
unpaired electrons needed for a quantum chemical calculation.
Only one charge/radical marker is displayed on the palette, but clicking on theicon will cause each marker to appear in turn. Examples of the use of reaction
arrows is provided in Chapter 23.
Reaction Arrows.
designates one or more curly arrows allowing access to
Spartan’s automated procedure for guessing transition states. The tail of thearrow corresponds to the source of the electron pair. If the source is a lone
pair, then select the atom that holds the lone pair. If the source is a bond,then select the bond. Clicking on an atom or bond highlights (colors gold)
the atom or bond. Clicking again on the same atom (or same bond) removes
the highlighting. The head of the arrow corresponds to the destination of theelectron303

pair. If the destination is an atom (leading to a lone pair), then select the atomthat will hold the lone pair by clicking on it two times. If the destination is anexisting bond (leading to an increase in bond order from single → doubleor double → triple), then select (click on) the bond. If no bond presently
exists, select (click on) the two atoms that will become bonded uponreaction. These operations result in a curved arrow being drawn on thereactant structure. This extends from an atom, or the center of a bond to an
atom, or the center of a bond, or the center of a dotted line that has beendrawn between atoms that are to be bonded.
Note that the head and tail do not need to reside on atoms or bonds on the samefragment. Also the tail may involve atoms of two detached fragments.
The process (tail selection followed by head selection) is repeated asnecessary to fully define the reaction. Incorrect reaction arrows may beremoved by clicking on from the palette and clicking on the arrow. You
then need to selectto continue arrow selection.
Once defined, reaction queries can be used to relate the properties of the
products of chemical reactions to those of the products for the purpose ofmining the Spartan Spectra and Properties Database. Full discussion isprovided in Databases in Chapter 23. Reaction queries can also be used tosearch the Spartan Reaction Database for transition-state structuresassociated with the defined reaction (also discussed in Databases). In bothof these cases, Open-Site Markers or structure queries (discussed in
Structure Query in Chapter 23) will also normally be employed. Finally,
reaction queries may be employed to automatically provide a guess at atransition state based on similarity to an entry in the Spartan Reaction
Database (see discussion in Transition State in Chapter 23). Here, noadditional information is required.
Drawing Tools.
undoes the most recent drawing operation.
removesor modifies parts of a drawing.
deletes an entire drawing (a warning isprovided). improves the readability of a drawing by applying a “clean up”
procedure.
exits sketch mode.

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Four icons (in addition to the Edit Sketch icon ) appear on top of the tool
palette. These allow “curly arrows” to be added to the sketch to define atransition state, input of experimental proton and 13C chemical shifts andidentification of observed HH and CH couplings.
Proton and 13C Chemical Shifts ()

Experimental proton and/or 13C chemical shifts can be added to a 2D
drawing. Starting from a 2D sketch (promophyllin A), click on above thesketch pad and then carbon on a carbon. If it is a quaternary carbon (asshown below) the only change to the sketch will be that the letter C willappear.

click on a carbon →Click on Edit to the right of Expt. Chem. Shift at the bottom right of thescreen, and enter a value for the experimental 13C shift using the keypad that
results. Click on Enter and the keypad will be dismissed and the chemical
shift will be attached to the sketch.

If the selected carbon had one or more attached hydrogens and experimental
chemical shifts were to be entered, these will be shown with the selectedcarbon.

305

Clicking on one of these hydrogens (only a single hydrogen in the example)
results in a keypad into which the experimental proton shift may be entered.
Clicking on Enter again dismisses the keypad and attaches the chemical
shift onto the sketch.

CH Couplings ()

Experimental 2-bond (H-C-C) and 3-bond (H-C-C-C) CH “observed”
couplings (not numerical values for coupling constants) may be attached toa 2D sketch (with or without experimental chemical shifts attached) byclicking on a carbon (H-C-C or H-C-C-C). If there is only one hydrogen as inthis first example, it will be drawn and all carbons which either 2 or 3-bondcoupling can occur will be highlighted by translucent red circles. Clicking
on one of these carbons (in this case three bonds removed)will remove thecircles and draw an arrow between the first selected carbon (corresponding to
the H in H-C-C-C) and the second selected carbon (corresponding to H-CC-C).

306

The arrow indicating a 3-bond coupling will remain in place.
If on the other hand, the initially selected carbon is bonded to more than one
hydrogen, an additional click is required to identify which hydrogen before
a destination (carbon) is selected.

HH Couplings ()

Experimental 3-bond HH observed couplings (not numerical coupling
constant values) (HCCH) may also be attached to a 2D stretch. There areseveral cases depending on whether more than one hydrogen is attached to
one or both of the carbons and whether or not one or both of the hydrogens
are explicit in the 2D sketch.
If one of the hydrogens is explicit, click on it following selection of JHH).
This results either in one or more carbons being marked with a translucent
green circle. Select the relevant carbon (there is only one
307

in this example) and click on it to display the hydrogens attached to it (there
are two in this example, if there were only one, the selection of the carbon
would have eliminated the step). These are also marked by translucent green
circles. Click on the appropriate hydrogen and the coupling will be
displayed by a green arrow.

If hydrogens are not explicit, click on the carbon to which they are attached.
Click on the appropriate hydrogen and a coupling arrow will appear.

As before, steps will be eliminated if they are not needed.
308

Making a Sketch
To start a sketch, first select (click on) an atom, group, ring or wildcard icon in
the sketch palette and then double click in the white portion of the screen (thedrawing area). To draw a bond, first click on an atom, group, ring or wildcard
icon in the sketch palette to designate what is at the end of the bond, thenposition the cursor over the atom in the drawing area where you want thebond to start, move the cursor while holding down the left button (“drag”
the cursor) to the place in the drawing area where you want the bond to end
and release the button. Multiple bonds are made by dragging over existing
bonds.

To make a bond touch the screen where you want it to start, move
one finger to where you want it to end and lift. Replace position bytouch, drag by move and release by lift in the previous diagram.

Manipulating a Sketch
To translate the sketch, move the mouse over the screen while holding down
the right button. To rotate the sketch (in the plane of the screen), move themouse up and down while holding down both the left button and Shift key.
Use the scroll wheel to resize the sketch.
To translate the sketch, move two fingers over the screen. To rotate
the sketch in the plane of the screen, “twist” two fingers on thescreen. To resize the sketch, pinch (or spread) two fingers on the screen.

309

Sketch Operations
Add an Atom, Ring, or Carbonyl Group. To add an atom, click on thatatom’s icon. Position the cursor over the atom in the drawing that will connect
to the new atom, drag it away and release the button. To add a common ringor carbonyl group, click on that ring’s (group’s) icon, position the cursor over
the atom in the drawing that will connect to the new ring (group) and drag it
away and release the button. The carboxylic acid/ester
and amide
icons contain an arrow that shows which atom in these groups will beconnected to the existing drawing. To change the location of this connection
point (arrow), click on the group’s icon until the arrow reaches the desired
location.
Add Multiple Bonds. To add a multiple bond, first draw a single bond at
the location where the multiple bond is needed, then redraw this line once tomake a double bond, and redraw it again to make a triple bond (in otherwords, position the cursor over one end of the bond, drag to the other end,
and release the button).
An alternative way of drawing a multiple bonds, is to double click (double tap
on touch-screen devices) on an existing single bond. Double clicking asecond time gives a triple bond and a third time reverts to a single bond. The
only restriction is this cannot be done if a ring has been selected from thepalette whereas here double clicking results in addition of the ring (ringfusing in the case where the single bond is incorporated into a ring).
Fuse Rings. Click on an icon for the first ring and double click (double tap fortouch-screen devices) on the screen. Next, click on the icon for the secondring and double tap the bond that the rings will share. This will create adrawing with a fused bicyclic ring system. Note that the (cis or trans)
stereochemistry of the ring juncture is ill-defined. This is addressed later(Add Stereochemical Markers).
This technique can also be used to add rings to an existing bond in any
drawing. Click on the icon for the ring to be added and double click on thebond that will become part of the ring.
Replace an Atom with Another. If a drawing contains atom A where atom B
is needed, click on the icon for B, then double click (double
310tap for touch-screen devices) on A in the drawing.
This simplifies the drawing of heterocycles. First, draw an all-carbon ring andthen replace specific carbons with heteroatoms.
Access an Element, Functional Group or Ligand from the Library. Clickon the icon underneath H and B (this icon will initially be labeled with More,or the name of the group that was previously selected and will change eachtime you select a new element or group). A tabbed dialog initially displaying
a Periodic Table results.

The Overlay menu allows the Periodic Table to be colored based on
availability of specific models or basis sets or to separate it into s, p, d andf blocks.
If a functional group is desired, click on the Groups tab and then on a groupfrom the dialog that results. Colors are intended to convey chemical
behavior, red represents electron donating, blue represents electron
accepting, and green represents relatively neutral groups.

311

Finally, if a ligand is desired, click on the Ligands tab (above the
Periodic Table) and then a ligand from the dialog which results.

An element, group or ligand defined in this way can be added to a drawing,
replaced, or removed using the same drawing techniques used for standard
atoms. The element/group can also be redefined. Double click on the icon
beneath H and B and select the desired element/group.
Add Stereochemical Markers (Dashes and Wedges). 3D
information can be added to a drawing by replacing single bonds withstereochemical markers: dashes or wedges. The single bond must be drawn
before a marker can be added.
To replace a single bond with a marker, click eitheror, then re-draw
the single bond. To reverse the orientation of the marker, re- draw the bond or
marker in the opposite direction. One type of marker can be replaced directlyby the other. Click on the desired marker
312and then re-draw the existing marker. Markers can also be converted backinto single bonds. Click on , then double click on the marker.
For best results during 2D-to-3D conversion, all substituent bonds to the ringshould be drawn with stereochemical markers.
Spartan’24 provides an alternative way of introducing stereochemical markers
either as “new” single bonds or by modifying existing single bonds. Once oneof the stereochemical markers ( or ) has been selected, drawing results
in an up or down wedge with the narrow end at the starting point. Clicking on
any other (thanor) icon in the tool palette reverts to selection of .
Additionally, with a single bond already drawn and with eitherorselected, the marker may be added by double clicking on the bond as analternative to swiping over the bond. In this case, the “broad” end of themarker (solid or dashed wedge) goes to the terminal atom or group (if one
end of the bond is a terminal atom or group). Double clicking a second time
reverses the direction of the marker and a third time removes it (reverts toan “unmarked” single bond).
Add an Axial or Equatorial Marker. The orientation of a hydrogen/substituent on a 6-member ring can be specified by marking one ring
substituent as either ax(ial) or eq(uatorial). If the molecule contains
multiple rings, the conformation of each ring can be specified by marking
one substituent per ring. Axial or equatorial markers can only be added tostereochemical markers (dashes, wedge) so the bond connecting thesubstituent to the ring must be drawn with a stereochemical marker first.
To add an axial or equatorial designation to a stereochemical marker, click oneitheror
within the sketch palette, then hold down the SHIFT key anddouble click on top of the stereochemical marker. This will be designated axial
and marked with an ax. To specify equatorial, with the SHIFT key still
depressed, double-click again, and the ax will be replaced with eq. A third
double-click operation will return to bond to a single bond without stereochemical designation.
Note: While it is possible to specify multiple centers as axial or equatorial,
Spartan only needs one designation to provide the anticipated 3D structure.

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Assign Charges and Radical Sites. Formal charges and unpaired electrons
can be assigned to individual atoms using charge/unpaired electron markers.
To assign a positive formal charge to an atom, click on
and double clickon the atom in the drawing. To assign a negative formal charge or unpaired
electron, click on the charge/ unpaired electron marker until the desired icon
appears (tapping the marker rotates it through three possibilities:,,and ) and double tap the atom in the drawing.
To replace a charge/unpaired electron marker on an atom with a different
marker, click on the desired charge/unpaired electron icon and double click
the marked atom. To remove a marker, click on
and double click on themarker.
Charge/unpaired electron markers play an important role during theconversion of 2D drawings into 3D models in that they determine thenumber of hydrogens that need to be added to the model (it is usually
unnecessary to draw hydrogens unless they are needed to markstereochemistry).
Hydrogens are not shown in 2D perspective drawings unless they have beendrawn explicitly (exceptions: hydrogens attached to neutral N, O, P, and S are
shown). When a drawing is converted into a 3D model, hydrogens are added
to the model according to conventional bonding rules. A neutral carbon atom
is assumed to form four bonds, nitrogen three bonds, oxygen two bonds, andso on. Analogous logic is used for atoms that carry a formal charge or
unpaired electron marker.
Charge and unpaired electron markers are carried over into specificationof quantum chemical calculations (Calculations... from the Setup menu;
Chapter 21). The total charge is set equal to the sum of the formal charges in
the 2D drawing. A model with one unpaired electron is treated as a free
radical (drawings that contain more than one unpaired electron may giveunanticipated results).
Specify “Open Site” Marker(s). To mark an “open site” for a substructure
search on the database, click on , locate the atom in the drawing that will
carry the open site, and draw a bond starting from this location. As many
open site markers as desired may be314added to the drawing.
To remove an “open site” marker, click onmarker in the drawing.

, then double click on the ?

Discussion of database searching is provided in Chapter 23.
Markers can also be placed on a 3D model (Structure Query in Chapter
23).

Undo the Last Action. Click on
to return to the drawing as it existed
before the last action. Only a single level of undo is presently supported.
Clean Up a Drawing. Click on
to “clean up” a drawing, that is, toequalize bond lengths, bond angles, and so on. “Clean up” can improve theappearance of a 2D drawing, but not every “clean up” will produce adesirable result. To undo an unsatisfactory clean up operation, click on.
Remove an Atom or Bond. Click on
and then double click on the atom
or bond. If you click an atom, all bonds to that atom will also be removed.
Removing a bond, either by clicking on an atom or by clicking on the bonditself, will also remove terminal atoms, that is, atoms not connected to any
other atoms in the drawing will be removed along with the bond.
Remove a Multiple Bond. To remove a multiple bond, click onthendouble click on the multiple bond. This reduces the bond order by one.
Repeated double clicks on a triple bond will reduce the bond order: triple→ double → single → no bond.
Remove a Reaction Arrow. To remove a reaction arrow, click on
and double click on the reaction arrow.
Remove a Stereochemical Marker. Click on, then double tap themarker. This replaces the marker with a single bond.
Change or Remove an Axial or Equatorial Label from a
Stereochemical Marker. Tap eitheror, then double click on thestereochemical marker where an axial or equatorial label appears.

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This cycles the label (in order) among ax (axial), eq (equatorial) andnothing. The stereochemical marker itself will not be affected.
Remove a Charge or Radical Marker. Click on
the marker.
Remove an “Open Site” Marker. Click onmarker in the drawing.
Clear the Screen. Click on
this operation.

and double click on

and double click on the ?

. A warning message will ask you to confirm

Copy/Paste/Delete Selected. Right clicking on screen brings up a menu
which allows the sketch to be copied to the clipboard (Copy), the contentsof the clipboard to be pasted on screen (Paste) or a selected portion of thesketch (or the entire sketch) to be deleted (Delete Selected).
A 3D structure is obtained from the 2D sketch by clicking on.

3D Builders
Spartan provides five different 3D builders for assembling a variety ofmolecular systems: an organic builder for most organic molecules, aninorganic builder for organic molecules not well represented in terms of an
uncharged (non-zwitterionic) valence structure, as well as inorganic andorganometallic molecules, builders for polypeptides and polynucleotides anda builder for attaching substituents (lists of chemical groups) to previouslybuilt molecules. The organic and inorganic builders utilize atomic
fragments, functional groups and rings (and ligands in the inorganic
builder), while the peptide builder uses the set of natural amino acids asbuilding blocks, and the nucleotide builder the set of nucleotide bases.
Additionally, two-dimensional molecular structures (drawings) produced
using ChemDraw* can also be brought into Spartan and converted to threedimensional structures. Spartan also provides its own 2D sketch capacity(with automatic conversion to 3D structures).
* Seamless access to ChemDraw is available for the Windows version only, turn on the ChemDraw
interface from the Preferences dialog, Chapter 25. All versions are able to read ChemDraw files.
ChemDraw is not included with Spartan and is a commercial 2D drawing program that must be obtained from
Perkin Elmer Informatics https://www.perkinelmer.com/product/chemoffice-chemoffice.

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3D molecule construction in Spartan proceeds much in the same manner asa chemist would assemble a structure from a model kit, that is, pieces are takenfrom the kit one at a time and added sequentially to the molecule underconstruction.
Organic Builder
The organic builder contains a suite of moleculebuilding/editing tools specifically designed toconstruct the most commonly- encounteredorganic molecules.
In the center of the builder is a selection of atomic
fragments, which from left to right and then top
to bottom, correspond to:C(sp3)
N(sp3)
C(sp2)
N(sp2)C(sp)N(sp)
C(aromatic) N(aromatic)
Si(sp3)N(planar)P(sp3)O(sp3)
O(sp2)
S(sp3)
S(sp2)

H
F
Cl
Br
I

A fragment is chosen by clicking on its icon,
which is then displayed at the top of the builder.
Once selected, the fragment may be used toinitiate building, to add
alongside of an existing structure or appended onto an existing structure.
To initiate building, double-click* anywhere on screen. To add alongside ofan existing structure, hold down the Insert key (option key on Mac), andthen click anywhere on screen or double click in a blank area on screen. To
bond to an existing structure, click on a free valence (not an atom). (Freevalences are colored yellow on the selected molecule.) Bond type in the caseof atomic fragments with multiple bond types, for example, sp2 carbon,
depends on the nature of the free valence selected.
* The default 3D building behavior requires a double-click operation to initiate building. This follows the2D building behavior. To switch to a single-click behavior, turn off the “Double- Click Start” preference(see Options menu, Chapter 25).

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While only H, C, N, O, F, Si, P, S, Cl, Br and I are available from theorganic builder, other elements may be substituted using atom replacement
feature available in the inorganic builder (see General Molecule Building
Functionality later in this chapter). Similarly, bond types may be altered in
the inorganic builder. The latter may be necessary in order to alter bondingin structures retrieved from the Cambridge Structural Database or ligands
obtained from PDB files. Atom and bond types may also be altered using
the Atom and Bond Properties dialogs, respectively (accessible from
Properties under the Display menu; Chapter 22). Note that bond type(or the fact that there is a bond) is not considered in quantum chemical
calculations. Only atom identities and coordinates are required. Bond types
are, however, necessary for molecular mechanics calculations.

Menus inside the organic model kit provide access to a number of pre-built
fragments corresponding to functional groups (Groups) and rings (Rings),
and to additional libraries of rings (as well as any user-defined structures)stored in Spartan’s file system (More). The builder also accesses the
clipboard (Clipboard).
GroupsClicking on Groups brings up a menu ofgroups, and displays an icon of one group in a
box at the top of the builder.
Once selected from the menu, a group may be
used to initiate building, to add alongside ofan existing structure on screen, or to add to an
existing structure.
The amide and carboxylic acid/ester groups
have more than one different free valence. The
free valence that is to be used is marked with agold • (in the icon at the top of the builder).
The marked position circulates among thepossible positions with repeated clicking on
the icon.

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RingsClicking on Rings brings up a menu of hydrocarbon rings, and displays an
icon of one ring in a box at the top of the builder.
Once selected from the menu, a ring may be used to initiate building, to add
alongside of an existing structure on screen, or to add to an existing
structure.
Cyclohexane,
cycloheptane,
naphthalene,
anthracene, phenanthrene, indene and fluorene havemore than one unique free valence. The one that is
to be used is marked with a gold • (in the icon). The
marked position circulates among the available
positions with repeated clicking on the icon.
Selection of an axial or equatorial free valence in
cyclohexane and cycloheptane is indicated by thelabel ax or eq appearing alongside the icon.
All rings in this menu are hydrocarbons, but heteroatoms may be substituted(see General Molecule Building Functionality later in this chapter).
MoreThis provides access to a broader selection of rings as well as to access userdefined entities (rings, groups, ligands, etc.). Upon initial entry, clicking onMore or on to its right brings up a file browser that has been set to point
toward a directory* containing a library of several Spartan documents ofcommon rings.

*

For Windows, the library directory is located in C:\ProgramFiles\Wavefunction\Spartan. For Linux, thelocation is /user/Spartan/Library. For Macintosh, the library folder is on the disc image and needs to becopied to a location on the hard drive. Once populated (after first time access) clicking on More will display
the previously selected file in the box at the top of the model kit, while clicking on
will bring up a filebrowser to allow a new selection to be made.

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nitrogen heterocycles
heterocycles
heterocycles
mixed heterocycles

saturated nitrogen rings oxygen
saturated oxygen rings sulfur
saturated sulfur rings
saturated mixed rings

Clicking on a document followed by clicking on Open or double clicking ona document fills the menu to the right of More. Menu entries are selected in
the usual way. In response, a ball-and-wire model of the selected ring willappear in a box at the top of the model kit. This may be manipulated (rotated,translated, zoomed) using the usual mouse/keyboard commands (you needto position the cursor inside the box) or with the usual one and two-finger
touch commands. The ring may be used to initiate building, to add alongsideof an existing structure, or to add to an existing structure. In the latter case, theattachment point (on the ring in the window) needs to be identified by clicking
on the appropriate free valence.
Three other collections (ligands, chelates and high-coordination fragments)
appear in the selected directory. They are intended for use with the inorganic
builder as discussed in the next section. User-defined libraries may also beaccessed (they are normal Spartan documents).
Clipboard
Clicking on Clipboard accesses the clipboard. A ball-and-wire model ofwhatever is on the clipboard is displayed in a box at the top of the builder.
This may be manipulated using the usual mouse/keyboard commands (youneed to position the cursor inside the box or with the usual one and two-finger
touch commands). Once selected, the contents of the clipboard may be used
to initiate building, to add alongside of an existing structure, or to add to an
existing structure. In the latter case, the attachment point needs to be
identified by clicking on the appropriate free valence.
An empty clipboard is signaled by:320

Smiles / InChI
Initially clicking on Smiles or InChI or on to its right of each will bringup an input dialog where the corresponding string can be entered either
manually, or more likely by using Copy/ Paste. Once the string is entered,click the OK button to release the dialog. A 3D rendering of the molecule(or fragment) will be displayed at the top of the model kit. The attachment
point is indicated with a yellow marker. To insert, rather than attach,double-click in the blank space of the 3D interface to the left of the modelkit. Subsequent clicking on the Smiles or InChI button will return focus to
the last entered string in the 3D area at the top of the model kit. To input a
new Smiles or InChi string, click the downward triangle immediately to theright of the string type you wish to input. Access to the Smiles or InChI
input dialog is available from both the organic and inorganic builders.
Inorganic Builder
Spartan’s inorganic builder allows construction of a much wider class ofmolecules (including inorganic and organometallic species) than possible
with the organic builder. Structures that violate conventional bonding rules
may be constructed, as this builder purposefully provides no valence
checking. The inorganic builder is reached by selecting Inorganic fromamong the tabs at the top of the builder.** Tabs may require too much vertical space on computers or tablets with very small screens. Alternative
Builder Selection Methods are available in the Miscellaneous tab (Preferences from the Options menu;
Chapter 25).

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Atoms may be selected by clicking on the selection bar near the center ofthe builder. This brings up a full Periodic Table. Main- group elements arecolored red, transition metals are colored green and lanthanides andactinides are colored blue. The Overlay menu inside the Periodic Table
contains a selection of theoretical models (basis sets except for semiempirical models).

322

Selecting an entry from this menu leads to re-coloring of the Periodic Table.
A light green color is used to indicate elements for which the selected model
may be used.* Immediately below is a selection of atomic hybrids.
Selection of atom type is effected by clicking on the appropriate element in
the Periodic Table. The entry will be highlighted. Selection of an atomic
hybrid follows by clicking on the appropriate icon which will then behighlighted.** This combination (atom type + atomic hybrid) may be used
to initiate building, to add alongside of an existing structure or to bond to an
existing molecular fragment. To initiate building, double click anywhere on
screen. To add alongside of an existing structure, hold down the Insert key(option key on Mac) and click anywhere on screen, or double click in ablank area on screen. To bond to an existing fragment, click on theappropriate free valence.
Two of the hybrids (trigonal bipyramidal and square-based pyramidal) may
bond either axially or equatorially. Selection of the appropriate bonding
point, marked by a •, is effected by repeatedly clicking on the icon; thebonding point alternates between the two sites.
Atoms are connected with whatever bond type (partial single, single,
aromatic, double, triple or quadruple) is selected from the bottom of thebuilder. A bond type may be changed by first selecting a type and thendouble clicking on the bond. Bond types have no impact on quantum
chemical calculations, but do affect molecular mechanics calculations
which reference a Lewis structure (including minimization in the builder;see discussion later in this chapter).
No valence checking is performed in the inorganic builder, and the user isfree to construct any arrangement of atoms.
Menus under Groups, Rings and More are the same as those described* The existence of either an all-electron basis set or a pseudopotential is sufficient to classify a model asavailable for a particular element. Note that while molecular mechanics models are available for all
elements, they have been carefully parameterized for only a relatively few of these. Use caution ininterpreting molecular mechanics geometries for molecules incorporating heavy main-group elements,
transition metals, lanthanides and actinides.
** Hybrids for a number of high-coordination centers are available as a library reachable from
More (see discussion under Organic Builder).

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for the organic builder as is Clipboard. One
additional fragment collection is provided:
Ligands
This provides access to a number of pre- built
ligands, useful in the construction of inorganic andorganometallic molecules. Its operation is
analogous to that for the Groups and Rings
menus. Clicking on Ligands brings up a menu ofavailable ligands, and results in an icon of one
ligand from this menu being displayed in a box at
the top of the builder.
A ligand may be used to initiate building or to add alongside or to an
existing structure.
Additional ligands are accessible from More (see previous discussion). Ligands
may also be built with the aid of ligand points (Define Ligand Point in theGeometry menu; Chapter 19).
Peptide Builder
This builder is not intended to be used forconstructing proteins (although this ispossible). Rather, it is primarily intended tobuild idealized helix and sheet structures.
Protein structures are best entered from theProtein Data Bank (see Access PDB
Online... under the File menu; Chapter
16). A builder for construction ofpolypeptides is reached by selecting
Peptide from among the tabs at the top of
the builder.
At the middle of the peptide builder areicons designating the amino acids(specified by their three-letter codes). An
amino acid is selected by clicking on its
three-letter code, following which either an icon of the amino acid324

is displayed in the box at the top of the model kit, or the three-letter code forthe amino acid is appended to the sequence of codes in the box. Amino acids
replace atoms, functional groups, rings and ligands as the building blocks inthe peptide builder. Because these other building blocks are missing,modifications of peptides, aside from modifications in sequence and in
overall conformation, need to be carried out using the organic or inorganic
builders.
There are two different modes of operation: single amino acid mode andpolypeptide mode. The former is used to initiate building with a single aminoacid, to add a single amino acid alongside of an existing structure or to add asingle amino acid to an existing structure, while the latter is used to constructamino acid sequences (polypeptides). Sequence off (unchecked)
corresponds to single amino acid mode, and on (checked) corresponds topolypeptide mode.
Peptide construction (Sequence on) is accomplished in three steps:
Specifying Amino Acid SequenceThis is accomplished by clicking in the desired order on the amino acid icons.
Building occurs from the N end to the C end of the peptide. In response toeach selection, the three-letter code is appended to the sequence of codes in thebox at the top of the builder. The stereochemical configuration of the aminoacid is by default the l configuration; this may be changed to the dconfiguration prior to selection of the amino acid, by checking d to the rightof stereoisomer in the builder. (It may be changed back to l by checking l). damino acids are indicated by .d following the code in the box.
The sequence may be altered by changing the text in the box. Existing
amino acid codes may be deleted or changed or new codes can be added.
The entire sequence may be specified in this way if desired. Specification ofa non-existent code will result in an error message. The sequence can becleared by clicking on the Clear button.

325

Specifying Macroscopic Structure
Once sequencing is complete, macroscopic structure ( and angles), is
specified by clicking on one of  Helix,  Sheet or Other. In the case of
the first two, preset angle values are displayed on the right. In the case of
specification of Other, boxes appear, into which the desired dihedral angles
may be entered.
Terminate
The peptide is not yet terminated, and the two ends are still set up for
addition of further amino acids.

where the * indicates a free valence. Clicking on Terminate at
the bottom of the model kit leads to the Terminate dialog.

C and N terminating groups may be selected by clicking on the desired
terminal group. Clicking on OK removes the dialog and terminates thepolypeptide. Clicking on Cancel orremoves the dialog but does not
terminate the polypeptide.
The peptide (or single amino acid) may now be used either to initiatebuilding, by double clicking anywhere on screen or added alongside of an
existing structure, by holding down the Insert key (option key on Mac) andclicking anywhere on screen, or by double clicking in a blank area on screen. If
unterminated, it may join an existing structure by clicking on a free valence.
In the latter case, attachment is made from the N end, unless the free valencecorresponds to an unterminated peptide fragment, in which case theappropriate end required to make an amide bond is used.
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Nucleotide Builder
Spartan provides a builder for construction of polynucleotides. It is reachedby selecting Nucleotide from among the tabs at the top of the builder.
At the middle of the builder is a menu designating the type ofpolynucleotide:DNA
DNA (single strand)
DNA-RNARNA
RNA (double strand)
RNA-DNA
Immediately below this menu areicons, designating the nucleotide
bases. Selection of DNA, DNA(single strand) or DNA- RNA fromthe menu leads to one set of icons.

Selection of RNA, RNA (double
strand) or RNA-DNA leads to asecond set, the only difference is thaturacil (U) has been substituted forthymine (T).

A nucleotide base is selected by clicking on its letter, following which either
an icon of the base is displayed in the box at the top of the builder, or theletter for the base is appended to the sequence of letters in the box.
Nucleotide bases replace atomic fragments, functional groups, rings andligands as the building blocks in the nucleotide builder. Because these otherbuilding blocks are missing, modifications of nucleotides, aside frommodifications in sequence and helical structure, need to be carried out using
either the organic or inorganic builders.
There are two different modes of operation: single base mode andpolynucleotide mode. The former is used to place a single base or base pair onscreen, to add a single base or base pair alongside of an existing327

structure, or to add a single base or base pair to an existing structure, while
the latter is used to construct strands of DNA or RNA (or mixed strands).
Sequence off (unchecked) corresponds to single base (base pair) mode andon (checked) corresponds to polynucleotide mode.
Polynucleotide construction (Sequence on) is accomplished in two steps:
Specifying Base SequenceThis is accomplished by clicking in order on the base codes. In response toeach selection, the letter code is appended to the sequence of codes in thebox at the top of the model kit. The sequence may be altered by editing thecontents of the box. Existing base codes may be deleted or changed or newcodes added. The entire sequence can be specified in this way if desired. The
sequence may be cleared by clicking on the Clear button.
Specifying Helical Structure
Once sequencing is complete, a helical structure may be specified by clicking
on A or B. These correspond to A and B helices, respectively. Selecting
Other allows user modification of the rise (in Å) per base (Rise/Base) andtwist (in degrees) per base (Twist/Base).
Note that the polynucleotide is not yet terminated, and the two ends are still
set up for addition of further bases or base pairs.

* indicates a free valence. Hydrogens occupy all free valences (except
the *’ed positions at the two ends of the chain).
The polynucleotide (or single base pair) may now be used to either initiatebuilding, by double clicking anywhere on screen, added alongside of an
existing structure, by first holding down the Insert key (option key on Mac)and clicking anywhere on screen, or double

328

clicking on a blank area on screen, or joined onto an existing structure byclicking on a free valence. In the latter case, attachment is made from thephosphate end.
Substituent Builder
The substituent builder designates one or more locations for libraries ofsubstituents to be added to a molecule. Additionally, it designates one ormore carbon hybrids for replacement by their heteroatom equivalents, forexample, sp3 carbon by sp3 nitrogen. There are two uses for the Substituent
builder. The first is to facilitate assembling lists of molecules that differ onlyin substitution and/or heteroatom. The second application is to use molecules
incorporating one or more substituent libraries as queries in searches of theSpartan Spectra and Properties Database (see Databases under the Searchmenu; Chapter 23) or as elements of reaction energy calculations (seeReactions under the Display menu; Chapter 22). Here, the search orreaction energy calculation is not confined to a single molecule but rather isopen to a set of molecules that are related by substitution. Further discussion
is provided in the appropriate sections of Chapters 22 and 23.
The substituent builder is accessed by
selecting Substituent from among thetabs at the top of the model kit.
At the center of the builder are four rowsof buttons. Buttons in the first two rows
provide access to predefined substituent
libraries: R (alkyl groups), Ar (aromaticgroups), OR (alkoxy groups), EDG(electron donor groups), EWG (electron
withdrawing groups) and LG (leavinggroups). Buttons in the third row allow
access to user-defined substituent libraries(Cust. A, Cust. B, Cust. C), while those in
the last row permit substitution ofheteroatom hybrids for sp3, sp2 and aromatic
carbons incorporated in a molecule.

329

Immediately below the buttons, a dialog lists the entries in the individuallibraries (the three custom libraries should be blank upon initial entry). As
entries are selected, they will appear in the window at the top of the builder.
Predefined libraries may not be altered and individual entries may not berenamed, but existing library entries in custom libraries may be renamed ordeleted and new entries added. Modifications to existing substituent
libraries need to be performed following attachment using the Substituent
Properties dialog (accessible from Properties under the Display menu;
Chapter 22).
Creating lists of substituted molecules starting from an unsubstituted
molecule occurs in three stages: library preparation, attachment and(optionally) list generation.
Library Preparation
Six substituent libraries have been provided.
R (alkyl group): methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, t-butyl, t-amyl
Ar (aromatic ring): phenyl, p-tolyl, p-nitrophenyl, 1-naphthyl, 2-naphthyl,2-pyridyl, 3-pyridyl, 4-pyridyl
OR (alkoxy group): methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy
EDG (electron donor group): hydroxy, methoxy, ethoxy, phenoxy, amino,
dimethylamino, mercapto, methylthio, phenylthio
EWG (electron withdrawing group): cyano, nitro, trifluoromethyl, carboxy,
formyl, methoxycarbonyl, ethoxycarbonyl, methyl sulfonyl, methyl
sulfoxyl
LG (leaving group): bromo, iodo, tosylate, triflate, mesylate

The contents of an existing library are displayed in the scroll box at thebottom of the builder by clicking the appropriate button. A ball-and-wiremodel of a substituent may be seen at the top of the builder by clicking on its
name in the scroll box. The model may be manipulated in the usual way. The
attachment point is indicated by a gold ball surrounding a free valence.

330

To create a custom substituent library, first click on the Cust. A, Cust. B or
Cust. C buttons inside the builder. The scroll box is empty. If a substituent(set of substituents) has previously been copied to the clipboard, it may bepasted into the library by right clicking inside the scroll box and selecting
Paste from the menu that appears. Alternatively, a substituent (set of
substituents) may be appended to the document (including an empty
document) by right clicking inside the scroll box, selecting Append fromthe menu that results and selecting a Spartan document comprising one ormore molecules from the browser. Finally, any Spartan document may be
dragged onto the scroll box from the file system. As many substituents (sets ofsubstituents) as desired may be pasted, appended and/or dragged into a library.
To remove a substituent from the library, right click on its name in the scroll
box and select Delete from the menu that appears. Ctrl (command for Mac)and Shift keys are used for multi-select or selection over a range.
Substituents need to be specified in terms of both their structure andtheir connection point. One way to specify the latter is to replace all freevalences except the one that will serve as the connection point byhydrogens. For example, to designate a 2-pyridyl substituent, addhydrogens (from the organic builder) to four of the five free valencesin pyridine, leaving only one free valence in the 2-position available.
Alternatively, a connection point can be specified by clicking on theappropriate position as the substituent displayed at the top of the builder.

The three buttons in the last row designate heteroatom equivalents ofcarbon-based hybrids.
sp2: carbon (), nitrogen ()
sp3: carbon (), nitrogen (), oxygen (Arom: carbon (), nitrogen ())

Attachment
Following selection, a substituent library may be used to initiate building, to
add alongside of an existing structure or to attach to an existing structure. The
model is augmented by an icon containing331the library name from the button, for example EWG, followed by a number.
As many substituent libraries as desired may be attached to a molecule. Eachlibrary is given a unique label that can be changed prior to list generation
using the Substituent Properties dialog. A substituent library may beremoved from the molecule by selecting Delete from the Build menu or
clicking on ( ) and then clicking on the substituent icon.
A document containing one or more molecules with attached substituent
libraries may be saved prior to list generation just as any other Spartan
document. Any queries (bond distances, angles, etc.) and calculations referto the unsubstituted molecule, that is, hydrogens replacing substituent
markers. Database searches on the Spartan Spectra and Properties
Database (SSPD) and reaction energy calculations based on entries in
SSPD pertain to all possible substituted molecules.

List Generation
Generation of a list of substituted molecules follows specification and(optionally) editing of one or more substituent libraries and attachment ofeach of these libraries at one or more positions in a molecule. Duplicates are
eliminated. Clicking on Generate List at the bottom of the builder, leads to
the Generate List dialog:

A box at the top of the dialog allows the user to specify (or modify) a Name
Template, from which the names of substituted molecules will be derived.
Upon entry, this takes the form.
Ax-By-Cz-molecule name332

A, B, C are the names of the substituent libraries (R, EWG, etc.), x, y, z are
integers and molecule name is the name of the unsubstituted molecule if
and as it appears in the SSPD. If the unsubstituted molecule is not in the
database, then the box below Name-Template will be blank. If thesubstituted molecule is in SSPD, its name in the database may be used
(instead of the name generated from the template) by checking the box tothe left of Use names from SSPD where possible.
Nulls are molecules with less than the full complement of substituents, forexample, monosubstituted molecules in the case where two different
positions have be substituted. These will not be included in the list of
substituted molecules unless Generate Nulls is checked.
Note, that the conformations of the substituted molecules have not been
subjected to energy minimization to relieve unfavorable crowding
interactions. Therefore, the list entries should be examined, conformations
adjusted as appropriate and minimized with molecular mechanics prior tousing them for quantum chemical calculations.
The list may either be written to a New Document or appended to the endof the Current Document.
Accessing ChemDraw (Windows Only)*
The ChemDraw program may be seamlessly accessed inside of Spartan**allowing chemical drawings to be produced in a familiar environment andthen brought over as 3D structures. The conversion is unambiguous as long as
all stereochemical cues are in place in the 2D drawing. Note that theconformation implied by the 2D drawing may be ambiguous and needadjusting.
To access ChemDraw, select ChemDraw from the menu at the top of* ChemDraw files (.cdx) may be read with all versions of Spartan.
** ChemDraw is not provided with Spartan but must be obtained from Perkin Elmer Informatics
http://www.cambridgesoft.com.

333the model kit, and click on New at the bottom of the panel that results.
ChemDraw will appear. To return to Spartan, close ChemDraw. The 2D
drawing will appear at the center of the panel and a manipulable 3D structure
will appear at the top of the panel. Double clicking on screen will move the
3D structure into Spartan’s main window.
General Molecule Building Functionality
Additional capabilities are available with Edit Build selected:
Multiple Fragments
Multiple fragments may result either from bond breakage (see Break Bondlater in this chapter) or from use of the Insert key (option key on Mac), or
double clicking in a blank area on screen. A fragment is selected by clicking
on it, following which the associated free valences are colored gold (freevalences for any non-selected fragments are colored white). All builder
functions apply to the selected fragment only. Rotation and translation also
apply to the entire set of fragments, but may be made to apply to the selectedfragment by holding down the Ctrl key while carrying out these operations.
Fragments may be attached using Make Bond (see discussion later in thischapter).
Rotate/Stretch Bonds
In addition to molecule rotation, translation and scaling, the mouse is used torotate about and stretch bonds not incorporated into rings. This is accomplished
via the following sequence of operations:(i)Clicking on the bond which is then marked by a red cylindrical arrow.
(The bond connecting the last atom, group, ring or substituent added to themolecule is automatically selected.)(ii)
Simultaneously holding down the Alt key (option key on Mac)and the left mouse button while dragging the mouse up and down, for bondrotation, or the Alt (option) key and the334

right mouse button for bond stretching. Bond rotation (only) also follows
from moving the cursor up and down inside the shaded area at the far left ofthe screen while holding down the left button.
Replace Atom/Fragment
Another function of the mouse is atom replacement. This behaves differently
in the organic and inorganic builders. Double clicking on an atom (not a freevalence) while an atomic fragment in the organic builder is highlighted,
replaces the atom by the selected fragment. Free valences are adjusted toaccommodate the replacement, for example, replacement of sp3 carbon by sp3
oxygen results in two free valences being removed. Atom replacements that
violate valence rules or that would disrupt substituents are not permitted.
Double clicking on an atom (not a free valence) while an element in the
Periodic Table from the inorganic builder is selected, replaces the atom by
the selected element, that is, changes the atomic number. No changes in thenumber or arrangement of free valences is made, and no checking is done.
Atom replacement is not available in the peptide, nucleotide and substituent
model builders.
Invert Chirality
In the Edit Build mode, double clicking on a chiral atom with the Ctrl key(command key on Mac) depressed inverts the chirality of the atom (R→S or
S→R). Double clicking on any atom with both Ctrl (command key onMac) and Shift keys depressed inverts the absolute configuration of themolecule.
Replace click with tap for multiple fragment selections. Replace
double click with double tap for atom/fragment replacement andchirality inversion. One finger movement up and down the shaded areaat the left of the screen results in rotation about the marked bond.

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Building/Editing Menu Functions
Molecule building/editing functions are found under the Build menu.

Icons for Delete, Make Bond, Break Bond and Minimize are included at
the bottom of the model kit. They may also be added to the set of icons
below the menus at the top of the interface.
View ()

This exits build mode, and removes the model kit from the screen.
Initial entry into the 3D builder is by way of New Build or Build
New Molecule under the File menu (Chapter 16). Edit Build,
Delete, Make Bond, Break Bond and Minimize are for modifying
existing structures.

Edit Build ()

In addition to the capabilities discussed under General Molecule Building
Functionality, this allows access to the libraries of atomic fragments,groups, rings, ligands and substituents, as well as the file system and the
clipboard. Clicking on any buttons or menus in the organic, inorganic,
peptide, nucleotide or substituent builders, leads to Edit Build. (If a builder is
not already on screen, selection brings up the last-accessed builder.) A
fragment may be used to initiate building by double clicking anywhere on
screen, to add alongside an existing structure on screen by holding down theInsert key (option key on Mac) or by double clicking in a blank area onscreen, or be added to an existing structure by clicking on the appropriate freevalence. Fragment addition can be terminated by selection of any otherfunction.

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Edit Sketch ()

This allows a 2D sketch to be modified in the 2D sketcher after it has been
converted to a 3D structure. Modifications to molecules brought into 3D canbe passed back to the 2D sketch builder, essentially allowing for structure
modifications in either 2D, 3D, or both.*
Delete ( )This allows atom, free valence and substituent library removal from astructure. Selection leads to a message at the bottom left of the screen.
Subsequent clicking on an atom, free valence or substituent library results in
its deletion. Deletion of an atom results in deletion of all of its associatedfree valences. Free valences for any atoms to which the deleted atom waspreviously connected are restored. Note that atom deletion may result in
one or more detached fragments. Clicking inside a selection box results indeletion of everything inside the box. Selection of Delete does not bring up amodel kit nor does it remove a model kit that is present on screen. In 3D, thedefault settings relegate Delete to a one-time operation. Upon deleting,whatever mode was previously selected is restored. This may be overridden
by checking Persistent Delete in the Settings tab (Preferences under the
Options menu; Chapter 24). Persistent mode is also enabled by double
clicking on
instead of single clicking.
Delete is also used to delete points and planes, CFD’s andpharmacophore elements as well as spectra and plots (or individual
curves that make up plots). Be careful!

Deletion may also be accomplished by holding down on the Delete key while
clicking on the item to be deleted. This mode allows multiple deletions.

* Problematic 2D
3D conversions can occur from time to time. We appreciate users
pointing out any they have found so that they can be addressed in future versions of Spartan.

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Make Bond ()

This allows bonds to be drawn between free valences and/or atoms. Selection
leads to a message at the bottom left of the screen:
Clicking on two free valences (on different atoms) will cause these atoms
to be linked by a single bond. Alternatively, double clicking on each of two
atoms will bond them, and clicking on a free valence on one atom and double
clicking on a different atom will bond the two atoms. Note that available
free valences are consumed as a result of bond formation, irrespective ofwhether free valences or atoms are selected.* If the selected atoms are
already bonded, this will result in the bond order being increased by one,that is, single → double, double → triple. Selection of Make Bond does
not bring up a model kit nor does it remove a model kit that is alreadypresent on screen. Make Bond may be terminated by selection of any otherfunction.
Break Bond ( )This allows breaking an existing bond resulting in free valences. Selection
leads to a message at the bottom left of the screen:

Clicking on a bond breaks it and restores free valences. Note that bondbreaking may result in detached fragments. Selection of Break Bond does
not bring up a model kit nor does it remove a model kit that is present onscreen. Break Bond may be terminated by selection of any other function.
Replace click with tap and double click with double tap for delete,
make bond and break bond operations.

* Free valences can be “protected” without altering the molecule by adding hydrogens to them ( fromthe organic builder).

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Minimize ()

This uses MMFF molecular mechanics to refine the geometry. Selection
leads to a message at the bottom left of the screen:
The molecular mechanics energy* in kJ/mol, displayed at the bottom rightof the screen, is continually updated during the minimization process.
Minimization may be stopped at any time by clicking on the icon at thebottom right of the screen. Any geometrical constraints imposed on the
structure (see Constrain Distance, Constrain Angle, Constrain Dihedral
under the Geometry menu; Chapter 19) are enforced during minimization.
NOE’s are not taken into account. Also, any frozen atoms in the structure(see Freeze Center under the Geometry menu; Chapter 19) remain frozen.
Guess Transition State ()

This allows transition state geometries to be “guessed” based on thesimilarity with one or more entries in Spartan’s reaction database**. An“exact hit” replaces the guess with transition state for the same reaction
with the particular theoretical model entered in the database***. Morecommonly, the procedure attempts to provide as close a match as possible
with a database entry, generally involving a less substituted system or one
with different substituents. In this case, those parts of the structure that arecommon with a transition state in the database will be “frozen” and theremaining parts will be optimized using molecular mechanics. No
conformational searching is performed. Note that it may be essential for thereactants to be properly oriented to reflect the desired stereochemicaloutcome of the reaction.
* The mechanics energy is a combination of the strain energy which is necessarily positive and the nonbonded or intramolecular interaction energy which can be either positive or negative. It will most commonly
be a positive quantity, although it can be slightly negative.
** The Spartan Reaction Database (SRD) may also be directly searched by substructure. See discussion
earlier in this chapter.
*** At the present time, the majority of database entries derive from very simple (semi-empirical andHartree-Fock) quantum chemical models.

339

Where a reaction is completely unknown to the database, a fallback
technique (linear synchronous transit) is invoked. This cannot be expected
to yield as good a guess as that provided by the database proceduredescribed above.
Input to transition-state guessing procedure has already been described(Reaction Query earlier in this chapter). It will be familiar to organic
chemists, in that it is based on curved arrows, where each arrow identifies
the movement of one electron pair. Curved arrows may either besuperimposed onto a three-dimensional structure or onto a two-dimensional
drawing.
After all reaction arrows have been properly designated, clicking onatthe bottom right of the screen replaces the reactant(s) with a guess at thetransition state. In the event that the guess seems to be unreasonable, thisoperation may be undone (select Undo from the Edit menu). This allows
you to review your assignment of arrows and make changes as needed.

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Chapter 21
The Setup Menu
This chapter describes functions available under the Setup menu.
Calculations... is used to specify molecular mechanics calculations, semiempirical calculations, Hartree-Fock molecular orbital calculations andcorrelated calculations, including density functional calculations,
Møller-Plesset calculations, coupled cluster calculations and quadratic
configuration interaction calculations for ground-state species, andconfiguration interaction calculations and (time dependent) density
functional calculations for excited-state species. Tasks include calculationof energy, equilibrium structure and conformation, transition-state
structure, as well as identifying low-energy conformers for calculating
Boltzmann weights and for constructing energy profiles. Not all tasks areavailable for all methods. Hartree-Fock and density functional calculations
may be extended to include a solvation term based on the C-PCM procedure,
allowing equilibrium and transition-state structures and molecularproperties to be obtained in the presence of an idealized solvent. A wide
variety of all-electron Gaussian basis sets are supported for Hartree-Fockand correlated calculations as are pseudopotentials for calculations onmolecules incorporating elements for which all- electron basis sets are notavailable. Also provided are the G3 (MP2), G3, G4 (MP2) and G4
thermochemical recipes, as well as the T1 recipe that has been
parameterized to closely reproduce G3 (MP2) heats of formation with 2-3
orders of magnitude less computation time.
New to Spartan'24 are a series of five neural nets that have been trained to(1), improve conformer energy differences obtained MMFF molecularmechanics, (2), estimate ωB97X-D/6-31G* equilibrium geometries startingfrom MMFF geometries, and (3-5), estimate ωB97X-V/6-311+G(2df,2p),
ωB97M-V/6-311+G(2df,2p), and ωB97M(2)/6-311+G(2df,2p) energies
starting from ωB97X-D/6-31G* equilibrium geometries and energies.
These offer the possibility of accurately reproducing the results of highlevel quantum chemical calculations at greatly reduced cost.
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The automated multi-step procedure for identifying the lowest-energy
conformer of a flexible molecule and for calculating accurate Boltzmann
weights,(first introduced in Spartan’18) is now available with the option ofutilizing the new (in Spartan’24) neural net (machine learning) routines –which open the procedure up to both larger and more flexible molecules.
The scheme can be seamlessly combined with NMR data on the individual
conformers to yield Boltzmann averaged chemical shifts and coupling
constants.
Calculations... also requests calculation of IR, Raman, both 1D and 2D
NMR and UV/visible spectra. IR spectra may be calculated using the C-PCM
solvent model but solvated NMR, Raman and UV/visible spectra are notavailable. 3-Bond HH and 2 and 3-bond CH coupling constants may either be
directly calculated or evaluated empirically, whereas longer range HH andCH coupling constants as well as CC coupling constants if needed may be
calculated. A variety of molecular properties, QSAR descriptors andthermodynamic quantities are available for calculation and printing.
Finally, Calculations... specifies conditions for identifying similarmolecules, based either on molecular structure or chemicalfunctionality, as well as for identifying molecules that are compatible with aparticular molecular environment (a pharmacophore).
Calculations performed by Spartan’24 take advantage of 64-bit
architecture. Multi-core processors may be used to simultaneously process
different jobs or for most tasks involving Hartree-Fock, density functional
and RI-MP2 models may be directed at a single job.
Surfaces is used to designate graphical surfaces, including electron and spin
densities, electrostatic potentials, local ionization potentials and molecularorbitals, for display as surfaces, property maps and contour plots.
Accessible regions on electron density surfaces and property maps basedon these surfaces may be demarked.
Submit is used to direct jobs for calculation either locally or on a remotemachine running a license of Spartan.
The Setup menu provides access to dialogs for specifying molecularmechanics and quantum chemical calculations including a variety ofproperties and spectra, for specifying conditions for similarity analysis as well342

as specifying surfaces and property maps and for submitting jobs forcalculation.

Calculations...()

Calculations modules perform: molecular mechanics calculations using the
MMFF and SYBYL force fields; MNDO (MNDO/d for second-row
elements), AM1, RM1, PM3 and PM6 semi-empirical calculations,
including PM3 and PM6 calculations on transition- metal inorganic andorganometallic systems; Hartree-Fock molecular orbital calculations; a wide
variety of density functional calculations including time-dependent density
functional calculations (for excited-state species); MP2 and RI-MP2 MøllerPlesset calculations; configuration interaction (CI) calculations (for excitedstate species). All are applicable to energy calculation, equilibrium andtransition- state geometry determination, conformational searching andenergy profile construction, although some methods may not be practicalfor some tasks. Available for energy calculations only, are a series of highorder correlated models, including a double-hybrid density functionalmodel, MP3 and MP4 Møller-Plesset models, coupled cluster models andquadratic configuration interaction models. Heats of formation may be
calculated from G3 (MP2), G3, G4 (MP2) and G4 procedures“approximations” to coupled-cluster models, and from the much faster T1
recipe that is perhaps best viewed as an approximation to G3(MP2).
Neural nets that have been trained to improve conformer energy
differences obtained MMFF molecular mechanics, estimate ωB97X-D/631G* equilibrium geometries starting from MMFF geometries andestimate ωB97X-V/6-311+G(2df,2p), ωB97M-V/6-311+G(2df,2p), andωB97M(2)/6-311+G(2df,2p) energies starting from ωB97X-D/6-31G*
equilibrium geometries and energies, are accessible as an option to
specific MMFF or QM calculations.
A wide selection of basis sets are supported, ranging from the STO-3G minimalbasis set (recommended for Hartree-Fock models only), to the 3-21G split343

valence basis set (also recommended for Hartree-Fock models only), to 631G*, 6-311G*, cc-pVDZ, cc-pVTZ and cc-pVQZ polarization basis sets
together with the corresponding augmented representations, the def2 series ofdouble, triple and quadruple  basis sets and the PCJ basis sets specificallydesigned for calculation of NMR coupling constants. The dual basis set
approximation has been implemented for some (but not all) basis sets,
typically providing as much as an order of magnitude reduction incomputation cost with very little change in either reaction energies ormolecular properties. In addition, pseudopotentials for elements which allelectron basis sets do not exist are available, in particular, second and thirdrow transition metals and lanthanides. Note, however, that first derivatives ofpseudopotentials in the case where the valence incorporates f-type andhigher-order functions are only available for lanthanides, and U, Np, and Pu
from the actinides. All basis sets, except STO-3G and 3-21G, may besupplemented with polarization functions on hydrogen, additional and/or
higher-order polarization functions on heavy atoms and/or diffuse functions
on hydrogens and/or heavy atoms.
Quantum chemical calculations also result in a variety of atomic andmolecular properties, QSAR descriptors and thermodynamic quantities as wellas IR, Raman, NMR and UV/visible spectra. IR spectra are available formolecular mechanics, semi-empirical, Hartree-Fock, density functional(except for double-hybrid functionals) and MP2 and RI-MP2 models. Other
spectra are available only for Hartree-Fock and density functional models.
Note, however, that NMR spectra are not presently available where
pseudopotentials are employed.
Solvent may be introduced into Hartree-Fock and density functional
calculations by way of the C-PCM continuum model. Equilibrium (andtransition-state) structures and vibrational frequencies in addition to energies
may be calculated in the presence of solvent. Additional solvent models areavailable (see Help menu inside Spartan’24).
Discussion of molecular mechanics and quantum chemical methods ingeneral, focusing on the specific methods available in Spartan, is provided
in Topics under the Activities menu.
* The dialog allows for selection of Energy, Equilibrium Geometry, Transition State Geometry,
Equilibrium Conformer, Conformer Distribution, Energy Profile, NMR Spectrum, Similarity
Library, or Similarity Analysis tasks, as documented in this chapter.

344

A more thorough discussion of specific quantum chemical models isprovided in the latest Q-Chem User’s Manual (≈version 5.4 at the time ofthis revision to the Spartan manual).
Finally, the Calculations dialog accesses a procedure to quantify the extent
to which two molecules or a molecule and a pharmacophore are similar.
This does not involve molecular mechanics or quantum chemical
calculations but depends only on the geometry of the system.
Selection of Calculations... results in the Calculations dialog*.

This contains a number of pull-down menus, buttons and check boxes.
CalculateThis section contains a series of menus and check boxes that specify the task
to be accomplished, the electronic state (ground or first excited), the type of
calculation, method, basis set and solvent to be employed, as well as details
specific to each calculation type.
Task
Specification of what is to be done is by way of a pull-down menu:

345

Energy specifies calculation of energy (and in the case of quantum
chemical methods, a wave function) at a single geometry.
By default, Spartan reports energies from molecular mechanics and heats of formationfrom semi-empirical calculations, T1, G3(MP2) and otherthermochemical recipes in kJ/mol. Energies from Hartree-Fock and electroncorrelated models are reported in atomic units (hartrees).
The molecular mechanics energy comprises two parts: the strain energy and the nonbonded energy. The strain energy is the difference in energy between a molecule and its“strain free” analog. It is nearly always positive and less than a few hundred kJ/mol* inmagnitude. The non-bonded energy accounts for attraction or repulsion between atomic
centers that are not connected due to van der Waals and Coulombic interactions. Because
the strain energy of every molecule relates to a different standard, molecular mechanics
energies cannot be used to obtain reaction energies (unless there are no changes inbonding between reactants and products).
The heat of formation is the enthalpy at 298K of a balanced chemical reaction in which
a molecule is converted to a set of standard products. For example, the heat of formationof ethylene is given by reaction:
C2H4 → 2C (graphite) + 2H2 (gas)Here, graphite and hydrogen molecule are the carbon and hydrogen standards,
respectively. In practice, the actual measurement is typically carried out for a
combustion reaction, for example, for ethylene:
C2H4 + 3O2 → 2CO2 + 2H2O
Heats of formation may either be positive or negative quantities and generally span arange of a few thousand kJ/mol.
Heats of formation are not suitable for presenting energy data from most quantum
chemical calculations (except thermochemical recipes), simply because the standards forseveral important elements (most notably, carbon) are not well-defined isolated species.
In its place is the energy of a reaction that splits a molecule into isolated nuclei andelectrons, for example, for ethylene:
C2H4 → 2C+6 + 4H+ + 16e–
Total energies, as the energies of such reactions are termed, are always negative and may
be very large (tens of thousands of kJ/mol). They are most commonly given in atomic
units (hartrees).
1 atomic unit = 2625 kJ/mol
346

Aside from a difference in units (see Appendix E), it makes no difference whatsoever
which standard is employed to investigate thermochemistry.
Note that we will generally treat enthalpy (what is measured experimentally) andenergy (what is calculated) as identical quantities. They are not identical but very similar
for the purpose of dealing with chemical reactions.

Equilibrium Geometry specifies that the nearest energy minimum
will be located, and Transition State Geometry that the nearest first-ordersaddle point, an energy maximum in one dimension and energy minima inall other dimensions, will be located. Note, however, that not all first-ordersaddle points will correspond to chemically-meaningful transition states.
Energy Profile steps along a user-defined set of coordinates.
Energy applies to all methods. Equilibrium Geometry and Energy
Profile do not apply to double-hybrid density functional methods,
wavefunction-based correlated methods or thermochemical recipes.
Transition State Geometry does not apply to molecular mechanics
methods, double-hybrid density functional methods, wave-function-based
correlated methods and thermochemical recipes.
Equilibrium Conformer / Conformer Distribution
Equilibrium Conformer replaces the initial conformer of a moleculewith its lowest-energy conformer. Conformer Distribution replaces the
structure with that of the lowest-energy conformer but substitutes theenergy, dipole moment and atomic charges with the corresponding
Boltzmann-weighted averages. A list of all conformers that make up the
average is also provided as a separate Spartan document. Both procedures
involve examination of all available conformers and may involve MMFF,
MMFF corrected by a neural net, or a variety of multi-step protocols startingwith MMFF and ending with a large basis set density functional model.
The neural net has been trained on conformer energy differences for ≈250k
flexible organic molecules taken from several sources including the Spartan
Structure and Properties Database (SSPD, collections of natural products
and pharmaceuticals and entries from the Cambridge Structural Database(CSD). In it involves a ~2M conformers. It is presently restricted to theelements H, C, N, O, F, S, Cl and Br. MMFF molecular mechanics
structures are employed.
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Selection of Molecular Mechanics from the top menu for both
Equilibrium Conformer and Conformer Distribution leads to nearly
identical dialogs (that for Conformer Distribution is shown).

Spartan automatically identifies conformational degrees of freedom (single bonds andflexible rings). Conformer Rules are set in the Settings Preferences dialog (Preferences
under the Options menu; Chapter 25). Finer control may be exercised using Set Torsions
under the Geometry menu (Chapter 19).
For molecular mechanics (only) two different search modes are available. A systematic
search looks everywhere and may not be practical for molecules with many degrees ofconformational freedom. In practice, that is accomplished in two steps for molecules thatincorporate medium to large flexible rings: search only degrees of freedom involving therings yielding a set of “stable” structures and then for each of these structures, search theacyclic degrees of freedom.
A Monte-Carlo search follows a path that biases in favor of low- energy conformers(but that does not completely exclude high-energy conformers). While there is no
guarantee that the lowest-energy conformer (the global minimum) will actually be located,
it can be shown that the set of conformers examined (and kept) approach a Boltzmann
distribution. (This is strictly true only for a large number of search steps, but appears to beclosely approximated for searches with reasonable numbers of steps.) Spartan chooses
which (systematic or Monte-Carlo) search procedure to use based on the number ofconformational degrees of freedom. Selection may be forced using the SEARCHMETHOD (SEARCHMETHOD=) keyword; Appendix D.
Both Equilibrium Conformer and Conformer Distribution may be restricted to“looking at” a user-specified maximum number of conformers (Maximum Conformers
Examined). If this number is less than the estimated number of actual conformers, thisforces a Monte-Carlo search.
Selection of Density Functional from the leftmost of the menus following both
Equilibrium Conformer and Conformer Distribution results in a menu to the right348

with two entries: either B97X-V or B97M-V functionals both with 6-311+G(2df,2p)[6-311G*] basis set.

The B97X-V functional is used for energy calculations only and is coupled withgeometries from B97X-D/6-31G*. Similarly, B97M-V is coupled with B3LYP/6-31G*
geometries. Experience suggests that the former combination yields more reliable resultsalbeit at a computation cost that can be close to twice the latter combination. Other
combinations of methods may be specified, although their performance has not beenassessed.
The second line in the dialog starting from using contains a single menu which controls
the geometry to be employed for the final step energy calculation. B97M-V is initiallyselected, it contains:

If B97X-V is initially selected, it contains:

These menus control two of the steps in the multi-step procedure used to determine thelowest-energy conformer or the set of Boltzmann weights. This actually involves
intermediate steps to gradually reduce the number of conformers from those produced by
the initial MMFF search. The full procedure can be seen by checking Details at thebottom of the dialog. Shown below are the settings corresponding to menu selections of
B97X-V (functional), 6-311+G(2df,2p) [6-311G*] (basis set) using
B97X-D/6-31G* (geometry).

With details exposed, the models used for each of the steps can be altered (or eliminated
together) and energy and number thresholds are adjustable.
Selection of MMFF instead of B3LYP/6-31G* or B97X-D/6-31G* for geometry
calculation eliminates all intermediate steps resulting in a much less costly (andpresumably less accurate) protocol.

349

The difference between Equilibrium Conformer and Conformer Distribution(after the full sequence of steps has been completed), is the number of conformers
retained, that is, both tasks have the same computation cost.

Neural Net extensions
Beginning in Spartan’24 the Molecular Mechanics options included
Corrected MMFF as an option:

Of significant utility, are the additional machine learning routines accessedfrom the Est. Density Functional option:

as this enables a wide full range of neural networks to be used in tandem ina number steps in the workflow:

NMR Spectrum
NMR Spectrum calculates chemical shifts and coupling constants* for a
flexible molecule or for a set of closely-related (regio and or stereo) isomers
of a flexible molecule. A variety of multi-step procedures are available, allstarting either from a systematic conformer search using MMFF molecularmechanics**, or from a user-supplied list of conformers. The best MMFF
350

conformer could then be directly used for NMR calculations or the search
could be refined using a selection of density functional models for geometry
and energy calculations, the latter resulting in a series of Boltzmann
weights. Only two models, B3LYP/6-31G* and ωB97X-D/6-31G* areavailable in menus for NMR calculations. Both have been extensively tested
and have been corrected empirically. While not recommended (and notcorrected), a wide variety of other calculation models may be specified (seediscussion later in this section). Inclusion of the neural network routines
associated with conformational searching are also available for the multistep NMR Spectrum calculation.
Selection of NMR Spectrum leads to a dialog:

Checking the Details check box will enable additional options at each stepin the workflow:* 3-bond HH and 2 and 3-bond CH coupling constants available from parameterized expressions are replaced
if coupling constant calculation is requested. Longer-range CH coupling constants as well as CC coupling
constants may also be calculated.

351

Three menus appear to the right of NMR Spectrum at the top, although
only the middle menu is accessible (the other two specify Density Functionaland 6-31G*). Choice of available functionals between B3LYP and B97X-D
dictates the contents of the menus on the second line. When B3LYP is
selected, they read:No further information is required for the Goodman DP4 recipe. For the
B97M-V/6-311+G(2df,2p)[6-311G*] weighted average calculation, themenu to the right contains two selections:

For the B3LYP-D3/6-31G* energy calculation, the menu to theright contains only a single selection.
Where B97X-D is selected, the menu underneath reads:

Either option leads to 3 additional choices for geometry:352

Checking Use Custom Structure List replaces the MMFF conformer
search by a user specified list of conformers. This is a Spartan document
and may be pasted or dragged into the dialog that appears.

As previously mentioned, coupling constants are not calculated by default,
although 3-bond HH coupling constants and 2 and 3-bond CH coupling
constants are provided from parameterized relationships. These as well as
longer-range HH and CC coupling constants may be calculated by selecting
Calculated or Calculated (Fermi Contact) in lieu of Empirical from the
Coupling Constants menu to the right at the center of the dialog. In manycases, empirical coupling constants are likely to be sufficient, and in almost
all cases, coupling constants obtained within the Fermi contact
approximation which are significantly less costly are typically very close to
calculated values, that is, those obtained without the approximation.
Full details of the multi-step procedures may be seen by checking Details at
the bottom of the dialog. Users are able to alter the default energy andmaximum number thresholds between steps in the procedure as well aschange the models employed (or to eliminate the individual steps).

353

There are at least two distinct uses for Spartan’s NMR capability. The first,
perhaps of greatest interest and value to the natural products community, isto provide an accurate NMR spectrum corresponding to a structure
proposed for a “new” compound. Serious disagreement between calculated
and experimental spectra, that is, outside previously established limits might
cast doubt on the validity of the latter, either the specific peak assignmentsor the proposed structure, while agreement between the two by no means
confirms the experiment although it does lend credence.
The second use may be of greatest interest and value to the synthetic organic
community, where the identity of the molecule is most likely certain aside
from “details” regarding regio and stereochemistry.* For example,
comparison of calculated and measured NMR spectra might be of value todecide which of the four distinct products that could arise from a Diels-Alder
cycloaddition of 2-methyl cyclopentadiene and acrylonitrile is actuallyformed.

These two applications have different requirements and may best be met
with two different approaches rather than a “one size fits all”. Specifically,
contesting or supporting the experimental assignment of an “unknown”
natural product is quite likely more demanding of the computations thanfinding the best match among the closely-related isomers than may result ina synthesis.
Similarity Library Similarity Analysis
Spartan provides a procedure to assess and quantify the similarity of one ormore molecules in a document to one or more molecules in one or moredifferent documents. Similarity may either be based on molecular structure(geometry) or on chemical function descriptors (CFD’s). Spartan also
assesses the similarity of one or more pharmacophores in a document to one
or more molecules in one or more different documents.

* The results from DP4 analysis are available for posting in the spreadsheet.

354

Three different similarity analysis modes are available, depending on thetemplate (the selected document in the graphical user interface) and thelibrary (one or more different documents specified in the Calculations
dialog).
template

library

pharmacophores

molecular structures for which CFD’s
are assigned on-the-fly

molecular structures

molecular structures

CFD’s from molecular
structures

molecular structures for which CFD’s
are assigned on-the-fly

Two types of libraries are supported for molecular structures (and CFD’s
generated on-the-fly from molecular structures). In the first, each entry
represents a single molecule. In the second, each entry represents a selectionof different conformers of a single molecule and spanning the possible
shapes that the molecule may take on. The latter are generated using
Similarity Library*, and may only be used as library entries in similarity
analysis and not as templates.
Of the three similarity analysis modes, only the second makes direct use ofmolecular structures (selected atomic centers for the molecules in thetemplate) as a similarity measure. The other two make use of CFD’s
generated (and optionally edited) for the template, and generated on-the-fly inthe library. Selection of structure or CFD as the basis of similarity measuremust be explicitly stated (see discussion following).
Seven different chemical function descriptors (CFD’s) are recognized by thesimilarity analysis procedure, the first six of which are attributes of a molecule
while the seventh derives from knowledge of a molecule bound to a protein or
nucleic acid.
hydrophobe (sterically crowded region)
aromatic hydrophobe (aromatic ring)hydrogen-bond donor* When generating similarity libraries, it is strongly recommended that users change Conformer Rules rulefrom the Settings tab in the Preferences dialog (Chapter 25) to skeletal. This will use a much fasterroutine for similarity library generation.

355

hydrogen-bond acceptor
positive ionizable sitenegative ionizable site
excluded volume
Discussion of CFD types has already been provided (see CFD’s under
the Model menu; Chapter 18).

The individual CFD’s for molecules in the template (only) may either be usedor ignored in the similarity procedure. This is specified from Set Similarity
Centers under the Geometry menu (Chapter 19). The CFD Properties
dialog (accessible from Properties under the Display menu; Chapter 22)
allows for changing or extending the definition of a CFD For example, thenitrogen in a dimethyl amino group might initially be assigned as a hydrogenbond acceptor CFD, but could be changed to a positive ionizable site (as sucha center could become positively-charged at biological pH) or could be
extended to cover both possibilities.
Spartan assumes that chiral molecules in a library are unresolved (theycomprise an equal mixture of enantiomers).* That is to say, similarity
comparisons are carried out on both the library molecules as they are
stored and (if the molecules are chiral) on their mirror images. This
procedure may be overridden (providing comparisons only to the stored
molecules) by way of the Single Enantiomer keyword entered in the
Options field. See discussion later in this chapter and also Appendix D.
Note that only a single enantiomer of a chiral template molecule isconsidered. If comparisons involving both enantiomers are desired, thesecond enantiomer must be added to the query.

Selection of Similarity Library from the Calculate menu with either amolecule or pharmacophore (list of molecules/pharmacophores) leads to a
dialog for setting up a similarity analysis.

* Properties from quantum chemical calculations (structures, energies, ...) are independent of absoluteconfiguration..

356

One or more libraries need to be identified. This is accomplished by clicking
on the Add Library... button, and gives rise to a file browser. Onceselected, clicking on Open adds the library to the list of templates. A library
may be deleted from the list by clicking on its name in the list and clicking
on the Remove Selected button at the bottom of the dialog. Shift and Ctrl
keys function in the usual manner in both library addition and removal.
Selection of Similarity Analysis from the Calculate menu leads to a second
dialog.

Prior to starting a similarity analysis, it is necessary to select either
structure or CFD from the Use menu near the bottom of the Calculations
dialog.
Similarity analysis is most valuable where the template molecule isconformationally flexible, and it is not apparent which (if any) of thedifferent shapes it adopts might match a particular target in a library.

357

Where the target is also flexible and its conformation is not established, the process
must be repeated for every template conformer-target conformer pair. However,if the purpose is simply to identify which target molecules a particular template
molecule might match, irrespective of conformer, the first good match concludes
the analysis. In this case, the user is left with the knowledge that template andtarget can be made to match (together with an example of a match).
The similarity algorithm incorporated in Spartan attempts to examine
template-target pairs that are most likely to lead to matches before examining pairsthat are less likely. It also allows early termination upon finding a single good match,or a user-specified number of good matches*. Taken together, these can lead toone or two orders of magnitude speedup in the analysis.

* Criteria for early termination are specified using program options. See Similarity Analysis
Options in Appendix D.

State
Specification of State (electronic state) is by way of a pull-down menu. The
default setting Ground (state) may be changed to First Excited (state) byclicking on to the right of the box and back again to Ground (state) byclicking on . In general, all models are available for Ground (state)calculations. Switching to First Excited (state) results in access to only twoclasses of models that handle excited state calculations, time-dependent
density functional models* and configuration interaction models.
In Gas/Solvent
By default, all calculations are performed in the gas state. Spartan also
supports energy, gradient and frequency calculations using both HartreeFock or density functional methods in the presence of solvent using the CPCM continuum model. This is specified from the menu to the right of in,for Energy, Equilibrium Geometry, Transition-State Geometry andEnergy Profile tasks. This depends only on the dielectric constant of thesolvent.

* Excited state calculations with time-dependent density functional models that incorporate explicit
account of dispersion (B97X-V, B97M-V and B97M-V) are not presently supported.

358

Solvent choices are limited to non-polar (small dielectric, 7.4 for THF) polar(large dielectric, 37 for DMF) and water (dielectric constant of 78).
Continuum models such as C-PCM do not account for explicit solvent-solute(or solvent-solvent) interactions such as hydrogen bonding. A nonhydrogen bonding solvent such as DMSO with a large dielectric constantwill behave similarly to a hydrogen bonding solvent such as water.
Additional solvent options are also provided.*
Type of Calculation
Specification of type of calculation is by way of a series of menus on twolines to the right of Calculate. Menus on the first line designate the task at
hand, indicate whether it applies to ground or excited electronic state andspecify solvent (if any). The class of methods along with associated“details” are specified in the menus on the second line. Available tasks forground state energy calculations:* Additional solvent choices and solvation models are also available via type-in from the Options
field. A discussion is provided in the Properties FAQ, accessible from Spartan’24 Help in the Helpmenu.
** w/o density signifies that a density matrix is not to be obtained greatly reducing computationcost.
*** A number of other wave function correlated methods are available, but need to be entered directly
into the Options field: CCSD(2), OD, OD(T), QCCD, QCCD(2), QCISD and QCISD (T).

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Density Functional*

Thermochemical Recipes**

Configuration Interaction
Selection of entry More which appears at the end of the list in several drop
down menus leads to a dialog that provides a wider selection of methods:
Selection of Equilibrium Geometry, Transition State Geometry or Energy
Profile removes Wave Function Based Correlated and Thermochemical
Recipes. Selection of Equilibrium Conformer or Conformer Distribution
leaves only Molecular Mechanics and Density Functional and selection of
NMR Spectrum leaves only Density Functional.
Molecular mechanics models have proven suitable for determining equilibriumgeometries of organic molecules. Calculations of compounds comprising
hundreds or even thousands of atoms are possible, one or two orders ofmagnitude more than what is practical with even the simplest quantum
mechanical models. Because molecular mechanics models require explicit
bond-type and identification, they may not be used to obtain reaction energies,
except where bond-types are identical. For example, they can be used toassess differences in energies among stereoisomers. Perhaps the mostimportant use of molecular mechanics is as a first step in determining
equilibrium conformation or distribution of low-energy conformers, where it
serves to remove high energy conformers.***

A variety of other functionals are available and may be entered directly into the Options field. A fulllisting is provided in Appendix B. Additionally, any combination of supported exchange and correlation
functionals may be specified.
** The older G2 recipe is also available but needs to be entered into the Options field.
*** While present-generation molecular mechanics calculations are not reliable enough to consistently
identify the lowest-energy conformer, let alone account quantitatively for conformer energy
differences, they appear to be suitable for distinguishing between conformers that are good candidates
from those that are not.

360Semi-empirical models are the simplest methods based on quantum
mechanics. They are applicable to molecules containing 100 - 200 atoms, but
not to molecules containing thousands of atoms, for example, proteins, atleast not routinely. The MNDO, AM1, RM1, PM3 and PM6 models
generally provide geometries in good accord with experimental structures.
The PM3 and PM6 models have also been parameterized for transition
metals and generally provide a reasonable account of equilibrium geometries.
While semi-empirical models are generally suitable for evaluation of suchproperties as polar surface area that depend solely on geometry, none of thepresent-generation of models is suitable for the calculation of relative energies
as might be required to conclude whether a chemical reaction is weakly orstrongly exothermic, thermoneutral or weakly or strongly endothermic, orwhether one isomeric product of a reaction is likely to be more or less stable
than another, or to identify the lowest-energy tautomer. Finally, semiempirical models do not provide an acceptable account of conformer energy
differences in flexible molecules. In fact, they do not appear to be superior tomolecular mechanics models. Semi- empirical models are available for the
calculation of IR spectra but do not provide a very good account. They are
not available for the calculation of Raman, NMR or UV/visible spectra.
Hartree-Fock models follow from the Schrödinger equation by requiringthat the electrons be independent particles, the Hartree- Fockapproximation. Here, the motions of electrons in molecules (molecularorbitals) are approximated by a sum of the motions of electrons in atoms(atomic orbitals). A second approximation, termed the LCAO or Linear
Combinations of Atomic Orbital approximation, distinguishes different
Hartree-Fock models. Different models use different basis sets, that is,different numbers and kinds of atomic orbitals. Two of the most popular small
basis sets are 3-21G and 6-31G*. The 3-21G split-valence basis set uses one
atomic orbital to describe each non-valence electron and two atomic orbitals
to describe each valence (core) electron, that is, it comprises one 1s atomic
orbital and two sets of 2s and 2p atomic orbitals.

361

1s
2s, 2px, 2py, 2pz
2s´, 2px´, 2py´, 2pz´
The 6-31G* polarization basis set increases the flexibility by including dtype atomic orbitals that, while not occupied in the atom, are used inmolecules.
1s
2s, 2px, 2py, 2pz
2s´, 2px´, 2py´, 2pz´dxx, dxy, dxz, dyy, dyz, dzz
Larger basis sets involving even higher splitting of valence shells, including
higher-order (f and g type) functions as well as diffuse functions have been
defined and are available in Spartan. Among the most commonly used are
the 6-311+G(2df,2p) basis sets proposed by Pople and the cc-pVQZ basis
set proposed by Dunning. Description of their makeup is provided in Topics
available under the Activities menu and in A Guide to Molecular Mechanics
and Quantum Chemical Calculations* which is provided as a PDF underthe Help menu.
3-21G, 6-31G* and larger basis set Hartree-Fock models generally
provide good account of the geometries of organic molecules. This extends
to unusual or unstable systems for which experimental data may be limited(and hence may be poorly represented in parameterization of the semiempirical models). However, Hartree-Fock models are not successful inaccounting for the equilibrium geometries of inorganic and organometallic
compounds incorporating transition metals. The 3-21G and 6-31G* models
provide at best a qualitative account of thermochemistry. For example, they
are usually able to say whether a particular reaction is weakly or strongly
exothermic or weakly or strongly endothermic, and to properly order thestabilities of closely-related isomeric products. Hartree-Fock models are,however, generally*This reference was written in 2003, and as such it does not include a full assessment or descriptionof many of the newer computational features included in Spartan’24. In particular many functionals andextended basis sets and no neural networks are not covered. An updated version is in preparation.

362

able to properly describe the energies of isodesmic reactions, that is,reactions where formal bond count is maintained.
The most conspicuous and most important flaw of Hartree-Fock models istheir inability to properly account for the energetics of reactions where bonds
are made or broken. This includes activation energies, that is, the difference
in energy between reactants and transition state. The problem can be traced
to the Hartree-Fock approximation, which in effect replaces interactions
between electrons by interactions between one electron and the average
field created by all other electrons. As a consequence, electrons get in eachother’s way to a greater extent than they should, leading to overestimationof the electron-electron repulsion energy, most significantly for electrons thatare paired. Because bond dissociation reduces the number of electron-pairs (byone), the overestimation will be greater for reactants than for products,
meaning that the calculated dissociation energy will be too small.*
Hartree-Fock models are available for calculation of IR, Raman, NMR andUV/visible spectra, the last in combination with CIS models for calculations
involving excited states. IR (Raman) frequencies are typicallyoverestimated by 10-15% and NMR chemical shifts show large variations
from experimental values.
Correlated Models
Models that lessen the effects of the Hartree-Fock approximation are termed
correlated models and divide into two broad categories, density functionalmodels and wave-function-based models.
Wave Function Based Models
Wave function-based models, typified by Møller-Plesset models andconfiguration interaction models extend the flexibility of Hartree-Fockmodels by mixing ground and excited-state wave functions. They are
significantly more costly than Hartree- Fock models and may or may not
be more costly than density functional models (see discussion following).

* Consider the bond dissociation energy of H2. The (limiting) Hartree-Fock energy of the products(hydrogen atoms each with only one electron) is exact, while the energy of the reactant (H2 with twoelectrons) is too large. Therefore, the calculated bond dissociation energy will be too small.

363

However, they offer the advantage over the latter by providing a clear path
to improvement. Both the so-called full configuration interaction model andthe Møller-Plesset model taken to infinite order lead to the exact energy.
Density Functional Models (DFT)
Density functional models explicitly introduce an approximate(“empirical”) correlation term (a functional). The advantage of density
functional models over wave-function-based correlated models is their
computation cost, which is of the same order as Hartree-Fock models. The
disadvantage of density functional models is that it is not apparent how to
improve on a particular choice of functional.
While it is common to view density functional models as an extension toHartree-Fock models in that an extra term, the so- called exchange
correlation functional is introduced, in practice, some functionals comprisedistinct exchange and correlation components while others do not draw aboundary. What is the “correct” exchange/correlation functional? The quest
has gone on for several decades and hundreds of functionals have been
proposed. What follows is short classification of these methods.
Local Density Approximation (LDA)
The functional first proposed stems from a purely hypothetical problem inwhich a uniform gas of non-interacting electrons moves in a positively
charged field. An analytical solution for the exchange energy is available andtakes the form of the density to the 4/3’s power. The form of the correlationenergy may be arrived at through numerical simulation, and is dependent on
only the local density at each point.
Functionals that depend only on the electron density () are said to follow
the local density approximation and are referred to as LDA functionals.
LDA functionals are not generally suitable for accurate calculation of thegeometries, energies and properties364

of molecules and have largely been supplanted by a variety of more-flexible
forms. These have traditionally been divided into several classes, although
the lines between them are blurred. In rough order of increasing complexity,
these are:Generalized Gradient Approximation (GGA)
These functionals depend on the gradient of the electron density, in addition
to the density itself. GGA functionals have been around since the mid 1980’s
and were the first to provide a reasonable account of the energies ofchemical reactions. In this sense, they were instrumental in drawing
attention to density functional theory as a viable “low-cost” alternative towave function based correlation techniques. The BLYP functional isperhaps the most well-known of the GGA functionals.
Global Hybrid Generalized Gradient Approximation (GH- GGA)
GH-GGA functionals (more commonly simply referred to as hybrid
functionals) replace a fixed fraction of the exchange by the “exact” HartreeFock exchange, the fraction being a parameter. It is likely that it was theintroduction of this class of functionals that caused the community torecognize (or at least admit) that density functional theory was “semiempirical” in nature, in the sense that it is “parameterized”. Adding the
Hartree-Fock exchange is “costly”, but led to significant improvements in thedescription of reaction energies. While GH-GGA functionals wereintroduced in the early 1990’s, they remain a mainstay in the application ofdensity functional theory to chemistry. The B3LYP functional, in particular,
is still widely used even though there are now much better choices.
Range Separated Hybrid Generalized Gradient Approximation (RSHGGA)The defining idea behind range separated GGA hybrids is that the “optimum”
amount of Hartree-Fock exchange varies with electron- electron distance, froma small percentage in the long range limit to a large percentage in the shortrange limit, in the extreme from365

0% to100%. Both B97X-D and B97X-V functionals are range- separated
GGA hybrids, and both incorporate additional features to account for
dispersive interactions. We consider the B97X-D functional combined withthe 6-31G* basis set to be a good model for geometry calculation, and theB97X-V functional with a large basis set such as 6-311+G(2df,2p) to bea good model for energy calculation.
meta Generalized Gradient Approximation (mGGA)
A meta GGA functional not only depends on the electron density and its
gradient (as does a GGA functional) but also on the Laplacian (second
derivative) of the electron density. As such, it can be construed as the next
logical step beyond GGA in constructing a Taylor series expansion of theelectron density. More commonly, meta GGA functionals are viewed asadding the so-called kinetic energy density to GGA. In either case, theaddition can be constructed as second-order term in a Taylor series expansionof the electron density. The B97M-V functional is an example of a “pure”
meta functional.
Global Hybrid meta Generalized Gradient Approximation (GHmGGA)
These are strictly akin to global hybrid GGA (GH-GGA) functionals in thata fixed percentage of the Hartree-Fock exchange is introduced. The “only”
difference is that a meta GGA functional including a second-order term
replaces a GGA functional. The M06-2X functional that is widely accepted
as an excellent choice for thermochemical comparisons is an example of a
GH-meta GGA functional.
Range Separated Hybrid
Approximation (RSH-mGGA)

meta

Generalized

Gradient

A range-separated meta GGA (RSH-mGGA) is identical to a rangeseparated GGA (RSH-GGA) functional except that a meta GGA functional
has replaced the underlying GGA functional. M11 and B97M-V are
examples of a range-separated meta GGA functionals.

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Double Hybrid meta Generalized Gradient Approximation (DH-RSHmGGA)
This class of functionals introduces a term that depends on excitations fromoccupied to unoccupied molecular orbitals
B97M(2) is an example of a double hybrid density functionalmodel. At present, it is available for energy calculations only.
Non Local Corrections
Aside from the classifications outlined above, functionals may also be
described as either strictly “local” or accounting for long- range dispersive
van der Waals interactions. “Local” functionals are described in terms of asingle integral over the three spatial coordinates, whereas non local
functionals involve a double integral over two sets of coordinates. This may
add significant cost to the calculations. For example, the range-separated
GGA hybrid ωB97X-V functional uses the VV10 non-local correlation
functional is 3-5 times more costly than the parent ωB97X functional. An
alternative and less costly way to account for dispersive interactions is to
add an empirical correction to the functional. So-called Grimme corrections
are designated by appending “-D” as in ωB97X-D, or “”D3” as in B3LYPD3, tothe end of the functional.

367

Which classes of functionals are “best” and which functionals
within each class are “best”?
1. LGA functionals are not suitable for chemical applications. While they are
generally able to reproduce molecular geometry, better documented HartreeFock models with very small basis sets are equally successful. Of greater
importance, LGA functionals present a poor account of the energetics ofchemical reactions.
2. While GGA functionals provide marked improvement over LGA
functionals they have largely been supplanted by GH- GGA functionals thatare typically only slightly more costly. B3LYP, in particular, may be viewed
as the first functional to be widely used (and continue to be used) amongchemists, providing solid accounts of both geometry and reaction energies.
3. RSH-GGA functionals offer noticeable improvement over GH- GGA
functionals for reaction energies, albeit with significant (factor of nearly 2)
increase in computational cost. We consider the B97X-D functional to be alikely contender to replace B3LYP for routine chemical applications.
4. meta GGA, GH-meta GGA and RSH-meta GGA functionals, typified by
B97M-V, M06-2X and M11 and B97M-V, respectively, appear to offer
little improvement over RSH- GGA functionals.
5. Double hybrid RSH meta GGA functionals such as B97M(2) offer some
improvement for reaction energies and conformational energy differences but at
a significant computational cost.
“Cost” of Density Functional Models
The computation “cost” of density functional models depends on the class,the number of basis functions, , and the number of points in the numericalintegration grid, κ. GGA and pure meta- GGA functionals that do not
require the Hartree-Fock exchange formally scale as O(2). The otherfunctionals combine this dependence with the cost of the Hartree-Fockexchange, which368

formally scales as O(4) but in practice is O(3) or lower. Finally, functionals
such as ωB97X-V that directly account for dispersion have a step that scalesas O(22). This typically dominates the calculation. Times for calculationof the energy together with its gradient (“one step” in the optimization ofmolecular geometry) with the 6-31G* basis set for morphine (C17H19NO3)
follow. The ωB97M(2) functional is not included as it is presently not
implemented for gradient calculation. The RI-MP2 model is provided forcomparison.
B3LYP (GH-GGA)ωB97X-D (RSH-GGA)ωB97X-V (RSH-GGA+dispersion)
ωB97M-V (mGGA)
M06-2X (GH-mGGA)
M11 (RSH-mGGA)
RI-MP27 mins.
15 mins.
41 mins.
50 mins.
19 mins.
22 mins.
10 mins.

Density functional and wave function-based correlated models make use of
the same basis sets as Hartree-Fock models, except that minimal and splitvalence basis sets do not yield satisfactory results. Among the most popularmodels are the B3LYP/6-31G* and ωB97X-D/ 6-31G* density functionalmodels and the MP2/ 6-31G* (second-order) Møller-Plesset model for
equilibrium and transition-state geometry calculations, the ωB97X-V/ 6311+G(2df,2p) density functional model for reaction energy calculations
and theωB97X-V/6-311+G(2df,2p)[6-311G*] and ωB97M-V/6311+G(2df,2p)[6-311G*] dual basis set density functional models forconformer energy (Boltzmann weight) calculations* (Dual basis sets aredescribed later in this chapter).
Density functional models and MP2 models provide an excellent account of
the equilibrium geometries of organic molecules, and are almost always tobe preferred over Hartree-Fock models for this purpose. The one exception
may be geometry calculation in*

The observation that geometry calculations require less costly models than either reaction or conformer
energy calculations suggests that significant computer time saving can be achieved by using two different
models to complete a task.

369

very large molecules where practical consideration may require use of avery small basis set. Here the Hartree-Fock model with the 3-21G basis set
may be the best choice. Note, however, that while density functionalmodels provide a good account of molecules incorporating transition metals(and lanthanides), MP2 models do not. Both density functional models andMP2 models offer a good account of thermochemistry, including forreactions in which bonds are made or broken, activation energies being animportant example.
Density functional models, with the exception of double-hybrid models, areavailable for the calculation of IR, Raman, NMR and UV/visible spectra,
the last in conjunction with so-called time-dependent density functionalmodels for calculations involving excited states. They are the methodsof choice.
Thermochemical Recipes
A number of thermochemical recipes (combinations of different
quantum chemical methods) have been formulated in an attempt toreproduce experimental heats of formation to within 4-8 kJ/mol. (Except
for very simple molecules, errors in experimental heats are seldom lessthan this.) We review the details for G3(MP2), the simplest of the Gx
recipes that have been formulated. (More costly procedures, G3, G4(MP2)and G4 are broadly similar.) G3(MP2) reproduces experimental heats offormation for a wide variety of small molecules to within 6 kJ/mol (meanabsolute error), with only a small number of systems showing errors twice
this amount. G3(MP2) may easily be applied to molecules comprising up
to 10-15 heavy (non- hydrogen) atoms, but applications to molecules
comprising more heavy atoms quickly become impractical.
Three different energies are required in the G3(MP2) recipe:
EA MP2/6-31G* using the MP2/6-31G* equilibrium geometry
EB MP2/6-311++G(2df, 2p) using the MP2/6-31G* equilibriumgeometry370

EC QCISD(T)/6-31G* using the MP2/6-31G* equilibriumgeometry
These are combined in order to take into account both the effects ofincreased basis set size and of electron correlation beyond the MP2 level.
Note, that the two effects are treated independently in order to avoid having
to perform a QCISD(T) calculation using a large basis set.
E = EA + (EB - EA) + (EC - EA)
Two corrections are needed to bring the calculated energy in line with whatis actually measured experimentally: a correction for zero-point energy;
Ezero-point, and a correction to the enthalpy (energy) to account for finite
temperature (298K), H(T).

h is Planck’s constant, k is the Boltzmann constant, R is the gas constantand N is Avogadro’s number. Both zero-point and temperature corrections
require vibrational frequencies. These are obtained from Hartree-Fock/631G* calculations and require the corresponding equilibrium geometry.
To summarize, the G3(MP2) recipe requires two equilibrium geometry
calculations (at HF/6-31G* and MP2/6-31G*), a HF/6-31G* frequency
calculation, a MP2/6-311++G (2df, 2p) energy calculation and a
QCISD(T)/6-31G* energy calculation. The QCISD(T) calculation
dominates with increasing molecular size. Next most costly is theMP2/ 6-31G* geometry optimization, although both the large basis set

371

MP2 energy and the HF/6-31G* frequency may be significant.
T1 is a simplified recipe intended to closely reproduce G3(MP2) heats offormation rather than experimental heats. It eliminates the QCISD(T)/6-31G*
energy calculation (EC), the zero-point energy calculation (Ezero-point) and thetemperature correction to the enthalpy (∆H(T)), and replaces the large basis
set MP2 energy calculation (EB) with a dual-basis-set RI-MP2 calculation,
where G3MP2large is the large basis set (the same basis set that is used in the
G3(MP2) recipe) and 6-311G* is the small basis set. To compensate, anempirical correction based on the Hartree-Fock and RI-MP2 energies andMulliken bond orders is introduced. This follows from a linear regression
analysis involving G3(MP2) heats of formation for ≈1,050 molecules. T1
uses HF/6-31G* equilibrium geometries, instead of MP2/6-31G*
geometries.
The T1 recipe reproduces G3(MP2) heats of formation with a mean absolute
error of <1 kJ/mol. It reproduces the full set of ~2,000 experimental heatsof formation in the NIST thermochemical database with a mean absolute
error of 9 kJ/mol, comparable to the error of the G3(MP2) calculation. The
T1 recipe also seems to provide a good account of conformational energy
differences (although the experimental dataset that has been examined is very
limited). This has been employed to identify the best (lowest heat offormation) conformer for the molecules in the Spartan Spectra andProperties Database (SSPD).
Except for semi-empirical methods and for thermochemical recipes, either
restricted or unrestricted scf methods may be used. The former restricts
paired electrons to the same orbital, whereas the latter allows the electrons to
occupy different orbitals. The default (singlets with restricted methods andnon-singlets with unrestricted methods) may be overridden using the SCF
keyword from the Options field (Appendix D). Semi-empirical methods
and thermochemical recipes are limited to unrestricted methods.

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Basis Sets
Except for molecular mechanics and semi-empirical methods and forthermochemical recipes, a basis set needs to be specified. Menus provide anumber of choices.* For Hartree-Fock methods:

For all other methods:

The 3-21G basis set for second-row and heavier main-group elements
incorporates a set of d-type functions. While these are not occupied
in the atomic ground state, they have been found necessary for proper
description of bonding in molecules. 6-311++G (2df,2p) uses the 6311++G (3d2f,2p) basis set for second-row elements.
The combination of a method, for example, B97X-D, and a basis set,for example, 6-31G*, constitutes a theoretical model or more simply amodel. The nomenclature is to separate method and basis set by a “/”, forexample, B97X-D/6-31G*. By convention, specification of Hartree-Fock(HF) as a method is optional. That is, specification of basis set alone refers
to Hartree-Fock models, for example, both HF/6-31G* and 6-31G* refer
to combination of the Hartree-Fock method and the 6-31G* basis set.
Methods where basis sets are not relevant for example, MMFF (molecularmechanics), or are not specified, for example, PM3 (semi-empirical) arethemselves models.

* Other basis sets may be conveniently accessed by clicking on More. These include the Pople 6-31G or 6311G basis sets followed by: (idjf) or (idjf, kpld) where i is the number of sets of d functions on nonhydrogen atoms, j is the number of sets of f functions on non- hydrogen atoms, k is the number of pfunctions on hydrogen atoms and l is the number of sets of d functions on hydrogen atoms. If 0 eliminate
p, d, f; if 1 eliminate the number; 6-31G or 6-311G with “+” or “++” inserted before G. The Dunning ccpVxZ and aug-cc- pVxZ (x = 2,3,4,5) and Ahlrich, Weigend def 2 basis sets are also available.

373

Dual Basis Sets
If turned on (from the Basis Set Selector dialog), Dual Basis signifies thata Hartree-Fock, density functional, MP2 or RI- MP2 energy calculation(only) with a “large” basis set will be approximated by a calculation inwhich SCF convergence is first achieved using a “smaller” basis set andthen corrected perturbatively for the effects of basis set extension. While thedual basis set approximation significantly affects total energies (andcalculations with and without the dual basis set approximation cannot bemixed in energy comparisons), it has only a small effect on calculated relative
energies, and can reduce the cost of large- basis-set energy calculations by
two to ten times (depending on the choice of the small and large basis sets)*.
The conjunction of the 6-311G* basis set (small) with the 6-311G(2df,2p)
basis set (large) is commonly employed for energy calculations with theB97X-V density functional model.
Pseudopotentials
Pseudopotentials are employed only where all-electron basis sets areunavailable, and are used in conjunction with all-electron basis sets forelements where they are available. This is primarily for elements heavier
than Kr, most importantly fourth-row main-group elements, second and thirdrow transition metals, and lanthanides. For example, an B97X-D/6-31G*
calculation on ruthenium ethylene tetracarbonyl would employ a
pseudopotential only for ruthenium and the all-electron 6-31G* basis set forhydrogen, carbon and oxygen. The overall method is referred to as B97X-D/631G*. Pseudopotentials pertain to Hartree-Fock, density functional, MP2 andwave function based correlated calculations only, but not to RI-MP2
calculations or calculations using the STO-3G and 3-21G basis sets.

*

It is important that the small basis set be a subset of the large basis set. The selections provided in
the menus and in the “more” dialogs satisfy this condition.

374

Start From
Energy calculations (only) from one model may be preceded by equilibrium
or transition-state-geometry calculations at another (simpler) model.
The menu immediately to the right of Start From provides three choices:

Selection of Equilibrium Geometry leads to a new set of menus, the leftmost
being the class of methods.

Selection of Molecular Mechanics leads to a menu.

Selection of Semi-Empirical leads to a menu.

Selection of Hartree-Fock leads to a menu of available basis set(with More providing access to additional choices).

Selection of Density Functional leads to two menus, thefirst comprising available functionals (with More providing access375

to additional choices)and the second comprising available basis sets (with Moreproviding access to additional choices).

These selections are the same for Transition State Geometry
except that Molecular Mechanics is not available.
Finally, Est. Density Functional leads to a single selection: ωB97X-D/631G*.
Subject toSpartan allows calculations to be carried out in the presence of geometricalconstraints and/or with atoms which have been frozen in place.
If checked, Constraints signifies use of any previously definedconstraints on distances, angles and dihedral angles into equilibrium andtransition-state geometry optimization, conformation searching andgeneration of energy profiles. This does not apply to energy calculation,
NMR spectrum calculation, similarity library generation or similarity
analysis. See Constrain Distance, Constrain Angle and Constrain
Dihedral under the Geometry menu (Chapter 19) for information about
constraining geometrical parameters.
Note that NOEs are not treated as constraints, but rather as post-calculation
filters in establishing conformer distributions.

If checked, Frozen Atoms signifies that the coordinates of any atoms
that have previously been frozen will not be moved during equilibrium and376

transition-state geometry optimization, conformation searching andgeneration of energy profiles. This does not apply to energy calculation,
NMR spectrum calculation, similarity library generation or similarity
analysis. See Freeze Center under the Geometry menu (Chapter 19) for
information about freezing atoms. See also discussion in Chapter 23
regarding the freezing of heavy atoms in structures resulting from a searchof the CSD.
ComputeEntries under this section request calculation of infrared, Raman, NMR andUV/visible spectra as well as a variety of descriptors used in QSAR analyses,
and in the case of transition state optimizations, optionally compute an
Intrinsic Reaction Coordinate or IRC.
IR
If checked, calculates vibrational frequencies and infrared intensities
together with the corresponding vibrational modes. These are available bothin the Spectra dialog (Spectra under the Display menu; Chapter 22) andin the output (Output under the Display menu; Chapter 22).
Thermodynamic properties (enthalpy, entropy, heat capacity and Gibbs
energy) are available from the Thermodynamics tab of the Molecule
Properties dialog accessible from Properties under the Display menu
(Chapter 22)*.
Note that vibrational frequencies for several commonly-employedmodels tabulated under Summary in the Output dialog have been
uniformly scaled, and resulting thermodynamic properties are basedon scaled frequencies. Scaling factors are as follows:
AM1

0.923

PM3

0.916 PM6

HF/3-21G
B3LYP/6-31G*

0.906
0.960

HF/6-31G*
EDF2/6-31G*

0.899
0.962

M11/6-31G*
0.947
B97M-V/6-31G* 0.949
MP2/6-31G*

*

1.050

B97X-D/6-31G* 0.949 M06-2X/6-31G*
0.947
B97M-V/6-31G* 0.949 B97X-V/6-31G* 0.949

0.943

Entropy (and Gibbs energy) calculations are problematic in large part due to the harmonic
approximation. Discussion is provided under Properties and Spectra in Appendix A.

377

Scale values may be changed from the Thermodynamics tab of the
Molecule Properties dialog (Properties under the Display menu;
Chapter 22).

Vibrational modes may be animated and an IR spectrum displayed from theSpectra* dialog (Spectra under the Display menu; Chapter 22).
Second derivatives required for frequency calculation are evaluatedanalytically for molecular mechanics, semi- empirical, Hartree-Fock anddensity functional models (except ωB97M(2)), but this involves numericaldifferentiation of analytical gradients for RI-MP2 and MP2 models. This ismuch more costly in terms of computation. Frequency calculations fordouble-hybrid density functional models and higher-order wave-functionbased correlated models are not available.
Raman
If checked, calculates vibrational frequencies (the same as infrared
frequencies) and Raman intensities. These are available both in the Spectra
dialog (Spectra under the Display menu; Chapter 22) and in the output(Output under the Display menu; Chapter 22). The Raman spectrum may
be displayed from either the simplified or more general form of the Spectra
dialog (Spectra under the Display menu; Chapter 22). Note that request fora Raman spectrum also results in an IR spectrum.
NMR
If checked, calculates NMR chemical shifts and empirical estimation of HH
and CH coupling constants. These are then available in the Spectra dialog(Spectra under the Display menu; Chapter 22), in the output (Output
under the Display menu; Chapter 22), from the Atom Properties dialog(accessible from Properties under the Display menu; Chapter 22) and as* A simplified spectra dialog is presented by default. A more general spectra dialog can be utilized by turning
off the spectra pane checkbox. (Settings tab, Preferences dialog, see Options menu, Chapter 25).

378

atom labels (Configure... under the Model menu; Chapter 18). 13C (proton
decoupled) and 1H (either with or without the influence of three-bond HH
coupling) spectra from Hartree-Fock or density functional calculations may
be displayed from either the simplified or more general form of the Spectra
dialog (Spectra under the Display menu; Chapter 22)*. DEPT spectra (13C
spectra in which carbons with one or three attached protons point up,
carbons with two attached protons point down and quaternary carbons areabsent) may only be displayed from the general form of the Spectra dialog.
Finally, 2D COSY (proton vs. proton) and HSQC and HMBC (proton vs.
13C) spectra using either empirically estimated or calculated HH and CH
coupling constants may be displayed from both simplified and moregeneral forms of the Spectra dialog.
Uncorrected chemical shifts (in particular, 13C shifts) are not sufficiently
accurate to be useful for NMR spectra prediction. 1H, 13C and 19F shifts
calculated from the EDF2/6-31G* model have been corrected using ascheme involving both topology and bond orders to neighboring atoms. 13C
shifts only from the B3LYP/6-31G*, ωB97X-D/6-31G* and ωB97X-D/ 6311G* models have been corrected by a more recent scheme involving
topology and bond lengths (as opposed to bond orders) to neighboring
atoms. Corrections for other quantum chemical models are not available.
Errors for corrected shifts are generally a half to a third of those foruncorrected shifts making them more appropriate for NMR spectra
prediction.
Note that 13C chemical shifts from the B3LYP/6-31G* model inprevious versions of Spartan (prior to Spartan’18) were correctedusing a less accurate scheme based on local topology.

NMR line intensities are assumed to be proportional to thenumber of equivalent carbons or hydrogens.

* Chemical shifts for other nuclei are available in the Output dialog (Output under the Display menu;
Chapter 22) and may also be attached as labels (Configure... under the Model menu; Chapter 18).
Chemical shifts for proton, carbon, nitrogen, fluorine, and phosphorous are given relative to standard
compounds, for example, TMS in the case of both proton and carbon. A table of standards is provided inAppendix L.

379

Coupling Constants (Empirical, Calculated (Fermi Contact) Calculated
Unless otherwise specified, coupling constants are not calculated, but 3bond HH coupling constants as well as both 2 and 3-bond CH coupling
constants are available from empirical relationships. Longer range HH andCH coupling constants as well as CC coupling constants may be calculated.
Coupling constant calculation within the Fermi contact approximation is 35 times more costly than chemical shift and without this approximation, anorder of magnitude more costly. It is advised that this be requested only whennecessary. Splitting patterns are based on the number of neighboringhydrogens and on estimated or calculated 3-bond HH coupling constants.
UV/visIf checked, specifies that a series of excited-state energy calculations will
be performed (following a ground-state calculation) and state-to-stateenergy differences will be computed. Excited state energies and absorption
intensities are available both in the Spectra dialog (Spectra under the
Display menu; Chapter 22) and from the output (Output under the Display
menu; Chapter 22). A UV/visible spectrum can be displayed from either
the simplified or general form of the Spectra dialog (Spectra under the
Display menu; Chapter 22). The default number of excited states is 6, but
may be changed using the UV States keyword (UVSTATES=X) from the
Options field (see discussion later in this chapter and in Appendix D).
UV/visible spectra calculations are available only for Hartree-Fock models(CIS for the excited states) and density functional models (time-dependent
density functional theory for the excited states).

380

QSAR
If checked, specifies calculation of a number of QSAR descriptors thatwould not otherwise be available. These include descriptors based on theelectron density surface, the electrostatic potential map and the local
ionization potential map, as well as polarizability and logP.*
Intrinsic Reaction Coordinate
An additional control, IRC (Intrinsic Reaction Coordinate), appears whena transition-state geometry has been requested. If checked, IRC signifies
that the resulting transition state will be used to generate a pathway (anintrinsic reaction coordinate) leading first to reactant and then to product.
(It is advisable to compute the IR spectrum prior to calculation of an
intrinsic reaction coordinate.) The sequence of steps: reactant → transition
state → product, will be placed in a new file document.IRC. identifier
where document is the name of the document submitted, IRC designates theorigin as an IRC calculation and identifier is the molecule identifier within
the document. The default number of steps (40) may be changed using the
keyword IRCSTEPS (see Appendix D). IRC is not available for semiempirical models.
Total Charge
Total charge on the molecule. The vast majority of molecules areuncharged (neutral).
Molecules constructed from any of the 3D model kits (or from
ChemDraw) are assumed to be neutral, that is Total Charge is Neutral.
Total Charge may be changed either by clicking on to the right of the box(up for Cation, Dication; down for Anion, Dianion) or by typing a
number in the box.
Molecules constructed from the 2D sketcher will, in almost all cases,“know” the total charge and the entry in the Calculations dialog will becorrect.

* LogP is estimated according to the method of Ghose, Pritchett and Crippen (J. Computational Chem., 9, 80(1988)). An alternative procedure due to Villar (J. Computational Chem., 6, 681 (1991); Int. J. Quantum
Chem., 44, 203 (1992)) is available.

381

Total Charge is ignored for molecular mechanics calculations.
Unpaired Electrons
The vast majority of stable molecules have an even number of electrons
arranged in pairs. These are referred to as singlets. Molecules with an evennumber of electrons but with two unpaired electrons are referred to as triplets.
For example, methylene, CH2, may either exist as a singlet or as a triplet.

The most common odd-electron molecules are referred to as doublets ormore commonly, radicals. Here, all but one of the electrons is paired.
Molecules constructed from any of the 3D model kits (or from ChemDraw)
assume that all electrons are paired, that is, Unpaired Electrons is 0.
Unpaired Electrons needs to be changed by clicking on to the right ofthe box.
Molecules constructed from the 2D sketcher will, in almost all cases,“know” the number of unpaired electrons and the entry in the Calculations
dialog will be correct.
Unpaired Electrons is ignored for molecular mechanics calculations.
Note that versions of Spartan prior to Spartan’14 used the term
Multiplicity to refer to the number of unpaired electrons: singlet = no
unpaired electrons; doublet = 1 unpaired electron; triplet = 2 unpaired
electrons.

Options
Program options may be specified using keywords entered into the Options
field. Keywords may be either single words or expressions. Keyword=N
indicates an integer argument, and keyword=F indicates a real argument.
Appendix D contains alisting of commonly-used keywords. Additional keywords are referenced
in the FAQ files accessed from Spartan’s Help menu.
382

Global Calculations
If checked, signifies that settings in the Calculations dialog are to be applied
to all molecules in the document.
The Calculations dialog may be exited by clicking on Submit, Cancel or
OK at the bottom right of the dialog, or onat the top. (Submit and OK
are not available if the job is already executing.) Clicking on OK or on
Submit overwrites any previous information. Additionally, Submit enters
the job in the execution queue (see discussion later this chapter). Clicking
on Cancel or on
exits the Calculations dialog without saving any
changes.
Surfaces ()

Spartan provides graphical display of the HOMO and LUMO among othermolecular orbitals, the electron density, the spin density for molecules with
unpaired electrons, the electrostatic potential, and the local ionization
potential.
The concentration of electrons at any point in space may be determinedusing X-ray diffraction. While this is non zero everywhere, the highest
concentrations are in the immediate vicinity of the atoms. We refer to theelectron density or more simply density as a surface that contains most(>99%) of a molecule’s electrons and roughly corresponds to a space-fillingmodel, that is, a van der Waals surface. It reveals overall molecular sizeand shape and demarks the steric barrier seen by encroaching molecules.
A surface that encloses ~80% of molecules electrons reveals connections
between atoms (“bonds”) and will be referred to as the bond density.
The spin density is the difference in the number of electrons of  and 
spin at a point in space. It indicates the location of the unpaired electron
in a radical or the two unpaired electrons in a triplet.
The electrostatic potential is the energy of interaction of a positive point
charge with a molecule, assuming a fixed electron distribution. It
represents a balance between repulsive interactions involving positivelycharged nuclei and attractive interactions involving negatively-charged
electrons. Regions where the balance tips toward attraction are said to be383

electron rich (basic) and subject to attack by electrophiles, while regions
where the balance tips toward repulsion are said to be electron poor
(acidic) and subject to attack by nucleophiles. Electron-rich regions suchas lone pairs are frequently located outside the van der Waals surface,which suggests that they may be easily identified by constructing asurface of negative (attractive) electrostatic potential. Areas of positiveelectrostatic outside the van der Waals surface may be used to identify
electron poor regions, such as those associated with acidic hydrogens.
Note however, that the electrostatic potential is also positive (repulsive)
throughout the region inside the van der Waals surface.
The local ionization potential indicates the ease or difficulty of electron
removal (ionization) at a point in space. Like the negative regions of theelectrostatic potential, regions of low local ionization potential are likely
to be subject to attack by electrophiles. Regions of high local ionization
potential have not proven to be useful indicators.
Note that neither the electrostatic potential nor the local ionization
potential are experimental observables, although both relate to quantities
that can be given clear chemical interpretation.

Aside from the electron density, any of the quantities listed above may bemapped onto any surface (except a molecular orbital surface). The only maps
to have actually received widespread attention are those based on theelectron density surface (depicting overall molecular size and shape). The
most common maps are the electrostatic potential map, the local ionization
potential map and the LUMO map.
The electrostatic potential map “paints” the value of the electrostatic
potential onto an electron density surface. By convention, colors toward
red depict negative potential*, while colors toward blue depict positive
potential, and colors in between (orange, yellow, green) depict
intermediate values of the potential. Thus, an electrostatic potential map for
p-tert-butylphenol will show oxygen to be red, its attached (acidic)
hydrogen to be blue, the π faces of benzene to be orange or yellow andthe tert-butyl group to be green. These are shown below with the banded(default) style as well as a continuous gradient style (with bands turned off).

*

The logic behind this convention is that red light is of lower energy than blue light. The color scale canbe reversed.

384

An alternative representation using only shadesof red and blue to designate negative and positive
areas, respectively, and white to designate allother areas is also available (see Surface
Properties from the Properties menu; Chapter
22).
The main advantages that electrostatic potential maps have over separate electron densityand electrostatic potential surfaces are clarity and compactness. The main disadvantage
is that it provides information only about the contact surface and does not reveal how far
electron-rich and electron-poor areas extend beyond the surface.
An alternative to an electrostatic potential map, referred to as an exposed electrostatic
potential surface, is a composite of three different surfaces: an electron density surface
depicting overall molecular size and shape, a negative electrostatic potential surface
identifying electron-rich regions and a positive electrostatic potential surface
identifying electron- poor regions. These surfaces need to be generated and thendisplayed simultaneously. The electron density may either be displayed as an opaque solidor as a transparent solid (in order for the molecular skeleton to be seen inside). The twopotential surfaces are best represented as transparent solids, the negative surface colored
red and the positive surface colored blue, for example, for p-tert-butyl phenol.
Some customization is required for best visualization of an exposed electrostatic
potential map. Request a density surface and two potential surfaces from the More
Surfaces. . . menu. All three should have “none” selected under properties options. First,
check the box to the left of one of the potential surfaces. Select Properties from the
Display menu and click on the surface to bring up the Surface Properties dialog.
Remove the negative sign from the number to the right of IsoVal: and change the Style
from Solid to Transparent. Click the downward arrow in the lower right corner of the
Surface Properties dialog to toggle this to the Surface Style dialog. Use the slider bars
to set the color of the surface to blue (Red 0%, Green 0%, and Blue 100%). Click the
upward arrow in the lower right corner to return to the Surface Properties view. From
the Surfaces dialog, check the box next to the other potential surface. A gray surface willappear above and below the aromatic ring and in the area around the lone pairs on the385oxygen atom. Click on this surface. From the updated Surface Properties dialog, selectTransparent for the surface Style. Again, click the downward arrow to toggle to theSurface Style view and set the color for this surface to red (Red 100%, Green 0%, Blue0%). Finally, from the Surfaces dialog, check the box next to the density surface. Threesurfaces are now simultaneously displayed, electron density in a neutral (gray) color, theexposed negative electrostatic potential in red (indicating a potential hydrogen bondacceptor and/or positive ionizable group), and the exposed positive electrostatic potential
in blue (indicating a potential hydrogen bond donor and/or negative ionizable group).
This kind of multiple display may also be constructed with other combinations ofsurfaces.
Note that the exposed electrostatic potential surface provides the same information as
the electrostatic potential map. Note also the broad similarity of this graphic to CFD
representations discussed previously (see CFD’s under the Model menu in Chapter 18).
Hydrogen-bond acceptors and/or positive ionizable sites are associated with protruding
negative potential surfaces, whereas hydrogen-bond donors and/or negative ionizablesites are associated with protruding positive potential surfaces.
The local ionization potential map “paints”
the value of the local ionization potential
onto an electron density surface. By
convention, colors toward red indicate low
ionization potential, while colors toward
blue indicate high ionization potential.
Thus, the local ionization the local
ionization potential map for aniline shows that the ortho and para ring positions have alower ionization potential than the meta positions, consistent with the known directing
ability of an amino group in electrophilic aromatic substitution.
The LUMO map “paints” the absolutevalue of the lowest- unoccupied molecularorbital (the LUMO) onto an electron density
surface. By convention, colors near blue
indicate high concentration of the LUMO,

386

while colors near red indicate low concentration. Given that the LUMO designates space
available for a pair of electrons, a LUMO map indicates where nucleophilic attack would
likely occur. For example, a LUMO map for cyclohexenone shows concentration in two
regions, one over the carbonyl carbon and the other over the  carbon, consistent with bothcarbonyl addition and Michael (conjugate) addition. Note, however, that the LUMO may
not be the “important” unoccupied molecular orbital in so far as designating the site ofnucleophilic addition. This may instead be an orbital of higher energy (LUMO+1,
LUMO+2, ...). These surfaces are also easily displayed and some exploration may beneeded before settling on an appropriate representation of nucleophilic reactivity.
The spin density map “paints” the value of the spin density onto an electron density
surface. It is applicable only to molecules with unpaired electrons, and will otherwise notappear in the menu. By convention, colors near blue indicate high concentration of spin
density, while colors near red indicate low concentration. For example, a spin density
map for the radical resulting from loss of hydrogen from 3,5-di-tertbutylhydroxytoluene (BHT) shows that the spin has delocalized from oxygen onto theortho and para ring positions.

This radical would be expected to be particularly stable, which explains why BHT acts as
an antioxidant (scavenging less favorable localized radicals).

All of these maps use an electron density surface and to delineate overallmolecular size and shape. However, not all regions on this surface are
actually accessible and therefore available for interaction with theirenvironment (or with an incoming reagent). Spartan allows these regions tobe identified.** By default, a region on a density surface is designated as inaccessible if a sphere of radius 1.0 Å centered ona line normal to the surface and touching a point in the middle of the region, impinges on any other regionsof the density surface. The sphere radius may be changed in the Settings Preferences dialog (Preferences
under the Options menu; Chapter 25).

387

Surfaces (including those underlying maps) connect points of equal value(they are isosurfaces), and may be displayed as an arrangement of dots, amesh, or an opaque or translucent solid. Examples of graphical output inorthogonal projection are provided in Figure 21-1. Surfaces (and maps)
may also be rendered in perspective (see Chapter 18) and in stereo (seeChapter 2).
Calculated quantities may also be displayed as two dimensional contour
plots (slices). Unlike surfaces and maps, these can be translated, rotated andzoomed independently of the molecular skeleton. An example of a slice
display is provided in Figure 21-1.
Several different surfaces, maps and slices may be simultaneously
displayed. In addition, any of the usual structure models may be displayed
along with the graphic. The total display can become very complex, andselective use of meshes and/or translucent solids (as opposed to opaquesolids) may facilitate visualization.
Discussion of the utility of graphical models for describing molecular
structure and chemical reactivity is provided in Topics available under the
Activities menu.
Selection of Surfaces from the Setup menu results in display of the
Surfaces dialog.

This contains a box at the top for listing requested surfaces and property
maps.

388

Figure 21-1: Examples of Graphical Displays Available in Spartan
Frontier orbitals for a symmetry-allowed
Diels-Alder reaction,

Space-filling model and electron density
surface of cyclohexanone,

showing interaction of the HOMO of
1,3-butadiene and the LUMO of ethylene.

showing overall molecular size and shape.

Electron density surface (0.08 electrons/ Electrostatic potential surfaces (-40 kJ/
au3) of transition structure for pyrolysis of mol) of trimethylamine (left) and dimethyl
ethyl formate,
ether (right),

showing bonding in the transition state.

showing the lone pairs on nitrogen andoxygen, respectively.

Electron density slice for acetic aciddimer,

Simultaneous display of the LUMO
and the electron density surfaces ofcyclohexanone,

showing hydrogen bonding.

showing accessibility for nucleophilic
attack.

389

Common Surfaces and Property Maps
Add at the bottom of the dialog is used to specify a number of commonlyused graphical surfaces and property maps*. Clicking on it leads to a menu.

Selection of all but the last entry in themenu leads to a request for the analogous
surface or map. This will be calculated at
medium resolution unless a different
resolution has been previously
selected (see below). Additional surfaces and maps or the same surfaces ormaps at different resolution may be requested by selecting More Surfaces...
from the menu (or by clicking on More Surfaces... at the bottom of the
Surfaces dialog). This leads to the Add Surfaces dialog that contains threemenus and a check box:
Surface
Available surface types appear under the Surface menu.

Density portrays overall molecular size**, density (bond) locates bonds,
HOMO{-}, HOMO, LUMO, LUMO{+}, SOMO are* Additional selections are provided if the molecule has unpaired electrons.
** An “electron density” surface, an electrostatic potential surface and an electrostatic potential map may
also be constructed based on a molecular mechanics calculation. In this case, the density will be based onvan der Waals radii and the potential will be based on charges.

390molecular orbitals, potential is the electrostatic potential, ionization is the local
ionization potential and spin density is the spin density. SOMO (the singlyoccupied molecular orbital) and spin density entries appear only formolecules with unpaired electrons.
Unlike the molecular orbitals, the electron density and the electrostatic
potential, the local ionization potential does not go to zero with increasing
distance. This makes its use as a surface problematic.

Selection of HOMO{-} and LUMO{+} results in display of a box todecrement the HOMO and increment the LUMO. This allows any molecularorbital to be specified.

Slice designates that a plane will cut through the graphic definedby Property (see discussion following).
Property
Properties to be color coded onto surfaces to make property maps
appear in the Property menu.

Available properties are the molecular orbitals (HOMO{-}, HOMO,
LUMO, LUMO{+}, SOMO), the electrostatic potential (potential), the local
ionization potential (ionization) and the spin density (spin density). none
indicates that no property is to be mapped onto the surface). SOMO (thesingly-occupied molecular orbital) and spin density entries appear only formolecules with unpaired electrons. SOMO (the singly-occupied molecularorbital) and spin density entries appear only for molecules with unpaired
electrons. As with Surface above, selection of HOMO{-} and LUMO{+}leads to a decrement (increment) box.

391

A spin control designating Alpha or Beta will be displayed if Unpaired
Electron (in the Calculations dialog) is set to a value other than 0, or if
SCF=UNRESTRICTED has been specified in the Options field(Calculations dialog; see also Appendix D) and if HOMO{-}, HOMO,
LUMO or LUMO{+} has been selected for Surface or for Property. Clicking
on it toggles it between Alpha and Beta. Alpha designates that the molecularorbital either to be displayed as a surface or mapped as a property
corresponds to spin; Beta designates that the molecular orbital corresponds
to spin.
Resolution
Selection of surface resolution is from the Resolution menu.

Medium resolution generally is intended for routine work, low resolution
is used to get rough images very quickly, while intermediate and highresolution may be employed to obtain publication quality graphics. Bothcalculation time and disk storage increase significantly with increasing
resolution.
IsoValue
This allows a fixed isosurface to be generated in place of a threedimensional grid of points (from which different isosurfaces, and/ or slices
can be constructed).* Fixed isosurfaces are particularly attractive forproperty maps (that are generally based on a density surface representing
molecular size and shape) as they require significantly less computer timeand disk storage. Note that a fixed density surface needs to be based on a
specific isovalue (see below) and not on percentage enclosure of the total
number of electrons.*** The “electron density” surface resulting from a molecular mechanics calculation is fixed as
it is based on use of van der Waals radii.
** When Fixed is not checked, isovalues may be computed on-the-fly to enclose a specified percentageof the total number of electrons. Discussion is provided in the Surface Properties dialog (Properties
under the Display menu; Chapter 22).

392

Checking the box to the left of Fixed leads to display of the isovalue(0.002 electrons/au3 in the case of density which corresponds to>99% enclosure of the total number of electrons). This value may be changed
prior to surface generation by editing the text box that appears to the right.
Fixed may not be specified in conjunction with Slice as a Surface.
Following Surface, Property, Resolution and (optionally) spin selection,
clicking on OK adds the requested graphic to the list and removes the (Add
Surfaces) dialog. Clicking on Apply adds the requested graphic to the list
but leaves the dialog on screen. Clicking on Cancel does not add a graphic
to the list but removes the (Add Surfaces) dialog.
The process (clicking on Add..., surface and property selection,
clicking on OK or Apply) may be repeated as required.
An existing graphic or a request for a graphic may be deleted from thelist by first highlighting (clicking on) it and then clicking on Delete.
Global Surfaces
If checked, Global Surfaces signifies that the requested surfaces
will be calculated for all members of the list.
Only one copy of the Surfaces dialog may appear on screen, and any actions
relate to the currently selected molecule. The dialog may be removed byclicking on.
Submit ()

Following setup of a molecular mechanics or quantum chemical
calculation, or a similarity analysis, as well as any requests for properties,
spectra and/or graphical displays, the required calculations will begin when
Submit is selected. If the job has not previously been named, selection ofSubmit triggers a request for a name. If the document being submitted
comprises a single molecule and the molecule exists in the Spartan Spectra
and Properties Database, the name in the database will be presented as adefault name. Otherwise, the default name presented will be spartan for
the first job and spartanX (X an integer starting with 1 for all successivejobs). After a name has been provided (or if a name already exists or if thedefault name is accepted) a dialog appears indicating that the job has actually
been submitted.*
393

Click on OK to remove it. After a job has started, and until it hascompleted, all associated files will be designated read only.
In addition to the local (Windows, Macintosh or Linux) machine,
Spartan’s computational codes may run on a remote (licensed) server. The
only exception is the similarity analysis code which at present must be runon the local machine. If remote submission has been set up (see Available
Servers from the Preferences dialog under the Options menu; Chapter 25),
selection of Submit will also request a name for the destination machine.

Another dialog appears following completion of a calculation.

Click on OK to remove it.
Some types of jobs, including requests for a conformer distribution and an
energy profile, lead to an additional document being created for eachmolecule in the original document. These new documents are named
document.task.identifier where document is the name given to the original
document, task is the type of job, Conf for a conformer distribution, NMR
for an NMR spectrum calculation and Prof for energy profile, and identifier
identifies the molecule inside the original document.
* The job is submitted to a job queue and will be submitted for execution only when released from thisqueue. See Monitor under the Options menu (Chapter 25) for discussion.

394

In the case where there is only one molecule in the original document,“.identifier” is not included in the name and a query dialog is provided asking
whether the resulting Spartan document is to be opened. Otherwise, theresulting documents (one for each molecule in the original document) willneed to be opened explicitly (Open under the File menu; Chapter 16).

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Chapter 22
The Display Menu
Functions available under the Display menu provide for text, dialog,
spreadsheet and graphical displays following molecular mechanics orquantum chemical calculations. Functions are also available to query avariety of on-screen objects, display and compare IR, Raman, 1 and 2D NMR
and UV/visible spectra, animate vibrational motions, construct relationships
among calculated properties or between reactants and products, perform
linear regression and prepare plots from spreadsheet data, display
similarities between molecular structures and between molecular structuresand pharmacophores and calculate reaction energies.

Output ()

Selection of Output opens a summary window.

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The tabs at the top of the dialog select the type of output.
Summary output is initially displayed and provides a snapshot of calculateddata, in particular, the energy and any spectral quantities. It is generated in realtime in the graphical interface using information provided by Spartan’s
compute codes as well as any filters present in the interface.* Spartan
provides savable/printable tables of IR/ Raman, NMR (chemical shifts andHH and CH coupling constants) and UV/visible spectra.** Output provides
standard text output. Verbose Output contains a more granular (and much
longer) output, which is mainly provided to aid in tracking down problems in“failed” calculations. This is “pruned” by default unless Keep Verbose ischecked in the Setting Preferences dialog (Preferences under the Options
menu; Chapter 25).*** Molecule Reference provides the literaturereference for data retrieved from CSD and/or PDB. Job Log contains
diagnostic information. The contents of the output window may be printed
by right clicking inside it and selecting Print from the menu, or copied to the
clipboard by right clicking inside it and selecting Copy from the menu.
Find..., Find Next, and Save As PDF functions are also available from thecontextual menu. An output window is associated with each document andpertains to the selected molecule. Several output windows associated withdifferent Spartan documents may be opened at once. To close click on at
the top right.
Text output is not accessible from the Output menu for jobs that are
actively running or are in the execution queue. However, standard Output
and Verbose Output for jobs that are actively running (both locally or
remotely) may be examined in “real time” by accessing the Monitor
under the Options menu (Chapter 25). In addition, the current structure(in a geometry or transition-state optimization) can be examined and* For example, calculated infrared/Raman frequencies and NMR chemical shifts are “corrected on the fly” asthey are opened in the interface. This means that, to take advantage of future improvements in the correction
scheme, you do not need to recalculate the uncorrected spectra. Coupling constants are not corrected.
** Contents of the tables in the summary output may be copied onto the clipboard by clicking onthen pasted into Excel (or another spreadsheet) for further analysis.

and*** Irrespective of the setting, the last 100 lines of the verbose output are kept if the jobs fails for any reason.

Chapter 22397

queried. Note that in most cases, the Monitor presents text output in acascading mode, you will need to “toggle” the triangle to the left of the
document name to get to specific molecule output, and in some cases,
an additional “toggle” of the molecule may be necessary in the case ofmulti-step calculations (conformational jobs, for example).

Properties ()

Spartan provides specialized dialogs for reporting (and in cases where theunderlying calculation is not affected), changing the properties ofmolecules, atoms, bonds, surfaces and constraints, and for editing CFD’s andsubstituent libraries. For plots created in Spartan’s main window (or brought
into this window from the spectra and plot panes), Properties may be used tochange default plot styles, plot limits and fitting functions. Properties
dialogs also quantify the difference between calculated and experimental
NMR chemical shifts (assuming that the latter are available), display 2D
drawings, alter model style and colors, atom labels and conformer settings
as well as “fix” problems with structure, for example, bond typing and bondlengths to hydrogen that may be in error. Note that the last of these will affectthe underlying calculation. Only one Properties dialog may be open, and thisrefers either to the selected molecule (Molecule Properties), or to the selectedcomponent (atom, bond, etc.) or attribute (graphical surface, substituent, etc.)of the selected molecule (Atom Properties, Bond Properties, Surface
Properties, Substituent Properties, etc.), or to a plot, including spectra
plot (Plot Properties, Curve Properties, etc.), or fitting function(Regression Properties). Selection of a different molecule leads to the
dialog of whatever tab was previously selected in the Molecule Properties
dialog for that molecule. Dialogs that refer to components/attributes of the(newly selected) molecule follow by clicking on the component/attribute.
With the Properties dialog on screen, clicking on a component/ attributebrings up the appropriate Properties dialog. For example, clicking on an
atom brings up the Atom Properties dialog. Clicking on a different
component/attribute brings up the appropriate Properties dialog. Clicking asecond time on the same component reverts to the dialog of whatever tab
was previously selected in the Molecule

Chapter 22398

Properties dialog.*
Properties dialogs have an associated Utilities or Style dialog. These provide
additional style and color controls useful for highlighting (or deemphasizing) a particular molecule, component or attribute, and are reachedby clicking on
at the bottom right of the appropriate Properties dialog.
Return to the Properties dialog follows from clicking on
at the bottom
right of the associated Utilities/Style dialog.
The Properties (or Utilities/Style) dialog may be removed from the screen
by clicking on.
Molecule
Properties:
Molecule,
QSAR
Thermodynamics, 2D Drawing, NMR, Utilities

Descriptors,

The Molecular Properties dialog comprises six tabs: Molecule, QSAR,
Thermodynamics, 2D Drawing, NMR and Utilities. Entries under the
Molecule tab relate to common molecular properties, only some of which
depend on the selected level of calculation.
Molecule* The only exception involves clicking on a graphical surface or property map, for example, clicking on
a property map to obtain the value of the property at a particular surface location. Clicking a second time on
the surface or map will report a new value of the property. Clicking on the background leads to the dialog
of whatever tab was previously selected in the Molecule Properties dialog.

Chapter 22399

Molecule properties include the name and molecular formula, the energy (inau), the heat of formation (in kJ/mol), or the sum of the strain energy andthe intramolecular interaction energy (in kJ/ mol) depending on thetheoretical model, the HOMO and LUMO energies (in eV), the dipole
moment (in Debye), the molecular weight* and mass* (both in amu), thepoint group, the predicted number of conformers, and if one or both areavailable from SSPD,** the energy resulting from a B97X-V/6311+G(2df,2p)//
B97X-D/6-31G* calculation (in hartrees) and the heat of formation fromthe T1 thermochemical recipe (in kJ/mol), as well as the experimental heat offormation (in kJ/mol) if it is available in the NIST thermochemical database.
These may be posted to the spreadsheet using the
buttons, or dragged into
the spreadsheet, the formula editor (see Formulas in this chapter), or onto
any of the dialogs associated with the Spartan Spectra and Properties
Database (see Database under the Search menu; Chapter 23). The dipole
moment vector may be added to the model by checking the box to the left of
Display Dipole Vector. Buttons at the bottom right of the dialog accessavailable Wikipedia and ChemSpider pages (based on InChi string). Label
identifies the molecule in a document and appears in the first column of the
spreadsheet (see Spreadsheet, later this chapter).
QSAR
Entries under the QSAR tab provide additional properties, some of which
may be important in QSAR type analyses.

* Molecular weight is what would be obtained from looking at a macroscopic sample, that is, consistingof a mixture of different atomic isotopes, for example, 35Cl and 37Cl. Molecular mass is what would beobserved from a mass spectrometry experiment of the dominant parent ion.
** Note that access to SSPD is based solely on the InChi string and data may correspond to a different
structure and conformation.

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These include: the area, volume, polar surface area (PSA)* and ovality
obtained from a space-filling model, as well as other structure-dependent
indicators: LogP, polarizability and the number of hydrogen-bond donor(HBD) and acceptor sites (HBA).** All of these are independent of the levelof calculation. Quantities that depend on the level of calculation and based on
the electron density surfaces as well as on electrostatic potential maps are alsoavailable: the accessible area, the polar area and accessible polar area
corresponding to absolute values of the electrostatic potential greater than75, 100 and 125 kJ/mol (selection is made by repeated clicking on ), theminimum and maximum values of the electrostatic potential (as mapped
onto an electron density surface) and the minimum value of the local
ionization potential (as mapped onto an electron density surface). These
quantities are not calculated unless explicitly requested by checking QSAR
inside the Calculations dialog (Calculations... under the Setup menu;
Chapter 21).

* Polar surface area is defined as the area due to nitrogen and oxygen and any attached hydrogens. Polar
surface areas corresponding to arbitrary alternative definitions are available for posting into the spreadsheet
using the PAREA function. See Table 22-3.
** Counts of hydrogen-bond donors and acceptors follow from atomic connectivity together with special
case designations for common organic functional groups.

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Thermodynamics
Entries under the Thermodynamics tab provide the zero-point energy, theenthalpy, the constant volume heat capacity, the entropy and the Gibbs energy.
Except for the zero-point energy, all depend on temperature. The default
setting (298.15 K) may be changed. All require vibrational frequencies,
which can be requested from the Calculations... dialog (Calculations...
under the Setup menu; Chapter 21).
Note that calculated frequencies are consistently larger than experimental
values due in part to the harmonic approximation. They can be (and usuallyare) scaled by a number <1. Several common models including EDF2/631G*, B3LYP/6-31G*, ωB97X-D/6-31G* and ωB97X-D/6-311G* areautomatically scaled. Other models can be scaled by typing into the keypad.

As discussed under Properties and Spectra in Appendix A, the entropy
and Gibbs energy are subject to considerable uncertainty due to theunderlying harmonic approximation. Specifically, low-frequency
vibrational motions which dominate the entropy and significantly contributeto the temperature dependence of the enthalpy are poorly described by the
harmonic approximations.** In practice, enthalpy is clamped at 1/2 RT (1.24 kJ/mol at 298K) and entropy is clamped at 1/2R (4.15
J/K mol).

Chapter 22402

2D Drawing
Displays a 2D drawing constructed on-the-fly from the 3D structure. (Thisis a change from the versions of Spartan prior to Spartan’18 which used alibrary of drawings obtained from ChemAxon software for molecules
contained in SSPD). Systematic names for molecules in SSPD prior to 2016
were obtained using ChemAxon software are reported.

NMR
This reports the RMS, maximum absolute and mean absolute errors in either
or both calculated proton and 13C chemical shifts from experimental values(assuming that the experimental data have been obtained from
NMRShiftDB or have been entered manually). Chemical shiftmisassignments can and do occur (especially for quaternary carbons) andcontrols are available to shuffle 13C experimental shifts assuming a fixedhydrogen count (C, CH, CH2, CH3) or ignoring hydrogen count. Reported
errors will change accordingly. Shuffling experimental proton chemical shiftassignments is presently not supported.

Chapter 22403

Utilities
This allows a variety of attributes of the selected molecule or all moleculesin the selected document to be adjusted.
Set Standard Labels relabels the molecule such that carbons start with C1,
nitrogens with N1,... Hydrogens start with H. Those associated with carbon
take its number and are followed by a, b, c if there is more than one, forexample, H5a. Hydrogens associated with elements other than carbon follow
H by the appropriate atomic symbol and number and a, b, c if there is morethan one hydrogen, for example, HN2a.
Add Hydrogens add any hydrogens that are missing, for example, in older
structure drawn from the Cambridge Structural Database. Requires
recalculation.
Reset Colors reverts to standard atom and bond colors.
Reset Model reverts to standard model type.
Fix Bonds repairs bonds that were either missing or were typed incorrectly.
Requires recalculation.
Change Absolute Configuration inverts all chiral (R/S) centers resulting
in a change of absolute configuration. Requires recalculation.

Chapter 22404

Restore Default Folds reverts single bond folds values and ring puckering
designates to standard values.
Adjust X-H Bond Lengths sets bond lengths to hydrogen to “reasonable”
values. Important for structures obtained from X-ray diffraction, for example,
from the Cambridge Structural Database, where bonds to hydrogen are
consistently too short. Requires recalculation.
Molecule Utilities
Clicking on at the bottom right of any of the Molecule Properties dialogs
brings up the same Molecule Utilities dialog (clicking on
returns to theMolecule Properties dialog):

This contains controls which are less frequently needed than those under theUtilities tab, specifically controls that provide alternative displays of aromatic
molecules, information about amino acids in polypeptides and about
CFD’s, and replace coordinates by standards based only on atomic
connectivity. The Set Standard Labels will attempt to use consistent rules
to number hydrogens by the heteroatom they are bonded to.
Atom Properties
Selecting an atom with a Properties dialog on screen, or selecting Properties
from the Display menu ( ) following selection of an atom, leads to the
Atom Properties dialog:

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This displays the element name and symbol, atomic number, mass number(isotope), R/S chirality, electrostatic-fit, Mulliken and natural charges (inelectrons), calculated and experimental NMR chemical shifts (in ppm relative
to standard) and the exposed surface area of a space-filling model (in Å2).
Experimental chemical shifts appear if proton or 13C spectra have been
retrieved from freely available online databases or have been manually entered.
Database values may be altered. Charges, chemical shifts and exposed area
may be posted into the spreadsheet. The dialog also allows changing theelement and/or the isotope and the default label.
Proton and 13C chemical shifts from B3LYP/6-31G*, EDF2/6-31G*,
B97X-D/6-31G* and B97X-D/6-311G* calculations have been
empirically corrected (see Appendix A). Corrections use both
topology and bond orders or bond lengths to neighboring atoms. The
correction schemes for B3LYP and B97X-D are significantly
improved over that for EDF2. Corrections have also been made to19
F chemical shifts for EDF2/6-31G* only.

Checking Freeze freezes the atom (see Freeze Center in Chapter 19).
Clicking on at the bottom right of the Atom Properties dialog brings up
the Atom Style dialog (not shown). This contains controls

Chapter 22406

for selecting atom color and changing model style. Clicking onbottom right of this dialog returns to the Atom Properties dialog.

at theBond Properties
Selecting a bond with a Properties dialog on screen, or selecting Properties
following selection of a bond leads to the Bond Properties dialog:

This displays the bond length, bond type and Mulliken and Löwdin bondorders.
Clicking on at the bottom right of the Bond Properties dialog brings up
the Bond Style dialog (not shown). This contains controls for changing
bond color. Clicking on
at the bottom right of this dialog returns to theBond Properties dialog.
Constraint Properties
Selecting a constraint marker with a Properties dialog on screen, or
selecting Properties from the Display menu ( ) following selection of aconstraint marker, leads to the Constraint Properties dialog. This allows
setting the value of a constraint, posting it to the spreadsheet and changing
the default constraint label. Checking Profile leads to an expanded dialog:

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This allows specifying a sequence of constraints for an energy profile (seeCalculations... under the Setup menu; Chapter 21). The value of thestarting constraint is given in the lefthand box to the right of Value, and thevalue of the ending constraint is given in the righthand box to the right ofValue. The number of steps in the profile is given in the box to the right ofSteps. Initially, the numbers in both boxes to the right of Value will be thesame, and Steps will be set to 1. These may be altered by clicking inside theappropriate box and entering the desired values from the number pad thatappears. This functionality may also be accessed from Constrain Distance(Angle, Dihedral) under the Geometry menu (Chapter 19). An energy
profile may involve constraints on more than one geometrical variable(changed in lock-step with one another). In this case, the constraint ranges
for the individual variables need to be selected. If Global Steps is checked,
the independent variables are moved in concert, meaning that the numberof steps must and will be the same for each variable. If unchecked, thevariables are moved independently and the number of steps may differ from one
to another. In this case, the total number of steps in the profile is the product of
the number of steps for each variable. Be careful as this number will quickly
become very large.
Clicking on
at the bottom right of the Constraint Properties dialog
brings up the Constraint Style dialog (not shown). This contains controls
for selecting the color of the constraint marker. Clicking on returns to theConstraint Properties dialog.

Chapter 22408

Point, Ligand Point and Plane Properties
Selecting a user-defined point, ligand point or plane with a Properties
dialog on screen, or selecting Properties from the Display menu ( )following selection of a point, ligand point or plane, leads to the Point
Properties, Ligand Point Properties or Plane Properties dialog (notshown). These allow changing point or plane labels and new in Spartan’24,
specifying Planes as opaque or transparent. Clicking on
at the bottom
right of the Point (Ligand Point, Plane) Properties dialog leads to the Point(Ligand Point, Plane) Style dialog (not shown), with controls for adjusting
point (plane) colors. Clicking on
returns to the Point (Ligand Point,
Plane) Properties dialog.
Surface Properties
Selecting a graphical display with a Properties dialog on screen, or selecting
Properties from the Display menu ( ) following selection of a graphicaldisplay, leads to the Surface Properties dialog:

This allows changing display style (Style), either dots, or a mesh ortransparent or opaque solid, selecting between continuous and banded
displays (Bands) for property maps and, in the case of the latter, setting thenumber of bands, specifying isovalue, and as an

Chapter 22409

alternative for electron density surfaces, percentage of the electrons contained
inside the surface, turning on mapped properties, setting the property range ofmaps, and changing default surface labels. Reset M/M will set the property
range to the minimum/maximum values. To revert to the default values, click
the Reset button. The dialog reports (and optionally posts) the area (Area),volume (Vol) and accessible area (Acc. Area)* of the surface, the polar area
(P-Area) and accessible polar area (Acc. P-Area) of an electrostatic
potential map**, the value of the mapped property at the cursor position(Val)*** and the area enclosed in a selected band (Selected Area). The dialog
also allows posting of the minimum and maximum value of the mapped
property. If checked, Legend displays a color scale. If checked, Selected
Area outlines the band containing the cursor. If checked, Display
Accessible Markers reveals regions that are inaccessible. If checked, Global
Surfaces designates that the settings in this dialog apply to all molecules inthe document.
Up to three independent clipping planes operate in toggle mode. Following
selection, a plane may be rotated, translated or zoomed with the usual mouse
operations.
Where the surface is a “slice”, the Slice Properties dialog appears:* A region on a density surface is designated as inaccessible if a sphere of radius 1.0 Å centered on a line
normal to the surface and touching a point in the middle of the region, impinges on any other regions of thesurface. The default radius (Accessible Area Radius) may be changed in the Settings Preferences dialog(Preferences under the Options menu; Chapter 25).
** This is defined as that part of the surface area for which the absolute value of the electrostatic potential
is > 100 kJ/mol. The cutoff (Polar Area Range) may be changed in the Settings Preferences dialog(Preferences under the Options menu; Chapter 25).
*** To determine property value at another position click on it. To bring up the Molecule Properties
dialog, click on the background.

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This contains controls to set the range of the property and to change the numberof contours displayed and to the type of slice (plane, cylinder or sphere). The
value of the property at the cursor position is displayed and, together with theminimum and maximum values of the property, may be posted to the
spreadsheet. Check boxes allow for a legend, a frame around the slice andfor a grid.
Clicking on at the bottom right of the Surface Properties dialog brings up
the Surface Style dialog (not shown). This contains controls for selecting
surface color. Clicking on at the bottom right of this dialog returns to theSurface Properties dialog.
Curve and Plot Properties
Plots created either using data from the spreadsheet or from spectra may bepresented in separate windows or in Spartan’s main window (see discussion
later in this chapter). The following discussion relates only to the latter andconcerns the way in which plots may be edited using a set of closely-related
dialogs. These refer to curves (a relationship between variables), and plots(a set of relationships that share variables).
Selecting a plot frame with a Properties from the Display menu ( ) dialog
on screen, or selecting Properties following selection of a plot frame, leads
to the Plot Properties dialog (XY Plot dialog shown):

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The X Axis menu and the Y Axes list duplicate functionality under the Plots
dialog (see Plots... later in this chapter) and allow specification of amolecular property to serve as the X axis of the plot and one or more properties
to serve as the Y axes. The contents of the Y-Axes list depends on selection
from the Type menu: By Molecule and Free Form reference explicit
entries in the spreadsheet (see discussion later in this chapter) while By
Atom references Spartan’s file of atom-based properties (the Property
Archive). Initial selections may be altered as desired. In addition, the aspectratio of the plot may be changed, the numerical scale of the X (horizontal)
axis turned on or off, a grid added to the plot, and the default plot labelchanged. Magnifier brings up a frame with which to magnify selected areasof a plot. The magnifier may be positioned by clicking on the frame and thenmoving the mouse while holding down the right button. Magnifier selection
results in the Plot Magnifier Properties dialog (not shown) with a single
control to alter the width. The magnifier may be removed from the plot using
Delete from the Build menu ( ) or the Delete key.
The range along the X (horizontal) axis may be altered from default settings byclicking on the X-Axis tab.

Chapter 22412

To alter the range, click inside the Range boxes, and enter the desired values
into the number pad that appears. Controls are also available to alter thenumber of tic marks on the X axis, the label size and precision and change
the scale from linear to logarithmic.
Clicking on
at the bottom right of the Plot Properties dialog brings up
the Plot Style dialog (not shown). This contains controls for selecting thecolor of the plot frame, as well as the label associated with the X axis.
Clicking on
at the bottom right of this dialog returns to the Plot
Properties dialog.
When the Plots Plane options is turned off (see Options menu; Chapter25), XYZ Plots are enabled. Selection of XYZ Plot leads to an extended XYZPlot Properties dialog:

This is identical to the XY Plot Properties dialog, except that it includes
an additional menu (Y Axis) from which a property
Chapter 22413

needs to be selected. In addition, the Y Axes list in the XY Plot Properties
dialog has been renamed to Z Axes.
Ranges along X and Y axes may be adjusted by clicking on X-Axis andY-Axis tabs to the left of the dialog. The resulting dialog (not shown)
contains controls that are analogous to those previously discussed for XY
plots.
Selecting an individual curve in a plot with a Properties dialog on screen, or
selecting Properties from the Display menu following selection of anindividual curve, leads to the Curve Properties dialog:

With the Curve tab selected, this allows changing the quantity that isplotted (Axis), provides a scale and error bars (obtained from the column inthe spreadsheet designated in the Error menu) and turns clipping on.
Controls are available to designate the kind of markers for the data points,
request marker labels, and designate the kind of fit to the data points and theline width of the fitting curve*. If checked, Focus marks the selected
molecule on the curve.
Clicking on the Axis tab changes the contents of the dialog and allows thescale along the Y axis of an XY plot or Z axis of an* Fitting functions include linear, quadratic and cubic least square, a Fourier series, a Lorentzian or a
Gaussian. The data points may also be connected by straight lines (point-to-point) or by a smooth curve(cubic spline) or be presented as a skyline. Finally, the fitting curve can be removed.

Chapter 22414

XYZ plot to be altered from the default (minimum to maximum value of
the Y or Z):

To alter the range, click inside the boxes underneath Range and enter thedesired values using the number pad that appears. Controls are alsoavailable to alter characteristics of the Y (XY plot) or Z axis (XYZ plot)labels.
Clicking on
at the bottom right of the Curve Properties dialog (witheither tab selected) brings up the Curve Style dialog (not shown). This
contains controls for selecting the color of the curve (and the label
associated with the Y (or Z) axis). Clicking on at the bottom right returns
to the original dialog.
Substituent Properties
Selecting a substituent icon with a Properties dialog on screen, or selecting
Properties from the Display menu ( ) following selection of a substituent icon,
leads to the Substituent Properties dialog:

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This allows substituent libraries already attached to a molecule to be edited,
and the label on the substituent icon to be changed. It does not allow for
attachment points to be reassigned. The dialog comprises a scroll box(listing the substituent names), a viewing window (showing a model of thesubstituent) and a label field.
To delete a substituent from the library, click on its name in the scroll box,
then right click and select Delete from the contextual menu that appears. To
add a new substituent that has previously been copied to the clipboard, rightclick inside the scroll box and select Paste from the contextual menu. Note,that if the clipboard contains several molecules, all will be added to thesubstituent library. To add a substituent (or list of substituents) in a Spartan
document to the library, right click inside the scroll box, select Append
from the contextual menu and choose a document from the browser.
Alternatively, drag the document that contains the substituent(s) from awindow into the scroll box.
Clicking on
at the bottom right of the Substituent Properties dialog
brings up the Substituent Style dialog (not shown). This contains controls
for selecting substituent (icon) color. Clicking on
returns to theSubstituent Properties dialog.
CFD Properties
Selecting a chemical function descriptor (CFD) or of an element of apharmacophore with a Properties dialog on screen, or selecting Properties
from the Display menu ( ) following selection of a CFD or
pharmacophore element, leads to the CFD Properties dialog:

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This allows changing the definition of the CFD, its label and the precisionof the fit (the bigger the radius of the CFD, the less precise the fit). If
checked, Global CFD specifies that CFD definitions will apply to allmolecules in the document.*
Clicking onin the dialog brings up the CFD Style dialog (not shown).
This contains controls for selecting CFD color. Clicking on in this dialog
returns to the CFD Properties dialog.
Regression Properties
Following a linear regression analysis, a new row, labeled Fit1**, appears near
the bottom of the spreadsheet. This contains information about the fit. Clicking
on this line with a Properties dialog on screen, or selecting Properties fromthe Display menu ( ) after clicking on the line, leads to the Regression
Properties dialog.

This reports RMSD and R2, as well as allows for changing what is to be fit(Fit) and what it is to be fit to (Using). The error statistics will immediately
update.
“Selected” Style
The “Selected” Style dialog is accessed either by defining a selection box(see Mouse/Keyboard Operations in Chapter 1) with a Properties dialog
on screen, or by selecting Properties from the Display menu ( ) after
defining a selection box.
*

This is generally applicable only where the molecules are conformers, or the CFD labels have beenadjusted to associate positions on different molecules. Label reassignment is accomplished using theAtom Properties dialog (see discussion earlier in this chapter).
** More precisely, a row will be written for each fit, and labeled Fit1, Fit2, . . ..
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This contains controls for changing the color and model type of whateveris included in the selection box.
Orbital Energies ()

Selecting Orbital Energies leads to the display of an orbital energy
diagram (this assumes that a wave function is available). This comprises up
to twelve occupied molecular orbitals and two unoccupied molecular orbitals,
the highest-occupied (HOMO) and lowest-unoccupied (LUMO) being
explicitly designated.*

Clicking on an energy level in the diagram leads to display of thecorresponding molecular orbital. This may be manipulated in the usual way
and the display style altered from the menu at the bottom right of the screen.
The energy (in eV) of the orbital is provided at the left of the menu. Afterone energy level has been selected and the associated orbital displayed,
moving the mouse up or down over the diagram while holding down the left
button (“swiping”) then releasing the button selects the next higher or lower
energy level.
*

Additional occupied and unoccupied molecular orbitals may be displayed by clicking on the orbital energy
plot to bring up the Orbital Energies Plot Properties dialog and altering the contents of the Maximum
Occupied Levels and Maximum Unoccupied Levels menus, respectively. The latter is restricted to 10
levels.

Chapter 22418

For touch screen devices, moving a finger up or down over the
diagram then lifting selects the next higher or lower energy level.

Surfaces ()

This accesses the same dialog previously described in Chapter 21.
Spectra ()

Spartan displays calculated IR, Raman, 1 and 2D NMR and UV/ visible
spectra. Spectra need to have been previously requested from the
Calculations dialog (Calculations... under the Setup menu; Chapter 21)
or accessed from the Spartan Spectra and Properties Database. In addition,
manual input as well as on-line access and display of experimental IR,
NMR and UV/visible spectra from publicly available collections is provided,
facilitating comparison with calculated spectra. Spartan allows two different
modes for spectra display; a general presentation scheme and a simpler andperhaps more familiar mode. The choice is up to the user in the form of apreference. The simpler presentation mode is described first.
Simplified Presentation of SpectraWith Spectra Pane in the Settings Preferences dialog checked(Preferences under the Options menu; Chapter 25), selecting Spectrafrom the Display menu leads to an empty display pane at the bottom of thescreen:The only accessible control (in a bar at the top of the pane) is
spectrum). Clicking on this leads to a palette:

Chapter 22(add a419

The right hand column lists the types of spectra for which calculations areavailable: IR, Raman, proton NMR with and without three- bond HH
coupling 13C NMR, COSY, HSQC and HMBC 2D NMR and UV/vis.
COSY and HMBC spectra require coupling constants be available inaddition to chemical shifts. COSY requires 3-bond HH coupling constantsand HMBC requires both 2 and 3-bond CH coupling constants. The entry
is “red” if a calculation has actually been performed and the corresponding
spectrum is available. The left hand column lists the types of spectra for which
experimental spectra may be available (manually input or from on-line
public databases): IR, proton NMR, 13C NMR and UV/vis. In addition, there
is an entry for an experimental Raman spectrum, selection of which leads toa file browser from which a JCamp (.dx) file containing the spectrum may
be chosen. These are shown in blue.
The procedure for displaying either a calculated or experimental spectrum(or both) is independent of the type of spectrum. For the purpose ofillustration, we use the IR spectrum of methyl trans- cinnamate. A
calculated spectrum is displayed by clicking on the appropriated (redhighlighted) entry, following which the palette is dismissed. Clicking on IR
results in an IR spectrum.

Chapter 22

420

Clicking on the probe indicator selects it. Once selected, moving the mouse
while holding down the left button moves the probe (triangle markers at the
top and bottom of the spectrum) over the spectrum. When positioned
directly over a special line, the triangles are darkened and connected by avertical yellow line, and a numerical value for the line is provided at thebottom of the spectrum. In the case of an IR spectrum, this is a frequency
in cm-1 and corresponds to a particular vibration of the atoms in themolecule. The molecular model (above the spectrum) vibrates to show thismotion. For methyl trans-cinnamate, the line near 1645 cm-1 closely
corresponds to the C=C stretch while the line near 1739 cm-1 almost entirely
corresponds to the C=O stretch.

Moving the mouse while holding down the right button slides the viewablescale from 4000 cm-1 to 500 cm-1 but does not change the overall range (of3500 cm-1). The range is changed by using the scroll wheel. The original
settings may be restored by clicking onin the bar at the top of the spectrapane.
On touch screen devices, move one finger over the spectrum toposition the cursor, move two fingers to slide the viewable scale
and pinch two fingers to change the range.

In the case of IR and Raman (only) three buttons appear at the left of thespectrum ( ), ( ) and ( ). Clicking on ( ) leads to a scrollable panel at
the left of the spectrum.
Chapter 22

421

This contains a listing of calculated infrared frequencies and intensities.
Checking the box to the left of an individual frequency moves the cursor on
the spectrum over this line and animates the vibrational motion.
With a frequency selected, clicking on the Make List icon (panel.

) leads to a newThis is used to make a list of structures centering around the minimum (ormaximum in the case of a transition state) with control over the amplitudeof vibration (maximum displacement in Å) and number of steps. Clicking on
the Make List button leads to a separate document.
If it exists, an experimental spectrum from the freely available NIST database
may be superimposed on top of the calculated spectrum. The IR spectrum of
methyl trans-cinnamate is available. Click onand selectfromthe palette.

Chapter 22422

Clicking on the Tables iconbrings up two lists of frequencies andintensities, the list on the left corresponding to the calculated spectrum (aspreviously described) and the list on the right corresponding to thecalculated spectrum.

The “experimental” frequencies and intensities have been obtained byfitting the measured infrared or Raman plot to a set of Lorentzian functions.
In the absence of an experimental infrared or Raman spectrum, therighthand list will be empty. You can drag a JCamp (.dx) file on top of thelist. It will take a few seconds for the spectrum to be displayed as a fit needs
to be performed.
Calculated infrared (and Raman) spectra that are initially displayed havebeen broadened to account for finite temperature. Unless they come from a
B3LYP/6-31G*, EDF2/6-31G* or B97X-D/6-31G* calculation, they areotherwise unaltered. Infrared (and Raman) frequencies from B3LYP/631G*, EDF2/6-31G* and B97X-D/ 6-31G* models have been uniformly
scaled to account for known systematic errors. In any event, a calculated
infrared or Raman spectrum can be fit to the corresponding experimental
spectrum (with

Chapter 22423

line width and scale factors as adjustable parameters), by clicking on the
button at the left of the spectra pane.
Additional spectra may be requested by clicking onin the bar above thespectra pane and then clicking on the appropriate entry in the resulting
palette. Each new spectrum adds a tab to the bar, although calculated andexperimental spectra share the tab. Switching between tabs changes thedisplay. A spectrum can be deleted by clicking onin the bar above thespectra pane. If both calculated and experimental spectra were displayed,
both will be deleted.
Controls at the top right of the spectra pane allow saving the spectrum as a
PNG, JPEG or Bitmap image file ( ), printing the file ( ), detaching thespectrum pane from the main window ( ) and closing the pane ( ).
Generalized Presentation of SpectraWith Spectra Pane (in the Settings tab of the Preferences dialog)
unchecked (Preferences under the Options menu; Chapter 25), selecting
Spectra from the Display menu leads to a tabbed dialog each of whichpertains to a different type of spectra, IR, Raman, NMR and UV/vis. These
allow different spectra for the same or for different molecules to be displayedon screen at the same time (as opposed to the one-spectra-at-a-time
restriction in the simplified mode) and allow additional controls foradjusting the displays as well as for fitting calculated to experimental
spectra.
IR, Raman (these two dialogs are nearly identical and will be discussed
together)
Clicking on the IR (or Raman) tab leads to the IR Spectra (or Raman
Spectra) dialog. This displays the calculated and (if available) experimental
infrared spectra, and allows for animated display of the vibrational modes aswell as for generation of a sequence of structures along a vibrational
coordinate.

Chapter 22424

At the left-hand side of the dialog is an ascending list of frequencies (in cm-1)*
together with (infrared) intensities and symmetry labels. A frequency is
selected for display (animation) by clicking on it. Clicking again deselects
it (stops the animation).
The amplitude of vibrational motion (the maximum displacement away fromequilibrium of any pair of atoms) may be changed from the default
amplitude (0.5Å which is much larger than appropriate for vibrationalmotion at room temperature) by altering the contents of the box to the rightof Amp at the lower left of the dialog. The default number of steps thatmake up the display (11) may be changed by altering the contents of thebox to the right of Steps** at the lower left of the dialog.
Clicking on Make List creates new document containing a sequence ofstructures corresponding to motion along the* Imaginary frequencies, for example, corresponding to the reaction coordinate for a transition
state, will appear first in the list, and will be designated by the letter i in front of the frequency
value.
** It is recommended that the number of steps be odd ensuring that the center point
corresponds to the actual equilibrium or transition-state structure.
Chapter 22425

selected vibrational mode. The original document is not closed andadditional sequences (corresponding to different vibrations) can be created.
Note that the information required to produce vibrational motions(animations) and to construct lists of structures along different vibrational
coordinates is available as part of the entry in the Spartan Spectra andProperties Database for the EDF2/6-31G* model (see discussion in
Chapter 23). They are not available for the B97X-D/6-31G* model.
The calculated spectrum may be drawn by clicking on Draw Calculated at
the top right of the dialog.

The experimental spectrum (if available) may be drawn on top of thecalculated spectrum (or by itself) by clicking on Draw Experimental at thecenter right of the dialog (IR spectrum shown).

Finally, a reference spectrum (a spectrum shared by all molecules in the
document; see discussion of the Spartan Infrared Database in Chapter 23)
if available, may be displayed along with the calculated and/or experimental
spectra by clicking on Draw Reference.

Chapter 22426

Draw operations for both calculated and experimental IR and Raman
spectra, apply to all molecules in the document (not just the selected
molecule). Note, however, that the reference spectrum is common to allmolecules in the document.
Experimental IR spectra are accessed from the NIST (National Instituteof Standards and Technology) website (http://webbook.nist.gov/
chemistry). This comprises approximately 7,000 IR spectra, primarily
for organic molecules. Alternatively, the user may supply a spectra file(see Appendix J). Selection (website vs. file) is made at the bottom rightof the dialog. Global Spectra controls whether spectra access pertains
to all molecules in the document (checked) or just the selected molecule(unchecked). Note that experimental spectra, once retrieved either online or from a file, are kept in the document (and need not be retrieved
again if they are deleted). They can be removed from the document byclicking on the Reset button.

The default range for calculated, experimental and (for infrared only)
reference IR and Raman spectra is from 4000 cm-1 to 500 cm-1. This
corresponds to the range commonly measured and reported. This range may
be changed by selecting Properties from the Display menu, clicking on thehorizontal axis to bring up the Plot Properties dialog, clicking on the X
Axis tab at the left of the dialog and editing the values under Range (seediscussion earlier in this chapter). The spectrum is treated like any othergraphical object, and may be translated and scaled using the appropriate
mouse operations. Touch screen operations also apply.
On touch screen devices, move two finger across the plot to translate
it and pinch two fingers to scale it. It may not be rotated.

The calculated spectrum may be removed by clicking on Delete Calculated
in the dialog. Similarly, the experimental spectrum may be removed byclicking on Delete Experimental and the reference spectrum may beremoved by clicking on Delete Reference. The last spectrum (calculated,
experimental or reference) removed will also cause removal of the plot axes.
These

Chapter 22427

operations apply to all molecules in the document (not just the selected
molecule). An individual (calculated or experimental) spectrum or entire
plot may also be removed by selecting Delete from the Build menu ( )and then clicking on a spectrum or on the plot axes, respectively, or holding
down the Delete key while clicking on the spectrum or plot axes.
Calculated IR (Raman) frequencies exhibit systematic errors. Frequencies
obtained from (limiting) Hartree-Fock models are typically 10-12% larger
than measured frequencies, while frequencies obtained from density
functional and MP2 models are typically 3-4% larger than measured
frequencies. Systematic errors may be revealed (and quantified) by firstsimultaneously displaying calculated and experimental spectra and thenscaling one of the spectra to provide a best visual fit. To scale the calculated
spectrum, use the slider bar to the right of Scale near the top right of the
dialog.
A scaling factor may be applied to frequencies, and to all properties thatmake use of frequencies, prior to reporting using the FreqScale keyword
typed into the Options box in the Calculations dialog (Calculations...
under the Setup menu, Chapter 21).

A second slider bar marked Temp controls peak width. This is loosely
connected with the temperature at which the experimental measurement iscarried out. Low “temperature” (slider to the left) will produce sharp spikes,
whereas high “temperatures” (slider to the right) will produce broad bands.
The default setting is intended to give calculated spectra that broadly
resemble experimental infrared spectra. Both Scale and Temp slider bars
actually control the fit of the calculated frequencies and intensities to a
Lorentzian function. The default settings can be restored by clicking on theStandard button. A best fit to an experimental spectrum superimposed onto
the calculated spectrum can be obtained by clicking on the Experimental
button. A best fit to an unknown reference spectrum (associated with all themolecules in the document rather than a single molecule) can be obtainedby clicking on the Reference button.

Chapter 22

428

NMR
NMR spectra may be subdivided into four categories*: 1H spectra with orwithout 3-bond HH coupling (the former being what is observed
experimentally), 13C and DEPT spectra, COSY spectra, and HSQC and
HMBC spectra. Access to Experimental 1D spectra proton and 13C isprovided either from an on-line database, by manually attaching chemical
shifts to either 2D sketches or 3D models or from a local file. While there
is no provision for entering numerical values for experimental 3-bond HH
and 2 and 3-bond CH coupling constants, couplings that are experimentallyobserved (or at least assigned) can be marked to either 2D sketches or 3Dmodels. This allows construction and display of experimental COSY and
HMBC spectra. Clicking on the NMR tab leads to the NMR Spectra
dialog.

*Chemical shifts for other nuclei are reported in the summary output (see Output earlier in thischapter) and may be displayed as labels (see Configure... under the Model menu; Chapter 18).

Chapter 22429

Calculated proton, 13C and DEPT spectra may be drawn by clicking on theirCalculated and DEPT buttons, respectively.* Proton and 13C from theB3LYP/6-31G*, EDF2/6-31G*, ωB97X-D/6-31G*, and ωB97X-D/6-311G*
models are corrected based on topology and bond orders. 19F shifts from the
EDF2/6-31G* model are also corrected. Shifts from other models are notcorrected.

Experimental 13C and DEPT spectra (if available) may be drawn together
with or independently of the calculated spectra by clicking on Draw
Experimental. Draw operations apply to all molecules in the document.

Experimental proton and 13C spectra are accessed from the freely
available NMR shift database (http://nmrshiftdb.uni-koeln.de). This
database contains over 50,000 experimental spectra, all for organic
molecules. Alternatively, may attach experimental shifts to either 2D
sketches or 3D models or the user may supply a spectra file (Appendix
J). Selection (website vs. file) is made at the bottom right of the dialog.
Global Spectra controls whether spectra access pertains to all moleculesin the document (checked) or just to the selected molecule (unchecked).
* DEPT spectra (both calculated and experimental) are simply derived from the corresponding 13C spectra by
drawing lines corresponding to quaternary and methylene carbons “down” rather than “up”.

Chapter 22

430

Note that experimental spectra, once retrieved either on-line or from afile, are kept in the document (and need not be retrieved again if they
are deleted). They can be removed from the document by clicking on
the Reset button.

Proton spectra may be drawn to reflect spin-spin coupling due toneighboring nuclei. Coupling constants are not calculated, but are estimatedempirically based on three-dimensional geometry. A magnifier is available
under the Plot Properties dialog (see discussion earlier in this chapter).

Default ranges for proton spectra (0 to 10 ppm) and 13C spectra (0 to 150ppm) may be changed by selecting Properties from the Display menu,
clicking on the horizontal axis to bring up the Plot Properties dialog,
clicking on the X Axis tab at the left of the dialog and editing the values
under Range. Spectral plots may be translated and scaled either with themouse or via two finger touch-screen operations.
A calculated spectrum may be removed by clicking on Delete Calculated(that has replaced Draw Calculated) and an experimental spectrum
removed by clicking on Delete Experimental. The last spectrum removed
will also cause removal of the plot axes. These operations apply to allmolecules in the document. An individual (calculated or experimental)

Chapter 22431

spectrum or entire plot may also be removed by selecting Delete from the
Build menu (or holding down the Delete key) and then clicking on the
spectrum or on the plot axes, respectively.
2D spectra are available from Draw Calculated buttons. COSY spectra
identify protons three bonds removed, HSQC spectra identify protons
directly attached to a carbon and HMBC spectra identify protons that are
three bonds removed from a carbon. Note that proton spectra “broadened”
because of the inclusion of spin-spin coupling are not used in construction of
2D spectra. The corresponding proton and carbon spectra axes may bedisplayed along with 2D spectra by selecting them in addition to the 2D
spectra. 2D spectra (and the 1D axes spectra) may be removed using the
Delete Calculated buttons (that have replaced the Draw Calculated
buttons). Experimental 2D spectra displays are not yet available. An HMBC
spectrum is shown below.

Uncorrected proton, 13C, DEPT and 19F spectra, that is, from models otherthan B3LYP/6-31G*, EDF2/6-31G*, ωB97X-D/6-31G* and ωB97X-D/6311G**, are likely to show significant systematic errors in chemical shifts. To
scale either the calculated or experimental spectra in order to provide a bestvisual fit, click on the spectra (not on an axis) to select and move the mouse up
and down while simultaneously depressing the Shift and Alt (option

Chapter 22432

on Mac) keys in addition to the right button. The scale factor (multiplying
the chemical shifts) will be displayed on the vertical axis. Scaling applies
uniformly to all molecules in the document.
UV/visClicking on the UV/vis tab leads to the UV/vis Spectra dialog that provides
for display of UV/visible spectra.

This lists wavelengths and intensities. Click on Draw Calculated
to draw the calculated spectrum.

Click on Draw Experimental to draw the corresponding experimental
spectrum. Draw operations for both calculated and experimental UV/visible
spectra and apply to all molecules in the document.

Chapter 22433

Experimental UV/visible spectra are accessed from the NIST (National
Institute of Standards and Technology) website (http://webbook.nist.
gov/chemistry). This comprises approximately 1,500 UV/visible spectra,
primarily for organic molecules. Alternatively, the user may supply aspectra file (see Appendix J). Selection (website vs. file) is made at thebottom right of the dialog. Global Spectra controls whether spectra
access pertains to all molecules in the document (checked) or just to theselected molecule (unchecked). Note that experimental spectra, once
retrieved either on-line or from a file, are kept in the document (andneed not be retrieved again if they are deleted). They can be removed
from the document by clicking on the Reset button.

The default range for both calculated and experimental UV/ visible spectra
is from 200 nm to 700 nm. This corresponds to the range commonlymeasured and reported. This range may be changed by selecting Properties
from the Display menu, clicking on the horizontal axis to bring up the Plot
Properties dialog, clicking on the X Axis tab at the left of the dialog andediting the values under Range (see discussion earlier in this chapter). The
spectrum is treated like any other graphical object, and may be translated
and scaled using the appropriate mouse or touch- screen operations.
The calculated spectrum may be removed by clicking on Delete Calculated(that has replaced Draw Calculated) in the dialog. Similarly, theexperimental spectrum may be removed by clicking on Delete Experimental(that has replaced Draw Experimental). The last spectrum removed will also
cause removal of the plot axes. These operations apply to all molecules in the
document (not just the selected molecule). An individual (calculated orexperimental) spectrum or entire plot may also be removed by selecting
DeleteChapter 22434

from the Build menu (or holding down the Delete key) and then clicking
on the spectrum or on the plot axes, respectively.
To help reveal similarities and differences between calculated andexperimental UV/visible spectra, one or the other may be scaled. To scale,click on the spectra (not on an axis) to select and move the mouse up anddown while simultaneously depressing the Shift and Alt (option on Mac)
keys in addition to the right button. The scale factor will be displayed on
the vertical axis. Scaling applies to all molecules in the document.
Only a single copy of one of the dialogs under Spectra may appear on
screen; scaling will relate to the currently selected molecule. The dialog
may be removed by clicking on .
Formulas ()

The molecular mechanics and quantum chemical methods available in
Spartan are able to provide a wide variety of molecular and atomic properties
and QSAR descriptors. Quantities related to structure are available throughfunctions under the Geometry menu (Chapter 19), while most otherproperties may be accessed from Properties dialogs (previously discussed
in this chapter) or from the spreadsheet (to be discussed later in this chapter).
In some cases, however, it is not the properties or descriptors themselvesthat are of interest, but rather relationships among them. For example, while
the energies of the HOMO and LUMO of a molecule may not be of interest,
the difference in their energies (the HOMO-LUMO gap) may be. Anotherimportant kind of relationship is that involving a change in property
between reactants and products of a chemical reaction, in particular, thechange in energy.
Spartan provides a formula editor to define relationships among propertiesof a single molecule or of a single property between the reactants andproducts of a chemical reaction. The former is discussed here and the latter
will be discussed in the next chapter in the context of data mining. The
Formula Editor dialog is accessed by selecting Formulas from the
Display menu.

Chapter 22

435

The bottom half of the dialog contains controls to build formulas, while the
top half stores the formulas. Aside from the energy and T1 heat offormation*, properties need to be dragged onto one of three “buttons” under
Properties at the lower right of the Formula Editor dialog from its onscreen display (for example, a bond distance from its display at the bottomof the screen following selection of Measure Distance from the Geometrymenu) or from one of the Properties dialogs (for example, the dipole
moment in the Molecule Properties dialog). Following this, the button takes
the name of the property. The property obtained from Spartan is now
available for use in a formula. Energy and T1 heat of formation are given
their own “permanent” buttons in the dialog.
Theoretical Model (under Context in the lower center of the Formula
Editor dialog) needs to be specified from among the models stored indatabases available to Spartan (see discussion in Chapter 23). Ambient
refers to the theoretical model actually used for the calculation of theselected molecule, and should not be selected if a calculation has not
actually been run. The Applied to menu under Context will be grayed out
if the molecule that Spartan* Heats of formation from the T1 recipe are available for most molecules in the SSPD.

Chapter 22436

is pointing to does not contain reaction information. Use of the formula
editor to relate information for the reactants and products of chemical
reactions is discussed in Chapter 23.
Pressing either the E or H(T1) buttons or a Property button onto which a
property has been dragged, builds a formula and places it inside the second
box at the center of the dialog. The default name (Fx, x=0, 1, 2...) appears
in the first box. Either the formula or its name may be edited. Pressing
Enter (return on Mac) stores the formula with the default or edited name.
Pressing Clear removes the formula. Double clicking on a formula instorage brings it back to the boxes at the center of the formula editor (butdoes not remove it from storage). The formula can then be edited andreturned to storage (by clicking on Enter). If the name of the formula has
not been changed, it will replace the original in storage. If it has beenchanged, it will be treated as a new formula. Once in storage, a formula canbe dragged to wherever it is needed, in particular, into the spreadsheet, thePlots dialog or any of the dialogs associated with the SSPD. To remove astored formula, right click on it and select Delete from the menu.
Formulas use the usual set of arithmetic operations and parentheses toconnect different properties. In addition, Boolean operators and standard
mathematical functions designated in Table 22-1 may be used. These need
to be typed into the box at the center of the dialog. For example, to construct
a formula for the HOMO-LUMO gap, first drag the LUMO energy from the
Molecule Properties dialog onto one of the properties buttons in the
Formula Editor dialog. Pressing the button leads to the text string@LUMO*@hart2eV at the center of the dialog. Insert (type) “-” at the endof the string. Next, drag the HOMO energy from the Molecule Properties
dialog onto a properties button in the editor and press the button. The text
string is now @ LUMO*@hart2eV-@HOMO*@hart2eV. Note that while
orbital energies are evaluated in atomic units (hartrees), the formula includes
a conversion factor @hart2eV to bring them into electron volts (eV). You canchange units by manually editing the text string using the expressions
provided in Table 22-2 (preceded by @). Change the title

Chapter 22437

Table 22-1: Arithmetic & Boolean Operations and Mathematical Functions
arithmetic operations+ addition_ subtraction* multiplication/ division^ raise to a power

Boolean operations> greater than>= greater than or equal to< less than<= less than or equal to== equal to!= not equal to
| or
& and

mathematical functions
ABS(x)
absolute value
ACOS(x)inverse cosine
ASIN(x)inverse sine
ATAN(x)inverse tangent
COS(x)
cosineEXP(x)
exponential

LN(x)
LOG(x)
SIN(x)SQRT(x)
TAN(x)

natural logarithmlog (base 10)
sinesquare root
tangent

Table 22-2: Conversion Factors and Constants

ANGS2AUÅngstroms to atomic units

AU2ANGSatomic units to Ångstroms

EV2HARTeV to atomic units (hartrees)

EV2KCALeV to kcal/mol

EV2KJ

eV to kJ/mol

HART2KCAL

atomic units (hartrees) to kcal/mol

HART2EVatomic units (hartrees) to eV

HART2KJ

atomic units (hartrees) to kJ/mol

KCAL2EVkcal/mol to eV

KCAL2HART

kcal/mol to atomic units (hartrees)

KCAL2KJ

kcal/mol to kJ/mol

KJ2EV

kJ/mol to eV

KJ2HART

kJ/mol to atomic units (hartrees)

KJ2KCAL

kJ/mol to kcal/molPIπ

Chapter 22438

to the left of the string from Fx to HOMO/LUMO gap, and press the Enter(return) key to the right of the string. The full formula is moved to the storage
area at the top of the dialog. Note that the formula will be evaluated andnumerical results presented if the appropriate data for the selected moleculewith the selected theoretical model are available in the database (in this case,
HOMO and LUMO energies).
A number of the quantities that are calculated by Spartan are not available
from the graphical interface, but must be extracted from the archive of
properties maintained by Spartan. Examples include orbital energies otherthan those corresponding to the HOMO and LUMO, and the polar surface
area defined to include sulfur and any attached atoms in addition to nitrogen,oxygen and any attached hydrogens (the default). However, these and otherquantities may be used in formulas by manually editing the text string. The
expressions provided in Table 22-3 need to be preceded by a @. For
example, @ HOMO(-1) accesses the energy of the molecular orbital
immediately below the HOMO, while @PAREA(7,8,16,7:,8:,16:) accesses
the polar area extended to sulfur and any attached hydrogens as well as thepolar area of nitrogen, oxygen and any attached hydrogens. The integer
arguments correspond to atomic numbers (sulfur is 16) while the integer
arguments followed by “:” specify attached hydrogens (16: means includehydrogens attached to sulfur).
Formulas are used in conjunction with spreadsheet manipulations andplotting (both discussed later in this chapter) and with data mining(discussed in Chapter 23).
Spreadsheet ()

Associated with each Spartan document (including documents comprising
a single molecule) is a spreadsheet. This may be displayed by selecting
Spreadsheet.
The spreadsheet comprises a series of rows (corresponding to different
molecules in the document and columns (corresponding to different
molecular properties). This gives rise to cells, the number of which is the
product of the number of rows (molecules) and the number of columns(molecular properties). The spreadsheet may

Chapter 22439

Table 22-3: Calculated Quantities

Table 22-4: Specialty Functions
AVG (column name)average of values in column

FITVAL (fit name)column of fit values from regression analysis

MIN (column name)minimum of values in column

MAX (column name)maximum of values in column

NUM (column name)number of defined entries in column

ROW

the number of the row in the spreadsheet

ROW(molecule name)the number of the row of molecule

REF(i, x)

the value of the x referenced to row i

STDEV (column name)standard deviation of values in column

SUM (column name)sum of values in column

Chapter 22440

be expanded or contracted by positioning the cursor at one of the corners,pressing the left mouse button and dragging the mouse.
Only one molecule from one document may be selected (although several
molecules may be simultaneously displayed). Molecule selection follows
either by clicking on the spreadsheet cell containing the molecule label oridentifier (leftmost column), or by using the andbuttons or the scroll
bar at the bottom left of the screen. Molecules may be animated (steppedthrough in succession) using the
button at the bottom left of the screen.
Animation speed may be adjusted from the Settings Preferences dialog(Preferences under the Options menu; Chapter 25). Selection of a newmolecule in the document results in deselection of the previously selected
molecule. A molecule may be designated for “permanent” display bychecking the box to the left of its identifier in the spreadsheet. The molecules
in a document may either be translated and rotated in concert ormanipulated independently. This is controlled by Coupled (which operates
in toggle mode) under the Model menu (Chapter 18). By default (Coupledchecked) molecules move in concert. Uncheck Coupled to move them
independently.
Upon initial entry, all columns of
the spreadsheet except the leftmost
column, are blank. The leftmost
column contains a label that may bechanged either by directly typing a
new label into the spreadsheet or
into the Label box in the Molecule
Properties dialog (see discussion
earlierin
thischapter).
Additionally, default identifiers(M0001, ...) may be replaced bychemical names if the molecule
exists in the Spartan Spectra
and Properties Database (SSPD)

Chapter 22441

by clicking on Label (the leftmost header cell), then right click inside theheader cell of the leftmost column and again select Rename Selectedusing SSPD.
Information may be added to the spreadsheet in several different ways:
From the Add Dialog
A selection of molecular properties may be entered into the spreadsheet by
first clicking on the header cell of an empty column, and then clicking on
Add... at the bottom of the spreadsheet. Alternatively, right click inside theheader cell and then to select Add... from the menu that results. This leads toa multi-tab dialog with Molecule selected.

Namemolecule name as it appears in SSPD
Formulamolecular formula
Molecular Weight molecular weight (in amu)
Eenergy (heat of formation, strain energy)
Pt Groupsymmetry point group
Expt. Heat (kJ/mol) experimental heat of formation in kJ/mol (ifavailable)
T1 Heat (kJ/mol) T1 heat of formation in kJ/mol
Conformers
number of conformers
E HOMO
energy of highest-occupied molecular orbital

Chapter 22442

E LUMO
Dipoleenergy of lowest-occupied molecular orbital
dipole moment (in debyes)

E B97X-V/
6-311+G(2df,2p)

energy from SSPD (with ωB97X-D/6-31G*
geometry)

One or more properties may be added to the spreadsheet byclicking on their entries.
An Energy Units menu is available to change from the defaults (autoselect) to au, kJ/mol or kcal/mol.
Clicking on the QSAR tab leads to another dialog.

CPK Area (Å2)
CPK Volume (Å3)
PSA (Å2)

CPK Ovality

Acc. Area (Å2)

Chapter 22

surface area of a space-filling (CPK) model (inÅ2)
volume of a space-filling (CPK) model (in Å3)
polar surface area of a space-filling (CPK)model (in Å2). Defined as the area due toelectronegative atoms (N, O) and hydrogens
attached to the atoms
measure of deviation from a spherical shape,where 1.0 = a sphere and values > 1.0 indicate
deviationaccessible surface area of an electron density
surface (in Å2). Surface is defined by electron

443

Chapter 22444

Clicking on the Thermodynamics tab leads to another dialog.

ZPE (kJ/mol)
S° (J/mol•K)
H° (au)G° (au)Cv (J/mol•K)zero-point energy (in kJ/mol)
entropy (in J/mol•K)enthalpy (in au). Sum of electronic energy and zeropoint energy adjusted for finite temperature
Gibbs energy (in au). Sum of enthalpy and entropy.
heat capacity at constant volume (in J/mol•K)

Scale Vibrational Frequencies by is used to scale calculated frequencies,
where default applies to the ambient model and is available for B3LYP/631G*, EDF2/6-31G* and B97X-D/ 6-31G* models. Temperature isused to set temperature. Note that vibrational frequencies need to beavailable for all quantities under the Thermodynamics tab.
Clicking on the Molecule List tab leads to another dialog. This allows
quantities for different molecules (or different conformers of the same
molecule) in a list to be related.

Chapter 22445

rel. E (kJ/mol)
Boltzmann Weights
Cumulative
Boltzmann Weights
Alignment Scores

Relative ωB97X-V/ 6311+G(2df,2p)
energy (kJ/mol)energy (heat of formation, strain energy) relative
to selected molecule
Boltzmann weightSum of the Boltzmann weights for the selected
molecule and all molecules with lower energy
than the selected molecule
1-R2/N, where R2 is the root mean square distanceand N is the number of alignment centers. 1 is aperfect scoreenergyfrom
ωB97X-V/6-311+G(2df,2p)//
ωB97X-D/6-31G* model relative to the selected
molecule. Only applicable if data are available in
SSPD

Units for relative energies and temperature for Boltzmann weights andcumulative Boltzmann weights may be selected from menus at the bottom.
Clicking on the Summaries tab leads to another dialog.

Chapter 22446

Totalsum of column values
Minimum
minimum of column values
Standard Deviation standard deviation of column values
Boltzmann Average Boltzmann weighted average of column values
Averageaverage of column values
Maximum
maximum of column values
RMS
rms of column values

The temperature (for Boltzmann average) may be changed from the default
value of 298.15K from the menu at the bottom of the dialog.
Linear regression analysis may be performed on data in the spreadsheet.
Clicking on the Linear Regression tab brings up a dialog.

Chapter 22447

Select one entry from the Fit menu and one or more entries from the list
under Using. Clicking on Apply performs the linear regression analysis andplaces the results in a row at the bottom of the spreadsheet identified by Fit.
As many regression analyses as desired may be performed on the data in the
spreadsheet. The individual results will be entered as separate rows in the
spreadsheet, with names Fit1, Fit2, etc. Additional information about the
regression analyses is available from the Regression Properties dialog (seediscussion earlier in this chapter).
From Post () Buttons

Post buttons ( ) found in a number of properties dialogs provide analternative method to the Add dialog for entering calculated properties into
the spreadsheet. Note that some properties may require user specification.
These include individual bond distances, angles and dihedral angles(available from Measure Distance, Measure Angle and Measure
Dihedral under the Geometry menu; Chapter 19), bond distance, angle
and dihedral angle constraints (available from Constrain Distance,
Constrain Angle and Constrain Dihedral under the Geometry menu;
Chapter 19), atomic charges, chemical shifts (available from the Atom
Properties dialog; this chapter), the accessible area of an electron density
surface, the polar area and accessible polar area of an electrostatic potential
map, the area of a selected region (band) of a banded property map, minimum
and maximum property values on a map and the value of the property at a
specific location on a property map (available from the Surfaces
Properties dialog; this chapter). With the exception of the property value
on a map and the area of a selected band, post generates an entire column.
Where atom labels are involved, for example, in defining a specific distance,
post can be expected to yield consistent results for all molecules in adocument only where the molecules are closely related, for example,
molecules resulting from a conformational search, or where labels havebeen explicitly reassigned*. The*

Label reassignment is accomplished using the Atom Properties dialog (see discussion earlier in thischapter).

Chapter 22448

property value and the area of a selected band on a map is posted only for theselected molecule. Post buttons are also available for experimental heats offormation contained in SSPD, as well as for ωB97X-V/6-311+G(2df,2p)
energies and T1 heats of formation.
From the Clipboard
Properties of one or more molecules in a document may be copied onto the
clipboard and then pasted into individual spreadsheet cells. These include(but are not restricted to) bond distances, angles and dihedral angles(Measure Distance, Measure Angle and Measure Dihedral under theGeometry menu; Chapter 19), bond distance, angle and dihedral angle
constraints (Constrain Distance, Constrain Angle and Constrain
Dihedral under the Geometry menu; Chapter 19), atomic charges andchemical shifts (Atom Properties dialog; this chapter), and the value of aproperty on a property map and the area of a selected band (Surface Properties
dialog; this chapter). To copy to the spreadsheet, first highlight the numericalvalue of the property in the appropriate screen location (distances, etc.) or
dialog (charges, etc.), then select Copy from the Edit menu, then click on
the appropriate (destination) cell in the spreadsheet, and finally select Pastefrom the Edit menu.
User-Defined Expressions
An expression may be entered either into a header cell (in which case it
refers to all molecules) or into an individual cell (in which case it refers only
to a single molecule). Expressions in the column header take the form
name=formula, where formula is made up of arithmetic operations (Table
22-1), specialty functions (Table 22-4), calculated quantities (Table 22-3),
conversion factors and constants (Table 22-2) in addition to numericalvalues. References to specialty functions, calculated quantities andconversion factors and constants must be preceded by @. For example,
mu=@DIPOLE typed into a header cell gives the dipole moment. Somefunctions have arguments, for example, c1 and c2 in the expression c12=
@DISTANCE (c1,c2) refer to

Chapter 22449

atoms c1 and c2, while 3 in the expression orbitalE=@HOMO (-3)
designates the energy of the molecular orbital three orbitals below the
HOMO. It is necessary to press the Enter key (return key on Mac)
following entry of the expression into a cell. The leading name= is optional
for individual entries.
Formula construction inside the spreadsheet uses the same rules andreferences the same set of functions described in Formulas earlier in thischapter (in addition to the specialty functions in Table 22-4). It may be moreconvenient to construct expressions in the formula editor and drag them into
the spreadsheet than to construct them in the spreadsheet. Note thatspreadsheet expressions refer to the molecules in the spreadsheet and not totheir reaction products.
Numerical Data
Numerical data may be entered by typing directly into the spreadsheet. A
column header first needs to be specified. Double click on an empty column
header cell, type in a name and press the Enter key (return key on Mac).
Then, type the data into individual cells of the new column (press the Enter(return) key following each data entry). Alternatively, use the ↓ key.
Each row in a spreadsheet corresponds to a molecule in a document, and newrows are automatically added in response to adding new molecules to the
document. New molecules may be added by building (Build New Molecule
under the File menu; Chapter 16) or sketching (Sketch New Molecule
under the File menu; Chapter 16), by appending one or more existing
documents each containing one or more molecules using either Append
Molecule(s)... under the File menu (Chapter 16), or by right clicking inside
the header cell of the first available row and selecting Append from thecontextual menu that appears, by pasting from the clipboard, or by dragging
from the file system. To copy a molecule onto the clipboard, first select(click on) it, and then select Copy from the Edit menu, or click on its
identifier (left most column) in its spreadsheet, and then select Copy fromthe Edit menu. Alternatively right click either on

Chapter 22450

the molecule or on its identifier in the spreadsheet and select Copy from themenu that appears. Several molecules may be selected (and copied) at once
using the Shift and Ctrl keys in the usual manner. To copy the contents ofthe clipboard to its destination, click on an empty row header in the
spreadsheet (for the destination document), and then select Paste from theEdit menu. An alternative to the two-step Copy-Paste procedure is to dragthe molecule or set of molecules from one spreadsheet to another.
A row (molecule) may be deleted from a spreadsheet, either by first
selecting the molecule and then selecting Delete Molecule from the Filemenu (Chapter 16), or by first clicking on its identifier in the spreadsheet(leftmost column) and then either clicking on the Delete button at the bottomof the spreadsheet, or by right clicking on its identifier in the spreadsheet
and then selecting Delete Selected from the contextual menu that appears.
A warning is provided prior to deletion. An entire column in the spreadsheet
may be deleted by first clicking inside its header cell and then clicking on the
Delete button (or Delete Selected from the contextual menu).
Rows in the spreadsheet may be sorted according to the numerical values
in any column either by first clicking inside the header cell and then clicking
on the Sort button at the bottom of the spreadsheet or by right clicking inside
the header cell and selecting Sort from the contextual menu that appears.
The rows are placed in ascending order, the smallest (least positive) valueof the selected property at the top, largest (most positive) value at thebottom. To sort in descending order, hold down the Shift key before
clicking on the Sort button or selecting Sort from the contextual menu.
Information in one or more columns of the spreadsheet may be formatted
by right clicking inside the header cell(s)and selecting Format Selectedfrom the contextual menu.
Format as desired and clickon OK to remove the dialog.
The full contents of the
spreadsheet
maybeformatted by right clicking

Chapter 22451

inside the header cell for the left most column and then selecting
Format Selected from the contextual menu.
A button at the bottom right of the spreadsheet toggles between numericalrepresentation of data, f(x), and formula presentation, =?.
The spreadsheet may be printed by right clicking inside the spreadsheet andselecting Print from the menu that results.
Spreadsheets are associated with individual documents and, where morethan one document is open on screen, multiple spreadsheets may bedisplayed. A spreadsheet is removed when the associated document isclosed and may also be removed by clicking on.
The contents of the spreadsheet may be brought into Excel™ using the
clipboard. Select whatever cells are to be copied, select Copy from theEdit menu. Alternatively, right click with the proper cells selected andselect Copy from the menu that appears. Paste into Excel.
The contents of an Excel spreadsheet may be brought into Spartan.
Copy whatever information is to be transferred to the clipboard, moveinto Spartan, then click on the appropriate cell and select Paste from theEdit menu (or right click on the appropriate cell and select Paste fromthe menu that appears). Note, that information on the clipboard that goesbeyond the number of rows in Spartan’s spreadsheet will be ignored.

Plots... ()

Plots may be constructed from data in a spreadsheet and a variety of simple
curves fit to these data. As with presentation of spectral data (see discussion
earlier this chapter), Spartan allows both simplified and more generalmodes for presentation, the choice of which being left to the user.
Simplified Presentation of Plots
With Plots Pane in the Settings Preferences
dialog checked (Preferences under the
Options menu; Chapter 25), selecting
Plots from the Display menu leads to an empty display pane at the right ofthe screen.

Chapter 22452

Clicking on
dialog.

(add plot) in the bar at the top of the plots pane leads to a

You need to select an item from the X Axis menu and one or more items
from the Y Axes list, and then click on the Add button at the bottom of the
dialog. A plot appears in the plot pane and the Add Plot dialog is dismissed.

By default, the scales for both horizontal and vertical axes are set to boundthe data trying to provide limits and increments that are “rounded”. Moving
the mouse left and right while holding down the right button slides thehorizontal scale but does not change the range. Similarly, moving the mouseup and down while holding down the right button slides the vertical scale.
The horizontal range may be changed by moving the mouse left and rightwhile holding down both the right button and shift key, and the vertical rangechanged by moving the mouse up and down while holding down both theright button
Chapter 22453

and the shift key. The scroll wheel may be used to simultaneously changeboth horizontal and vertical ranges. The original settings may be restored byclicking onin the bar at the top of the plots pane.
On a touch screen device, move two fingers left and right and up
and down to slide the viewable horizontal and vertical scales,
respectively. Pinch two fingers left and right and up and down to change
the horizontal and vertical scales, respectively.

The plot ranges may also be changed by clicking onof the plots pane.

in the bar at the top

The resulting dialog also allows axis labels to be altered (from their initialvalues designated in the spreadsheet) the number of “ticks” of horizontal
and vertical axes to be changed and a plot title to be added. Finally, the“curve” can be changed to Point to Point, Smooth, Least Squares or
Fourier.
Additional plots may be added by clicking onin the bar at the top of theplots pane. Each plot is given a tab. Only one plot may be displayed at atime as controlled by which tab is selected. The selected (and displayed)plot may be deleted by clicking on.
Generalized Presentation of Plots
With Plots Pane in the Settings Preferences dialog unchecked(Preferences under the Options menu; Chapter 25), selecting Plots fromthe Display menu leads to the Plots dialog.

Chapter 22454

A tab at the top of the dialog selects between XY Plot (two dimensions) or
XYZ Plot (three dimensions). Common to both is the Plot Type menu.

This distinguishes between plots based on the entire set of molecules in adocument (By Molecule), to those based on the atoms in a single molecule(By Atom). The latter is the mode used to plot calculated IR, Raman and
NMR spectra. The third choice (Free Form) is used to construct single
molecule plots, for example, calculated, UV/ vis spectra as well as plots ofexperimental IR, Raman, NMR and UV/visible spectra. This is normallydone automatically from the appropriate spectra dialog (see discussion
earlier in this chapter).
By atom and free form plots make use of vector capabilities in Spartan’s
spreadsheet. See the FAQ Equations in Spartan available under Help fromthe Help menu (Chapter 27).
Also common to both is the Properties checkbox at the bottom left of the
dialog. Unchecked, this provides access for the X-Axis (X-Axis and Y-Axis
for an XYZ plot) menu and Y-Axes (Z-Axes for an XYZ plot) only toquantities that have been entered in the spreadsheet. Checked, it provides
access to all quantities in the Spartan’s Property Archive resulting from a
calculation or from retrieval of information from SSPD.

Chapter 22455

XY Plots
The XY Plot dialog incorporates an X Axis menu designating the molecularproperty to be displayed among the X (horizontal) axis, and a list of
properties to be displayed along the Y (vertical) axis. These properties
correspond one to one to the columns in the associated spreadsheet. To
construct a 2D plot, select an item from the X Axis menu, then click on one
or more items from the Y Axes list and finally click on OK. (Repeatedclicking on a property in the Y Axes turns the list on and off.) The dialog
is removed from the screen and a plot appears.

The plot may be moved about the screen. Select (click on) either the frameor on one of the curves (it will turn gold in response), then hold down theright mouse button and drag the mouse. The plot may also be scaled(expanded or shrunk) by first selecting either the frame or one of the curves
and dragging the mouse while holding down both the right button and theShift key. The plot may not be rotated. Touch-screen operations are alsoavailable. Move two fingers across the plot to translate it and pinch two
fingers to scale it.
XYZ Plots
The XYZ Plot is reached by clicking on the XYZ Plot tab at the top of the
dialog. This leads to a new dialog.

Chapter 22456

This is very similar to the XY Plot, except that it incorporates X Axis andY Axes menus to designate quantities to be displayed along the X and Y
axes, respectively, as well as a list of properties to be displayed along the Z
axis. To construct a 3D plot, select one item from each of the X Axis and Y
Axis menus, then click on one or more items from the Z Axes list and finally
click on OK. A plot appears.
The plot can be moved about thescreen. Select (click on) either theframe or on one of the curves (it willturn gold in response), then hold down
the right mouse button and drag themouse. The plot may also be scaled(expanded or shrunk) by first selecting
either the frame or one of the curves
and dragging the mouse while
holding down both the right button
and the Shift key.
Finally, 3D plots (unlike 2D plots discussed earlier) may be rotated, by first
selecting either the frame or one of the curves and dragging the mouse
while holding down the left button. Touch-screen operations also apply.
Move two fingers across the plot to translate it, move one finger to rotate
it and pinch two fingers to scale it.

Chapter 22457

Plots initially presented connect the data points with cubic splines. A varietyof curve fits (linear, least squares, Fourier, etc.) as well as a variety ofdifferent presentation formats are available under the Plot Properties andassociated dialogs (see Properties earlier in this chapter).
A plot may be deleted by first selecting (clicking on) Delete from the Buildmenu ( ), or holding down the Delete key, and then clicking on either theplot frame or on an individual curve. Clicking on the frame removes it andall associated curves, while clicking on a curve removes only this curve.
However, the last curve deleted also deletes the frame. IR, Raman, NMR
and UV/ vis spectral plots may also be removed from the corresponding
Spectra dialog.
Similarities... ()

The results of a similarity analysis based either on selected atoms in a
structure or on a set of CFD’s as a template may be viewed using the
Similarities dialog.

The box at the right of the dialog identifies each hit in terms of the identityof the Template Molecule, the Library Molecule, and in the case where alibrary molecule has been expanded in terms of a set of diverse conformers,
the identity of the conformer. It also provides

Chapter 22458

a score* and, in the case where excluded volume CFD’s are present in thetemplate, the number of collisions between these elements and the librarymolecule. Finally, it indicates whether the enantiomer for the molecule
included in the library has been inverted. Entries in the dialog may be sorted
by score or number of collisions (as well as by the names of the templateand library molecules) by clicking on the appropriate column header at the
top of the box.
A minimum score can be set from the Minimum Score menu at the bottom
right of the dialog. The number of matches that satisfy this minimum isreported.
As hits are selected by clicking on them in the box, the library entry
superimposed onto the template will be displayed in the window at the leftof the dialog. This graphic may be manipulated (rotated, translated, scaled)with the usual mouse/keyboard commands (the cursor needs to bepositioned inside the window). The display style cannot be altered, nor can
any measurements be made.
The library entry associated with a particular hit may be retrieved (brought
into Spartan’s main window) by first selecting it and then clicking on the
Retrieve button at the bottom of the Similarities dialog. The templatecannot be retrieved. Retrieval can either be to a New Document or to theCurrent Document depending on the setting in the Retrieve Options
dialog accessed by clicking on to the right of the Retrieve button.

* The score is defined as [(1-R2)/N]-penalty, where R2 is the root mean square distance between templateand library molecule centers and N is the number of similarity centers. Whereas molecule alignment as aprelude to similarity scoring is based on atomic, CFD and pharmacophore centers only, penalties are given
for alignments that lead to unfavorable steric interactions between template and library entries or (in the caseof molecule alignment by CFD’s) to incorrect orientation of hydrogen bond donor or acceptor CFD’s.
These are subtracted from the score based on R2. 1 is a perfect score.
Chapter 22459

Retrieval to the Current Document (that with the template) allows boththe template and one or more hits from the library to be displayed
simultaneously, with a full range of model styles and display options.
The Similarities dialog is closed by clicking on the Done button.
Reactions... ()

Data entered in a Spartan document may be used to calculate reaction energies
including activation energies.
∆E = Eproduct1 + Eproduct2 – Ereactant1 + Ereactant2

Selection of Reactions... from the Display menu leads to theReactions dialog.

Two menus under Reactants: and two menus under Products: identify thereactants and products of reaction. They correspond to the labels(identifiers) of the molecules in the document, plus a null entry <none>.
Note that the overall reaction needs to be mass balanced.
The Use menu identifies the source of the energies to be used in the reactionenergy calculation, either the SSPD or the Current Document.
Selection of SSPD (from the Source menu) requires
specification from Calculate: menu:

Chapter 22460

∆E uses the B97X-V/6-311G(2df,2p) energy at the B97X-D/ 6-31G*
geometry. ∆H° and ∆G° use the same energies but apply thermodynamic
corrections based on EDF2-6-31G* frequencies.
∆H°(T1) uses data from the T1 thermochemical recipe.
The Reaction Energy Units menu allows for selection of units.

A reaction energy is computed by selecting an energy from the drop- downmenu next to Calculate: at the bottom left of the dialog.

Substituted molecules can be used in place of real molecules as reactants
and products. By accessing SSPD, this means that the energies for a seriesof related (by substitution) reactions can be computed at once.
The results of a reaction energy calculation may be printed by right clicking
inside the display area of the Reactions dialog and selecting Print from themenu that results.
The Reactions dialog is closed by clicking on

Chapter 22.

461

Chapter 23
The Search Menu
Functions available under the Search menu provide for defining structure
and reaction queries to be used in searches of databases licensed andattached to Spartan. These include the Cambridge Structural Database(CSD) of experimental X-ray structures, the Spartan Spectra andProperties Database (SSPD) of calculated spectra, properties, QSAR
descriptors and thermodynamic quantities, the Spartan Infrared Database(SIRD) of calculated infrared spectra, the NIST database of experimental
infrared spectra (XIRD) and the Spartan Reaction Database (SRD) of
calculated transition states. CSD is searchable by substructure, name, author
and internal reference code, SRD is searchable by substructure, SSPD issearchable by substructure, name, formula, molecular weight and isomer and
SIRD and XIRD are searched based on matching to an unknown infrared
spectrum.

Structure Query ()

This designates one or more free valences on a structure as attachment points.
Clicking on the free valence marks it with an orange cone and designates it as
an attachment point. This means that anything directly bonded to the valence(including hydrogen) is an acceptable hit for a search on a database. For
example, clicking on the para free valence in toluene designates that any
para-substituted toluene (including toluene itself) is an acceptable hit.
Clicking on both free valences of hydrogen peroxide means that all
peroxides (including hydrogen peroxide and all hydroperoxides) are
acceptable hits. Free valences not designated as attachment points are
assumed to be hydrogens. Clicking on a free valence previously designatedas an attachment point removes the cone and its designation as an
attachment point.

Chapter 23

462

One or more structure queries may also be associated with a 2D sketch(see Chapter 20). These appear as ?’s on the sketch but as orange coneson the 3D structures.

Reaction Query ()

The main use of Reaction Query is to access a previously calculatedtransition state from the Reaction Database, or to identify similar transition
states. As we shall see later in the chapter, it also serves to identify the
product or products of a chemical reaction from the reactants to be used formining the Spartan Spectra and Properties Database. The query comprises
a set of curled arrows familiar to generations of organic chemists andformally corresponding to the movement of a pair of electrons.

Chapter 23463

Selecting Reaction Query results in a message at the bottom left of thescreen.
The tail of the arrow corresponds to the source of the electron pair. If thesource is a lone pair, then select the atom that holds the lone pair. If the source
is a bond, then select the bond. Clicking on an atom or bond highlights(colors gold) the atom or bond and leads to a new message at the bottom
left of the screen.
Clicking again on the same atom (or same bond) removes the highlighting
and returns the first message. The head of the arrow corresponds to thedestination of the electron pair. If the destination is an atom (leading to alone pair), then double click on it. If the destination is an existing bond(leading to an increase in bond order from single → double or double →triple), then click on the bond. If no bond presently exists, click on the two
atoms that will become bonded upon reaction. These operations result in a
curved arrow being drawn on the reactant structure. This extends from anatom, or the center of a bond to an atom, or the center of a bond, or the centerof a dotted line that has been drawn between atoms that are to be bonded.
The original message returns to the bottom left of the screen.
Note that the head and tail do not need to reside on atoms or bonds on the samefragment. Also the tail may involve atoms on two detached fragments.
The process (tail selection followed by head selection) is repeated asnecessary to fully define the reaction. Incorrect reaction arrows may beremoved by selecting Delete from the Build menu ( ) followed byclicking on the arrow to be deleted. You need to again select Reaction
Query ( ) in order to continue arrow selection. Alternatively, click on thearrow(s) to be deleted while holding down the Delete key.
Once defined, reaction queries can be used to search the Spartan Reaction
Database (SRD) for transition-state structures associated with the defined
reaction (discussed in Databases). Unless one or

Chapter 23464

more structure queries have been specified, the search will only return anexact match (if it exists in SRD). More commonly, structure queries will be
specified in which the objective is to provide a guess at a transition statebased on its similarity to an entry in the SRD (see discussion in Guess
Transition State later in this chapter).
One or more reaction queries may also be associated with a 2D sketch(see Chapter 20). These appear as curled arrows ( ) on the sketch andon the resulting 3D structures.

Examples of Reaction Queries
Diels-Alder reaction of 1,3-butadiene and ethylene

a, b. double bond to empty space leading to single bond and single
bondc.
double bond to single bond leading to single bond and double bondSN2 reaction of chloride and methyl iodidel–a. lone pair on Cl– to empty space leading to ClC bondc. CI bond leading to lone pair on I
Ene reaction of 1-pentene

a. CH bond to empty space leading to CH bondb. double bond to single bond leading to single bond and double bondc. single bond to single bond leading to empty space and double bond

Chapter 23465

Ring closure of 1-hexenyl radical to methylcyclopentyl radicala. radical center to empty space (between C2 and C6) leading to single
bond
b. double bond to terminal carbon leading to single bond and radical
center

Databases ()

This provides access to the Cambridge Structural Database (CSD) of
experimental X-ray crystal structures, the Spartan Spectra and Properties
Database (SSPD) of structures, IR and NMR spectra and a variety ofmolecular properties, the Spartan Reaction Database (SRD) of calculatedtransition states, the Spartan Infrared Database (SIRD) of calculated infrared
spectra and the NIST database (XIRD) of experimental infrared spectra.
CSD may be searched by substructure, molecule, name, author name, andCSD reference code. SSPD, CSD and SRD may be searched based on
substructure. SSPD may also be searched by name, formula, molecular weightand isomer. If a selected molecule on screen exists in SSPD, it may bereplaced by a database entry and, even if it is not replaced, the molecule
name in SSPD may be used. SRD may only be searched by substructure.
SIRD and XIRD are searched by comparison with an input infrared
spectrum.
Cambridge Structural Database (CSD)
The Cambridge Structural Database (CSD) is a collection of more than
950,000 experimental X-ray crystal structures for organic andorganometallic molecules.* It is maintained by the Cambridge
Crystallographic Data Centre (CCDC) and grows approximately 10% per
year. CSD not only contains information about the molecular geometry, butalso about the manner in which molecules pack in the* CSD is not included with Spartan but is available by subscription from CCDC (http://www.ccdc. cam.ac.uk/).
For installation instructions, see Appendix G.

Chapter 23466

solid state*. In short, the CSD represents a gold mine of detailed
experimental structural information, and also serves to identify moleculesthat can be (and have been) synthesized and purified through crystallization.
Tutorials illustrating the use of CSD from Spartan are provided in
Chapter 15.

Access to the data in CSD is via a substructure searching procedure. A
molecule is first constructed and one or more attachment points are
identified. Clicking on the CSD tab at the top of the Database dialog leads
to the CSD dialog.

This contains a window at the left for previewing structures, a box at the rightfor listing hits on CSD and buttons at the bottom to control aspects of thesearch and subsequent transfer of CSD data into the file system. Both thepreview window and the text box may be scaled independently. A
substructure search is set up by designating one or more free valences asattachment points. Selecting Structure Query from the Search menu andthen clicking on a free valence marks it with an orange cone. Clicking again
removes the cone and designation as an attachment point. Anything may begrown off an attachment point (including hydrogen), although substituentsare not permitted.
* Spartan’s interface to CSD accesses only molecular information. Additional information related to packing in the
crystal may be accessed using CCDC’s program ConQuest, that is supplied as part of the CSD subscription.

Chapter 23

467

Free valences not designated as attachment points are assumed to behydrogens.*
To limit a CSD search either to organic
molecules (about half the total collection) or
to molecules containing transition metals,
lanthanides or actinides, bring up the Search
Options dialog by clicking on to the rightof the Search button at the bottom rightof the dialog, and check Organics or Inorganics, respectively. To search
all molecules in CSD, check Organics and Inorganics from the Search
Options dialog.
After a substructure has been specified, a search of CSD is initiated byclicking on the Search button at the bottom right of the dialog. If there arehits to be found, these will appear in the scroll box at the right of the dialog.
The search can be terminated at any time by clicking onto the right of
the Search button at the bottom of the dialog. Once completed (or stopped),
hits designated by their CSD reference codes (REFCODE) and thecompound names (Name) are displayed at the right of the CSD dialog.**
The total number of hits is indicated immediately below. Structural data are
available only for entries preceded by a filled yellow circle, althoughexperimental references are available for all entries (Molecule Reference tab
under Output in the Display menu; Chapter 22). A ball-and-wire model forany entry for which a structure is available may be displayed in the windowat the left of the dialog by clicking on its name in the box.

* If no attachment points are specified, a search for an exact match is carried out assuming that all atoms
and bonds are exactly as given in the query and that all free valences are assumed to be hydrogens.
** Additional information is available from a contextual menu. Right click in the first blankheader cell at the right of the CSD dialog.

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The model can be manipulated (rotated, translated, scaled) inside thewindow with the usual mouse/keyboard touch commands.
The structure is exactly as it appears in CSD. In particular, it may containtwo or more different molecules, two or more different conformations of
the same molecule and/or extraneous molecules (most commonly solvent
molecules and counterions). Hydrogens will be present only where they havebeen assigned in the experimental structure. The structure may also containerrors in bonding due to uncertainties in the original data. Modifications
to the CSD entry
to address these issues may be made prior
to transfer to the file system using theRetrieve Options dialog. This isaccessed by clicking on to the right of
the Retrieve button at the bottom of the
CSD dialog.
(i)Delete Extraneous Fragments
If checked, deletes any detached molecules that do not contain the
search query.

(ii)

Repair Bonds
If checked, attempts to fix bonding errors based on the actual
geometry in CSD and on normal valence rules.

(iii)

Add Hydrogens
If checked, adds hydrogens wherever they appear to be missing, basedon the actual geometry and on normal valence rules.
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This function is also available under Add Hydrogens in the Utilities
tab of the Molecule Properties dialog (Display menu; Chapter 22).
(iv)

Freeze Heavy Atoms
If checked, freezes all atoms except for hydrogens. This allows
experimental X-ray hydrogen positions that are often poorly
determined, to be refined using molecular mechanics or quantum
chemical methods, while maintaining the heavy atom skeleton.*(v)

Retrieve to:
Selection of New Document means that the search results are to be
stored in a new document and leads to a request for a document
name, whereas selection of Current Document results in the
retrieved molecules being appended to the end of the current
document.
The Retrieve Options dialog is dismissed with all changes to existing
settings maintained by clicking on OK. Clicking on Cancel or on
also dismissed the dialog but any changes to settings are lost.
Retrieval is accomplished by first selecting (clicking on) one or morehits in the scroll box and then pressing the Retrieve button at thebottom of the CSD dialog. The Shift and Ctrl keys may be used in
the usual way to specify retrieval of multiple hits. Retrieval can be
stopped at any time by clicking onto the right of the Retrieve
button at the bottom of the CSD dialog.

Any molecules retrieved from CSD will be identified by the internal(CCDC) reference code (REFCODE). The molecule name can be accessedby bringing up a spreadsheet and typing “comp” into an empty column
header.

* Hydrogen positions may be refined using molecular mechanics using Minimize under the Build
menu; Chapter 20. Refinement using quantum chemical models is specified in the Calculations dialog(Calculations... under the Setup menu; Chapter 21) by way of Frozen Atoms (Freeze Center under theGeometry menu; Chapter 19).

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Spartan Spectra and Properties Database (SSPD)
The Spartan Spectra and Properties Database (SSPD) comprises over 300,000
molecules, most of which have been obtained from two different density
functional models, EDF2/6-31G* and B97X-D/ 6-31G*. Both theB97X-D/6-31G* and the EDF2/6-31G* density functional models
consistently yield reliable structures, spectra and properties. However,except where reactants and products are very similar, for example,
stereoisomers, so as to benefit from error cancellation, neither model isreliable for the calculation of reaction energies. With this in mind, heats offormation (in kJ/mol) from the T1 thermochemical recipe have been
provided as a “property” for most molecules in both EDF2/6-31G* andB97X-D/6-31G* collections, as well as energies (in atomic units) from theB97X-V/ 6-311+G (2df,2p)/B97X-D/6-31G* density functional model
for most molecules.
Additionally, experimental heats of formation for a small number ofmolecules from public NIST database are also available.

SSPD entries for most molecules use the best conformation assigned from theT1 thermochemical recipe rather than from MMFF molecular mechanics. T1
has been shown to reliably account for conformational energy differences insmall molecules (where experimental data are available), which suggeststhat it should be able to reliably identify the lowest-energy conformer. Note,however, that T1 is presently defined only for uncharged, closed-shellmolecules incorporating H, C, N, O, F, Si, P, S, Cl and Br. The
conformations of molecules outside of these limits (perhaps 2% of theentries in SSPD) use the MMFF method for assigning the lowest-energy
conformer.
The following recipe has been used to create the majority of individual
entries in SSPD:
1. Perform a systematic conformer search using MMFF molecularmechanics for systems with up to 1,000 conformers. For systems
exceeding 1,000 conformers, perform a systematic search in which
conformers are removed at random (leaving approximately 1,000
conformers).

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2. Keep the lowest-energy conformer and up to five additional(higher-energy) conformers. Choice is based on energy (lower isbetter) and on diversity (more diverse is better).
3. Perform up to six HF/6-31G* geometry optimizations.
4. Perform T1 calculations on the two lowest energy (HF/6-31G*)
conformers.
5. Perform B97X-D/6-31G* and EDF2/6-31G* geometry
optimizations on the lower energy (T1) conformer.
6. Perform B97X-V/6-311+G(2df,2p)//B97X-D/6-31G* energy
calculations
This procedure for providing T1 heats of formation for conformationally
flexible molecules is completely automated and has previously been
described in Calculations... under the Setup menu (Chapter 20).

Additionally, the vast majority of SSPD entries include both the infrared*
and NMR spectra. The vibrational motions associated with selected lines in
the calculated infrared spectrum can be animated. Proton, 13C and 19F(EDF2/6-31G* only) NMR chemical shifts have been empirically corrected
and 3-bond HH and both 2 and 3-bond CH coupling constants have beenobtained from parameterized expressions. COSY, HSQC** and HMBC
NMR spectra (2D spectra) to be generated on-the-fly from the informationin SSPD.
Each SSPD entry includes information useful for QSAR type analyses,
specifically, information based on electrostatic potential and local
ionization potential maps, a variety of thermochemical quantities and (inspecific cases) gas-phase acidities and basicities. Each SSPD entry also
includes B97X-V/6-311+G (2df,2p)//B97X-D/6-31G* energy as well as both
T1 and (where available) experimental heats of formation.
All SSPD entries include the wave function, allowing on-the-fly generationof any graphical surface and property maps available to Spartan.
Because of inclusion of the wave function (and to a lesser extent* Infrared spectra in SSPD are only available from the EDF2/6-31G* model.
** HSQC spectra do not require coupling constants and all 1-bond CH interactions are assured to beobservable.

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inclusion of the vibrational motions for the EDF2/6-31G* model only),
SSPD has a significant disk footprint (>23 GB). The in-memory footprint of
SSPD is ~300 MB.
Accessing and Processing Data From SSPD
There are two ways to access data from SSPD. The first way is to replace astructure that has been built (or read in) with a matching database entry. All
structures in a document for which there are matches in SSPD may bereplaced in a single operation. The second way is to search SSPD for entries
that share particular structural features, or have part of a name in commonor are isomers.
Molecule Replacement
Molecule replacement is initiated byclicking on the molecule namedisplayed at thebottom of Spartan’s screen. (Thefact that a name appears means thatthe molecule is in SSPD.) Clicking
on the name leads to a dialog at thebottom of the screen.
Selection between EDF2/6-31G* and B97X-D/6-31G* is done fromthe menu at the bottom left of the dialog.
The model in the viewing window may be manipulated using the usual
mouse/keyboard commands (you need to position the cursor inside theviewing area). Touch commands are also supported. Ball- and-spoke modelstyle may not be changed.
The selected model may bereplaced by the selected database
entry by clicking on Replace at thebottom right of the dialog.
(Replacement can be undone byselecting Undo from the Editmenu; Chapter 17.) If the box tothe left of “Update
Chapter 23473

molecule names when replaced” is checked, replacement destroys all
information. If it is not checked, replacement destroys all information
except the molecular identifier (“Label”) in the leftmost column of the
spreadsheet (see Spreadsheet under the Display menu; Chapter 22). The
Tear-Offbutton moves the database preview into the Spartan
interface where it behaves as a standard dialog. To close it, click on thein the upper right corner.
Entries are selected as before, after which they may be examined in theviewing screen and used to replace the on-screen molecule.
In the event that the selected (onscreen) molecule is part of a multimolecule document, a second
dialog will result following clicking on
Replace.
Clicking on All replaces all molecules for which database entries areavailable, while clicking on Current replaces only the selected entry.
Molecules in the document for which there are no database entries are notaffected. As with single molecule replacement, all information (with thepossible exception of the molecule identifier) is replaced by that in the
database.
Substructure and Other Modes of Searching SSPD
Access to data from SSPD follows from selecting Databases, and then clicking
on the SSPD tab (at the top left of the resulting window). This comprises threedifferent panels, Search, Plot and Analysis, selection of which is controlled
by tabs at the bottom left of the window. A search of SSPD is carried out
from the Search panel, plotting of the search results from the Plot panel andregression analysis of search results from the Analysis panel.
Substructure searching of SSPD is similar to that already described for
substructure searching of the Cambridge Structural Database (CSD). The
only required input is a three-dimensional structure. While one or more
growth points (see Structure Query earlier in this chapter) will normallybe specified, they are optional and in their absence an

Chapter 23474

exact search will be carried out. One or more substituents may be attachedto the structure (see Substituent Model Kit under the Build menu; Chapter20), in effect allowing multiple starting structures. (This capability is notavailable for CSD searches.) Name searching requires a name (or partialname), formula searching requires an exact formula, weight searchingrequires a molecular weight and isomer searching requires a threedimensional structure.
Following a search on SSPD, hits will be listed on the right and the structureof the selected hit will be shown in a window at the left. In addition to themolecule Name, the molecular weight and the theoretical model areavailable from a contextual menu. Right click in an empty header cell.
Controls along the bottom right access the Search Options dialog which
specifies which directories to be searched, the kind of search, and thetheoretical model(s) to be searched. They are also used to initiate andterminate a search and to designate the location for any results that are
retrieved from the search.
Clicking onto the right of the
Search button leads to the Search
Options
dialog.
Using
Directories lists the collections
that make up SSPD.
Method Filters specifies
the theoretical models,
EDF2/6-31G* or ωB97X-D/6-31G* to be included in the Search Other
accesses data with models that are not explicitly listed. Search By designates
the type of search: Structure, Name, Formula, Weight or Isomer.
(i)NameSelection followed by clicking on OK in the Search Options dialog
leads to a box By Name at the bottom right of the dialog. The search
will return all entries that contain the string that is entered into the box.
For example, typing toluene will

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not only result in toluene, but also in molecules such as paratoluenesulfonic acid and 4-chloro-2-fluorotoluene.
(ii) Formula
Selection followed by clicking on OK in the Search Options dialog
leads to a box By Formula at the bottom right of the dialog. A formulaof the form CcHhHett, where “Het” corresponds to elements other thancarbon and hydrogen (each element needs to be specified explicitly).
c, h, t are integers and are required. For example, the formula for
nitrobenzene needs to be written as C6H5N1O2. The order of atoms isirrelevant. The search will return all entries with this formula. For
example, the formula C6H5N1O2 will return not only nitrobenzene but
also molecules such as phenyl nitrite and pyridine-4-carboxylic acid.
(iii) Weight
Selection followed by clicking on OK in the Search Options dialog
leads to a box By Weight at the bottom right of the dialog. The search
will contain all entries with the specified molecular weight ± 0.05 amu.
(iv) Isomer
Selection followed by clicking on OK in the Search Options dialog
specifies that all isomers of the selected molecule will be returned. The
result is the same as specification of a molecular formula.
Clicking on OK removes the Search Options dialog with all settings
maintained. Clicking on Cancel orremoves the dialog withoutmaintaining the settings.
A search is carried out by clicking on the Search button at the bottom
right of the database dialog, following which hits will appear at theright. The search may be terminated at any time by clicking on
tothe right of the Search button. Any hits that have already been
identified will be kept. A ball-and spoke model of a hit may be
examined at any time by clicking on its name in the box. It may be
manipulated with the usual mouse/keyboard or touch-screen
operations, although the model style cannot be changed.

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Properties may be added to the hit list by dragging them (names notnumerical values) from one of the properties dialogs (see Properties under
the Display menu; Chapter 22), the formula editor (Formulas under the
Display menu; Chapter 22) or from the main Spartan screen, primarily
entries associated with the Geometry menu; Chapter 19. The hit list canbe sorted using the property, by right clicking on the column header cell andselecting Sort from the menu.
The results of a search on SSPD as well as any subsequent plotting andanalyses are saved in the Spartan document corresponding to the original
structure query or to the blank document that was used for a name or spectra
query.
A much larger number of molecules can be handled in the SSPD window
than in Spartan’s main window (several tens of thousands compared toa few thousand). This is because prior to retrieval each entry comprises
very little information, whereas following retrieval each entry is muchlarger, the primary difference being inclusion of the wave function. Thus,
plots and analysis can be carried out on large datasets.

Plotting Data Resulting from an SSPD Search
Data resulting from a search on SSPD may be displayed either as ahistogram (property value vs. number of occurrences) or as a 2D scatter plot
(property value vs. property value). Access to plotting is via the Plot tab at
the bottom left of the dialog.

Chapter 23477

Selection of plot type and variable ranges is from the Plot Options
dialog accessible from to the right of the Plot button.

Default plot ranges are from minimum to maximum property values.
Checking Linear Least Squares Fit (Scatter Settings) fits a straight line
to the data. (A more general multi-variable regression analysis can be carriedout from Analysis; see discussion following.) Number of Intervals(Histogram Settings) sets the number of bars in the histogram. Clicking on
OK removes the dialog with all settings maintained. Clicking on Cancel orremoves the dialog without maintaining the settings.
A plot is drawn by clicking on the Plot button at the bottom left of the dialog.
The points will not appear instantaneously as the data need to be extracted
from the file system. Plotting may be terminated at any time by clicking onto the right of the Plot button. If a least- squares line has been requested,
it will be based on the accumulated data. At any time, the name of themolecule associated with a point on a scatter plot can be displayed bypositioning the cursor over that point. The point can be deleted by rightclicking and selecting Delete from the resulting menu. The plot will rescale
as appropriate.

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Regression Analysis of Data Resulting from an SSPD Search
A regression analysis of data resulting from a search may be carried out by
selecting the Analysis tab at the bottom left of the dialog.

The name (not the numerical value) of the property to be fit is dragged fromone of the properties dialogs, the formula editor or from the main Spartan
screen, into the box to the right of Fit. The names of one or more properties
to be used in the fit are dragged into the box to the right of Using. The fitting
procedure (singular value decomposition) will use only variables that havebeen selected (clicked on) from among the list, up to a maximum numberof independent variables (the most important in terms of their contribution
to the fit from among this list) specified in the menu at the bottom right ofthe dialog. Note that the number of variables actually used in the fit may besmaller than the maximum number selected (from the menu at the lower
right of the dialog), as variables that are linearly dependent and/or do notcontribute significantly to the fit will be discarded. The analysis is started
by clicking on the Analysis button at the bottom left of the dialog. As withplotting, this does not occur instantaneously as the underlying data needs tobe extracted from the file system. Analysis may be terminated at any timeby clicking onto the right of the Analysis button, following which
results from a fit to a portion of the data will be displayed.
Upon completion, or upon user termination, the fit function will be
displayed at the lower left of the dialog. This can be copied to the clipboard(right click and select Copy from the menu) and then pasted (right click andselect Paste from the menu) in the Plot dialog.

Chapter 23479

Relationships Involving Chemical Reactions
We have previously discussed how the formula editor may be used toconstruct relationships among properties for a single molecule (seeFormulas under the Display menu; Chapter 22). The formula editor canalso be employed to construct relationships between the reactants and the
products of a chemical reaction. This is possible because the products of areaction are completely and unambiguously defined given the structure of
the reactant (or reactants) and a set of curled arrows (see Reaction Queryearlier in this chapter). The same information can also be used to guess atransition state for the reaction (see Guess Transition State later in thischapter).
For example, consider the difference in energies between 2,4cyclohexadieneone and phenol. Whereas the normal preference is for ketoforms be favored over enols, here the reverse is certainly true as phenol
benefits from aromatic stabilization. Three steps are needed to use SSPD toquery the extent to which substituents alter the preference in the parent
compound. First, a reactant must be built, reaction queries placed todesignate the product of reaction and one or more structure queries(indicated below by red wedges) added to define the limits of the search.
For example limit substituents in 2,4-cyclohexadieneone to the 4 position.

Next, a formula for the energy of reaction needs to be constructed. Inclusionof arrows extends the formula from the query itself (a 4-substituted 2,4cyclohexadieneone), to the product of reaction (a para-substituted phenol)
and to the difference between product and reactant. Selection of which is tobe employed in the formula follows from the Applied to menu underContext in the formula editor (highlighted only if arrows are present). In
this case, the choices are (R) 2,4-cyclohexadieneone, (P1) phenol or (P-R)
reaction. The formula for the reaction energy, @energy*@hart2kj, appears
in theChapter 23

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box at the center of the dialog following selection of (P-R) reaction fromthe Applied to menu and clicking on E under Energies. The default namemay be changed by editing the text inside the box to the left of the formula.
Clicking on Enter enters the (renamed) formula @ rea(@energy*@hart2kj)
into the list at the top of the formula editor.
Finally, a search may be carried out by clicking on the Search button inside
the SSPD Search dialog. After it has completed, dragging the formula forthe reaction energy onto an empty header cell of the hit list inside the SSPD
Search dialog will result in reaction energies for all entries to appear.
As a second example, consider the energy for addition of hydrogen fluoride
to propene, leading to 1-fluoropropane. Here there are two reactants(hydrogen fluoride and propene), but only the latter will be provided growth
points*. Thus, the query is for information about the energy of HF addition
as a function of substitution on the alkene.
The query starts from an intramolecular complex of propene and hydrogen
fluoride, oriented such that the C=C and H–F bonds parallel with fluorine on
the unsubstituted side of the alkene. Two arrows (reaction queries), one
from the CC bond to the space between the unsubstituted carbon andfluorine and the other from the HF bond to the space between the substitutedcarbon and hydrogen, define the product (1-fluoropropane). Structure queries
attached to all three open valences extend the search to all available
substituted propenes (for which analogous substituted 1-fluoropropanes
are also available).

A formula for the energy of reaction may be constructed using the same
sequence as in the previous example, selecting (P-R) reaction from theApplied to menu under Context in the formula editor, clicking on E,
changing the default name and clicking on Enter.
Following a search using the query, dragging the formula for the reactionenergy onto an empty header cell of the hit list inside the*While there can be two or more reactants, only one can be provided structure queries, that is, all otherreactants need to be single molecules.
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SSPD Search dialog adds a column of reaction energies to the list.

It is possible to apply different queries to the same set of search results, forexample, to ask about the energy of addition of HCl (instead of HF) to a
substituted propene. Whereas the query changes (the reaction of HCl andpropene rather than of HF and propene), the underlying search (on propene)
does not. The result is two sets of energies. (Results designated No DB Entry
indicate that the required information is not available.)

A plot of HCl vs. HF reaction energies from the SSPD Plot dialog showsthe extent to which they are actually correlated.

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The analysis and plotting capabilities applied to the data in SSPD are
certainly more difficult to master than most of the other aspects ofSpartan. However, the size and diversity of the collection of organic
molecules in SSPD means that the capabilities may be of considerable
value in exploring molecular properties and reaction energies in advanceof calculations on closely-related systems of interest.

Retrieving Data from an SSPD SearchPrior to retrieval, it is necessary to specify adestination from the Retrieve Options dialog.
Click on to the right of the Retrieve button.
Selection of New Document results in a new document; selection of
Current Document results in the retrieved molecules being appended tothe end of the current document. The Retrieve Options dialog is dismissedby clicking on OK. Clicking on Cancel or on
also dismisses the dialog
but any changes to settings are lost.
To retrieve, select (click on) one or more hits in the box and press the
Retrieve button. The Shift and Ctrl keys may be used to specify retrieval of
multiple hits. Retrieval may be stopped at any time by clicking onto theright of the Retrieve button.
Spartan Reaction Databases (SRD)
The Spartan Reaction Database (SRD) is a collection of transition states forapproximately 1,500 organic and organometallic reactions obtained fromone or more of the following theoretical models: AM1, PM3, HF/3-21G and
HF/6-31G*.* Each entry contains the infrared spectrum, which should becharacterized by a single imaginary frequency corresponding to the reaction
coordinate.
An entry in SRD is in terms of a three-dimensional structure (corresponding
to the reactants or the product), together with an appropriate set of curved
arrows (connecting the reactants to the product or vice versa) anddesignation of theoretical model.
* Efforts are underway to update SRD to include entries obtained from the B97X-D/
6-31G* model.
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Instructions for drawing reaction arrows has been provided earlier in thischapter (Reaction Query).

For example, an entry for the Diels-Alder reaction of cyclopentadiene andacrylonitrile is given below.

Note, that stereoisomers are distinguished by the way the reactants are
positioned. For example, reactions leading to endo and exo Diels- Alderadducts are distinct.

Like SSPD, SRD is open-ended and users may construct their own datacollections with additional reactions and/or results from additional
theoretical models on existing reactions (Appendix H).
Substructure Searching
Substructure searching from SRD is very similar to that from SSPD. Accessto SRD is provided by clicking on the SRD tab at the top of the Databasedialog. This gives rise to the SRD dialog.

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The SRD dialog contains a window on the left for previewing structures
and a box on the right for listing hits on SRD, as well as buttons at thebottom to control various aspects of the search and subsequent transfer ofdata into Spartan’s file system.
A substructure search is set up by specifying one or more attachment points
on the reactant structure (see Structure Query earlier in this chapter) thathas been augmented with reaction arrows (see Reaction Query earlier in thischapter). Structure queries and reaction arrows can also be added to 2D
sketches (see discussion under 2D Sketch Palette in Chapter 20). Prior tostarting the actual search, it is necessary
to specify which theoretical model or setof models are to be included. This isdone from the Search Options dialog,
and is reached by clicking onto theright of the Search button at the bottom
right of the dialog.
Using Directories indicates the libraries to be searched. One is suppliedwith Spartan and users may replace or supplement this with their own
collections (see Appendix H). Checking one or more boxes under the
Method Filters specifies the theoretical model(s) to be searched. Clicking
on OK removes the dialog. (Clicking on Cancel oralso removes the
dialog, but changes are not saved.)
Following specification of structure/reaction arrows, attachment

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points and designation of theory level(s), a search on SRD is carried out byclicking on the Search button at the bottom right of the dialog. If there arehits, they will begin to appear in a few seconds in the box at the right of the
dialog. The search may be terminated at any time by clicking onto theright of the Search button at the bottom right of the dialog.

Database hits are displayed in the box at the right of the dialog. They may besorted by name, molecular weight and theoretical model by clicking on theappropriate tab. A 3D structure for a particular hit may be previewed byclicking on its name in the box. A ball-and- wire model of the transition
state with bonding consistent with the reactant and associated reaction
arrows is displayed in the window at the left of the dialog, and its nameappears immediately below the window. The model may be manipulated
inside the window in the usual way, but the model style cannot be changed.
Retrieving Data from an SRD SearchPrior to retrieval of one or more database hits,
it is necessary to specify a destination. This isaccomplished with the Retrieve Options dialog,
brought up by clicking onto the right of theRetrieve button.
Selection of New Document results in a new document; selection of
Current Document results in the retrieved molecules being

Chapter 23486

appended to the end of the current document. The Retrieve Options dialog
is dismissed by clicking on OK. Clicking on Cancel or on also dismisses
the dialog but any changes to settings are lost.
Retrieval is accomplished by first selecting (clicking on) one or more hits inthe box and then pressing the Retrieve button at the bottom of the SRD
dialog. The Shift and Ctrl keys may be used to specify retrieval of multiple
hits. Retrieval may be stopped at any time by clicking onto the right of
the Retrieve button.
Spartan Infrared Database (SIRD)
The Spartan Infrared Database (SIRD) is actually a second access point
into the Spartan Spectra and Properties Database (SSPD) discussed earlier
in this chapter. It comprises infrared spectra for >300,000 molecules
calculated from the EDF2/6-31G* model. Unlike the other databases ofcalculated information attached to Spartan, SIRD is searched not on
substructure but rather on a measured (or calculated) infrared spectrum. This
is input in JCAMP format (.dx).* The search is carried out in two steps: a fast
search on the full database is performed first to identify a small set of possible
matches which are then examined more thoroughly.
Spectra Searching
Access to SIRD is provided by clicking on the SIRD tab at the top of the
Database dialog. A Spartan document must be open even if it is an empty
document (New from the File menu). This gives rise to the SIRD dialog.

* A sample .dx file is provided in Appendix J.

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This dialog is quite unlike those associated with other databases accessible
from Spartan, although it shares two aspects: a window at the lower left for
examining the 3D structure of the selected hit and a box at the lower rightfor listing all hits. The window at the top right is for examining the match
between the unknown (measured) infrared spectrum and that of a hit in the
database, and boxes at the top left list the frequencies and intensities for both
unknown and database spectra. Finally, buttons at the bottom of the dialog
access the unknown spectrum, provide (optional) filters for its search against
spectra in the database and control transfer of any search results into
Spartan’s file system.
A search is initiated by clicking on Select Spectrum at the bottom right ofthe dialog. This leads to a file browser that only recognizes .dx files.
Selection of a file in the usual manner followed by clicking on Open (ordouble clicking on the name) displays the unknown spectrum (in blue) in
the window at the top right of the dialog with the name underneath.

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The spectrum has been fit to a Lorentzian function, allowing a set ofvibrational frequencies and intensities to be extracted are displayed in thebox marked Unknown: immediately to the left of the spectrum.* Features in
the unknown spectrum with very low intensity cannot be fit. The fit isshown in black.
Filters
Conditions under which the search is carried out may be specified by clicking
on the Filters button at the bottom of the dialog. (This step is optional.)

The Filters dialog contains a window for constructing a substructure
filter on the left, a listing of common functional groups in the middle, andcontrols to limit the molecular formula of hits on the database on the top
right. Controls at the bottom right govern the number of preliminary hits
that are moved from the first pass of the search to the (more costly) second
pass and the number of hits that are finally kept.
To build a substructure, click on Edit below the (empty) Substructure
Filter window at the top left of the screen. Alternatively, you can start withthe currently selected molecule by clicking on Copy Current Molecule prior
to clicking on Edit.
* The number of frequencies obtained by the fit will almost certainly be smaller than theactual number of vibrational frequencies (3N-6 for a non-linear molecule with N atoms).

Chapter 23

489

The resulting dialog contains most of the functionality in the organic modelkit (see Chapter 20) as well as the ability to define one or more attachment
points (see Structure Query earlier in this chapter). The substructure needs
to be in the hit, and if no attachment points are designated, it is the only
acceptable hit. Click on OK to exit the build panel.
Functional Group Filters allow the search to be restricted to moleculesthat incorporate one or more of the functional groups. Check to select anduncheck to deselect.
Formula Filter allows selection of the minimum and maximum molecular
formula (or both) to be considered in the search. The format of the input is
CcNnOo ..., where C, N, O, etc. are atomic symbols and c, n, o are the numberof each of the designated atoms. Neither hydrogens nor any elements that are
not explicitly designated are considered.
Keep Following Pass 1 controls the number of entries that are kept following
the initial pass of Spartan’s spectra matching algorithm. The larger thenumber, the more computer time will be needed, but the more likely it will beto produce a good hit (assuming that the unknown or a closely-related
molecule is actually in the database).
Keep Following Pass 2 controls the number of hits that are returned to theuser. Does not affect the time required for the search.

Chapter 23490

Clicking on OK exits the dialog. Clicking on Cancel orthe dialog but any changes to the settings are lost.

also dismisses

In addition, the search may be restricted to a specific frequency range. Thisis controlled by the two grey slider bars displayed inside the dialog
containing the spectrum of the unknown. Note that the experimental
spectrum often concludes at 500-600 cm-1.Frequencies below this range(the “far infrared”) typically correspond to torsional motions and likely dependon conformation. Also, while the experimental spectrum usually extends to4500 cm-1, the region beyond ~2800 cm-1 is dominated by CH stretchingvibrations and may be too crowded to be of value in spectral searching. Our
experience suggests that a reasonable range for fitting calculated toexperimental infrared spectra is from 700- 2200 cm-1.
A search on the reference spectrum restricted by whatever conditions are
specified in the Search Options dialog is carried out by clicking on the Searchbutton at the bottom of the SIRD dialog. The search is carried out in twopasses. The first pass may require several tens of seconds depending on thesize of the database and the filters that have been set. The second pass may
require several minutes (depending on the number of hits kept following theinitial pass as specified in the Search Options dialog). Searching may be
stopped at any time by clicking on ( ) to the right of the Search button at
the bottom of the SIRD dialog. However no results will be returned if thesearch is stopped prematurely.
When the search has completed a listing of hits (the number of which is
specified by Keep Following Pass 2 in the Search Options dialog) orderedby their fit errors (lowest is best) appears in the box at the right of the SIRD
dialog. As each hit is selected (clicked on in the list), its spectrum (displayedin red) will be superimposed onto the spectrum of the unknown.

Chapter 23491

Calculated vibrational frequencies and intensities for the hit are displayed
in a box at the top left of the dialog (to the left of the corresponding values
for the unknown). Clicking inside the box to the left of a (calculated) frequency
animates the vibrational motion.
Retrieving Data from an SIRD SearchPrior to retrieval on one or more database hits,
click on to the right of the Retrieve button tobring up the Retrieve Options dialog. Selecting
New Document creates a new document, while
selecting Current Document
appends the retrieved molecules to the end of the current document. Click on
OK to dismiss the dialog. Clicking on Cancel oralso dismisses the
dialog but any changes are lost.
Retrieval is accomplished by first selecting (clicking on) one or more hits
in the box and then pressing the Retrieve button at the bottom of the SIRD
dialog. The Shift and Ctrl keys may be used to specify retrieval of multiple
hits. Retrieval may be stopped at any time by clicking on ( ) to the rightof the Retrieve button.
Whichever database dialog is open may be closed by clicking on
alternatively by again selecting Databases from the Search menu (The control operates in toggle mode.

Chapter 23

, or
).

492

External Infrared Database (XIRD)This uses the same setup and search logic as the Spartan Infrared
Database (SIRD) to search the public NIST collection of experimental
infrared spectra. Note that retrieval of a hit transfers only a 3D structure.

Chapter 23493

Chapter 24
The Expt. Data Menu
Functions available under the Data menu allow for attaching experimental
proton and 13C chemical shifts to a 3D structure and for designating observed
3-bond HH couplings (for constructing COSY spectra) and 2 and 3-bond
CH couplings (for constructing HMBC spectra).

1

H/13C ()

Experimental proton and/or 13C chemical shifts may be placed on a 3D
molecular model by clicking on the appropriate proton or carbon, clicking on
Edit to the right of Expt.Chem.Shift at the bottom right of the screen,entering a shift value (2 decimal places for hydrogen and one for 13C) into
the number pad and finally clicking on Enter. As a result, the shift (in redlabel) will be attached to the atom. This is illustrated below for both protonand 13C shifts.

Note that chemical shifts can also be added to a 3D structure from the Atom
Properties dialog (Display menu; Chapter 22), and to a 2D drawing from
New Sketch or in the File menu (Chapter 16) or Edit
Chapter 24494

Sketch in the Build menu (Chapter 20). While 2D representatives arecertainly more familiar, an extra step is required for proton shifts ashydrogens are generally not shown.
JHH (

)

Observed 3-bond HH couplings (not numerical values of HH coupling
constants) may be placed on a 3D model by clicking on one of thehydrogens following which all possible hydrogens which might couple
through 3 bonds will be highlighted in green. Clicking on one of these willconnect the two with a double headed green arrow.

JCH (

)

In a similar way, observed 2 and 3-bond CH couplings are added to a 3Dmodel by clicking on the carbon following which all possible hydrogens 2
or 3 bonds removed will be highlighted in red. Clicking on one of these willconnect the two with a red arrow with the head being on the carbon.

Both HH and CH couplings may be added to a 2D drawing from New Sketchin the File menu (Chapter 16) or Edit Sketch in the Build menu (Chapter
20). This requires added steps as hydrogens are not generally shown in 2D
drawings.

Chapter 24495

Chapter 25
The Options Menu
Functions under the Options menu* set default colors, fonts, user
preferences and van der Waals radii, locate databases, identify remote servers,
set program queue’s, set icon displays and identify/change URL’s for online accesses and configure Spartan’24. They also allow for changing default
colors and fonts and for monitoring executing jobs.

Preferences...()*

This sets up preferences relating to the graphical user interface (Settings),
and to molecule displays (Molecule). It permits changes to default van der
Waals radii used for space-filling models as well as for calculating molecularsurface areas and volumes (VDW Radii). It also specifies the locations of
databases (Databases), sets job queues (Jobs), specifies miscellaneous
features (Miscellaneous), specifies which icons are to be displayed (Icons)and specifies URLs (URLs) for on-line connections, identifies available(remote) compute servers (Available Servers) and configures Spartan’24
as a server for remote devices (Embedded Server). Selection results in oneof ten Preference panels, depending on which tab is. Clicking on a tabbrings up the associated preferences. To exit the Preferences dialog click on
OK. Clicking on Cancel orexits the dialog without instituting any
changes.

* Consistent with OS X, Preferences is also found under the Spartan’24 menu in the Macintosh version.

Chapter 24496

Settings Tab

Style
View: Orthogonal/Perspective
Controls the view of structural models and graphics.
Menus: Classic List/Button Pad
Controls presentation of menus either as lists (Classic List) or as icon
palettes (Button Pad). The latter is likely to be better suited to touch screen
computers and tablets.
Interface: Classic/Touch
Under the Touch setting, some menu/dialog items (including up/ downarrows) are displayed in a larger size to better support touch screen computers
and tablets.
Icons: Small/Medium/Large/Extra Large/Jumbo
Controls size of program icons in the tool bar.
Sketch Pad: Small/Medium/Large
Controls the size of the sketch pad (palette of sketch tools) for
Spartan’s 2D builder.
Stereo: Off/Red-CyanTurns stereographic display on and off.
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Global Rotate: Screen Centered/Molecule Centered
Screen Centered rotates all molecules about a common center.
Molecule Centered rotates each molecule about its own center.
Document Tabs
Hide will revert display style to that of versions of Spartan prior to
Spartan’14, that is, all open documents will be visible when in View mode.
If Show is checked, this displays a tab at the bottom of the screen for each
open document. This allows for displaying molecules from documents otherthan the currently selected document by checking the box to the left of the tab.
Show closable is the same as Show but includes the ability to close thedocument by clicking on the
button at the right of the tab
New Document: Pin
If checked, defaults to display of any new documents (from building or
brought in from the File menu) irrespective of whether or no they have been
explicitly selected. Does not affect the status of existing open documents. Pinsetting is only applicable if either Show or Show closable is selected (seeDocuments Tabs above).
Animation Speed
Slider bar controls the speed for animations.
Ball and Spoke Model
Sets the ratio of the radius of the balls in ball-and-spoke model tothe VDW radius. The default value is 0.25.
Conformer Rules: Normal/Skeletal/ThoroughChooses between rule sets for conformational searching. Normal is thedefault and should be used for Equilibrium Conformer and Conformer
Distribution calculations where the Monte Carlo approach is involved.
Skeletal (in versions prior to Spartan’18 this was called Trimmed)
eliminates degrees of freedom and should be used for Similarity Librarycalculations where a systematic approach is carried out. Thorough considers
twist-boat conformers of six-membered rings (in addition to chairconformers).
Calculations Dialog
Controls the default task that is displayed upon entering

Chapter 24498

Calculations... ( ) from the Setup menu. The default is Equilibrium
Geometry with the ωB97X-D/6-31G* model, this can be modified byclicking the Edit button, which leads to a sample Calculations dialog.
Clicking on Reset restores the default task.
Miscellaneous Double-Click Start
If checked, double-click as opposed to single-click is required to place theinitial atom, group, ring, ligand, etc. on screen when using the 3D builder(consistent with the 2D Sketch builder behavior).
Persistent Delete
If checked, delete function is persistent. If not checked, delete will revert tothe previously selected function after a single delete operation.
Auto-Gen Graphics
If checked, graphics calculations will be performed by the graphicalinterface (without having to submit a calculation) as long as theinformation necessary to generate the surface is available (a previous
calculation has been run, or the molecule has been retrieved from the SSPD).
Note, however, that graphics calculations will not be auto-generated on
documents containing more than 25 molecules. These will need to besubmitted as a calculation.
ChemDraw Interface (Windows only)
If checked, adds ChemDraw as a tab at the top of the model kit. This allows
for use of the ChemDraw program (version 10 or newer) as an alternative
for sketching molecules
Spectra PaneIf checked, utilizes a simple dedicated Spectra dialog for visualization andexploration of calculated and experimental spectra. If unchecked, thepresentation reverts to the spectra display style available in versions prior torelease of Spartan’14. The latter allows finer control over details in thedisplay (axis

Chapter 24499

ranges, line width, etc.) which can be transferred back to thesimpler display.
Plots Plane
If checked, utilizes a simple dedicated Plots dialog for visualization andexploration of user generated plots. If unchecked, the presentation reverts
to the plots style available in versions prior to release of Spartan’14. The
latter allows finer control over plot details (axis ranges, markers, etc.) which
can be transferred back to the simpler plots presentation. Note: support for 3D(XYZ) plots is not yet implemented in the Plots Pane, and is only available
if this preference not checked.
Gradient
If checked, this replaces the single color background by a color gradientbackground.
TumbleIf checked, allows automatic tumbling of molecules. To tumble a molecule,select it, press the left mouse button, move the mouse and release the button.
To stop tumbling, left click.
To start tumbling on touch screen devices, swipe one finger overthe screen. To stop, tap anywhere on screen.

Keep Verbose
If checked, keeps extended Q-Chem output. Normally discarded uponsuccessful completion of submitted calculations, this may be useful for
identifying the source of problems for calculations that have not successfullycompleted or have led to suspicious results. (The last 100 lines of the verbose
output is automatically kept for a job that has abnormally terminated).
Verbose output significantly increases the size of the Spartan document.
Sketch Pad Tooltips
If checked, provides brief description of the tools available in the sketch padby hovering over the icon.

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Transparent Planes
If checked, planes (Define Plane under the Geometry menu;
Chapter 18) will be transparent rather than opaque.
Database Interfaces
Controls what database options are available from the Databases entry(Search menu, see Chapter 23). Turns on or off access to Spartan
Molecular Database (SMD), Spartan Infrared Database (SIRD), External
Infrared Database (XIRD), Spartan Reactions Database (SRD), andCambridge Structural Database (CSD). The CSD must be licensed throughthe Cambridge Crystallographic Data Centre, in order to access thisresource.
Import Filters PDB Water Filter
If checked, removes water molecules from imported PDB files.
MDL Water Filter
If checked, removes water molecules from SD files.
MDL HCl Filter
If checked, removes HCl molecules from SD files.
DP4 Parameters H|C
Select Hydrogen (H) or 13C to alter respective DP4 parameters.

Alter  parameter.

Alter  parameter.
IR/Raman Spectra Correction Parameters Laser Wavelength
Raman intensities are dependent on the wave length of the laser in the
spectrometer. This setting allows for adjustment of calculated intensities
based on Laser Wavelength. Click inside the box and use the number padthat appears.

Chapter 24

501Sample Temperature
Raman intensities are also dependent on temperature. This setting allows foradjustment of Sample Temperature for Raman spectra calculations. Clickinside the box and use the number pad that appears.
NMR Spectrometer Frequency
The frequency of the spectrometer, used in coupling constantcalculations.
SurfaceMax. Ligand Distance (Å)
Sets the maximum distance (in Å) for an amino acid residue (in a protein) tobe recognized as bonded to a ligand. Click inside the box and use thenumber pad that appears.
Polar Area Range (kJ/mol)
Sets the potential (in kJ/mol) for calculating polar area from the electrostatic
potential map. The range is given as a single number but represents the range
between –value to +value, for example, the default range of 100 kJ/mol means arange from -100 to +100 kJ/mol. Values above and below the range areconsidered when determining polar area. Click inside the box and use the number
pad that appears.
Accessible Area Radius (Å)
Sets sphere radius (in Å) for determining accessible area, the default is
1.0Å. Click inside the box and use the number pad that appears.

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Molecule Tab

This specifies default settings for model appearance. These settings may beoverridden for individual molecules in a document using entries under the
Model menu and for specific portions of a molecule using Utilities/Style
dialogs associated with Properties dialogs (Properties under the Display
menu; Chapter 22).
Energy Units
Auto Select, where units depend on the model and on whether they refer toabsolute or relative quantities, au (atomic units), kJ/ mol and kcal/mol
Relative Energy Unitsau (atomic units), kJ/mol and kcal/mol
Reaction Energy Unitsau (atomic units), kJ/mol and kcal/mol
Model: Wire/Ball and Wire/Tube/Ball/Spoke/Space Filling/Line
Controls default model style.
Surface Style
If Bands is checked, this specifies that graphical surfaces, for example
electrostatic potential maps, are to be displayed in terms of a series of color
bands, rather than as a continuous spectrum. The number of bands isselected from the menu to the right. This
Chapter 24503

setting can be changed at the document level and individual surface level
as well (Surface Properties under the Display menu; Chapter 22).
Show Objects: Constraints/Frozens/Points/Planes/Reactions/
CFD’s/Images/Annotations/CH Couplings/HH Couplings
If checked, constraints and frozen markers, points and planes, reaction
arrows, CFD’s and attached images, user-supplied annotations andexperimental CH and HH couplings will always be shown as part of themodel. Otherwise, they will be shown only in the appropriate mode.
Atom Labeling: Label/Element/Mass Number/Mulliken
Charge/Electrostatic Charge/Natural Charge/Strand:
Residue/Label/R/S/Exposed Area/Cal Chem Shift/Exp Chem
Shift/(Cal-Exp) Chem Shift/Custom
Controls default label type. Custom allows the user to enter an expression
designating a label. These are of the same form as used in the spreadsheet. See
the section on User-Defined Expressions under Spreadsheet in the Display
menu (Chapter 21).
Bond Labeling: Label/Custom
Controls default label type. Custom allows the user to enter an expression
designating a label. These are of the same form as used in the spreadsheet. See
the section on User-Defined Expressions under Spreadsheet in the Display
menu (Chapter 21).
Other Labeling: Hydrogen/Constraint/Plane/CFD/Reaction/
Coupling/Residue/Point
If checked, corresponding labels will be shown.
CFD Display: Descriptors/Excluded Volume
If checked, corresponding labels will be shown.

Chapter 24504

vdW Radii Tab
This provides a list of van der Waals radii

To order the list by element name click on Element, and by atomic radius clickon vdW Radius. Individual entries may be changed from default values by
first clicking on the entry and then entering a new value. The currently
selected entry may be returned to its default radius by clicking on Reset
Selected at the bottom of the dialog, and the full set of radii may be returnedto their default values by clicking on Reset All at the bottom of the dialog.

Chapter 24505

Databases Tab
This allows setting up of paths for Wavefunction database
directories.

Several directories may appear for each database. Specification of which
directory (or directories) will be searched in the Search Options dialogs
associated with SSPD, SIRD, SRD and XIRD (Databases under the Searchmenu; Chapter 23). Note that SIRD is the same database as SSPD*, and only
the method of access (spectral matching vs. substructure matching) are
different.
User-defined collections may be added (see Appendix H).

* More precisely, it is the subset of entries in SSPD that contain infrared spectra.
Chapter 24506

Jobs Tab
This allows setting of job limits.

Maximum Concurrent Jobs
Designates the maximum number of jobs that can be run at one
time.
You need to use caution that the maximum number of jobs does not
significantly exceed the number of physical processors (cores) on
your computer and also that you have sufficient memory to support
this maximum number.

Job Settings
Toggles between Automatic and Manual. Automatic will assign all
available cores to a single document (single molecule inside a Spartan
document if there is only one molecule in the document) and will divide thecores among the molecules in the document if there is more than one. Manual
will follow settings under Manual Limits.
Manual Limits
Concurrent Molecules Per Job sets the number of jobs (molecules inside a
Spartan document) that will run simultaneously and Cores Per Molecule *sets
the number of cores used on a single molecule.

Chapter 24507

If you are simultaneously working with two or more documents, youneed to use caution. It is very easy (and, depending on available
memory, potentially very inefficient) to demand more threads than are
actually available. This is not an issue if you are working only with asingle document even if it contains more than one molecule.

Scratch Space Directory: (used by compute codes)
Allows users to customize the temporary location Spartan uses during
calculations. The default is the same location your operating system uses.
Configuring to utilize a solid state drive has been shown to increase
performance.
Checking Expert at the bottom right brings up an extended dialog,
containing controls for individual job memory and scratch disk limits. Theseshould only be needed in exceptional circumstances.

* Cores are physical processors (typically between 2 and 64 for current generation Intel and AMD
chips) whereas threads are virtual processors, the number of which is an integer multiple of the number ofcores (typically 2). Optimum performance in numerical applications such as Spartan restricts the number ofsimultaneous processes (number of molecules x number of cores used per molecule) to the number ofcores.
Chapter 24508

Miscellaneous Tab
Items here refer to primarily cross-platform applications.

Document Style
Toggles between File Based and Directory Based. The latter is forcompatibility between Windows and previous Macintosh and Linuxversions prior to Spartan’16.
Dialog Set for File Based Docs
Where Document Style is set to File Based, restricts the file browser toread File Based documents only or both File Based and Directory Baseddocuments.
Atom Color Set
Toggles between Standard atom colors shared by Spartan and Odyssey
software and a color scheme used by older versions of Spartan (Classic).
Dialog Style
Menu selects between several dialog formats: Windows, Macintosh,
and KDE and Gnome Linux. Default uses the style associated with themachine on which Spartan is installed.
Data Compression Options
Allows compression of text files (Gzip text files) and switches to

Chapter 24509

binary for full archive storage (Use binary archive). By default both are
selected to minimize file sizes of Spartan documents. Deselection may berequired for file compatibility with earlier versions of Spartan.
Builder Options Selection Method
Toggles among Buttons on top, Tabs on side and Menu to control
selection of the model kits in the 3D builder. The second and third choices
use less vertical space and may be required on small-screen laptops andtablets.
Show Toolbar
If checked, places the toolbar (Delete, Make Bond, Break Bond andMinimize) at the bottom of the 3D builder. Can be removed to save spaceon small screens.
Use Kekulé Rings
If checked, aromatic rings from 3D builders are shown in Kekulé (alternating
single and double bond) form. Otherwise, they are shown with partial double
bonds. Aromatic rings from 2D sketcher are always shown in Kekulé form.
Use Alternative Builder
If checked, provides a different presentation of the model kits inthe 3D builder. Try both and see which one you like.
Temporary Directory (used by interface)
Allows users to specify the temp location used for graphics calculations
when using the Auto-Gen Graphics preference (on by default).
Configuring to utilize a solid state drive has been shown to significantly
increase performance.
Use HTTP Proxy
Allows setting up of an alternative path for access to external websites, forexample, experimental spectra databases.
Text File End-Of-Line Marker
Controls line terminator for text files. May be needed to support file transfer
to earlier versions of Spartan and to external programs specific to Windows,
Mac or Linux environments.

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WebDoc V2.0
If checked (the default), this optimizes file transfers to and from remote
servers. It may need to be unchecked where the servers are running earlier
versions of Spartan.
Max Output Characters
Sets maximum number of characters for output files.
Pick System
Toggles between OpenGL, Color and Color+Geometric selection models.
OpenGL is the standard but causes problems for some Intel on chipgraphics, where either Color or Color+Geometric should be used.
Graphics chip is automatically detected at installation and this control
should be properly set.
Multisampling
If checked invokes multisampling which results in improved graphicalimages (removes jagged lines). Likely to be unnecessary for very highresolution displays. Will slow down graphics performance.

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511

Icons Tab
Icons for all menu entries as well as for the Spectra panel are listed (youwill need to use the horizontal slider bar to see them all). If checked, theicon will appear in the tool bar at the top of the Spartan screen and in theSpectra panel.

Icon display is limited to one “permanent” row and approximately 20 medium
size icons will fit on screen. Exceeding screen space will result in the
inclusion of arrows [>>] at the end of the toolbar. Clicking the [>>] button
will expose any hidden icons.

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URLs Tab
Lists URLs for access to experimental structural and spectral databases
and to Wikipedia.

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Available Servers Tab
In addition to processing molecular mechanics and quantum chemical
calculations “locally”, Spartan’24 is able to submit calculations to alicensed remote server. Remote accounts need to be set up using theEmbedded Server (Windows) tab in the Preferences dialog or Service
Control (Macintosh or Linux) in the Options menu (see later in thischapter). Available Servers Tab is used to request accounts on one or more
remote servers.

A server is added by first clicking on New at thebottom of the Available Servers dialog.
“Submit To” Name
The name of the server. This will appear in the
Submit to menu inside the Save As - Submit
dialog.
Host URL
The URL of the server. This can either be provided as a text string (FQDN,
or Fully Qualified Domain Name suffix) or as an IP address.

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Username
A text string used by the administrator of the server to identify you.
E-mailYour e-mail address. This is needed by the administrator of theserver in order to contact you.
Key
This is required only in the event that the server operates in high- security(Remote Registration: Disabled) mode. This is controlled by the administratorof the server from the Embedded Server tab in the Preferences dialog(Windows) or Server Control in the Options menu (Macintosh and Linux)(see later in this chapter).
Retain Job On Server After Completion
If checked, retains the job on the server after it has completed. It can be
retrieved at any time.
Clicking on Register/Verify will setup an account (or will respond with any
error conditions).

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Embedded Server Tab/Service Control
In addition to its local capabilities, Spartan’24 be used as a server for licensed
copies of Spartan’24 running on other machines as well as iSpartan runningon iPads and iPhones (remote devices).

Operation requires communication between the server and the remotedevice. At the lowest level of security (the default), nothing is required at
the server end (except turning on the server) and each of the remote devices
simply needs to be registered on the host. Higher security levels require
explicit action on the part of the administrator of the server, and the highestlevel security requires explicit exchange of “keys” between theadministrator of the server and the users of the remote devices. Content
below describes general operations, see Appendix K for a complete
description of functionality, including a description of platform
dependencies.
Turning the Server On and Off
Checking the box to the left of Server (On/Off) in the Embedded
Server/Service Control dialog turns the server on. Unchecking the box
turns the server off. When switched on, the IP of the server will be provided
under Status. You will need to click the Apply button after making any
changes.

Chapter 24516

Remote Registration
From simplest and least secure to more complicated and most secure, there
are three ways to “register” remote devices with the server: Automatic,
Sign-Off Required and Disabled. This is designated in the Remote
Registration menu at the bottom of the dialog.
Automatic. In this mode, anyone with Spartan’24 or iSpartan can set up an
account without the administrator needing to take any action. The only
exception might be to limit the number of jobs that can be executed at one
time by an individual account on the server. This is controlled by the Job
Quota menu at the bottom of the dialog.
Sign-Off Required. In this mode, anyone can set up an account (as inAutomatic), but the administrator must activate the account. Prior toactivation, Status is pending. This may be changed to activated by double
clicking inside the cell corresponding to the status of the pending accountfollowed by clicking on Accept in the dialog that results and then clicking
on Apply at the bottom of the Server dialog.
Disabled. In this mode, the administrator is required to set-up a user’s account.
This requires that the user supplies the administrator with the Machine ID of
the computer. For Spartan’24, this is available from

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the About Spartan’24 dialog (Help menu). For iOS devices, leave theMachine ID blank (all zeroes). The Machine ID is used by the administrator
to generate a key which is then sent back to the user. This needs to be enteredalong with the other information (associated with lower-security accounts)
during the registration process (see discussion in Available Servers earlier
in this chapter).
User Accounts
Associated with each user account is a series of attributes. These identify
the account, provide contact information of the user and allow the server
administrator to set limits.
Username
This is the name of the account provided by the user at the time theaccount was set up.
StatusThis is marked either Activated or Pending. Activated means that an
account is available for use. Pending means that the administrator needs totake further action in order for the account to be available.
E-mail AddressThis is the e-mail address of the user provided at the time theaccount was set-up.
Key
This is the key supplied to the user by the administrator and then used to set
up an account. This only applies for the highest-security setting for
Remote Registration (Disabled).
PrivilegesThis allows the administrator to give an account the permission to startjobs that are in the job queue.
Job Quota
This is the maximum number of jobs that a particular user account ispermitted to run at one time. It overrides (for this account) the global job
quota discussed earlier. The administrator selects a number (or“unlimited”) from the menu inside the Edit Job Quota dialog.
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Device ID/NameThis identifies the device (computer, tablet, or iOS device) associatedwith a user account.
Colors ()

This alters default colors. Selection leads to the Colors dialog.

After selecting an object, its color may be set by choosing from thepalette, moving the cursor inside the window of colors, or by selecting
either a set of hue, saturation and values, or red, green and blue settings orwith the HTML designator. The default color may be reset by clicking on
Restore Default Color. Color selection applies to all objects of the same
type, for example, all carbon atoms, and not just to the selected carbon.
Further control of colors is available from Utilities/Style dialogs
associated with Properties dialogs (Properties under the Display menu;
Chapter 22). Clicking on
removes the dialog.
Fonts/Graphics Fonts (/)

This selects fonts, style and size of labels attached to molecules (Labels andConfigure... under the Model menu; Chapter 18), and plots (Plots... under
the Display menu; Chapter 22). Selection leads to the Fonts dialog.

Chapter 24519

Selections are made from the Font, Font Style and Size menus. Clicking
on OK dismisses the dialog with selections kept. Clicking on Cancel or on
dismisses the dialog but selections are lost.
Monitor ()

This provides a listing of all executing/queued jobs and their status; both
locally submitted and remotely submitted jobs are listed. To see accumulated
output for an executing job, click on the triangle to the left of the documentname and then select the name of the molecule. A ball-and-spoke model ofthe selected (executing) job will be displayed in a window to the right of the
dialog. It can be manipulated using the usual mouse commands (you need toposition the cursor inside the window). Touch-screen commands arepresently limited to
Chapter 24520

rotation (move one finger). Model style cannot be changed. Note that (except
for molecular mechanics and semi-empirical calculations) the structure is
updated throughout an equilibrium geometry of transition state optimization,and bond lengths, angles and dihedral angles can be queried.
To stop a job, right-click on its name, and then select Terminate from theActions menu at the top of the dialog (or right click on its name and selectTerminate from the menu that appears). To start a queued job (irrespectiveof the imposed queue limits; see previous discussions under Jobs), rightclick on its name and select Start from the Control Actions menu.
The Monitor may be removed either by selecting Exit from the Filemenu or by clicking on
at the top of the dialog.
Calculator ()

Selection brings up a Calculator. This functions the same way as a normal
pocket calculator. The Calculator is removed by clicking on.
Icons ()

Toggles the set of icons that appear above the menus on and off.

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Chapter 26
The Activities Menu
The Activities menu permits on-screen display of the full set of Spartan tutorials
and a series of topics of practical relevance to molecular modeling. It also
allows a Wikipedia page to be brought up (external to Spartan).

Tutorials/Topics (/)

Selection of Tutorials or Topics brings up a dialog with either the
Tutorials or Topics tab selected (Tutorials tab shown).

Selection of an entry results in opening of a chapter from the Tutorials as a pdf
file which can be displayed alongside Spartan while working through thechapter’s content.
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Look Up in Wikipedia... ()

Selection results in a dialog.

By default, the query is the name of the selected molecule. Clicking on OK
or entering a different query followed by clicking on OK leads to a
Wikipedia page. This occupies a window that is external to Spartan.

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Chapter 27
The Help Menu
This chapter describes help.
Spartan’24 Help ()
This provides information relating to application ofcomputational methods available in Spartan, as wellas technical details regarding the program’s
operation.

A number of topics are dealt with under Help;
including General Operating Features,
Selecting a Theoretical Model, Calculation, and anumber of FAQ documents (Properties,
Quantum Mechanics Energy Questions, Basis Sets, Molecular
Mechanics Questions, Convergence Questions, Conformation andEnergy Profile Questions, Memory Questions) related to computationalquestions. Help also provides a link to Wavefunction’s website. Help files
are HTML documents.
The Spartan Tutorial and User’s Guide (this document) and A Guide to
Molecular Mechanics and Quantum Chemical Calculations are alsoavailable (as PDF files) under Help.
Finally, note that several dialogs, in particular, the Calculations dialog
incorporate imbedded help messages. Clicking on
at the upper right,
followed by clicking on a menu, button, etc. in the dialog gives rise to a brief
informative message about the object queried.
Spartan’24 Manual ()

Provides access to the Spartan’24 Tutorial and User’s Guide (thisdocument) as a PDF file.

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License Utility ()

Provides access to the License Utility dialog. From here you can access the
Key ID for your license and reference available Features and Maintenancedate, change license option from the originally specified choice (Individualor Network) by clicking the Back button, Update the license, or request alicense Transfer.

About Spartan’24 ()

Provides information about the user’s release of Spartan.

Chapter 26525

Appendix A
TopicsEssays address topics that are important to molecular modeling in generaland to modeling applications of Spartan in particular. Most of these essays
are at an elementary level and provide only fundamentals. More detailed
information is provided in the essays dealing with flexible molecules andwith NMR spectroscopy to address the protocols in Spartan.
The first two essays are foundational. Potential Energy Surfaces relates
two of the quantities that directly result from a quantum chemical
calculation, geometry and energy. Theoretical Models outlines the steps
taken in moving from the Schrödinger equation to practical techniques andbroadly outlines the scope of these techniques.
Finding and Verifying Equilibrium and Transition-State Geometries
and Total Energies and Thermodynamic and Kinetic Data provide
specifics about the relationship between geometry and energy in the context
of practical quantum chemical models. Calculating Accurate Heats ofFormation details procedures that are available in Spartan to reliably
reproduce the experimental heats of formation.
Dealing with Conformationally-Flexible Molecules describes what must be
done in order to identify the lowest-energy conformer of a flexible
molecule. Multistep protocols introduced with Spartan’18 expanded thecoverage to high-level quantum chemical models able to provide accurate
Boltzmann-weighted averages.
Interpreting Conformational Preferences shows how information
resulting from a calculated energy profile for single-bond rotation may berelated to familiar chemical notions.
Calculating Infrared Spectra shows how the raw data resulting
from a quantum chemical calculation may be combined with

Appendix A

526

two empirical parameters to produce accurate infrared spectra. Calculating
NMR Spectra describes a multi-parameter scheme to obtain 13C chemical
shifts into close agreement with experiment.
Calculating Chemical Shifts in Conformationally Flexible Molecules
describes protocols for efficiently calculating NMR chemical shifts formolecules with multiple degrees of conformational freedom. One set of
protocols introduced with Spartan’18 obtains accurate Boltzmann weights
to form proper averages while the set of protocols introduced with
Spartan’20 introduced much simpler and lower-cost methods to select theconformer that best agrees with measured shifts. Assigning Stereo andRegioisomers from Calculated Chemical Shifts ranks chemical shifts ofisomers according to DP4 scores. Calculating HH and CH Coupling
Constants assesses practical methods for calculation of 3-bond HH and 2
and 3-bond CH coupling constants and in addition describes an empirical
scheme for obtaining CH coupling constants. Calculating COSY and
HMBC Spectra describes presentation modes for 2D NMR spectra andcomparison with experimentally assigned couplings.
Atomic and Molecular Orbitals describes how molecular orbitals arise
from atomic orbitals in the context of the practical quantum chemical
models introduced previously, and illustrates the information that can be
drawn from them. Electron Densities: Sizes and Shapes of Molecules
describes molecular size and shape from the perspective of quantum
mechanics and in so doing provides a “platform” from which to evaluate
how a molecule interacts with its environment. Electrostatic Potential
Maps: Charge Distributions describes a model that uses color to “map” theelectrostatic potential (the energy of a positive point charge with the nuclei
and electrons of a molecule) in order to distinguish neutral, positive andnegative regions on an accessible surface. Local Ionization Potential
Maps and LUMO Maps: Electrophilic and Nucleophilic Reactivities
show how maps colored using the energy of ionization and the absolute valueof the lowest-unoccupied molecular orbital, respectively, may be used toaccount for electrophilic and nucleophilic reactivity.

Appendix A

527

POTENTIAL ENERGY SURFACESOne Dimensional Energy Surfaces
Every chemist has encountered a plot depicting the change in energy of
ethane as a function of the angle of torsion (dihedral angle) around the carboncarbon bond.

Full 360° rotation leads to three identical energy minima in which thehydrogens are staggered, and three identical energy maxima in which thehydrogens are eclipsed. The difference in energy between eclipsed andstaggered structures of ethane, termed the barrier to rotation, is known
experimentally to be approximately 12 kJ/mol. Note that any physicalmeasurements on ethane pertain only to its staggered structure, or more
precisely the set of three identical staggered structures. Eclipsed ethane does
not exist in the sense that it cannot be isolated and characterized. Rather, it
can only be imagined as a structure in between equivalent staggered forms.
Open ethane rotation in the topics directory*. The image which appears is
one frame in a sequence depicting rotation about the carbon-carbon bondin ethane. Click on the andkeys at the bottom left of the screen tolook at other frames. Verify that the staggered structures correspond tominima on the energy plot and that the eclipsed structures correspond to
maxima. Click on the key to animate the sequence. Close ethane
rotation when you are finished.
Appendix A

528

Somewhat more complicated but also familiar is a plot of energy vs. thedihedral angle involving the central carbon-carbon bond in n-butane.

This plot also reveals three energy minima, corresponding to staggered
structures, and three energy maxima, corresponding to eclipsed*

For Windows, the Topics directory is found in Program Files/Wavefunction/Spartan24. It needs to becopied to another location available to the user prior to opening it in Spartan. For Macintosh, this is locatedat the top of the Spartan24 disc image. For Linux, the Topics directory is found in the install directory.
Copy the Topics directory to a location that allows write permission, typically the user’s home directory.

Appendix A

529

structures. In the case of n-butane, however, the three structures in each set
are not identical. Rather, one of the minima, corresponding to a dihedral
angle of 180° (the anti structure), is lower in energy and distinct from the othertwo gauche minima (dihedral angles around 60° and 300°), which are
identical. Similarly, one of the energy maxima corresponding to a dihedral
angle of 0°, is distinct from the other two maxima (with dihedral angles
around 120° and 240°), which are identical. As with eclipsed ethane,
eclipsed forms of n-butane do not exist, and correspond only to hypotheticalstructures in between anti and gauche minima. Unlike ethane, which is asingle compound, any sample of n-butane is made up of two distinct
compounds, anti n-butane and gauche n-butane. The relative abundance ofthe two compounds as a function of temperature is given by the Boltzmann
equation (see the topic Total Energies and Thermodynamic and Kinetic
Data).
Open n-butane rotation in the topics directory. The image which appears
is one frame of a sequence depicting rotation about the central carboncarbon bond in n-butane. Click on theandkeys at the bottom leftof the screen to look at other frames. Verify that the staggered structures
correspond to minima on the energy plot and that the eclipsed structures
correspond to maxima. Also, verify that the anti structure is lower inenergy than the gauche structure. Click on
to animate the sequence.
Close n-butane rotation when you are finished.

The important geometrical coordinate in n-butane may clearly be identified
as a torsion about the central carbon-carbon bond. This is anoversimplification, as bond lengths and angles no doubt change during
rotation around the carbon-carbon bond.
Quantum chemical models available in Spartan are able to account forthe subtle changes in bond lengths and angles which result from changes
in conformation. Open n-butane geometry changes in the topics
directory. The two plots depict the variation in central CC bond distanceand in CCC bond angle as a function of the CCCC torsional angle. The
variation in energy is superimposed on each plot. Note how closely thebond distance and energy changes parallel each other. Note also that the

Appendix A

530

bond angle is insensitive to conformation except in the region of the syn(0° torsional angle) structure where it has opened up by several degrees.
Close n-butane geometry changes when you are finished.

Many Dimensional Energy Surfaces
It will usually not be possible to identify a simple geometrical coordinate todesignate a chemical transformation. A good example of this is provided by
the potential energy surface for ring inversion in cyclohexane.

transition
stateenergytransition
state

twist boat
chair

chair
reaction coordinate

In this case, the geometrical coordinate connecting stable forms is not
specified in detail (as it was in the previous two examples), but is referred tosimply as the reaction coordinate. The two energy maxima on the reaction
coordinate diagram have been designated as transition states to indicate that
their structures may not be simply described (as are the energy maxima
for rotation in ethane and n-butane).
The energy surface for ring inversion in cyclohexane, like that for n-butane,
contains three distinct energy minima, two of lower energy referred to as
chair forms, and one of higher energy referred to as a twist boat form. In
fact, the energy difference between the chair and twist boat structures isaround 23 kJ/mol and, only the former can be observed at normal
temperatures. For a discussion, see the topic Total Energies andThermodynamic and Kinetic Data.
All six carbons are equivalent in the chair form of cyclohexane, but thehydrogens divide into two sets of six equivalent equatorial

Appendix A

531

hydrogens and six equivalent axial hydrogens.

Hequatorial
HaxialHowever, only one kind of hydrogen can normally be observed, meaningthat equatorial and axial positions interconvert via some low-energy
process. This is the ring inversion process just described, in which one sideof the ring is bent upward while the other side is bent downward.

As shown in the potential energy diagram on the previous page, the overallring inversion process appears to occur in two steps, with a twist boat structure asa midway point (an intermediate). The two (equivalent) transition states leading
to this intermediate adopt structures in which five of the ring carbons lie(approximately) in one plane.
The energy profile for ring inversion in cyclohexane may be rationalized
given what we have already said about single-bond rotation in n-butane.
Basically, the interconversion of the reactant into the twist-boatintermediate via the transition state can be viewed as a restricted rotation
about one of the ring bonds.

Correspondingly, the interconversion of the twist boat intermediate into the
product can be viewed as rotation about the opposite ring bond. Overall,
two independent bond rotations, pausing at the high- energy (but stable)
twist-boat intermediate effect conversion of one chair structure into anotherequivalent chair, and at the same time switch axial and equatorialhydrogens.

Appendix A

532

Open cyclohexane ring inversion in the topics directory. The image
which appears is one frame in a sequence depicting ring inversion in
cyclohexane. Click on the and keys at the bottom left of the screen
to look at other frames. Verify that the three minima on the energy plotcorrespond to staggered structures and that the two maxima correspondto eclipsed structures. Also, verify that the twist boat structure is higher
in energy than the chair structures. Click on to animate the sequence.
Note that the overall ring inversion appears to occur in two steps, one
step leading up to the twist boat and the other step leading away from it.
Close cyclohexane ring inversion when you are finished.

Ethane, n-butane and cyclohexane are all examples of the types of
motions which molecules may undergo. Their potential energy surfaces are
special cases of a general type of plot in which the variation in energy is
given as a function of reaction coordinate.
transition stateenergyreactant

product
reaction coordinate

Diagrams like this provide essential connections between importantchemical observables - structure, stability, reactivity and selectivity- and energy.
The positions of the energy minima along the reaction coordinate give theequilibrium structures of the reactant and product. Similarly, the position of
the energy maximum gives the structure of the transition state. Both energy
minima (which correspond to stable molecules) and the energy maximum(which may correspond to a transition state) are well defined. However, thepath connecting them (reaction coordinate) is not well defined, in the sensethat there are many possible paths. Liken this to climbing a mountain. The
starting and ending points are well defined as is the summit, but there can be
many possible routes.
Appendix A

533

transition state structuretransition stateenergyreactant

product
equilibrium structures
reaction coordinate

The reaction coordinate for some processes may be quite simple. For
example, where the “reaction” is rotation about the carbon-carbon bond inethane, the reaction coordinate may be thought of as the HCCH torsion
angle, and the structure may be thought of in terms of this angle alone. Thus,
staggered ethane (both the reactant and the product) is a molecule for which
this angle is 60° and eclipsed ethane is a molecule for which this angle is 0°.

A similar description applies to “reaction” of gauche n-butane leading to themore stable anti conformer. Again, the reaction coordinate may be thought ofas a torsion about the central carbon-carbon bond, and the individual
reactant, transition state and product structures in terms of this coordinate.

Appendix A

534

Equilibrium structure (geometry) may be determined from experiment, giventhat the molecule can be prepared and is sufficiently long-lived to be subject
to measurement. On the other hand, the geometry of a transition state may
not be experimentally established. This is simply because a transition state
is not an energy well which can trap molecules. Therefore, it is impossible
to establish a population of molecules on which measurements may be
performed.
Both equilibrium and transition-state structures may be determined fromquantum chemical calculations. The fact that a molecule may not be stableenough to be detected and characterized (or even exist) is not important. It
would seem from our discussion that equilibrium and transition-state
structures can be distinguished from one another simply by inspecting theshape of the potential energy surface in the vicinity of the structure. Of
course, such a surface cannot actually be visualized for a system with morethan one or at most two degrees of freedom. However, the set of frequencies
associated with the vibrational motions around the structure, the same
quantities measured by infrared spectroscopy, will all be real numbers for stablemolecules (energy minima), whereas there will be one (and only one)vibrational frequency which is an imaginary number for a transition state.
This does not guarantee that this is the transition state “of interest”, but if it is,the coordinate (vibrational motion) associated with it is the reaction
coordinate. Further discussion is provided in the topic Calculating Infrared
Spectra.

Appendix A

535

THEORETICAL MODELS
A variety of different procedures based on quantum mechanics (so- called
quantum chemical models) have been developed to calculate molecular
structure and properties as well as infrared, NMR and UV/visible spectra.
All follow from a deceptively simple looking Schrödinger equation firstwritten down in 1927.
Ĥ  = Ĥ (the Hamiltonian or more precisely Hamiltonian operator) is the only
known. It describes the kinetic energies of the particles that make up amolecule and the Coulombic interactions between the individual particles.
Positively-charged nuclei repel other nuclei, and negatively-charged
electrons repel other electrons, but nuclei
attract electrons.  (the wave function) is a function of the Cartesian
coordinates, and  (the energy) is a number. The goal in solving the
Schrödinger equation is to find a function that when operated on by
the Hamiltonian yields the same function multiplied by a number. Note that
there are many (actually an infinite number of) solutions to the Schrödinger
equation. These correspond to the ground and numerous excited states ofan atomic or molecular system.
The energy of a molecule can be measured. On the other hand, the wave function
has no physical meaning, and is not subject to experimental measurement,
although the square of the wave function times a small volume element gives
the probability of finding an electron inside that volume. This exactly
corresponds to what is actually measured in an X-ray diffraction
experiment.
The Schrödinger equation has been solved exactly for the hydrogen atom (aone-electron system), where the wave functions are familiar to chemists as thes, p, d, ... atomic orbitals. The lowest-energy s orbital corresponds to theground state of the hydrogen atom, whereas the higher-energy solutions
correspond to excited states.

s orbital

Appendix A

p orbitald orbital

536

The Schrödinger equation may easily be written down for many- electron
atoms as well as for molecules, although it cannot be solved. Even something
as seemingly simple as the helium atom with only two-electrons presents aninsurmountable problem. Approximations must be made.
Hartree-Fock Molecular Orbital Models
Hartree-Fock molecular orbital models or molecular orbital models, as
they are commonly referred to, were the first practical quantum chemical
models to be formulated. They result from making three approximations to
the Schrödinger equation:
1. Separate nuclear and electron motions. The Born-Oppenheimer
approximation says that “from the point of view of the electrons”, the nuclei
are stationary. This eliminates nuclear motion and leads to an electronic
Schrödinger equation which can be solved for the H + molecule, but cannot
be solved 2 for molecules with more than one-electron. The BornOppenheimer approximation is of little consequence for the description ofmolecular properties, for example, equilibrium geometries and reactionenergies, and may be used without concern.
2. Separate electron motions. The Hartree-Fock approximation eliminates
the need of having to simultaneously account for the motions of several
electrons. It leads to a much simpler set of equations in which the motion ofeach electron in an environment made up of the nuclei and all the otherelectrons is sought.
3. Represent each one-electron solution or molecular orbital by a linear
combination of atom-centered functions or atomic orbitals. The LCAO
(Linear Combinations of Atomic Orbitals) approximation reduces the
problem of finding the best functional form for the molecular orbitals to themuch simpler problem of finding the best set of linear coefficients. As thenumber and complexity of the atomic orbitals increases, the energy andother properties approach limiting values. However, computational costalso increases. The goal is to provide as few functions as possible to yield avalue for the property of interest that adequately

Appendix A

537

reflects its limit. Note, that the limiting values of properties are not expected
to be the same as experimental values, but rather reflect the behavior of the
Hartree-Fock model.
Basis Sets
Gaussian functions are polynomials in the Cartesian coordinates times an
exponential in the square of the distance from the origin. They are distinct
although very closely related to the exact solutions of the hydrogen atom
(exponential functions in the distance), and are labeled 1s, 2s, 2p, ... , thesame nomenclature used to describe hydrogen atom solutions.
A minimal basis set includes only sufficient functions to hold all theelectrons on an atom and to maintain its spherical shape. This involves asingle 1s orbital for each hydrogen atom, and a set of five orbitals (1s, 2s,2px, 2py and 2pz) for each carbon atom. Because a minimal basis set
incorporates only one set valence p functions, the components of which are
the same size, atoms in nearly spherical environments will be better
described than atoms in aspherical environments. A split-valence basis set
addresses this problem by providing two different sets of valence pfunctions, one compact set and one loose set. This allows different linear
combinations for different directions. For example, the compact p orbital
can be emphasized to construct a  bond while the loose p orbital can beemphasized to construct a  bond.
ps = inner

pp = inner+ outer+ outer

Because the functions in a minimal or split valence basis set are centeredon the atoms, they may have difficulty describing electron distributions thatfall in between atoms (that is, bonds). Polarization basis sets address thisproblem by providing a set of d-type functions (polarization functions) on
main-group elements, and (optionally) a

Appendix A

538

set of p-type functions on hydrogen. The resulting combinations can bethought of as hybrid orbitals, for example, the pd and sp hybrids shown
below.
+ + 

The so-called 6-31G* basis set will be used for the infrared and NMR
calculations described in future topics. The number “6” to the left of the “-”in the name indicates that 6 functions are used to describe each inner-shell(core) atomic orbital. The numbers, “31” to the right of the “-” indicate thatgroups of 3 and 1 functions are used to describe each valence-shell atomic
orbital. “*” designates that polarization functions are supplied for nonhydrogen atoms. Were two stars to be present (as in 6-31G**) this would
indicate that p-type polarization functions would also be placed onhydrogen atoms.
The valence basis functions can be further split and additional polarization
functions can be added including f-type functions. A commonly used basis
set is designated 6-311+G(2df,2p). “311” indicates a triply-split valence,“2df” indicates that two sets of d-type functions and a set of f-type functions
are added to the valence of heavy atoms, and “2p” indicates that two sets ofp-type functions are added to the valence of hydrogen atoms.
Taken together, these three approximations lead to a set of equations known
as the Roothaan-Hall equations. They increase in computational cost as
the cube of the size (number of basis functions), and can easily be applied
to molecules incorporating up to 100 heavy (non- hydrogen) atoms.
Beyond Hartree-Fock Models
Of the three approximations we have made to reach Hartree-Fock models,
the second is to be taken most seriously. According to the Hartree-Fockapproximation, electrons “move independently”,

Appendix A

539

which means that both the electron-electron repulsion energy and the totalenergy will be too large. The limiting Hartree-Fock energy is, therefore,
necessarily higher (less negative) than the experimental energy. Electron
correlation is the term give to describe the coupling or correlation ofelectron motions. The correlation energy is defined as the difference
between the Hartree-Fock energy and the experimental energy and isnecessarily a negative quantity.
There are two conceptually different approaches for calculating thecorrelation energy, and numerous specific models arising from each of theseapproaches. Wave function based models start from the Hartree- Fock wave
function combining it with wave functions resulting from electron excitations
from filled to empty molecular orbitals. Density functional models
supplement the Hartree-Fock Hamiltonian.
Configuration Interaction Models
Configuration interaction models are archetypal of wave function based
correlated models. In the unachievable limit, so-called full configurationinteraction, all possible single and multiple electron promotions fromoccupied to unoccupied Hartree-Fock molecular orbitals and assuming acomplete basis set, the energy is same as would be achieved by solution of
the electronic Schrödinger equation. More practical limited configurationinteraction schemes have been formulated by limiting the number ofelectron simultaneously promoted (1-electron, 2-electron, ...) and thenumber of filled and unfilled molecular orbitals involved in the promotions.
Møller Plesset Models
An alternative and more commonly used wave function based model is
Møller-Plesset theory. This assumes that the Hartree-Fock energy E0 andwave function Ψ0 are solutions to an equation involving a Hamiltonian,
Ĥ0, that is very close to the exact Schrödinger Hamiltonian, Ĥ. This being
the case, Ĥ can be written as a sum of Ĥ0 and a small correction, V. λ is adimensionless parameter.
Ĥ = Ĥ0 + Vˆ

Appendix A

540

Expanding the exact energy in terms of a power series of the HartreeFock energy yields:
E = E(0) + E(1) + 2E(2) + 3E(3) + ...

Substituting this expansion into the Schrödinger equation and collecting
terms in powers of  leads to an explicit expression for the energy correction.
The sum of E(0) and E(1) is the Hartree-Fock energy. Including the next term
gives rise to the so-called MP2 (second-order Møller-Plesset) model.
Both the simplest configuration interaction (limited to single and double
electron excitations only) and the MP2 models increase in computational
cost as the power of the total number of basis 5th functions. In practice, thislimits them to molecules incorporating 25-50 heavy (non-hydrogen) atoms
at most.
Density functional theory or simply DFT, is based on two theorems
elaborated by Hohenberg and Kohn, which taken together, prove that theenergy and other properties of a many-electron system in its ground state
may be correctly and uniquely described in terms of a function of theelectron density. The term “functional” or a function of a function arises
because the electron density is itself a function of the three spatial coordinates.
What the two Hohenberg-Kohn theorems imply is that the Schrödinger
equation can actually be solved; that is, the completely “intractable” problem
involving the coupled motions of n electrons in a static field due to the nuclei(a “molecule”) may be replaced by an eminently “solvable” problem thattreats the electrons as independent (that is, non-interacting) particles.
Because the electron density is a function of only three coordinates, in effecta 3 dimensional problem is substituted for a 3n dimensional problem.
Unfortunately, the Hohenberg-Kohn theorems do not tell us anything about
the functional itself.
In the density functional formalism, the electronic energy, Eel, is written asa sum of the kinetic energy, ET, the electron-nuclear interaction energy, EV,
the Coulomb energy, EJ, and a term combining the exchange and correlationenergies, EXC.
Eel = ET + EV + EJ + EXC

Appendix A

541

What is “the” exchange/correlation functional? The quest has gone on forseveral decades and hundreds of functionals have actually been proposed anddivided into several distinct classes.
Local Density Approximation (LDA)
The functional first proposed stems from a purely hypothetical problem inwhich a uniform gas of non-interacting electrons moves in a positively
charged field. An analytical solution for the exchange energy is available andtakes the form of the density raised to the 4/3’s power. The correlation energy
may be arrived at through numerical simulation, and is also only dependent on
only the local density at each point.
EXC = E(ρ)

Functionals that depend only on the electron density (ρ) are referred to as
LDA functionals. They are not very successful in describing the properties ofmolecules and have largely been replaced.
Generalized Gradient Approximation (GGA)GGA functionals depend on the gradient of the electron density, ρ,in addition to the density itself.
EXC = E (ρ, ∇ρ)

They have been around since the mid 1980’s and were the first to provide
a reasonable account of molecular properties and in particular the energies
of chemical reactions. In this sense, they were instrumental in drawing
attention to density functional theory as a viable “low-cost” alternative towave function based correlation techniques, something that LDA
functionals had failed to do. The BLYP functional is representative.
Global Hybrid Generalized Gradient Approximation (GH-GGA)
GH-GGA functionals often referred to as hybrid functionals) replace a fixed
fraction of the exchange by the “exact” Hartree-Fock exchange, the fraction
being an adjustable parameter. It is likely that it was the introduction of
hybrid functionals that caused the community

Appendix A

542

to recognize that density functional theory was “semi-empirical” in nature.
Adding the Hartree-Fock exchange is “costly”, but led to significant
improvements in the description of reaction energies. While GH-GGA
functionals were introduced in the early 1990’s, they remain a mainstay in theapplication of density functional theory to chemistry. The B3LYP
functional, in particular, is perhaps still more widely used than any otherfunctional, even though there are now much better choices.
Range Separated Hybrid Generalized Gradient Approximation (RSHGGA)
The idea behind range separated GGA hybrid functionals is that the“optimum” amount of Hartree-Fock exchange varies with electron- electron
distance, from a small percentage in the long range limit to a large
percentage in the short range limit, in the extreme from 0% to100%. Both
ωB97X-D and ωB97X-V functionals are range- separated GGA hybrids.
Both incorporate so-called local corrections to account for dispersiveinteractions (see discussion following).
meta Generalized Gradient Approximation (mGGA)
A meta GGA functional not only depends on the electron density and its
gradient (as does a GGA functional) but also on the Laplacian of the electron
density. As such, it can be construed as the next logical step beyond GGA
in constructing a Taylor series expansion of the electron density.
E = E (ρ, ∇ρ,∇2ρ)More commonly, meta GGA functionals are viewed as adding theso-called kinetic energy density to GGA.
E = E (ρ, ∇ρ,∇2ψ)In either case, the addition can be construed as second-order term in a
Taylor series expansion of the electron density. The B97M-V functional isan example of a “pure” meta functional.

Appendix A

543

Global Hybrid meta Generalized Gradient Approximation (GHmGGA)
These are strictly akin to global hybrid GGA (GH-GGA) functionals in thata fixed percentage of the Hartree-Fock exchange is introduced. The “only”
difference is that a meta GGA functional including a second-order term
replaces a GGA functional. The M06-2X functional, widely accepted as an
excellent choice for thermochemical comparisons, is an example of a GHmeta GGA functional.
Range Separated Hybrid meta Generalized Gradient Approximation(RSH-mGGA)
A range-separated meta GGA (RSH-mGGA) functional is identical to arange-separated GGA (RSH-GGA) functional except that a meta GGA
functional has replaced the underlying GGA functional. M11 and ωB97M-V
are examples of range-separated meta GGA functionals.
Double Hybrid meta Generalized Gradient Approximation (DH-RSHmGGA)
A double hybrid meta GGA (DH-RSH-mGGA) functional accounts forcontributions of unoccupied molecular orbitals as well as occupied orbitals, by
way of a MP2 like approach. The B97M(2) functional is now supported forenergy calculations only.
Non Local Corrections
The previous functional classes are all considered “local” in that they aredescribed in terms of a single integral over the three spatial coordinates. In
order to capture dispersive van der Waals interactions, so-called non local
correlation functionals are needed. These involve a double integral over two
sets of coordinates, these may add significant cost to the calculations. For
example, the range-separated GGA hybrid ωB97X-V functional usedthroughout this text, incorporates theVV10 non-local correlation functional
and is 3-5 times more costly than the parent ωB97X functional. An
alternative and less costly way to account for dispersive interactions is to
add an empirical correction to the functional. So-called Grimme
corrections are designated by
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appending “-D” as in ωB97X-D, or “D3” as in B3LYP-D3, to theend of the functional.
A graphical summary of a number of commonly-used functionals
stemming from different classes is provided in the figure below.

Which classes of functionals are “best” and which functionals within eachclass are “best”? A broad base of experience allows some general remarks to
be made.
Numerical Integration
Unlike both Hartree-Fock and wave function based correlated models, density
functional models cannot be evaluated wholly analytically. Some
components require numerical integration, which introduces anothervariable into the mix, specifically the form and size of the integration grid.
An oversimplified description places the grid points along a set number ofangular directions and at a set number of distances from the origin. This isreferred to as a Lebedev grid.

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“Cost” of Density Functional Models
The computation “cost” of density functional models depends on the class,the number of basis functions, η, and the number of points in the numericalintegration grid, κ, where κ >> η. GGA and pure meta-GGA functionals suchas B97M-V that do not require the Hartree-Fock exchange formally scaleas O(η2κ). The other functionals combine this dependence with the cost of
the Hartree-Fock exchange, which formally scales as O(η4) but in practiceis O(η3) or lower. Finally, functionals such as ωB97X-V that directly accountfor dispersion have a step that scales as O(η2κ2). This typically dominates thecalculation. Times (in minutes) for calculation of the energy together with
its gradient (“one step” in the optimization of molecular geometry) for
morphine (C17H19NO3) with the B3LYP (GH-GGA), ωB97X-D (RSHGGA), ωB97X-V (RSH-GGA + dispersion), B97M-V (mGGA), M06-2X(GH-mGGA) and M11 and ωB97M-V (RSH-mGGA)
functionals, as well as with RI-MP2, which formally scales as O(η5), with the
6-31G* basis set are provided in Table A-1. These have been obtained using
a single core of a 3.3 GHz Intel i7 5820K processor. Table A-2provides
times for 6-311+G(2df,2p) calculation, a dual basis set 6-311+G(2df,2p)
calculation and a dual basis set cc-pVQZ-g (cc-pVQZ minus the set of gfunctions) energy calculation, relative to the corresponding 6-31G*
energy/gradient calculations. For example, the value of 26 for the dual basis
set cc-pVQZ–g ωB97X-D energy calculation given in Table A-2, meansthat this calculation is 26 times more costly than the ωB97X-D
energy/gradient calculation. Put another way, a structure optimization
requiring 26 cycles would cost the same as an energy obtained using thelarger basis set.
The manner of reporting is deliberate. The 6-31G* basis set is usually deemedsatisfactory for calculation of equilibrium geometry, whereas larger basis sets(for example, 6-311+G(2df,2p) and cc-pVQZ-g) are known to be required for
accurate descriptions of the energies of most chemical reactions.
Determination of geometry for molecules of the complexity of morphine
typically requires upwards of 10-20 energy/ gradient cycles, that is, an orderof magnitude or more greater than the time reported in the first column of
the table. Both parts must be considered in order to correctly access cost andpracticality.
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Table A-1: Times for energy and gradient calculations on morphine with
B3LYP, ωB97X-D, ωB97X-V, B97M-V, M06-2X, M11 andωB97M-V density functional models and RI-MP2 model with the
6-31G* basis set (need ωB97M-V times)
6-31G* + gradient
B3LYP
ωB97X-DωB97X-V
B97M-V
M06-2X
M11
RI-MP2

7
15
41
50
19
22
10

Table A-2: Times for B3LYP, ωB97X-D, ωB97X-V, B97M-V, M06-2X, M11 andωB97M-V density functional and RI-MP2 energy calculations with 6311+G(2df,2p), dual 6-311+G(2df,2p) and dual cc-pVQZ-g basis sets
relative to the corresponding times for energy and gradientcalculations with the 6-31G* basis set give in Table A-1.
6-311G(2df,2p)

6-311+G(2df,2p) [6- cc-pVQZ-g
311G*][rcc-pVQZ]

B3LYP
ωB97X-DωB97X-V
B97M-V
M06-2X
M11
RI-MP2

26
14
6
5
13
11
18

5
3
2
2
3
3
3

48
26
10
6
21
20
33

Several conclusions may be drawn:
1. Times for calculation of the energy together with its gradient vary by close
to an order of magnitude among the seven models. The B3LYP model is theleast costly and the ωB97X-V, B97M-V and ωB97M-V models most costly.
The latter result suggests that calculation of the gradient of dispersion
functional common to both models is to blame. In terms of cost, theωB97X-D model is closest to B3LYP. The surprising result is perhaps thegood performance of the RI-MP2 model, surpassed only by B3LYP.

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2. 6-311+G(2df,2p) energy calculations are roughly an order of magnitude
more costly than the corresponding energy/gradient calculations. At thehigh end and low ends is the factor of 26 for the B3LYP model and a factorof 5 for the B97M-V model. Structure optimization typically requires
upwards of 20 steps (energy/gradient), and will likely dominate the overalltask.
3. The dual basis set approximation applied to 6-311+G(2df,2p) basis set leads tosignificant cost savings. If this is the chosen energy method, the costly step
will most certainly be determination of geometry.
4. Except for the ωB97X-V and B97M-V functionals, dual basis set cc-pVQZg calculations are roughly an order of magnitude more costly than thecorresponding 6-311+G(2df,2p) calculations. This means that geometry andenergy steps are likely to contribute equally to overall cost. The muchsmaller increase in cost for B97M-V is presumably due to its lack of the
Hartree-Fock exchange.
5. The RI-MP2 model is clearly competitive, greater in overall cost only to the
B3LYP models. Because of its inherent O(η5) scaling, RI-MP2 will
eventually fall significantly behind density functional models in performanceas molecular size is increased.
Disadvantages of Density Functional Models
Low computation cost relative to wave function based electron correlation
models is the principal attraction of density functional models. Aside fromthe RI-MP2 model, density functional models are the only procedures thatare both reliable and routinely applicable to molecules of moderate size.
However, density functional models come with some disadvantages notshared by wave function based procedures. By far the most serious of theseis that they do not offer a clear pathway to improvement. Whereas wave
function based procedures return a higher and higher percentage of thecorrelation energy with increasing degree of complexity, for example, in
successively adding orders in the Møller-Plesset models,Appendix A

548

there is no guarantee that increasing the flexibility (and complexity) of aparticular functional will actually lead to improvement. It is clear that present
generation functionals are “better” than those of previous generations, forexample, ωB97X-D and M06-2X are significantly better than B3LYP, inparticular for calculation of reaction energies. What is less clear is whether
the improvement is to large extent due to careful parameterization to highquality reference data (and to an increased number of parameters) rather
than from insight into the “proper” functional form. Functional selection,even while guided by clear physical models, certainly has an uncertain
component, and at least at present it is not possible to say from firstprinciples which of several functionals is likely to provide the “best” results.
This can only be done by way of thorough comparisons with “known” data.
In practice, density functional models increase in computational cost as the
cube of the total number of basis functions (the same dependence seen for
Hartree-Fock models). Because most functionals require calculation of the
Hartree-Fock exchange energy, they are necessarily more costly than HartreeFock models, but can easily be applied to molecules incorporating up to
100 heavy (non-hydrogen) atoms.
Models for Open-Shell Molecules
Thus far, discussion has been limited to molecules with closed- shellelectron configurations, that is, with all electrons being paired. This covers
the vast majority of organic molecules as well as most organometallic
molecules. There are two ways to think about molecules with unpaired
electrons. The obvious way is to insist that electrons are either paired or are
unpaired.

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This is referred to as restricted and the individual models as restricted
models, for example, the restricted Hartree-Fock (or RHF) model.
The restricted procedure does not necessarily yield the lowest possible energy,
simply because it forces the “paired” electron into the same spatial orbitals.
Removing this constrains provides greater flexibility and generally lead to alower energy. This is termed unrestricted and the resulting models are termedunrestricted models, for example, the unrestricted Hartree-Fock (or UHF)model.

Aside from yielding lower energy, unrestricted models are generally lesscostly than restricted models, and are much more widely used and is thedefault procedure in Spartan.
Semi-Empirical Molecular Orbital Models
The principal disadvantage of Hartree-Fock, density functional and MP2models is their computational cost. It is possible to introduce further
approximations together with empirical parameters in order to significantly
reduce cost while still retaining the underlying quantum mechanicalformalism. So-called semi-empirical molecular orbital models follow in astraightforward way from Hartree-Fock models:
1. Insist that basis functions on different atoms do not overlap (“see eachother”). The so-called NDDO approximation is rather drastic but reduces
the computation effort by more than an order of magnitude over HartreeFock models.
2. Restrict to a minimal valence basis set of atomic functions. This means that
there are no inner-shell (core) functions in the basis set. As a consequence,the cost of doing a calculation involving a second-row element such as
silicon, is no more than that incurred for the corresponding first-row element
such as carbon.
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3. Introduce adjustable parameters to reproduce specific experimental data. This
is what distinguishes the various semi-empirical models currently available.
Choice of parameters, more than anything else, appears to be the key toformulating successful semi-empirical models.
Molecular Mechanics Models
The alternative to quantum chemical models are molecular mechanics models.
These do not start from the Schrödinger equation, but rather from a simple
but chemically reasonable picture of molecular structure, a so-called force
field. In this picture, just as with a Lewis structure, molecules are made up
of atoms (as opposed to nuclei and electrons), some of which are connected(bonded). Both crowding (van der Waals) and charge-charge (Coulombic)
interactions between atoms are then considered, and atom positions areadjusted to best match known structural data (bond lengths and angles).
Molecular mechanics is much simpler than attempts at solving an“approximate” Schrödinger equation, but requires an explicit description ofchemical bonding, as well as a large amount of information about thestructures of molecules. This biases results and seriously limits the predictive
value of molecular mechanics models. Nevertheless, molecular mechanics
has found an important role in molecular modeling as a tool to establish
equilibrium geometries of proteins and other large molecules. It has also
been widely used to establish the preferred conformation of molecules withmultiple degrees of conformational freedom and hundreds or eventhousands of accessible conformers. With regard to the latter, comparisonswith results of high-level quantum chemical calculations have, however,clearly shown that present-generation molecular mechanics models areoften not satisfactory in identifying the “best” (lowest-energy) conformer
and are not to be trusted for obtaining Boltzmann weighed averages.
However, they have proven to be useful for identifying highly unfavorable
conformers allowing some shortening of the initial list of possible structures.

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Choosing a Theoretical ModelNo single method of calculation is likely to be ideal for all applications. A great
deal of effort has been expended to define the limits of different molecularmechanics and quantum chemical models, and to judge the degree ofsuccess of different models. The latter follows from the ability of a model toconsistently reproduce known (experimental) data. Molecular mechanics
models are restricted to determination of geometries and conformations ofstable molecules. Quantum chemical models also provide energy data,
which may in turn be directly compared with experimental thermochemical
data, as well as infrared, Raman, UV/visible and NMR spectra andproperties such as dipole moments, which may be compared directly with thecorresponding experimental quantities. Quantum chemical models may also
be applied to transition states. While there are no experimental structureswith which to compare (see the topic Potential Energy Surfaces),
experimental kinetic data may be interpreted to provide information about
activation energies (see the topic Total Energies and Thermodynamic andKinetic Data).
Success is not an absolute. Different properties, and certainly different
problems may require different levels of confidence to be placed in thecalculation to actually be of value. Neither is success sufficient. A model also
needs to be practical for the task at hand. Were this not the case, there would
be no reason to look further than the Schrödinger equation itself. Models
that may be practical for small to medium size organic molecules cannot be
expected to be applied to proteins. Models that are successful and practicalfor organic molecules may not necessarily meet either criterion for
inorganic molecules or transition-metal organometallics. Not only does thenature and size of the system needs to be taken into account, with due
attention to the available computational resources and the experience (andpatience) of the practitioner. Specifics aside, practical models usually share
one common feature in that they are not likely to be the best possible
treatments which have been formulated. Compromise is almost always anessential component of model selection. Continued advances in both digitalcomputers and computer software will continue to raise the bar, but it will
be some time before fully reliable models will be

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routinely applicable to all chemical systems of interest.
The MMFF molecular mechanics model generally provides a satisfactory
description of equilibrium geometry where, at least for organic molecules. It has also proven to be suitable for removing high-energy conformers formolecules with multiple degrees of freedom in preface to quantum chemical
calculations of conformer energy differences.
Semi-empirical model are appropriate for:i) Equilibrium geometry determinations for large molecules.
ii) Transition-state geometry determinations.
iii) Equilibrium and transition-state geometry determinations
involving transition metals.
Semi-empirical models are unsuitable for:i) Calculation of reaction energies.
ii) Calculation of conformer energy differences.
Small basis set Hartree-Fock models such as HF/3-21G and HF/631G* are appropriate for:i) Equilibrium and transition-state structure determinations oforganic molecules.
ii) Calculation of energies of isodesmic reactions, including
comparisons of regio and stereoisomers.
They are unsuitable for:i) Calculation of reaction energies that involve bond making or breaking
and calculation of absolute activation energies.
ii) Comparison of isomer energies of molecules with different
bond types.
iii) Equilibrium and transition-state structure determinations fortransition-metal organometallic molecules.
iv) Calculation of conformer energy differences.

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Small basis set density functional models such as B3LYP/6-31G*and B97X-D/6-31G* are appropriate for:i) Equilibrium and transition-state structure determinations for organic
molecules as well as molecules incorporating transition metals.
ii) Calculation of all types of reaction energies, although some caution isneeded.
iii) Calculation of conformer energy differences, although caution isneeded.
The RI-MP2/6-31G* model is appropriate for:i) Equilibrium and transition-state structure determinations except
for molecules including transition metals.
ii) Calculation of all types of reaction energies, although some caution isneeded.
It is unsuitable for:i) Equilibrium and transition-state structure determinations fortransition-metal organometallic molecules.
ii) Calculation of reaction and activation energies where transitionmetals are involved.
The B97X-V/6-311+G(2df,2p) model is appropriate for calculating all typesof reaction energies. Implemented together with a dual basis set, it provides apractical and reliable means to establish conformer energy differences.

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FINDING AND VERIFYING EQUILIBRIUM AND TRANSITIONSTATE GEOMETRIESThe energy of a molecule depends on its geometry. Even small changes instructure can lead to quite large changes in total energy. What is the “best”
choice of geometry for use in a molecular modeling study? While
experimental structures, where available, would at first glance seem to beideal, there are multiple problems with this. First, while upwards of one
million structures have been established experimentally, many, many more
have not been. Second, the vast majority of experimental structures follow
from X-ray crystallography on solid samples and may differ significantly
from those of isolated molecules to which the calculations pertain. An
additional problem with X-ray structures is that bonds to hydrogen are too
short (by as much as 0.1 - 0.2Å). Finally, experimental data for reactive orotherwise short-lived molecules are scarce, and data for transition states arecompletely lacking. In the final analysis, there is no alternative to obtaining
geometries from calculation. Fortunately, this is not difficult, although it
may be demanding in terms of computer time.
Determination of geometry (geometry optimization) is an iterative process.
The energy and energy gradient (first derivative of the energy with respect toall geometrical coordinates) are calculated for the initial geometry, and thisinformation is then used to project a new geometry. This process continues
until three criteria are satisfied. First, the gradient must closely approachzero. This ensures that the optimization is terminating in a flat region of thepotential surface (either the bottom of an energy well in the case of equilibriumgeometry or the top of an energy hill in the case of transition-state geometry).
Second, successive iterations must not change any geometrical parameter bymore than specified (small) value. Third, successive iterations must notchange the total energy by more than a specified (small) value.
Equilibrium Geometries
In order for a geometry to correspond to an energy minimum, the curvatureof the energy surface must be positive, that is, the structure must lie at thebottom of an energy well. The surface’s curvature is defined by the Hessian(the matrix of second derivatives of the energy

Appendix A

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with respect to geometrical coordinates).
What is actually done is to transform from the original coordinates to a
new set of geometrical coordinates (normal coordinates) for which theHessian will be diagonal, that is, all off-diagonal elements will be zero.
In this representation, all (diagonal) elements must be positive for thegeometry to correspond to an energy minimum. Normal coordinate
analysis, as it is termed, is required for the calculation of vibrationalfrequencies, which relate directly to the square root of the elements ofthe (diagonal) Hessian. Positive Hessian elements yield real frequencies;
negative Hessian elements yield imaginary frequencies.

Geometry optimization does not guarantee that the final structure has alower energy than any other structure of the same molecular formula. All
that it guarantees is a local minimum, that is, a geometry with a lower energy
than that of any similar geometry, although not necessarily the lowest
energy geometry possible for the molecule. The number and types ofchemical bonds are maintained in the optimization process as are single bondand flexible-ring conformers. Altering bond types would lead to isomers(stable molecules of the same molecular formula) which under normal
conditions could not be reached, whereas altering conformation would leadto different “shapes” of the same molecule, which would be in equilibrium
under the same conditions. Finding the best conformer or global minimum
requires repeated optimization starting with different initial geometries
corresponding to different initial conformers. Only when all local minima
have been located is it possible to say with certainty that the lowest energy
geometry has been identified. This process is termed conformational
analysis.
In principle, geometry optimization carried out in the absence of symmetry,that is, with C1 symmetry, must result in a local minimum. On the other hand,
imposition of symmetry may result in a geometry that is not a local
minimum. For example, optimization of ammonia constrained to a planar
trigonal geometry (D3h symmetry) will result in a structure that corresponds
to an energy maximum in the direction of motion toward a puckered trigonal
geometry (C3v symmetry). This is the transition state for inversion at
nitrogen in ammonia.

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556

The most conservative tactic is always to optimize geometry in the absenceof symmetry. If this is not done, it is always possible to verify that the structure
located indeed corresponds to a local minimum by calculating thevibrational frequencies on the final (optimized) structure. If one or more
frequencies are imaginary, then the geometry does not correspond to anenergy minimum.
Transition-State Geometries
Chemists recognize a transition state as the structure that lies at the top of apotential energy surface connecting reactant and product (see the topic
Potential Energy Surfaces).
transition state

Energyreactant

product
reaction coordinate

More precisely, a transition state is a point on the potential energy surface
for which the gradient is zero (just as it is for an equilibrium geometry), but
for which the diagonal representation of the Hessian has one and only one
negative element, corresponding to the reaction coordinate (see diagram
above). All the other elements are positive. In other words, a transition state isa structure that is an energy minimum in all dimensions except one, for which
it is an energy maximum. Mathematically, such a structure is referred to as
a first-order saddle point.
The geometries of transition states on the pathway between reactants andproducts are not as easily anticipated as the equilibrium geometries of thereactants and products themselves. This is not to say that transition-stategeometries do not exhibit the same systematic behavior as equilibriumgeometries, but rather that there is not sufficient experience to identify what
systematics do exist, and more

Appendix A

557

importantly how to capitalize on structural similarities. It needs to berecognized that transition states cannot even be detected let alone
characterized experimentally, at least not directly. While measured
activation energies relate to the energies of transition states above reactants,
and while activation entropies and activation volumes as well as kinetic
isotope effects may be interpreted in terms of transition- state structure, no
experiment can actually provide direct information about the detailed
geometries and/or other physical properties of transition states. Quite simply,
transition states do not exist in terms of a stable population of molecules on
which experimental measurements may be made. Experimental activation
parameters may act as a guide, although here too it needs to be pointed outthat their interpretation is in terms of transition state theory. This assumes
that all molecules proceed over a single transition state (the high point along
the reaction coordinate) on their way to products. Even then, experiments telllittle about what actually transpires in going from reactants to products.
Lack of experience about “what transition states look like” is one reason
why their detailed geometries are more difficult to obtain than equilibriumgeometries. Other reasons include:i)Algorithms for locating transition states are less well developed thanprocedures for finding equilibrium structures. After all, minimization is an
important task in many diverse fields of science and technology, whereas
saddle point location has few if any important applications outside ofchemistry.
ii) It is likely that the potential energy surface in the vicinity of a transition
state is more “flat” than the surface in the vicinity of a local minimum. Afterall, transition states represent a delicate balance of bond breaking and bondmaking, whereas overall bonding is maximized in equilibrium structures. As aconsequence, the potential energy surface in the vicinity of a transition stateis likely to be less well described in terms of a simple quadratic function(assumed in all common optimization procedures) than the surface in thevicinity of a local minimum.
iii) To the extent that transition states incorporate partially (orcompletely) broken bonds, it might be anticipated that very

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simple theoretical models lacking adequate treatment of electron correlation
will not be able to provide entirely satisfactory descriptions.
In time, all of these problems will be overcome, and finding transition states
will be as routine as finding equilibrium geometries is today. Chemists canlook forward to the day when reliable tools become available for the
elucidation of reaction mechanisms.
While the same iterative procedure previously described for optimizationof equilibrium geometry applies as well to transition states, the number ofsteps required for satisfactory completion is likely to be somewhat larger.
This is due to the factors discussed earlier. Note, however, that the task oftransition state determination may be completely automated and needs nomore human intervention than that involved in locating equilibriumgeometries.
Having found a transition-state geometry, two tests need to be performed inorder to verify that it actually corresponds to a proper transition state, andfurther that it actually corresponds to the transition state for the process ofinterest, that is, it smoothly connects energy minima corresponding toreactant and product:i)Verify that the Hessian (matrix of second energy derivatives) yields one
and only one imaginary frequency. This requires that a normal mode
analysis be carried out on the proposed transition-state geometry. The
imaginary frequency will typically be in the range of 400-2000 cm-1,
quite similar to real vibrational frequencies. In the case of flexible
rotors, for example, methyl groups or floppy rings, the analysis may yield
one or more additional imaginary frequencies with very small (<100 cm1) values. These can be difficult to “get rid of” simply because energychanges are likely to be very small and inside the precision settings ofthe optimization procedure. Small imaginary frequencies can almost
always be ignored, but make certain to verify what motions these small
imaginary frequencies actually correspond to (see discussion following)
before doing so. Most important, be wary of structures that yield only
very small imaginary frequencies. This suggests a very low energy

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transition state, which quite likely will not correspond to the particular
reaction of interest.
ii) Verify that the normal coordinate corresponding to the imaginary
frequency smoothly connects reactants and products. A simple way to
do this which requires no additional calculations, is to animate thenormal coordinate corresponding to the imaginary frequency, that is, towalk along this coordinate without any additional optimization. This
does not necessarily require any additional calculations beyond thenormal mode analysis already performed. “Incorrect” transition states
located by calculation, that is, transition states that do not link the reactant
to the expected product, may indicate new chemistry, so don’t discardthem too quickly! There are more costly procedures that actually involve“walking” the geometry down from the transition state to both reactants
and products. In our view these are rarely worth the effort.
Reactions Without Transition States
Not all chemical reactions have transition states, and that the rates of somereactions depend only on the speed with which reactants diffuse into one
another (so-called, diffusion controlled reactions). In fact, reactions without
energy barriers are quite common. Two radicals will typically (but notalways*) combine without activation, for example, two methyl radicals toform ethane.
H3C• + •CH3

H3C

CH3

Radicals will often add to paired-electron species with no (or very small)
activation, for example, methyl radical and ethylene forming 1-propyl
radical.
H3C• + H2C

CH2

H3C–CH2–CH2•

Exothermic ion-molecule reactions that have activation energies in solution,
do not necessarily have activation energies in the gas phase. Any complex of
an ion and a neutral molecule is likely to be lower in energy than the separated
species and the entire reaction coordinate for*

Exceptions may occur where both radicals are delocalized, for example, combing two benzyl
radicals.

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an ion-molecule reaction might lie below the energy of the separated
reactants for example, nucleophilic attack by OH– on CH3Cl to give CH3OH
and Cl–.
Failure to find a transition state, and location instead of what appears to be astable intermediate or even the final product, does not necessarily mean failureof the theoretical model (nor does it rule this out). It may simply mean that
there is no transition state!
Calculations Using Approximate Geometries
Given that small-basis set Hartree-Fock models, semi-empirical models andeven molecular mechanics models generally provide geometries for organic
molecules that are quite close to those obtained from Hartree-Fock, density
functional and MP2 models, it is legitimate to ask whether or not structuresfrom these techniques may be used as the basis for energy and property
calculations.* It would be of great help were this the case as geometry
optimization is a major cost in any modeling investigation.
“Exact” geometries must be used for frequency (infrared and Raman spectra)
calculations. The reason for this is that frequencies are related to the first finite
term in a Taylor series expansion of the energy (as a function of geometry).
This is (assumed to be) the second-derivative term, which will not be true if
the first-derivative term (the gradient) is not precisely zero. (Cubic andhigher order terms are assumed to be small and are ignored.) Frequencies
evaluated at non-equilibrium (or non-transition-state) geometries aremeaningless.

* Molecular mechanics models are not applicable to transition states as they have been parameterized toaccount for the structures of stable molecules. This is not to say that molecular mechanics
parameterizations could not be developed for transition states, simply that they have not been.

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TOTAL ENERGIES AND THERMODYNAMIC AND KINETICDATA
In addition to molecular geometry, energy is certainly the most important
quantity to come out of molecular modeling. Energy can be used to reveal
which of several isomers is most stable, to determine whether a particularchemical reaction will have a thermodynamic driving force (an exothermic
reaction) or be thermodynamically uphill (an endothermic reaction), and toascertain how fast a reaction is likely to proceed. Other molecular properties,
such as dipole moment, and infrared, Raman, UV/visible and mostimportantly NMR spectra are also of great interest, but energy plays aspecial role.
There is more than one way to express the energy of a molecule. Most
common to chemists is the heat of formation, ∆H f. This is the heat of ahypothetical chemical reaction that creates a molecule from well defined(but arbitrary) standard states of each of its constituent elements. Note thatthe heat of formation, which most commonly assumes a value between 1,000 and +500 kJ/mol, cannot be directly measured, but must be obtained
indirectly.
An alternative, total energy, is the heat of a hypothetical reaction that createsa molecule from a collection of separated nuclei and electrons. Like the heatof formation, total energy cannot be measured directly, and is used solely toprovide a standard method for expressing and comparing energies. Totalenergies are always negative numbers and are much larger than the sum of thebond energies By convention, they are expressed in so-called atomic units* orau, but may be converted to other units as desired:
1 au = 2625 kJ/mol

It makes no difference which reference reaction (heat of formation or totalenergy) is used to calculate the thermochemistry of a balanced chemical
reaction (reactant 1 + reactant 2 + . . . → product 1 + product 2 + . . .):E(reaction) = Eproduct 1 + Eproduct 2 + … – Ereactant 1 - Ereactant 2 – …

* The exact energy of hydrogen atom is -0.5 atomic units.

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562

Total energies will be used in the discussion that follows. A negative∆E indicates an exothermic (thermodynamically favorable) reaction, while apositive ∆E an endothermic (thermodynamically unfavorable) reaction.
A special case involves energy differences among isomers. Eachcomparison may be viewed as a chemical reaction involving only twomolecules:
E(isomer) = Eisomer 2 – Eisomer 1

A negative ∆E means that isomer 2 is more stable than isomer 1. Totalenergies may also be used to calculate activation energies,∆E‡:
E‡ = Etransition state – Ereactant 1 – Ereactant 2 – …

Here, Etransition state is the total energy of the transition state, and Ereactant1, Ereactant2,... are the total energies of the reactants. Activation energies are expected to
be positive numbers*, meaning that the transition state is less stable thatreactants.
Reaction and activation energies are sufficient to know whether a reaction
is exothermic or endothermic and whether it proceeds with small or large
activation barrier. There are, however, situations where energies need to be
replaced by Gibbs energies in order to take proper account contributions due
to entropy.** For example, a proper account of the equilibrium concentrationsof reactants and products requires calculation of the equilibrium constant,Keq, which according to the Boltzmann equation, is related to the Gibbs
energy of reaction, ∆Grxn:
Keq = exp(– Grxn/RT)

Here R is the gas constant and T is the temperature (in K). At room
temperature (298K) and for ∆Grxn in au, this is given by:*

Referred to separated reactants, "negative activation energies" are possible. This is due to the formationof a complex, the total energy of which is lower than the sum of the total energies of the reactants. Also
note that some reactions proceed with zero activation energy, meaning that there is no transition state.
** Entropy contributions will be largest where the numbers of reactants and products differ. On the other hand,entropy might be expected to largely cancel where reactants and products are very similar.

Keq = exp(–1060 Grxn)∆Grxn has two components, the enthalpy of reaction, ∆Hrxn, and theentropy of reaction, ∆Srxn. These are defined as follows:
Appendix A

563

Although ∆Grxn depends on both enthalpy and entropy, it is often assumed
that the entropy contribution will be small, and can be neglected. Further
assuming that ∆Hrxn ≈ ∆Erxn, equilibrium constants can then be estimatedaccording to the “Boltzmann” equation:

Appendix A564

krxn = 6.2x1012 exp(-1060 E‡)

Another way to describe reaction rates is by half-life, t1/2, the amount of time
it takes for the reactant concentration to drop to one half of its original value.
When the reaction follows a first-order rate law, rate = -krxn[reactant], t1/2 isgiven by:t1/2 = ln2/krxn = 0.69/krxn

It is useful to associate reaction energies and reaction rates with potential
energy diagrams introduced earlier. The thermodynamics of reaction is givenby the relative energies of the reactant and product on the potential surface.

For situations such as bond rotation in ethane and ring inversion in
cyclohexane, the reactant and product are the same and the reaction is said
to be thermoneutral. The most common case, as depicted in the above
diagram, is where the energy of the products is lower than that of thereactants. The reaction is said to be exothermic, and the difference instabilities of reactant and product is simply the difference in their energies. For
example, the “reaction” of gauche n-butane to anti n-butane is exothermic,
and the difference in stabilities of the two conformers is simply the differencein the energies (~3.8 kJ/mol).
Chemical reactions can also be endothermic, which give rise to areaction profile.

Appendix A

565

transition stateenergyproduct

reactant
reaction coordinate

Where two or more different products may form in a reaction,
thermodynamics tells us that if we wait long enough, the product formed ingreatest abundance will be that with the lowest energy irrespective of
pathway.

energythermodynamic productreaction coordinate

In this case, the product is referred to as the thermodynamic productand the reaction is said to be thermodynamically controlled.
The energy of the transition state above the reactants (the activation energy)
provides the connection with reaction rate (kinetics). Of course, such aninterpretation is based on the notion that all reactions actually pass through asingle transition state.

Appendix A

566

transition state"kinetics"
energyreactant

product
reaction coordinate

Aside from the obvious dependence on the concentration of reactants, absolute
reaction rates also depend on the percentage that encounters between
molecules will actually lead to reaction (the so-called pre- exponential or A
factor). The hope is that pre-exponential factors for closely-related reactions
will be very similar and therefore can be ignored. Thus, it is not at allevident that activation energies for disparate reactions will parallelmeasured reaction rates.
The product formed in greatest amount in a kinetically controlled reaction(the kinetic product) is that proceeding via the lowest energy transition state,irrespective of whether or not this is lowest energy product (thethermodynamic product).

energykinetic productreaction coordinate

Kinetic product ratios show dependence with activation energy differences
which are identical to thermodynamic product ratios with difference inreactant and product energies.

Appendix A

567

THERMOCHEMICAL RECIPES AND CALCULATING
ACCURATE HEATS OF FORMATION
The “energy” of a molecule is most commonly reported as a heat offormation. As noted in the previous topic, this is defined as the enthalpy at298.15K of a hypothetical chemical reaction in which the molecule istransformed into a set of products that correspond to the most stable forms of
its constituent pure elements at room temperature. For example, the heat offormation of ethylene corresponds to the enthalpy of a reaction to yieldgraphite and molecular hydrogen.
C2H4 → 2C (graphite) + 2H2

Differences in heats of formation between the products and reactants(reaction enthalpies) indicate the extent to which the reaction will befavorable (exothermic) or unfavorable (endothermic), and allow
thermodynamic product distributions to be established.*
In almost all cases, the heat of formation is obtained from a heat of
combustion. For example, the heat of formation of ethylene would likely
have been established from its reaction with oxygen to produce carbon
dioxide and water.
C2H4 + 3O2 → 2CO2 + 2H2O

Experimental heats of formation are available for ~2000 compounds. While
much of the data is accurate to within 4-8 kJ/mol, a significant portion is
subject to greater uncertainty. The most egregious source of error is that thereported heat actually does not correspond to the reported structure. Morecommon sources of error include impure samples, incomplete combustion
and most importantly, poorly characterized combustion products.
Hydrocarbons and oxycarbons present fewest problems as combustion
leads only to carbon dioxide and water. However, combustion of moleculeswith other elements may give rise to a complex mixture of products andgreater uncertainty, with nitrogen compounds being particularly problematic.
*

Of course, other references are equally suitable for examining mass balanced reactions. For example, totalenergies from quantum chemical calculations are referenced to separated nuclei and electrons, in the caseof ethylene.
C2H4 → 2C6+ + 4H+ + 16C–

Appendix A

568

Despite their fundamental importance, heats of formation are not routinely
determined for new compounds. While the combustion experiment isstraightforward and does not require particularly expensive
instrumentation, accurate measurements may require (and will likely
destroy) significant quantities of compound. Very few chemists are willingto part with hundreds of mg of a compound that they have just spent days,
weeks or months preparing.
Because of the lack of experimental data and serious concerns over theaccuracy of part of the data that do exist, considerable attention has been
directed at the use of quantum chemical calculations to obtain heats offormation. One avenue that has been pursued relies on the knowledge that
CCSD (T) calculations (coupled cluster singles and doubles with triples
corrections introduced perturbatively) reliably reproduce the energetics ofa wide variety of organic reactions. The problem is that the singles anddoubles contribution scale as O(6), where  is the number of basis functions,and the triples correction scales as O(7). This limits practical applications of
the method to very small molecules (<15 non-hydrogen atoms).
A simplified account of the “solution” first proposed by John Pople is depictedin the next page. The essential idea is that the energy obtained using a “good”
electron correlation method and a large basis set may be closely
approximated by combining the energy calculated using the goodcorrelation method with a small basis set with difference in calculated
energies for a “simple” correlation method with small and large basis sets. In
principle, only three calculations are required: small and large basis set
calculations with the simple correlation method and a small basis set
calculation with the good correlation method. In practice, some of theschemes that have been formulated do exactly this while others employ a
combination of simple correlation methods.

Appendix A

569

The original Pople implementation and subsequent developments primarily
by Larry Curtiss are now collectively known as Gx methods. G1 relied on
MP4 as the “good” correlation method with a gradual shift to the morecostly and more accurate CCSD(T) method. To some extent, the overall
objective has also broadened, from a means to approximate correlationenergy to a stand-alone source of thermochemical data (298° heats offormation). Our focus is on the former, as possible low-cost replacements of
the CCSD(T) correlation method.
The two most widely-used methods are G3(MP2) and G3, and the two mostrecent additions to the series are G4(MP2) and G4. A summary of theprocedures involved in calculating electronic energy using these four
methods is provided on the next page. The full recipes lead to heat offormation in addition to electronic energy, and require specifying anequilibrium geometry and a procedure for obtaining vibrational frequencies
in addition to “empirical” corrections to account for the standard states ofeach of the elements. While each the four procedures involves several steps,
these can be carried out in proper sequence without user intervention.
simple correlation method

good correlation method

limiting steps

G3(MP2)MP2QCISD(T)/6-31G*

T in QCISD(T)G3

MP2 & MP4QCISD(T)/6-31G*

MP4 and T in QCISD(T)

G4(MP2)MP2

CCSD(T)/6-31G*

T in CCSD(T)G4

MP2 & MP4

CCSD(T)/6-31G*

MP4 and T in CCSD(T)

Appendix A

570

The T1 Thermochemical Recipe
The simplest of the GX recipes, termed G3(MP2), involves several costly
steps, most significantly an MP2/6-31G* geometry calculation, a HF/6-31G*
frequency calculation and a QCISD(T)/6-31G* energy calculation. In
practice, G3(MP2) scales as the 7th power of size and is applicable only tomolecules with molecular weights less than 150 amu. Clearly, even simpler
procedures are required for routine application to larger molecules.
The goal behind the T1 recipe was to maintain the accuracy of G3(MP2)
but at significantly reduced computation cost. It is limited to uncharged,
closed-shell molecules comprising H, C, N, O, F, Si, P, S, Cl and Br. T1
substitutes the MP2/6-31G* geometry used in G3(MP2) by a HF/6-31G*
geometry, eliminates both the HF/6-31G* frequency and the QCISD(T)/631G* energy calculations and approximates the MP2 energy calculation
with the G3MP2 large basis set by an analogous calculation using a dual
basis set RI-MP2 model. Taken together, these changes reduce computation
time by 2-3 orders of magnitude, and T1 calculations on molecules in themolecular weight range of 400-500 amu are practical.
The T1 recipe, unlike G3(MP2), involves parameters, specifically atom
counts, Mulliken bond orders and HF/6-31G* and RI-MP2 energies. These
have been determined using linear regression as a best fit to G3(MP2) (notexperimental) heats of formation for >1100 small molecules. It reproduces
these values with mean absolute and RMS errors of 1.8 and 2.5 kJ/mol,
respectively. More important, the T1 recipe reproduces experimental heatsof formation for a set of>1800 diverse organic molecules from the NIST thermochemical databasewith mean absolute and RMS errors of 8.5 and 11.5 kJ/ mol, respectively.
The plot provided below covers the data from-1000 to +500 kJ/mol.

Appendix A

571

Heats of formation from the T1 recipe are included as a property in the
Spartan Spectra and Properties Database (SSPD), a database that presently
comprises more than 315,000 entries.

Appendix A

572

Dealing with Conformationally flexible
MOLECULES
Very few molecules are rigid and adequately described in terms of a single
conformer. More commonly, two or more distinct conformers resulting fromrotation around single bonds or changes in flexible rings are likely to exist.
For example and as previously discussed in the topic Potential Energy
Surfaces, three conformers result from rotation around the central carboncarbon bond in n-butane, one anti conformer (CCCC dihedral angle = 180o)and two (equivalent) gauche conformers (CCCC dihedral angle = ± ~60o).
Two chair conformers result from ring inversion in methylcyclohexane, onewith the methyl group equatorial and the other with it axial. Because energy
barriers to single-bond rotation and to ring inversion are generally verysmall (on the order of <10-20 kJ/mol), the different conformers will be in
equilibrium and the influence of any particular conformer on the propertiesof the molecule will depend on its energy and on the temperature. As aconsequence, experimental measurements will either reveal the presence of
the individual conformers or result from a weighted average of conformers.
For example, the IR spectrum of a flexible molecule will show features due
to individual conformers, whereas the NMR spectrum of the same molecule
will show an average. The different behavior may be traced to the different
timescales of the two experiments; IR is fast whereas NMR is slow.
Identifying the lowest-energy conformer of a molecule with multiple degrees
of conformational freedom presents a serious challenge for calculation.
Even more so is providing accurate Boltzmann weights allowing proper
description of average energies, properties and perhaps most important,
NMR spectra. Until recently, molecular mechanics provided the only
practical alternative for molecules with hundreds or even thousands ofaccessible conformers. Expectations were high for molecular mechanics
force fields such as MMFF which were after all developed and parameterized
to account for conformer energetics, albeit for very small molecules with asingle degree of conformational freedom for which experimental data wasavailable.** While much is known about the preferred conformation of molecules with multiple degrees

Appendix A

573

However, recent comparisons with conformer energies obtained from highlevel quantum chemical calculations for (very few) molecules with multiple
degrees of freedom show that MMFF actually provides a poor account.
Furthermore, it has been shown that neither semi- empirical nor HartreeFock models provides a suitable account and that either density functionalor MP2 models with moderate to large basis sets are required.
Direct application of correlated models is not presently practical or at leastroutine for molecules where hundreds or more conformers need to be
examined. What is practical are multi-step procedures starting from anextensive molecular mechanics search and ending with an appropriate modelfor energy calculation. The idea is that intermediate steps with successively
better models will gradually reduce the number of conformers that need to beconsidered (passed on to the next step). Several present recipes (available
from menus) are supported in Spartan. The simplest (least costly and likely
least reliable) use either B3LYP/6-31G* or ωB97X-D in the final step andMMFF equilibrium geometries. Improvement (and increased computationcost) follows by using B3LYP/6-31G* or ωB97X-D geometries. The mostreliable (and most costly) models use B97M-V/6-311+G(2df,2p)[6-311G*] orωB97X-V/6-311+G(2df,2p)[6-311G*] for final energy (Boltzmann weight)
calculations together with B3LYP/6-31G* or ωB97X-D/6-31G*
geometries, respectively. Whatever the recipe employed, the resulting
Boltzmann weights are available to determine average quantities.

of conformational freedom in the solid (crystalline) state, almost exclusively from X-ray diffraction, there
is very little known about preferred conformation of isolated molecules. Furthermore, there is very little
overlap between gas and solid-phase structures because small molecules tend not to crystallize and larger
molecules that do crystallize are not easily investigated by gas-phase techniques such as microwave
spectroscopy. This means that it is difficult to separate inherent (gas-phase) conformational preferencesfrom those associated with the requirements of crystal packing.

Appendix A

574

One of the menu-selected multi-step protocols is outlined below.

Step 1: Conformer Search Using the MMFF Molecular Mechanics Model
The first and least costly step in the protocol involves a systematic conformational
search using the MMFF molecular mechanics model, keeping all distinct conformers withenergies less than 40 kJ/mol than that of the lowest-energy conformer found. The energy
threshold is needed to control the number of conformers passed on to the next step,
recognizing that a molecule with 8 degrees of conformational freedom may give rise to
several thousand distinct conformers and one with 10 degrees of freedom to several tensof thousands of conformers. In addition, a limit on the total number of conformers needs
to be imposed. If exceeded, a subset of the most “geometrically diverse” set is kept. This
number is typically in the range of 200-1000 conformers.
Step 2: Calculate Conformer Geometries Using the HF/3-21G Model
Obtain the equilibrium geometry for each of the conformers using the Hartree-Fockmethod with the 3-21G basis set (HF/3-21G or simply 3-21G). Eliminate any
conformers that are outside a 40 kJ/mol threshold as well as duplicate conformers. This
step is necessary because MMFF commonly results in structures that are not energy
minima, and further optimization using the HF/3-21G model allows these to be removed.
Note, however, that this model is not able to reliably identify the “best” conformer let
alone provide accurate Boltzmann weights, which is why

Appendix A

575

the 40 kJ/mol energy threshold needs to be maintained.
Step 3: Calculate Conformer energies Using the ωB97X-D/6-31G*
Model
Use the ωB97X-D/6-31G* model to calculate energies for each of the conformers,
keeping only those that are within 15 kJ/mol of the lowest energy conformer. The much
lower energy threshold reflects experience that, even with a small basis set, the ωB97X-D
model provides conformer energy differences that are much more reliable than those fromother MMFF or HF/3-21G models.
Step 4: Calculate Conformer Geometries Using the ωB97X-D/6-31G*
Model
Recalculate equilibrium geometries using the ωB97X-D/6-31G* model, keeping only
conformers that are within 10 kJ/mol of the lowest energy conformer. The slight
lowering of the energy threshold anticipates that better equilibrium geometries will leadto more reliable conformer energy differences.
Step 5: Calculate Conformer energies Using the ωB97X-V/ 6311+G(2df,2p)[6-311G*] Model
The final step in the protocol is to replace ωB97X-D/6-31G* conformer energies withthose obtained from the ωB97X-V/6-311+G(2df,2p) model. In practice, the so-called dual
basis set approximation is employed, reducing the cost of this step by as much as anorder of magnitude.
In terms of computation, the last two steps in the protocol outlined above are the most
costly: calculation of equilibrium geometries with the ωB97X-D/6-31G* model andcalculation of energies with the ωB97X- V/6-311+G(2df,2p)[6-311G*] model.
A less costly (factor of two) protocol has also been examined and found to produce
comparable albeit less reliable results. This replaces ωB97X-D/ 6-31G* by B3LYP/631G* and ωB97X-V/6-6311+G(2df,2p)[6-311G**] by B97M-V/6-311+G(2df,2p)[6311G*].

Where only the identity of the lowest-energy conformer is required, Spartan
employs the so-called Monte Carlo procedure. It moves randomly in asingle (randomly chosen) dimension in conformational space deciding toabandon the move (returning to the starting point for another random move) or
keep the move (using it for the starting point for the next random move) basedon the energy relative to that of the

Appendix A

576

lowest-energy conformer yet found. In practice, a Monte-Carlo search will
nearly always find the lowest-energy conformer by considering only 5-10%of the possible number of conformers.
A Monte-Carlo search is probably not an appropriate starting point where
the objective is to establish a Boltzmann distribution. The reason is that it
rapidly finds the “best” region, at the expense of other regions, which, given
the known deficiencies of molecular mechanics, may exclude the actual
important contributors (or even the actual most important contributor). The
only alternative is a systematic search which “looks everywhere”.
However, this rapidly becomes impractical as the number of conformers
increases very rapidly with the number of rotatable single bonds and flexible
rings. The solution employed in Spartan is a so-called sparse systematic
search where systematic steps are accepted (and energies evaluated) or
rejected based solely on a random number criterion. For example, if at theoutset only 10% of the possible conformers can be examined, then only
those generating a random number between say 0 and 0.1 (out of a possible
range of 0 to 1, will be accepted.

Appendix A

577

INTERPRETING CONFORMATIONAL PREFERENCES
Rotation about single bonds is periodic, retracing itself every 360°, and any
function that seeks to describe the energy of internal rotation must also repeat
itself every 360°. In practice, the energy function, Etorsion, is written as a
combination of simpler functions, Vn, in the torsion angle , each ofwhich repeats n times in a 360° interval.
Etorsion () = V1 () + V2 () + V3 ()...

The first three terms, V1, V2, and V3 repeat every 360°, 180°, and 120°,
respectively, and are referred to as one-fold, two-fold, and three-foldpotentials.*
Separation into distinct n-fold potentials is a useful concept because eachcan be associated with a particular chemical phenomenon. For example, aone-fold potential describes the different energies of anti (COOC=180°) andsyn (COOC=0°) conformers of dimethylperoxide, while a two-fold potential
describes the different energies of planar and perpendicular conformers ofbenzyl cation. Three-fold potentials, which are more familiar to chemists,
describe the difference between staggered and eclipsed conformers inmolecules like ethane.

While rotation in some molecules might be adequately described using only
one of the components or a combination of two components, othermolecules require more complex combination. This is illustrated byfluoromethylamine.

*

The torsional potential in most organic molecules will be adequately described in terms of one, two andthree-fold components, and only rarely will higher-order terms be needed.
Appendix A

578

The heavy solid line describes Etorsion for rotation about the CN bond, while
the light solid line, the dashed line and the dotted line correspond to the onefold, two-fold and three-fold components, respectively. There are two
distinct minima.

Appendix A

579

The three-fold term reflects the preference for staggered over eclipsed
structures, and contributes less to the variation in E torsion than either of theone-fold or two-fold terms.
What is most interesting, and perhaps not have been easily anticipated without
this type of analysis, is the large contribution made by the two-foldpotential, which reflects a strong preference for a planar arrangement of
FCN:. This can be attributed to stabilization resulting from donation of thelone pair orbital on nitrogen into low-energy unfilled molecular orbital
associated with the CF bond, requiring that the molecule adopts either a synplanar or anti planar conformation and not a perpendicular conformation.

CN

syn planarCN

antiplanarCN

perpendicular

Note that the terms that contribute to Etorsion are completely independent of eachother, and each may be treated as one part of a larger picture. Thus, theobservation that electron donation from the nitrogen lone pair into theempty orbital associated with the CF bond is optimal when the two groups
are planar is independent of the observation that cis coplanar structure isdestabilized, relative to the anti structure, by dipole-dipole interactions.

Appendix A

580

CALCULATING INFRARED SPECTRA
The infrared spectrum of a molecule arises because of transitions between
vibrational energy levels. Each line in an infrared spectrum is characterized
by a frequency (energy) and an intensity. In one dimension (a diatomic
molecule), it is common practice to assume that the frequency is
proportional to the square root of the ratio of the second-derivative of theenergy with respect to the internuclear distance, r, and the reduced mass(the product of the masses of the two atoms divided by their sum).
vibrational frequency  √ [(d2E(r)/dr2/)reduced mass]This is referred to as the harmonic approximation, the origin of which
can be seen by expanding the energy in a Taylor series.
E(r) = E(r0) + (dE(r)/dr) r + (d2E(r)/dr2) r2 + higher-order terms

E(r0) is a constant and dE(r)/dr (the gradient) is assumed to be zero. The
latter implies that the underlying structure corresponds precisely to aminimum (or a maximum) on the potential energy curve. Were this not thecase, the first derivative would be non-zero and the calculated frequency
would be meaningless. Nearly all practical calculations ignore cubic andhigher-order terms (anharmonic terms), leaving only the second derivative
term (the force constant). This said, the frequency may be interpreted as therelative ease or difficulty of stretching the bond away from its equilibrium
position, that is, the curvature of the energy surface at the minimum. Where
distortion away from the equilibrium position is easy, the result is a low
frequency; where it is difficult the result is a high frequency. High (reduced)
mass leads to a low frequency while low mass leads to high frequency.
The expression for vibrational frequency qualitatively accounts for masseffects on reaction energies (equilibrium isotope effects). Even at 0K
molecules vibrate, giving rise to the so-called zero-point vibrationalenergy (or simply zero-point energy). Zero-point energy is directly
proportional to the sum of the vibrational frequencies and decreases withincreasing mass. For example, the zero-point energy of HCl is lowered
upon replacement of hydrogen by deuterium. Thus, the measured energy

Appendix A

581

(enthalpy) decreases with increasing mass and the energy of DCl is smaller(more negative) than that for HCl.

Because the potential energy has been approximated by a quadratic
function, calculated frequencies will almost always be larger than measured
frequencies. This is because a quadratic function goes to infinity withincrease in distance rather than going asymptotically to a constant (separated
atoms), meaning that the potential curve will be too steep.

It is possible to extract the harmonic frequency from an experimental
spectrum by measuring the spacing of the energy levels associated with theground and excited states of a particular vibration. (The lines would beevenly spaced were the potential quadratic.) However, such an analysis is
impractical for any but diatomic and very simple polyatomic molecules.

Generalization from a diatomic to a polyatomic molecule is straightforward.
The energy of displacement away from the equilibrium position is expandedin the same way as before, the only difference being that a vector quantity, x,
replaces a scalar quantity, x.
E(x) = E(x0) + Σi(∂E(x)/∂xi)xi + ½Σij(∂2E(x)/∂xi∂xj)xixj + higher-order terms

As with the expression for a diatomic molecule, the leading term is aconstant, the first derivative term is zero and cubic and higher-order terms
are ignored. For a molecule with N atoms, the dimension of x is 3N (x,y,z
Cartesian coordinates for each atom), although there are only 3N-6

Appendix A

582

(3N-5 for a linear molecule) vibrational frequencies. Six dimensions (fivefor a linear molecule) correspond to translation away from and rotation
around the center of mass.
The first (and only computationally expensive) step involved in calculating
the vibrational spectrum of a polyatomic molecule is evaluation of the fullset of second energy derivatives in Cartesian coordinates. These then need
to be mass weighted. Diagonal terms (∂2E(x)/∂xi2) are divided by the massof the atom associated with xi, and off-diagonal terms (∂2E(x)/∂xi∂xj) are
divided by the product of the square root of the masses of the atoms
associated with xi and xj. These expressions reduce to that already provided
for the one- dimensional case.
The second step involves replacing the Cartesian coordinates by a new
set of coordinates ζ, such that the matrix of mass-weighted second
derivatives is diagonal. δij is the so-called Kronecker delta function whichis 1 if i=j and 0 otherwise.
[∂2E(ζ)/∂ ζi∂ ζj]/(√Mi√Mj) = δij [∂2E(ζ)/∂ ζi2]/Mi

These new coordinates are referred to as normal coordinates. While thenormal coordinates for some vibrations may be described in terms ofstretching of one bond or bending of one angle, more commonly they will
be made up of mixtures of several bond stretches, angle bends and othermotions.
The third step involves removing the six coordinates corresponding to thethree translations and three rotations, leaving 3N-6 vibrational coordinates.
The intensity of a line in the infrared spectrum is proportional to the change
in the dipole moment along the vibrational coordinate. It follows that where
there is no change in dipole moment, for example, in a homonuclear diatomic
molecule, the infrared intensity is zero.
The two major components of the earth’s atmosphere, N2 and O2, arehomonuclear diatomics and do not absorb in the infrared, that is, theintensity is zero. However, two of the four vibrational motions of CO2,
the third most common but very minor molecular component in the

Appendix A

583

atmosphere, have non-zero infrared intensities. As a result, carbon
dioxide absorbs radiation reflected from the earth’s surface thereby
trapping heat and leading to an increase in temperature (the so-calledgreenhouse effect).

Lack of a line in the infrared spectrum does not mean that the molecule does
not vibrate or that the vibrational energy for this line does not contribute to
the zero-point energy. Rather, it means that absorption of radiation does notoccur leading to a change in vibrational energy state. It should also be notedthat a particular line that is infrared inactive might be visible in the Raman
spectrum (an alternative form of vibrational spectroscopy based onreflectance rather than absorption). Here the intensity is related to the change
in the polarizability rather than the change in dipole moment.
The application of quantum chemical models to infrared spectroscopy requires
calculation of the second energy derivatives and first dipole momentderivatives with regard to changes in geometrical coordinate. The former
completely dominates and scales as the fifth power of the size (number ofbasis functions). Infrared spectra may be calculated using semi-empiricalmolecular orbital models, for example, the PM3 models available in
Spartan, Hartree-Fock molecular orbital models, density functional models
and MP2 models. Of the theoretical models available in Spartan, semiempirical models provide a poor account, Hartree-Fock models provide a
reasonable account but density functional and MP2 models withpolarization or larger basis sets perform best. Density functional models are
the obvious choice for infrared spectra calculations, offering better results
than Hartree- Fock models at comparable cost, and comparable results atmuch lower cost than MP2 models.
For two reasons, we recommend EDF2/6-31G* over the B97X-D/ 6-31G*
model for infrared spectra calculations. First, EDF2/ 6-31G* wasspecifically formulated to reproduce measured infrared frequencies. Second,
it is significantly (factor of two) less costly than
B97X-D for frequency calculation and is easily applicable to thecalculation of infrared spectra of organic molecules of moderate size (up to
400-500 amu). There are two major deficiencies with infrared

Appendix A584

spectra obtained directly from the EDF2/6-31G* model. The first is that
calculated frequencies are almost always too large, typically by 3-5%. Thiscan be directly traced to the harmonic approximation and to a potential
energy curve that is too steep.
Other density functional models and the MP2 model show similar
behavior. Vibrational frequencies obtained from Hartree-Fock models
show an even larger systematic error in the same direction (frequencies
too large), typically by 12-14%. Here two factors contribute. The first is
the insistence on a quadratic potential, the same problem associated withdensity functional and MP2 models. The second is due to the fact thatbond dissociation is improperly described by Hartree-Fock models, asevidenced by the fact that Hartree-Fock bond lengths are uniformly
shorter than experimental distances. This suggests that the potential
energy surface will be too steep and the frequency will be too large.

The second and more conspicuous deficiency is due to the fact that the lines
in an infrared spectrum measured at finite temperature are broadened due
primarily to rotational structure, whereas the lines in a calculated spectrum
correspond to an isolated molecule at 0K and are sharp. There may be other
differences, such as the absence of overtones, that is, vibrational transitions
originating from excited vibrational states and, more importantly, lack ofsolvent. Although these are more difficult to quantify.
It is straightforward to correct the calculated spectrum to account for both
deficiencies. First the spectrum may be uniformly scaled (multiplied by aparameter in the range of 0.95-0.97 for density functional models). Second,the calculated frequencies and intensities may be fit to a Lorentzian function
with peak width and half peak height being treated as a second parameter.
Quality of Calculated Infrared Spectra
An infrared spectrometer records frequencies in the range 500- 4500 cm-1.
Frequencies below this range (which may require special instrumentation tomeasure) typically correspond to torsional motions and may depend
strongly on conformation. It should be noted that the spectral region
beyond ~2800 cm-1 is dominated by

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CH stretching vibrations and may be too crowded to be of value.
Calculated infrared spectra from the EDF2/6-31G* model that have beenscaled to account for the systematic error in frequency and broadened toaccount for finite temperature are visually quite similar to the corresponding
experimental spectra (taken from the NIST database). The four examples that
follow, benzamide, (dimethylmethylidene) cyclopentadiene, 1,2-epoxy-cis4-vinylcyclohexane and camphor are typical of the ~1000 comparisons thathave been made.
benzamide(dimethylmethylidene)cyclopentadiene

1,2-epoxy-cis-4-vinylcyclohexane

camphorAppendix A

586

Even though scale and line-broadening parameters have been individually
adjusted for these four examples, the values of the parameters are quite
similar. Default parameters could have been substituted with little change.
Database of Infrared SpectraMore than 300,000 infrared spectra from the EDF2/6-31G* model areavailable in the Spartan Spectra and Properties Database. B97X-D entries
in SSPD presently do not include infrared spectra.
Raman Spectra
Spartan is also able to calculate Raman spectra. The frequencies are
identical to infrared frequencies but the intensities depend on the charge inpolarizability rather than the change in dipole moment.

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587

CALCULATING NMR SPECTRA
There are several reasons why NMR spectroscopy, in particular proton and
13
C NMR, is the most important analytical technique for characterizingorganic molecules. The experiment is straightforward and can be carried out
rapidly. It requires relatively small samples and is nondestructive. The socalled proton-decoupled 13C NMR is particularly simple, comprising a single
line (resonance) for each and every unique carbon. Despite its simplicity (orperhaps because of it), associating an 13C spectra to a particular molecular
structure can be problematic and prone to error, in particular, where
alternative structures might be very similar. 2D spectra, in particular, COSY
and HMBC spectra that combine chemical shifts and HH and CH coupling
constants are more and more commonly employed to assist in assignment.
A routine and reliable method to predict 13C chemical shifts as a functionof three-dimensional structure would clearly be of value in helping to assign
experimental NMR spectra of complex molecules, at the very least, either
providing supporting evidence or casting doubt on a proposed assignment.
One might argue that such a method already exists in the form of extensive
NMR spectral databases. An exact match to an existing spectrum provides
a definitive structure, while one or more close matches to entries in a databasesuggest what types of structures are reasonable. Of course, entirely newcompounds will never give exact matches, simply because the spectrum is
not in the database. Closely related are empirical relationships based
primarily on connectivity and obtained from fitting previously assigned(and presumed correctly assigned) spectra. While these can achieve somedegree of success, the fact that NMR chemical shifts (and of course threebond HH and CH coupling constants) are sensitive to conformation meansthat molecules that appear to be very similar may give rise to entirely
different spectra. Closely related to this is the fact that most organic
molecules are not rigid and described by a single 3D structure. Rather, they
comprise a connection of different 3D structures (conformers) and theresulting spectrum is a weighted average of energy weighted spectra of theindividual conformer.

Appendix A

588

One alternative to databases and purely empirical schemes would be to
calculate chemical shifts a priori using quantum mechanics.* In so doing,
differences in structure and conformation are directly taken into account.
The underlying methodology has been available for several decades for both
Hartree-Fock and density functional models. However, calculations have
only rarely been used to actually assist in the interpretation of spectra, andfew practicing chemists seem to be aware that quantum chemical
calculations are now possible (and practical) for real molecules, and how
well calculations perform in accounting for chemical shifts. Those who areaware, are confronted and all too often stymied, with what must seem to be
an endless list of calculation methods. We believe that the full potential ofquantum chemical calculations as assists to assigning NMR spectra will
only be realized after a small number of alternatives or standard models areelaborated and their limits and reliability clearly defined. Stated differently,
chemists need to approach quantum chemical calculations much in the same
way that they now approach a spectrometer.
Underlying Theory
Application of an external magnetic field causes the nuclear spins to aligneither parallel or antiparallel to the field. The difference in energy (ΔE)
between nuclear spin states is given by.
ΔE = ħB0

γ is the gyromagnetic ratio, a constant that depends on the magnetic momentof the nucleus, ħ is Planck’s constant/2π and B0 is the strength of themagnetic field at the nucleus. What makes nuclear magnetic resonance(NMR) spectroscopy useful to chemists is that the magnetic field felt at thenucleus is different for each chemically distinct nucleus in a molecule. Thisis because the applied magnetic field is slightly weakened by electrons
around the nucleus and the extent of this weakening depends on thedetailed chemical environment. Nuclei that are well shielded by the electron
cloud experience a lesser field than those that are poorly shielded and, as* Neural nets offer another alternative, the downside being that their construction requires very large datasets.
We are in the process of exploring this replacing experimental chemical shifts as reference data by values
calculated from quantum chemical models.

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a result, show a smaller energy splitting. The splitting, relative to a standard,is termed a chemical shift.
Two additional comments need to be made. First, not all nuclei possess nonzero magnetic moments and, therefore, give rise to an NMR signal. The
magnetic moment for the proton is non-zero, although that of the dominantisotope of carbon (12C) is not. Fortunately, the minor (1%) isotope 13C
possesses a finite magnetic moment. The fact that the dominant isotope ofcarbon has a zero magnetic moment is both a "curse" and a "blessing". A
curse because it certainly slowed the application of carbon NMR to organic
chemistry by several decades (waiting for magnet and spectrometer
technology to catch up). A blessing because it results in a 13C spectrum
being much simpler (and easier to interpret) than a proton NMR spectrum.
The second comment is that proximate nuclei with finite magnetic moments
will contribute to the magnetic field felt by the nuclei under investigation.
Whereas nearby protons interact (couple) leading to splitting of theindividual lines in the proton NMR spectrum, the very low probability (1%x 1%) that two 13C nuclei will be adjacent all but eliminates carbon-carbon
coupling. Proton-13C coupling does occur but can be (and nearly almost
always is) removed. The result is that the 13C NMR spectrum contains only
one line per unique carbon.
From the perspective of the experiment, the fact that the difference inenergy between nuclear spin states (and ultimately the ability of an NMR
spectrometer to distinguish chemically-different nuclei) is directly
proportional to the magnetic field strength is disheartening. Magnets usedin NMR spectrometers are now approaching practical and perhaps
theoretical limits, and a mere 10-20% increase in field strength (translating
to an equivalent increase in resolution) can mean more than doubling thecost of the spectrometer. Without a major breakthrough in magnet
technology, the prognosis for greatly improved resolution over what is now
possible (practical) is bleak. On the other hand, computer performancecontinues to double every few years (anticipated by Moore’s law), and
NMR spectra calculations on larger and ever more complex molecules
continue to become more routine.

Appendix A

590

Correcting 13C Chemical Shifts from B3LYP/6-31G*, B97X-D/ 6-31G*and B97X-V/6-31G* Density functional Models
Spartan can calculate NMR chemical shifts using Hartree-Fock models aswell as a range of density functional models. We have focused on andcarefully examined three density functional models, specifically B3LYP,B97X-D and B97X-V models with the 6-31G* basis set. Used directly,
all three models lead to rms errors in 13C chemical shifts on the order of 56 ppm (over a range from 0-250 ppm), and are not reduced by replacing 631G* by a larger more complete basis set. Errors of this magnitude are likely
to be too large for reliably assigning the lines in an experimental 13C spectrum,
for supporting a proposed structure assignment or perhaps most importantfor casting doubt on one.
Empirically Corrected 13C Chemical Shifts
Empirical schemes have been developed to dramatically reduce errors in 13C
chemical shifts, specifically for B3LYP/6-31G*, B97X-D/6- 31G* andB97X-V/6-31G* models. These utilize the same dataset for the linear
regression comprising ~8000 sp3 carbons, ~6200 sp2 carbons (including
aromatic carbons) and ~450 sp carbons.* The functional form is as follows:(2)2
Ci = 13Ci•Scale + Σk [X(0)+ X(1)kk (Ri,k - 1) + X k (Ri,k - 1) ]13

13

C is the corrected chemical shift and13C is the uncorrected chemical shift
and Scale is a scaling factor. Summation is carried out over all bonds (1 or
2 for sp carbons, 3 for sp2 carbons and 4 for sp3 carbons). X(0)k , X(1)k and X(2)kare parameters that depend on the atom bonded to carbon (H, C, N, O, F, Si,
P, S, Cl or Br) and Ri,k are bond lengths to carbon. Different expressions
apply to sp, sp2 and sp3 carbons. The equation for sp carbon involves fourX(0)parameters, four X(1) parameters and one X(2) parameter (11 parameters
in total), that for sp2 carbon involves all ten X(0) parameters, six X(1)parameters and four X(2) parameters (21 parameters in total), and that for sp3
carbon involves all ten X(0) parameters but no X(0)or X(1) parameters (11*Care has been taken to select either rigid molecules or molecules where a single conformer dominates theequilibrium (Boltzmann) distribution.

Appendix A

591

parameters in total).*Resulting rms errors are 2.4, 2.1 and 2.1 ppm for B3LYP, B97X-D, andB97X-V models, all significantly (factor of 2-3) smaller than theuncorrected shifts. In our view, these are close to experimental deviationsin 13C shifts commonly noted due to changes in solvent.

* Parameter files are available for review from: http://downloads.wavefun.com/NMR_
Correction_Parameters.zip.
Appendix A

592

CALCULATING CHEMICAL SHIFTSIN CONFORMATINOALLY FLEXIBLE MOLECULES
Spartan’18 introduced a protocol for calculating 13C chemical shifts inconformationally-flexible organic molecules, targeted at the natural
products community with the goal of being able to identify problematic
structure assignments [J. Nat. Prod. 2019, 82, 8, 2299– 2306]. The protocol
comprises a multi-step procedure to determine accurate Boltzmann weights
starting from a systematic conformational search using MMFF molecularmechanics and terminating with a series of large basis set density functionalenergy calculations, and small basis set density functional chemical shift
calculations that have been empirically corrected each of which ismultiplied by its respective weight to produce a proper Boltzmann-averaged
proton or 13C spectrum. The procedure is depicted below.

The protocol is fully automated requiring only input of a single conformer
and designation of rotatable single bonds and flexible rings. Steps in the
protocol may be eliminated, different quantum chemical methods employed
and energy filters between steps adjusted. While the protocol has only beenthoroughly assessed for 13C chemical shifts, proton chemical shifts can be
added to supplement (or replace) the 13C data.
The performance of the protocol was first evaluated using 13C chemical shifts
for ~900 natural products the structures of which have been confirmed
either by an X-ray crystal structure or by independent

Appendix A

593

synthesis. Only a very few outliers (rms deviations > 4 ppm) were noted,
almost all of which can be attributed to line misassignments rather thatincorrect structures. The protocol was then applied to a second set of ~2500
natural products, the structures of which rely solely on NMR data. Here,fully10-15% fall outside the anticipated error range and furthermore cannot
readily be explained by line misassignments. These problematic structure
assignments perhaps warrant further examination.
A major downside of the protocol available in Spartan’18 is its highcomputation cost, due almost entirely due to the two final two steps required
for evaluation of the Boltzmann weights. While present- generation
personal computers allow its application to molecules with weights <500
amu and with limited conformational flexibility, computation times forlarger natural products or those with more than a few hundred accessible
conformers may in some cases exceed several days.
Spartan’20 introduced a lower-cost protocol that, instead of constructing aproper Boltzmann-weighted average, selects from the set of “reasonable”
low-energy conformers the one that best matches the experimental 13C
and/or proton chemical shifts based on its DP4 score [J. Am. Chem. Soc.
2010, 132, 37, 12946–12959]. Because this does not require calculation of
accurate Boltzmann weights, it relies on simpler quantum chemical models
and is roughly an order of magnitude less costly than the previous protocol,
greatly extending its practical range. Of course it does require an
experimental spectrum! The protocol is depicted below.

As with the previous protocol, alternative quantum chemical models andenergy cutoff values may be substituted for those depicted

Appendix A594

above. In particular, the B3LYP/6-31G* density functional model may besubstituted for ωB97X-D/6-31G* for both energy and NMR calculations,leading to an additional reduction in computation cost.
The two histograms below compare the performance of the original protocol
based on Boltzmann averages (blue bars) and the alternative based on the bestindividual DP4 conformer score (red bars), for a subset of the natural
products collection for which NMR structure assignments have been
confirmed either by X-ray or independent synthesis. The metric is thesmallest RMS deviation between calculated and experimental 13C chemical
shifts. The important conclusion is that the results are nearly identical. The
fact that errors resulting from the new protocol are actually slightly smaller
than those from the original should not be surprising as selection is based on
the conformer that provides the best fit to the experimental data, irrespectiveof its energy.

The second pair of histograms compares the performance of the two
protocols for the same natural products subset for which structure
assignments are based solely on NMR, and with overall RMS errors fromthe original protocol of 5 ppm or greater. Errors near the lower end of thisrange have previously been interpreted to indicate the possibility ofstructure or peak misassignments while those in the middle or higher
range are symptomatic of structure or peak assignments that are most likely
incorrect. Aside from the fact that roughly 10% of the RMS values from thenew protocol fall below 5 ppm, the two histograms are similar.

Appendix A

595

Appendix A

596

ASSIGNING STEREO AND REGIOISOMERS FROMCALCULATED CHEMICAL SHIFTSBoth protocols described in a previous topic allow calculated chemical shifts tobe compared with measured values in order to choose to among possible
stereoisomers. The simpler protocol introduced in Spartan’20 is morepractical for larger molecules with multiple degrees of conformational freedom
and for which more than a few isomers need to be considered. Following
the work of Goodman [J. Am. Chem. Soc. 2010, 132, 37, 12946–12959],
selection is based on DP4 score, using either the Boltzmann average ofchemical shifts over accessible conformers for each of the isomers (original
protocol) or the conformer for each isomer with the highest DP4 score (newprotocol).
Spartan’24 provides a mechanism for isomer generation, requiring the user
to designate which stereocenters are to be inverted (Generate Isomers under
the Geometry menu; Chapter 19). Duplicate stereoisomers as well asstereoisomers that differ in absolute configuration are automaticallyremoved. Isomer identification can be done with a single job submission,requiring input of a single conformer of one of the stereoisomers, designationof rotatable single bonds and flexible rings for this isomer (which are in turnapplied to all isomers) and designation of stereocenters that are to be
inverted. A more cautious approach, requiring two sequential jobs may also
be followed: generate a list of stereoisomers and remove any that are highenergy or otherwise “unrealistic” and run the NMR analysis on each in turn.
As before, assessment draws on structures from the natural products
literature that have been confirmed by X-ray crystallography or byindependent synthesis. This involves more than 600 molecules, each ofwhich yields two or more distinct isomers (most commonly either four oreight isomers), leading to over 4000 distinct stereoisomers.
The histogram below documents the performance of the NMR protocol
introduced in Spartan’2. ~70% of the molecules have DP4 scores above
75%, suggesting that the protocol successfully identifies the isomer that isobserved. On the other hand, ~20% of the molecules have DP4 scores below
50%, suggesting that protocol

Appendix A

597

is not successful. The remaining 10% of the molecules with DP4 scores
between 50 and 75% may be interpreted to mean that while the calculations
identify the correct isomer, one or more alternative isomers are competitive.
These results are consistent with those obtained by Goodman based on adifferent and somewhat more computationally demanding procedure andapplied to proton as well as 13C chemical shifts for a different and smaller
set of molecules.

There are at least two reasons for the failure of the calculations to correctly
identify the isomer corresponding to the observed NMR spectrum. For one,it is likely that in some cases 13C shifts for different isomers will be
indistinguishable within the error limits of the calculations. Indeed, themajority of the “failures” involve change in chirality of just a single center.
A second source of error may arise from the assumption that chemical shifts
for the conformer that best fits the experimental 13C data, as opposed to thatfrom a properly Boltzmann-weighted average of chemical shifts over all
conformers. This is of course what distinguishes the newer protocol in
Spartan’20 from both the original protocol in Spartan’18 as well as from
Goodman’s work. It is also directly responsible for the large saving incomputation cost. While it is not practical to obtain DP4 statistics overisomers for the full set of molecules using the previous protocol, we haveobtained them for the 20% of the molecules with DP4 scores less than 50%.
Data for this subset are provided below as a histogram.

Appendix A

598

In only about a third of the cases does the “correct” isomer exhibit a DP4score of 75% or higher, and half of the problem cases have DP4 scores
below 50% are satisfactorily resolved. This suggests that the previous
protocol which aimed to establish 13C shifts that were Boltzmann-averaged
over accessible conformers is unlikely to be more successful than thesimplified procedure available in Spartan’20.

Appendix A

599

CALCULATING HH AND CH COUPLING CONSTANTS
Coupling constants may be calculated, either “exactly” or within the socalled Fermi-contact approximation. The latter approach is significantly
the less demanding both in terms of computation time and memory
required. 3-bond HH coupling constants may be estimated using the Karplus
relationship [reference]. A parameterized variation on Karplus have long
been provided in Spartan, and extended to estimate both 2 and 3-bond CH
coupling constants.
So-called “range-separated-hybrid” functionals such as B97X-D used for
determining geometry and chemical shifts are not presently available in
Spartan for coupling constant calculations. The popular B3LYP “global
hybrid” functional has instead been used. In addition, the 6-31G* basis set
used for chemical shift calculations has been replaced by one of a series ofbasis sets that have been expressly developed for coupling constantcalculations. The smallest of these is PCJ-0, which is similar in construction to
6-31G* and readily applicable to molecules of comparable size. PCJ-1 and PCJ2 basis sets are larger and therefore more limited in their practical range ofapplication.
The first comparison relates coupling constants calculated within the Fermicontact approximation and using the PCJ-0, PCJ-1 and PCJ-2 basis sets withexperimental data for two sets of small molecules taken from the Reich website [reference]. Data for 3-bond HH coupling constants with ~300
comparisons, and (combined together) 2 and 3-bond CH coupling constants
with ~200 comparisons are shown below at the left and right, respectively.
HH coupling constants range from roughly 0 to 20 Hz and are almost entirely
positive. (The few small negative values have been excluded from the plot
as have HH coupling constants larger than 20 Hz.) The overall range of CH
coupling constants is similar although there are a significant number ofnegative values, almost entirely for 2-bond coupling. It should be noted thatthe sign of measured coupling constants is rarely reported and theexperimental data from the Reich web site is almost entirely unsigned. We
have adjusted the sign on experimental coupling constants to be in accord
with the calculated values.

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600

The second comparison examines the effect of the Fermi-contact
approximation on coupling constants obtained using the PCJ-0 basis set.
Results for 3-bond HH (left) and (combined together) 2 and 3-bond CH(right) coupling constants are shown below where the “full” calculations act
as reference. The RMS deviations here, x.x and y.y for HH and CH coupling
constants, respectively, are smaller than the previously mentioned RMS
errors referenced to experiment.

Given that the primary objective for calculating coupling constants is to
identify couplings between pairs of hydrogens that are large enough to beobserved in a COSY spectrum and those between carbon and hydrogen thatare large enough to be observed in an HMBC spectrum, it is likely conclude
that calculations within the framework of the Fermi approximation using
the PCJ-0 basis set are adequate.* As previously mentioned, current
generation personal computers allow application to molecules withmolecular weights on the order of 500 amu.

*

It is also likely that empirically derived HH and CH coupling constants will be adequate for constructionof COSY and HMBC spectra.

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601

CALCULATING COSY AND HMBC SPECTRA
While coupling constants are rarely reported, they are of course required todetermine splitting patterns in proton spectra and in providing 2D spectra,
specifically HH coupling constants for COSY spectra and CH coupling
constants for HMBC spectra, both of which are essential tools for assignmentof structure. The “raw” experimental data are in presented in the form ofcontour plots, while calculated results are given in terms of a series ofcircles on a 2D plot corresponding to large couplings. A large degree ofconcurrence suggests that they are likely to be referring to the same or a very
similar molecule whereas significant differences signals that something isamiss.
Two different display modes for calculated COSY and HMBC spectra aresupported. The first displays all couplings (3JHH for COSY and both 2JCH and
3 CH
J for HMBC) where the absolute value of the coupling constant is greaterthan a set magnitude. These take the form of open circles the size of which is
independent of the magnitude of the coupling constant, but for HMBC thecolor of which depends on whether it is 2 or 3-bond. Rather than displaying
the contour plot obtained directly from the COSY or HMBC experiment,
assigned couplings are entered manually. Matching calculated andexperimental data (that is, involving the same atoms) can be “linked” withellipses drawn connecting the circles and crosses. The second mode, applicable
only where experimental data have been provided, displays only calculated
couplings for which an experimental coupling has been provided. As it ismuch less crowded (depending on the threshold set for displaying calculated
couplings), it is likely to be the more useful of the two in trying to see if
calculated and experimental HMBC spectra closely match.

Appendix A

602

Machine Learning and Neural Network Models
The advent of machine learning (ML) or neural net (NN) technology offers
the possibility of a new class of models that potentially afford both highreliability and quality as well as low (computational) cost. Implemented in
the initial release of Spartan’24, are a series of 5 neural nets designed to (i)improve conformer energy differences provided by MMFF molecularmechanics, (ii) accurately estimate ωB97X-D/6-31G* equilibriumgeometries starting from MMFF geometries, and (iii) accurately estimate
total energies from:
ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G*
ωB97M-V/6-311+G(2df,2p)//ωB97X-D/6-31G*
ωB97M(2)/6-311+G(2df,2p)//ωB97X-D/6-31G*
models starting from ωB97X-D/6-31G* equilibrium geometries and energies
or estimated ωB97X-D/6-31G* equilibrium geometries and ωB97X-D/631G* energies. There are five neural nets in total, all of which are supported
for closed shell uncharged molecules comprising the elements: H, C, N, O,
F, S, Cl and Br (only).
SpookyNet* has been used to generate all five neural nets. Data sets comprise≈150k molecules with ≈1.8 million conformers obtained from ωB97X-V/6311+G(2df,2p)[6-311G*]//MMFF calculations for the MMFF correction
neural net, ≈120,000 molecules each with both equilibrium and 50 distorted
geometries (times ≈6.1 million structures) obtained from ωB97X-D/6-31G*
calculations for the estimated ωB97X-D/6-31G* geometry neural net,
≈295,000 molecules obtained from ωB97X-V/6-311+G(2df,2p)//ωB97XD/6-31G* calculations for the estimated ωB97X-V/6-311+G(2df,2p) energy
neural net, ≈289,000 molecules obtained from ωB97M-V/6311+G(2df,2p)//ωB97X-D/6-31G* calculations for the estimated ωB97MV/6-311+G(2df,2p) energy neural net, and the same ≈289,000 molecules
obtained from ωB97M(2)/6-311+G(2df,2p)//ωB97X-D/6-31G* calculations
for the estimated ωB97M(2)/6-311+G(2df,2p) energy neural net.

*Nat. Commun. 12(1), 2021, 1-14. (https://github.com/OUnke/SpookyNet).

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603

Improving MMFF Molecular Mechanics
Molecular mechanics is perhaps the only class or methods that is routinely
practical for calculations of conformer energy differences for flexible
molecules with several degrees of conformational freedom. All accessible
conformers, or at the very least a representative sample of these conformers,
need to be identified and ranked based on energy. Assuming three-fold rotors,
two and three degrees of freedom lead to only 9 and 27 conformers,
respectively, whereas a molecule with 9 degrees of freedom (not at all
unusual in natural products) leads to nearly 20,000 conformers. While only arelatively few conformers are likely to seriously affect calculated molecularproperties, all must be examined to determine which few.
The MMFF94 approach has been shown to closely reproduce experimental
conformational energy differences for small molecules with a single degreeof conformational freedom. However, as suggested from the plot below, fora diverse series moderate size organic molecules with multiple degrees ofconformational freedom, MMFF is not satisfactory. As experimental data arecompletely lacking, the reference energy is ωB97X-V/6-311+G(2df,2p)[6311G*] density functional energy using MMFF equilibrium geometries, thesame quantum chemical model used to train the neural net.

Comparison of Conformational Energy Differences Obtained from
MMFF and ωB97X-V/6-311+G(2df,2p)[6-311G*] Calculations

Appendix A

604

MMFF structures corrected by neural net energies provides a far betteraccounting with only a modest (factor of two) increase in computer time. The
overall RMS error reduces from 10.2 kJ/mol for MMFF to 1.8 kJ/mol with
the neural net correction.

Comparison of Conformational Energy Differences Obtained from
Neural Net and ωB97X-V/6-311+G(2df,2p)[6-311G*] Calculations

Estimating ωB97X-D/6-31G* Equilibrium Geometries
Two considerations generally dictate model selection, quality of the results
and computation time. It is generally accepted that density functional models
provide more consistent and better results than Hartree-Fock molecularorbital models but are also more time consuming, sometimes significantly so.
The ωB97X-D/6-31G* density functional model is among the mostcommonly-used quantum chemical models for geometry calculation. It isboth accurate and reliable, properly accounting for the geometries ofmolecules that are often poorly dealt with using Hartree-Fock models. While
it is generally not sufficiently accurate for use in determining reactionenergies, or energy differences among conformers, ωB97X-D/6-31G*
structures provide a good foundation for energy calculations with more
rigorous functionals and larger (more complete) basis sets.
The neural net fit to ωB97X-D/6-31G* incorporated into Spartan’24 is manyorders of magnitude faster than the underlying density functional model.
Structures that previously required hours of computer time may now be
closely approximated in seconds (at most a few minutes). It must beemphasized each one of these neural network calculations is unique andAppendix A

605

specific to the underlying computational model it is trained to reproduce (aparticular property (or properties) from a specific functional and with a
specific basis set. A neural net constructed to reproduce equilibriumgeometries from the popular B3LYP-D3/6-31G* model will be distinct fromthat directed at ωB97X-D/6-31G*. Also acknowledged: different training
sets and different convergence criteria (as well as different starting
geometries) will ultimately lead to different neural network definitions. The
hope is that subtle differences in training sets will lead to nearly the same
final (or very similar) equilibrium geometries.
We’ve applied three criteria to assess how well the geometry neural network
performs, using a test set comprising 430 natural products with molecularweights ranging from ≈ 200 to 700 amu (mean of 447 amu), none of whichwere used in neural net training or validation.
The most obvious criterion is structure (itself): bond lengths, bond angles,
and dihedral angles [excluding those involving hydrogen(s)]. The
performance was substantive, with only 14 molecules showing bond lengths
that deviate from ωB97X-D/6-31G* values by more than 0.02 Ǻ. Similar
results were observed in bond angles; only 4 and 7 molecules incorporate abond angle that differs by more than 10o and 5o, respectively. Less than aquarter of the molecules show individual bond-angle deviations of more than2o.
Dihedral angles are perhaps the most important structural parameter in thatlarge deviations may result in molecular shapes that differ greatly from thoseobtained using ωB97X-D/6-31G* (the training model). One concern is thatfurther calculation of NMR chemical shifts, which are sensitive to medium
to long-range interactions, will be impacted. Only two molecules show verylarge (>50o) deviations; 34 (8%) show deviations >20; 30% of molecules
show deviations of >10o.
The second criterion involves differences in energies resulting from use ofneural net equilibrium geometries in lieu of ωB97X-D/6-31G* geometries.
The RMS error for the neural net is 8 kJ/mol and the energies of only 11
molecules deviate from ωB97X-D/6-31G* by more than 20 kJ/mol, thelargest of which is 42 kJ/mol. 54 molecules deviate by more than 10 kJ/mol.
Perhaps the most important metric is the effect of equilibrium geometry on
proton and especially 13C NMR chemical shifts. This is because geometry
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calculation is key in any effort to realize an accurate rapid procedure to
calculate chemical shifts of conformationally flexible organic molecules,
natural products among them, and to distinguish among stereoisomers thatclosely reproduces the results of the accurate (but time consuming) multi-step
protocols now in place*.
Only 4 and 29 molecules exhibit individual deviations greater than 1 and 0.5
ppm, respectively, more than a third of the molecules have one or more
protons with chemical shifts that deviate from ωB97X-D/6-31G* values bymore than 0.2 ppm.
Statistics for 13C chemical shifts mimic those for proton shifts. Only one
molecule exhibits an individual deviation >10 ppm and only 11 exhibit
individual deviations >5 ppm. Roughly a third of the molecules based onneural net geometries show at least one individual deviation >2 ppm. The
overall RMS (all carbons) and the RMS of the maximum individual 13C shifterrors (per molecule) from the neural net geometries are 0.8 ppm and 2.3
ppm, respectively.
Improved Reaction and Conformer Energy Calculations
Reaction energies and conformer energies differences are among the mostimportant quantities obtained from quantum chemical calculations. Organic
chemists, natural products chemists in particular, will benefit from
calculations able to identify the dominant stereoisomer arising from achemical reaction, and from determination of conformer energy differences,providing Boltzmann weights and with these, accurate prediction of NMR
shifts of flexible molecules.
The “gold standard” CCSD(T)/CBS calculations scale formally as theseventh power of the number of basis functions, and can take many hours(even days) to complete. Reducing computational cost while achieving
CCSD(T) accuracy has been the primary motivation for development ofmany density functional models. In previous versions of Spartan, the primary
focus has been on the Head-Gordon functionals: ωB97X-V, ωB97M-V andωB97M(2), all with the 6-311+G(2df,2p) basis set and all starting from
ωB97X-D/6-31G* geometries.
*J. Nat. Prod. 2019, 82 8, 2299-2306. (https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00603)
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The CCSD(T) procedure is superior to these three functionals, and while the6-311+G(2df,2p) basis set is moderately large and diverse, the recipedeveloped to yield a “complete basis set” (CBS) ensures that further additions
will at most have modest effect on the energy. Finally, the geometry isdifferent from that used in CCSD(T) calculations (MP2/aug-cc-pVDZ basis
set vs. ωB97X-D/6-31G*).
The two models ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G* and (to alesser extent) ωB97M-V/6-311+G(2df,2p)//ωB97X-D/6-31G* are practical
for routine calculations on rigid molecules (or those with only a few degrees
of conformational freedom) up to molecular weights <400 amu, although
they may require tens of minutes to several hours to complete. They areclearly impractical, at least routinely so, for significantly larger systems, orfor molecules with multiple degrees of conformational freedom. The
ωB97M(2)/6-311+G(2df,2p)//ωB97X-D/6-31G* is more computationallycostly and practical ranges are even smaller.
Spartan’24 provides neural networks trained to these three density functionalmodels. These require an ωB97X-D/6-31G* geometry (or an estimatedgeometry from the Est. ωB97X-D/6-31G* neural network along with a single
point ωB97X-D/6-31G* energy). Because of these requirements, applicationof these neural nets is not “instantaneous” (unlike the two previous describedmachine learning models, these three are not devoid of quantum chemical
calculations as input). This said, the overall performance is easily an order ofmagnitude faster utilizing these neural nets to provide energies (compared tothe pure quantum chemical calculations). As quality conformer energy
differences are needed to establish accurate Conformer Distributions (aswell as Boltzmann weighted NMR shifts), these energy-focused neuralnetworks provide significant computational savings in tasks including
conformational searching, in particular the multi-step NMR Spectrum task.

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ATOMIC AND MOLECULAR ORBITALS
Chemists have developed a variety of methods for describing electrons inmolecules. Lewis structures are the most familiar. These drawings assign
pairs of electrons either to single atoms (lone pairs) or pairs of atoms(bonds)*. The quantum mechanical equivalents are atomic and molecularorbitals which arise from solution of (approximate) Schrödinger equations
for atoms and molecules, respectively. Molecular orbitals are spreadthroughout the entire molecule, that is, they are delocalized.** Because ofthis, they are typically more difficult to interpret than Lewis structures.
Orbital Surfaces
Molecular orbitals may be able to provide important clues about chemical
reactivity, but before we can use this information we first need to understandthe fundamentals for very simple molecules. The following figure shows
two representations, a hand drawing and a Spartan-generated image of anunoccupied molecular orbital of hydrogen molecule, H2.

unoccupied molecular orbital in hydrogen

Open hydrogen empty in the topics directory. Note that except for thecolors (sign of the orbital) the two sides of the graphic are identical. The
junction between red and blue regions is where the value of the orbitalis zero. Close hydrogen empty when you are finished.

The familiar hand drawing shows the orbital as two circles and a dashedline. The circles identify regions where the orbital takes on a
* The present discussion is limited to molecules in which all electrons are paired. Molecules with
one or more unpaired electrons (radicals, triplet states, etc.) may also be treated.
** Is it possible to localize molecular orbitals such that they correspond more closely toconventional Lewis structures. Because this is costly in terms of computation and to some extent "illdefined" (the need to specify what conditions are to be met) localization is only rarely performed.

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significant value, either positive (shaded) or negative (unshaded). The dashedline identifies locations where the orbital’s value is exactly zero (a node).
The drawing is useful, but it is also limited. We only obtain information
about the orbital in two dimensions, and we only learn the location ofsignificant regions and not how the orbital builds and decays inside andoutside of these regions.
The Spartan-generated image depicts the same orbital as a surface ofconstant value. The surface is accurate in that it is derived from an authentic(but approximate) calculated solution to the quantum mechanical equationsof electron motion (the Schrödinger equation). Equally important, the imageis three-dimensional, and can be manipulated and looked at from a variety
of different perspectives. It is not unexpected that the orbital consists of two
distinct surfaces represented by different colors. The two surfaces have thesame meaning as the two circles in the orbital drawing. They identify
regions where the orbital takes on a significant value, either positive (blue)or negative (red). The orbital node is not shown, but we can guess that itlies midway between the two surfaces (this follows from the fact that theorbital’s value can only change from positive to negative by passing
through zero).
Atomic Orbitals
Atomic orbitals (descriptions of atoms) are the fundamental building blocks
from which molecular orbitals (descriptions of molecules) are assembled.
The familiar atomic orbitals for the hydrogen atom are in fact exact solutionsof the Schrödinger equation which can actually be solved exactly for thisone electron system. They form an infinite collection (a complete set), thelowest-energy member representing the best location for the electron, andhigher-energy members representing alternative locations. Orbitals for real
many-electron atoms are normally (and necessarily) assumed to be similar
in form to those of hydrogen atom, the only difference being that, unlike
hydrogen, more than the lowest-energy atomic orbital is utilized. In
practical quantum chemical calculations, atomic orbitals for many-electron
atoms are made up of sums and differences of a finite collection of hydrogenlike orbitals (see the topic Theoretical Models).

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It is common practice to divide the full set of atomic orbitals into core andvalence orbitals, and further to ignore the former. Valence orbitals for anelement in the first long row of the Periodic Table are 2s, 2px, 2py and 2pz,
and for the second long row are 3s, 3px, 3py and 3pz. In the case of first-row
elements, a single orbital, 1s, lies underneath (is a core orbital) while in thecase of second-row elements, a set of five orbitals, 1s, 2s, 2px, 2py and 2pz,
lie underneath.
Open fluoride and chloride in the topics directory. On the top row are
the four valence orbitals of fluoride anion and on the bottom row the fourvalence orbitals of chloride anion. You can select among them by clicking(left mouse button) on each in turn. First note that the three 2p orbitals
in fluoride are identical except for the direction in which they point. The
same is true for the three 3p orbitals in chloride. Next, note that the valenceorbitals in chloride are larger than those in fluoride. Atoms further downin the Periodic Table are generally larger than analogous atoms further
up. Close fluoride and chloride when you are finished.

Orbitals and Chemical Bonds
Although molecular orbitals and Lewis structures are both used todescribe electron distributions in molecules, they are used for different
purposes. Lewis structures are used to count the number of bonding andnon-bonding electrons around each atom. Molecular orbitals are not usefulas counting tools, but orbitals and associated orbital energies are useful tools
for describing chemical bonding and reactivity. This section describes a few
common orbital shapes and illustrates their use.
Molecular orbital surfaces can extend over varying numbers of atoms. If theorbital surface (or surfaces) is confined to a single atom or to atoms which
are not close together, the orbital is regarded as non- bonding. If the orbital
contains a surface that extends continuously over two neighboring atoms,
the orbital is regarded as bonding with respect to these atoms. Adding
electrons to such an orbital will strengthen the bond between these atoms
and cause them to draw closer together, while removing electrons will havethe opposite effect. Two different kinds of bonding orbitals are depicted
below.

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The drawing and surface on the left correspond to a  bond while thedrawing and surface on the right correspond to a π bond.

Open nitrogen bonding in the topics directory. The image on the left
corresponds to the  bonding orbital of N2, while that on the rightcorresponds to one of two equivalent π bonding orbitals. Switch to atransparent or mesh model to see the underlying molecular skeleton.
Note that the  orbitals is drawn in a single color (insofar as NN bonding
is concerned) while the π orbital is made up of red and blue parts. This
indicates a node or a break in the latter, although not involving the NN
bond. Close nitrogen bonding when you are finished.

It is also possible for an orbital to contain a node that divides the region
between two neighboring atoms into separate atomic regions. Such an orbital
is regarded as antibonding with respect to these atoms. Adding electrons toan antibonding orbital weakens the bond and pushes the atoms apart, whileremoving electrons from such an orbital has the opposite effect. The
following pictures show drawings and orbital surfaces for two different
kinds of antibonding orbitals. As above, the left and right-hand sides
correspond to  and π type arrangements, respectively.

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Open nitrogen antibonding in the topics directory. The image on theleft corresponds to the  antibonding (so-called *) orbital of N2 whilethat on the right corresponds to one of the two equivalent π antibonding(so-called π*) orbitals. Switch to a mesh or transparent surface to see
the underlying molecular skeleton. Note that the * orbital has a single
node (change in color from red to blue) in the middle of the NN bond,while the π* orbital has two nodes (one in the middle of the NN bondand to the other along the bond). Close nitrogen antibonding when you
are finished.

To summarize, bonds can be strengthened in two different ways, by adding
electrons to bonding orbitals, or by removing electrons from antibonding
orbitals. The converse also holds. Bonds can be weakened either byremoving electrons from bonding orbitals or by adding electrons to
antibonding orbitals.
Singlet Methylene
Molecular orbitals in molecules which contain many atoms are typicallyspread throughout the molecule (they are delocalized). Delocalized orbitals
have complicated shapes and contain multiple interactions that may bebonding, non-bonding, antibonding, or any mixture of all three.
Nevertheless, these shapes can usually be broken down into two-atominteractions and analyzed using the principles outlined earlier. This process
is illustrated for a triatomic molecule, singlet methylene, CH2. (Singlet
refers to the fact that the eight electrons in this highly reactive molecule areorganized into four pairs, and that each pair of electrons occupies a different
molecular orbital. The lowest-energy state of methylene is actually a triplet
with three electron pairs and two unpaired electrons.)
The lowest energy molecular orbital of singlet methylene is not very
interesting in that it looks like a 1s atomic orbital on carbon. The electrons
occupying this orbital restrict their motion to the immediate region of the
carbon nucleus and do not significantly affect bonding. Because of thisrestriction, and because the orbital’s energy is very low, this orbital isreferred to as a core orbital and its electrons are referred to as coreelectrons.

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core orbital for methylene

The next orbital is much higher in energy. It consists of a single surface thatis delocalized over all three atoms. This means that it is simultaneously ()bonding with respect to each CH atom pair.

core orbital for methylene

The next higher energy orbital is described by two surfaces, a positive (blue)
surface that encloses one CH bonding region and a negative (red) surface
that encloses the other CH bonding region*. Since each surface encloses abonding region, this orbital is also () bonding with respect to each CH atom
pair. This reinforces the bonding character of the previous orbital. The nodethat separates the two surfaces passes through the carbon nucleus, but not
through either of the CH bonding regions, so it does not affect bonding.

core orbital for methylene

Thus, the two CH bonds in the Lewis structure for singlet methylene are
replaced by two bonding molecular orbitals.*** While the absolute signs (colors) of a molecular orbital are arbitrary, the relative signs (colors) indicate
bonding and antibonding character.
** Unlike the two Lewis structures, the two CH bonding molecular orbitals reflect the fact that the two CH
bonds in methylene are identical. Specifically, the square of each of the orbitals, corresponding to theelectron distribution or electron density, has the same 2-fold symmetry as the molecule. The square ofeither the molecular orbitals themselves or a combination of so-called degenerate (same energy) molecularorbitals must have the same symmetry as the underlying nuclear skeleton.

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The highest-occupied molecular orbital (the HOMO) is also described by twoorbital surfaces. One surface extends into carbon’s non-bonding region opposite
the two hydrogens. The other surface encompasses the two CH bonding
regions. Although it is hard to track the exact path of the orbital node in thispicture, it happens to pass almost exactly through the carbon. This meansthat this particular orbital possesses only weak CH bonding character (it is H--H bonding). It turns out that the non-bonding character of the orbital is much
more important than the bonding character, in that it leads to the fact thatsinglet methylene is able to behave as an electron-pair donor (a nucleophile).

core orbital for methylene

In addition to two CH bonds, the Lewis structure for singlet methylene showsa lone pair on carbon.

The above analysis shows that while the occupied orbitals of singlet
methylene are spread over all three atoms, they are comprehensible. The
orbitals divide into two groups, a single low-energy core orbital and threehigher-energy valence orbitals. The latter consist of two CH bonding orbitals
and a non-bonding orbital on carbon. There is no one- to-one correspondence
between these orbitals and the Lewis structure. The bonding orbitals are notassociated with particular bonds, and the non-bonding orbital contains
bonding interactions as well.
Open methylene bonding in the topics directory. Four images appear
corresponding to the core and three valence orbitals of singlet methylene.
Switch to a mesh or transparent surface to see the underlying molecularskeleton. Close methylene bonding when you are finished.

Singlet methylene also possesses unoccupied molecular orbitals. The
unoccupied orbitals have higher (more positive) energies than the

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occupied orbitals, and these orbitals, because they are unoccupied, do notdescribe the electron distribution in singlet methylene.* Nevertheless, theshapes of unoccupied orbitals, in particular, the lowest-unoccupied orbital(LUMO), is worth considering because it provides valuable insight into themethylene’s chemical reactivity.
The LUMO in methylene has non-bonding character, and looks like a 2p
atomic orbital on carbon. This suggests that singlet methylene should be able
to behave as an electron-pair acceptor (an electrophile). Note, however, thatwere the molecule to accept electrons, these would go into non-bonding
orbital; carbon would become more electron- rich, but the CH bonds would
not be much affected.

LUMO of methylene

Open methylene LUMO in the topics directory and switch to a mesh ortransparent surface to see the underlying skeleton. Close methylene
LUMO when you are finished.

Frontier Molecular Orbitals and Chemical Reactivity
Chemical reactions often involve movement of electrons from an electron
donor (base, nucleophile, reducing agent) to an electron acceptor (acid,
electrophile, oxidizing agent). This electron movement between molecules
can also be thought of as electron movement between molecular orbitals,
and the shapes and energies of orbitals that act as electron donors or electron
acceptors may provide considerable insight into chemical reactivity.
The first step in constructing a molecular orbital picture of a chemical reaction
is to decide which orbitals are most likely to act as electron*

Because Lewis structures describe electron pair bonds and non-bonding electron pairs, they may not
be related to unoccupied molecular orbitals.

donors and acceptors. It is obvious that an electron-donor orbital must be
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drawn from the set of occupied orbitals, and an electron-acceptor orbitalmust be an unoccupied orbital, but there are many orbitals in each set tochoose from.
Orbital energy is usually the deciding factor. The highest-energy occupied
orbital (the HOMO) is most commonly assumed to be the relevant electrondonor orbital and the lowest-energy unoccupied orbital (the LUMO) is mostcommonly assumed to be the relevant electron-acceptor orbital. For
example, the HOMO and LUMO of singlet methylene ( and π non-bonding
orbitals, respectively) would serve as the donor and acceptor orbitals. The
HOMO and LUMO are collectively referred to as the frontier molecularorbitals, and most chemical reactions involve electron movement between
them. In this way, the energy input required for electron movement is kept
to a minimum.

Closely related to chemical reactivity (reaction rate) is chemical selectivity.
The relevant question is, where more than one combination of reagents canreact, which combination will react more quickly? The answer can often be
found by examining the energies of the frontier orbitals. Consider ranking
the rates of a series of reagents, where chemical reaction requires electron
donation from the donor’s HOMO. It is reasonable to expect that the donor
with the highest energy HOMO will give up its electrons most easily and be
the most reactive. Electron-acceptor reagents should follow the opposite
pattern. The reagent with the lowest energy LUMO should be able to accept
electrons most easily and be the most reactive. For a mixture of several
donor and acceptor reagents, the fastest chemical reaction

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would be expected to involve the reagent combination that yields the smallest
HOMO-LUMO energy gap.
The Fukui-Woodward-Hoffmann Rules
In certain cases, multiple frontier orbital interactions must be considered. A
good example is provided by so-called cycloaddition reactions, such as theDiels-Alder reaction between 1,3-butadiene and ethylene.

The key feature of this reaction is that the reactants combine in a way thatallows two bonds to form simultaneously. This implies two different sites ofsatisfactory frontier orbital interaction (the two new bonds that form are
sufficiently far apart that they do not interact with each other during thereaction). If we focus exclusively on the interactions of the terminal carbons
in each molecule, then three different frontier orbital combinations made up
of upper and lower components can be imagined.

The upper orbital components are the same sign in all three combinations,meaning that their overlap is positive. In the two cases on the left, the lower
orbital components also lead to positive overlap. Thus, the two interactions
reinforce, and the total frontier orbital interaction is non zero. Electron
movement (leading to chemical reaction) can occur. The right-most case isdifferent. Here the lower orbital components lead to negative overlap (theorbitals have opposite signs at the interacting sites), and the total overlap is zero.
No electron movement and no chemical reaction can occur in this case.
As it happens, the frontier orbital interactions in the Diels-Alder
cycloaddition shown above correspond to those found in the middle

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drawing, that is, the upper and lower interactions reinforce and thereaction proceeds.
Open 1,3-butadiene+ethylene in the topics directory. The image on top
is the LUMO of ethylene while that on the bottom is the HOMO of 1,3butadiene. They are properly poised to interact, but you can manipulatethem independently. Close 1,3-butadiene+ethylene when you arefinished.

The same arguments suggest that cycloaddition of two ethylene molecules
is unlikely to occur. This is because it involves a frontier orbital interaction
like that found in the right drawing.
+

X

Open ethylene+ethylene in the topics directory. The image on top
corresponds to the LUMO of one ethylene while that on the bottom
corresponds to the HOMO of the other ethylene. You can manipulate them
independently or in concert (hold down on the Ctrl key while you carryout rotation and translation). Note, that in this case, the two individual
atom-atom interactions cancel. Close ethylene+ethylene when you arefinished.

The importance of orbital overlap in determining why certain chemical
reactions proceed easily while other seemingly similar reactions are
sluggish or do not go at all was first advanced by Fukui and then beautifully
elaborated by Woodward and Hoffmann, and collectively their ideas are now
known as the Fukui-Woodward-Hoffmann rules.

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619

ELECTRON DENSITIES: SIZES AND SHAPES OF MOLECULES
How big is an atom or a molecule? Atoms and molecules require a certain
amount of space, but how much? We know that gases can be compressed intoa smaller volume but only so far, and that liquids and solids are very difficult
is not nearly impossible to compress. While the individual atoms or
molecules in a gas are widely separated and can be pushed into a muchsmaller volume, the atoms or molecules in a liquid or a solid are already close
together and cannot be squeezed much further. Atoms can be talked about as
having well-defined size. What is it?
Space-Filling Models
Chemists have long tried to answer the size question by using a special set ofmolecular models known as space-filling or CPK models. The space-fillingmodel for an atom is simply a sphere of fixed radius. A different radius ischosen for each element in order to reproduce certain experimental
observations, such as the compressibility of a gas, or the spacing between
atoms in a crystal. Space-filling models for molecules consist of a set ofinterpenetrating atomic spheres. This reflects the idea that the chemicalbonds that hold the molecule together cause the atoms to move closer
together than the sum of the radii for the individual space-filling models.
Interpenetration can be used as a criterion for chemical bonding. If two
atomic spheres in a space-filling model strongly interpenetrate then theatoms must be bonded. Space-filling models not only show how big
molecules are, but also show which parts of the molecule are shielded andwhich are exposed.

space-filling models for ammonia (left), trimethylamine (center) and1-azaadamantane (right)

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Open amines space filling in the topics directory. Space-filling models
for ammonia, trimethylamine and 1-azaadamantane all appear on screen.
Carbon atoms are colored dark grey, hydrogen atoms white and nitrogenblue. Note that the models clearly reveal the extent to which the nitrogenis exposed. Close amines space filling when you are finished.

Electron Density Surfaces
An alternative technique for portraying molecular size and shape relies on
the molecule’s own electron cloud. Atoms and molecules are made up of
positively-charged nuclei surrounded by a negatively- charged electron
cloud, and it is the size and shape of the electron cloud and not that of thenuclear skeleton that defines the size and shape of an atom or molecule. The
size and shape of an electron cloud is described by the electron density (thenumber of electrons per unit volume). Consider a graph of electron density
in the hydrogen atom as a function of distance from the nucleus.

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This suggests that molecular size and shape is ill defined and that the best thatcan be done is to pick a value of the electron density, and to connect together
all the points that have this value. The criteria for selecting this value isexactly the same as that for selecting atomic radii in space-filling models, theonly difference being that only a single parameter (the value of the electron
density) is involved (rather than a different radius for each element). The
result is an electron density surface which, just like a space-filling model, isintended to depict overall molecular size and shape.

electron density surfaces for ammonia (left), trimethylamine (center)and 1-azaadamantane (right)

Open amines electron density in the topics directory. Electron density
surfaces for ammonia, trimethylamine and 1-azaadamantane all appear
on screen. Switch to a mesh or transparent surface in order to see theunderlying skeletal model. Click on one of the surfaces, and select Meshor Transparent from the menu which appears at the bottom right of thescreen. With mesh selected, change the model to Space Filling (Modelmenu). This allows you to see how similar the electron density
representation is to that offered by a simple space-filling model. Close
amines electron density when you are finished.

Both space-filling models (atomic radii) and electron density models can bechosen to yield similar molecular volumes, and both show differences inoverall size among molecules. Because the electron density surfaces provide
no discernible boundaries between atoms, the surfaces may appear to be lessinformative than space-filling models in helping to decide to what extent a
particular atom is exposed. This raises an important point. Electrons areassociated with a molecule as a whole and not with individual atoms. The
space-filling representation of a molecule with its discernible atomic
boundaries does not reflect reality.

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Bond Density Surfaces
More closely representing a conventional Lewis structure is a so- calledbond density surface, where the boundary corresponds to a much higher
value of the electron density*. As such a surface is located much closer to theatomic nuclei, it encloses a relatively small volume, and does not give a
correct impression of molecular size.
The bond density surface for hex-5-ene-1-yne clearly shows which atoms
are connected, although it does not clearly distinguish single, double andtriple carbon-carbon bonds.

bond density surface for hex-5-ene-1-yne

Open hex-5-ene-1-yne bond density in the topics directory, and switch toa mesh or transparent surface to see the connection between the chemicalbonds in a conventional model and the electron density. Close hex-5ene-1-yne bond density when you are finished.

The usefulness of the bond density surface is more apparent in the following
model of diborane. The surface clearly shows that there is relatively little
electron density between the two borons, suggesting the absence of a boronboron bond. This is information extracted from the bond density surface
model, and has been obtained without reference to any preconceived ideas
about the bonding in diborane.

*

An even higher value of the electron density leads to a surface in which only nearly spherical regions ofelectron density around the non-hydrogen atoms are portrayed. This serves to locate the positions of theseatoms and is the basis of the X-ray diffraction experiment.
Appendix A
623

Open diborane bond density in the topics directory, and switch to a meshor transparent surface to see how few electrons actually accumulate in
the region between the two borons. Close diborane bond density when
you are finished.

Bond density surfaces can also be informative in describing changes inbonding in moving from reactants to products through a transition state in achemical reaction. For example, heating ethyl formate causes the molecule tofragment into two new molecules, formic acid and ethylene. A line drawing
can show which bonds are affected by the overall reaction, but it cannot tell
us if these changes occur all at once, sequentially, or in some other fashion.

Comparison of the bond density surface in the pyrolysis transition state withthose of the reactant and the products suggests that the CO single bond of thereactant is clearly broken in the transition state and that the migratinghydrogen seems more tightly bound to oxygen (as in the product) than tocarbon (as in the reactant). It can be concluded that the transition state moreclosely resembles the products than the reactants, and this provides anexample of what chemists refer to as a late (product-like) transition state.

Appendix A624

To see the smooth change in electron density throughout the course of
the ethyl formate pyrolysis reaction, open pyrolysis bond density in the
topics directory. Click on at the bottom left of the screen to animate
the graphic (click on
to stop the animation). Switch to a mesh ortransparent surface to follow the change in bonding. Close pyrolysis bonddensity when you are finished.

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ELECTROSTATIC POTENTIAL MAPS: CHARGEDISTRIBUTIONS
The charge distribution in a molecule can provide critical insight into its
physical and chemical properties. For example, molecules that are charged, or
highly polar, tend to be water-soluble, and polar molecules may stick togetherin specific geometries, such as the double helix in DNA. Chemical reactions
are also associated with charged sites, and the most highly-charged
molecule, or the most highly-charged site in a molecule, is often the mostreactive. The sign of the charge is also important. Positively-charged sites ina molecule invite attack by bases and nucleophiles, while negatively-charged
sites are usually targeted by acids and electrophiles.
One way to describe a molecule’s charge distribution is to give a numericalatomic charge for each atom. A particularly simple and familiar recipe
yields so-called formal charges directly from Lewis structures.
Unfortunately, formal charges are arbitrary. In fact, all methods for
assigning charge are arbitrary and necessarily bias the calculated charges in
one way or another. This includes methods based on quantum mechanics. The
reason may be traced back to the notion that atomic boundaries arethemselves ill-defined and it is impossible to decide which electrons areassociated with which nuclei.
An attractive alternative for describing molecular charge distributions makes
use of a quantity termed the electrostatic potential. This is the energy ofinteraction of a point positive charge with the nuclei and electrons of amolecule. The value of the electrostatic potential depends on the location of
the point positive charge. If the point charge is placed in a region of excess
positive charge (an electron- poor region), the point charge-moleculeinteraction is repulsive and the electrostatic potential will be positive.
Conversely, if the point charge is placed in a region of excess negative charge(an electron-rich region), the interaction is attractive and the electrostatic
potential will be negative. Thus, by moving the point charge around themolecule, the molecular charge distribution can be surveyed.
Electrostatic potentials can be depicted in various ways. For example, it ispossible to make an electrostatic potential surface by finding all

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of the points in space where the electrostatic potential matches someparticular value. This is precisely what was previously done for both
molecular orbitals and electron densities. A much more useful way to show
molecular charge distribution is to construct a so-called electrostatic
potential map. This is done first by constructing an electron density surface
corresponding to a space-filling model (see the topic Electron Densities:
Sizes and Shapes of Molecules). The electrostatic potential is then mapped
onto this surface using different colors to represent the different values of theelectrostatic potential. Mapping requires an arbitrary choice for a color
scale. Spartan uses the rainbow. Red, the low energy end of the spectrum,
depicts regions of most negative (least positive) electrostatic potential, andblue depicts the regions of most positive (least negative) electrostatic
potential. Intermediate colors represent intermediate values of theelectrostatic potential, so that potential increases in the order: red < orange< yellow < green < blue.
The connection between a molecule’s electron density surface, its
electrostatic potential surface, and an electrostatic potential map is
illustrated below for benzene. The electron density surface defines
molecular shape and size, and performs the same function as a conventional
space-filling model by indicating how close two benzenes can get in a liquid
or in a crystal.

space-filling model
for benzene

electron density surface
for benzene

Open benzene electron density in the topics directory. Two different
images, a space-filling model and an electron density surface, appear side
by side. You can switch between the two models (in order to manipulatethem) by clicking on each in turn. Notice how similar they are. To get an
even clearer impression, switch to a mesh surface. Click on the graphic
and select Mesh from the menu which appears at the bottom right of thescreen. Switch to a space-filling model (Space Filling from the Model

Appendix A

627

menu). The two are now superimposed. Close benzene electron density
when you are finished.

The electrostatic potential corresponding to points where the potential isnegative shows two different surfaces, one above the face of the ring andthe other below. Since the molecule’s π electrons lie closest to these surfaces,
we conclude that these electrons are responsible for the attraction of a point
positive charge (or an electrophile) to the molecule. An electrostatic
potential surface corresponding to points where the potential is positive has
a completely different shape. It is disk-shaped and wrapped fairly tightly
around the nuclei. The shape and location of this surface indicates that apoint positive charge is repelled by this region, or that a point negative charge(a nucleophile) would be attracted here.

negative (left) and positive (right) electrostatic potential surfaces for benzene

Open benzene electrostatic potential in the topics directory. Two different
images appear side by side. The one on the left depicts a surface ofconstant negative potential, while the one on the right depicts a surfaceof equal positive potential. You can switch between the two models (inorder to manipulate them) by clicking on each in turn. Close benzene
electrostatic potential when you are finished.

Next, combine the electron density and electrostatic potential surfaces to
produce an electrostatic potential map. This simultaneously conveys both themolecule’s size and shape as well as its charge distribution in a compact andeasily interpretable manner. The size and shape of the map are, of course,
identical to that of the electron density surface, and indicates what parts of themolecule are easily accessible to other molecules (the outside world). The
colors reveal the overall charge

Appendix A

628

distribution. The faces of the ring, the π system, are red (electron rich), while
the plane of the molecule and especially the hydrogens are blue (electronpoor).

electrostatic potential map for benzene

Open benzene electrostatic potential map in the topics directory.
Manipulate the image to convince yourself that the red regions are on
the π faces and the blue regions are around the edges. Close benzene
electrostatic potential map when you are finished.

Electrostatic potential maps have made their way into mainstream generaland (especially) organic chemistry textbooks as a means of displaying
charge distributions in molecules. In addition, they have found application
as a natural step beyond steric models for interpreting and predicting the way
in which molecules fit together. A good example of this follows from theelectrostatic potential map for benzene, which recall is negative on the πfaces and positive around the periphery. The benzene dimer would,
therefore, be expected to exhibit a perpendicular geometry, to best
accommodate Coulombic interactions, instead of a parallel arrangement.

electrostatic potential maps for parallel (left) and perpendicular (right)
benzene dimers

Appendix A

629

Open benzene dimer electrostatic potential map in the topics directory.
Note that the parallel arrangement forces the negative region of one
benzene onto the negative region of the other, while the perpendicular
structure associates the negative region of one benzene with a positive
region of the other. Close benzene dimer electrostatic potential map
when you are finished.

Of greater interest is the structure of benzene in solid state. Intuition suggests
a parallel stack. After all, benzene is flat and flat things (plates, pancakes,
hamburgers) make stacks. However, Coulombs law clearly favors aperpendicular arrangement.

parallelperpendicular

The experimental X-ray crystal structure indeed shows a perpendiculararrangement, albeit in three dimensions. There are two lessons here.
Intermolecular interactions go beyond steric interactions and sometimes our
simple one and two-dimensional views of the world will lead us astray.

Appendix A

630

X-ray crystal structure of benzene

Open benzene crystal in the topics directory. Manipulate in order to see
the packing of benzene molecules. Close benzene crystal when you arefinished.

Electrostatic potential maps may also be used to describe in great detail theworkings of chemical reactions. For example, a map may be used to show thetransfer of negative charge during the Sn2 reaction of cyanide with methyl
iodide.
C–

CH3 I

N C CH3 + I –Open Sn2 cyanide+methyl iodide in the topics directory. One frame of asequence of electrostatic potential maps for the Sn2 reaction will appear.
Animate by clicking on
at the bottom left of the screen (stop theanimation by clicking on ). Note that the negative charge (red color)flows smoothly from cyanide to iodide during the reaction. Note also, thatcyanide (as the reactant) is more red than iodide (as the product). Iodide isbetter able to carry negative charge, that is, it is the better leaving group.
Switch to mesh or transparent map to see the making and breaking ofbonds. Close Sn2 cyanide+methyl iodide when you are finished.

LOCAL IONIZATIONPOTENTIAL MAPS AND
LUMO MAPS:ELECTROPHILIC AND
NUCLEOPHILICREACTIVITIESAppendix A

The Hammond Postulate states that thetransition state in a (one-step) reaction
will more closely resemble the side of
the reaction that is higher in energy.
Thus, the transition state of an
endothermic reaction will more closely
resemble the products, and the transition
631

state of an exothermic reaction will
resemble the reactants. One way torationalize
theHammondpostulate is to suggest thatsimilarity in energy implies
similarity in structure. That is,
the transition state will resemble

whichever reactants or products towhich it is closer in energy. As seen in
the reaction coordinate diagrams below
this is the product in an endothermic
reaction and the reactants in an
exothermic reaction.

The Hammond Postulate provides a conceptual basis both for the FukuiWoodward-Hoffmann rules (see the topic Atomic and Molecular Orbitals)
and for the use of graphical models. Both consider the properties ofreactants as an alternative to direct calculations of transition states andreaction pathways as a way to assess chemical reactivity and selectivity. In
this context, two models stand out as being particularly useful: the local
ionization potential map for electrophilic reactions and (with some caveats)
the LUMO map for nucleophilic reactions.

Appendix A

632

Local Ionization Potential Maps and Electrophilic Reactivity
The local ionization potential provides a measure of the relative ease ofelectron removal (ionization) at any location around a molecule. For
example, a surface of low local ionization potential for sulfur tetrafluoride
demarks the areas which are most easily ionized, and is clearly recognizable
as a lone pair on sulfur.

local ionization potential for sulfur tetrafluoride

While the local ionization potential by itself is not a particularly useful model,
a map of the local ionization potential onto an electron density surface (a local
ionization potential map) has proven to be of value in revealing regions fromwhich electrons are most easily ionized and susceptible to electrophilic
attack.

"electron density"

For example, they show both the positional selectivity in electrophilicaromatic substitution (NH2 directs ortho/para, and NO2 directs meta), andthe fact that π-donor groups (NH2) activate benzene while electronwithdrawing groups (NO2) deactivate benzene.

Appendix A

633

Open benzene, aniline, nitrobenzene local ionization potential maps in
the topics directory. Here, the color red corresponds to regions of lowest
ionization potential (most accessible to electrophiles). Note, that the πsystem in aniline is more accessible than the π system in benzene (thestandard) and that the ortho and para positions are more accessible thanmeta positions. Note also, that the π system in nitrobenzene is lessaccessible than the π system in benzene and that here the meta positions
are more accessible than the ortho and para positions, in accord withobservation. Close benzene, aniline, nitrobenzene local ionization
potential maps when you are finished.

LUMO Maps and Nucleophilic Reactivity
As elaborated in the topic Atomic and Molecular Orbitals, the energies andshapes of the frontier molecular orbitals may anticipate chemistry of amolecule. Molecular orbital maps may also lead to informative models. The
most common of these is the so-called LUMO map, in which the (absolutevalue) of the LUMO is mapped onto an electron density surface. This
anticipates where an electron pair (a nucleophile) might attack.

Appendix A

634

A good example is provided by the LUMO map for cyclohexenone.

The LUMO shows which regions of a molecule are most electron deficient,and hence most subject to nucleophilic attack. In this case, one such region
is over the carbonyl carbon, consistent with the observation that carbonylcompounds undergo nucleophilic addition at the carbonyl carbon. Anotherregion is over the  carbon, again consistent with the known chemistry of
,-unsaturated carbonyl compounds, in this case conjugate or Michael
addition.
HO

O

CH3
CH3Li
carbonyl addition

O(CH3)2CuLi
Michael addition
CH3

The buildup of positive charge on the  carbon leading to possibility of
Michael addition could have been anticipated from resonance arguments,
although the LUMO map, like an experiment, has the advantage of showing
the result (“you don’t have to ask”).
Open cyclohexenone LUMO map in the topics directory and click on
the resulting surface. Switch to a mesh or transparent surface in order to
see the underlying skeletal model. On Windows, click on the graphic andselect Mesh or Transparent from the menu which appears at the bottom
right of the screen. On the Mac, position the cursor over the graphic, holddown on either the left or right button and select from the menu whichappears alongside. Orient the molecule such that the two “blue regions”
are positioned over the appropriate carbons and then switch back to a solid
surface. Close cyclohexenone LUMO map when you are finished.

Appendix A

635

Some caution needs to be exercised. Specifically the LUMO may not be theimportant molecular orbital for the chemical reaction of interest, and it may
be necessary to base the map on a higher-energy unoccupied molecularorbital (LUMO+1, LUMO+2, ...).

Appendix A

636

Appendix B
Capabilities and Limitations
Molecular Mechanics Models
The molecular mechanics module calculates the energy (acombination of strain energy and intramolecular interaction energy),
equilibrium geometry and vibrational frequencies, as well as provides forconformational searching*. SYBYL (Tripos, Inc.) and MMFF** (Merck
Pharmaceuticals) force fields are available. There are no atom limits.
Semi-Empirical Models
The semi-empirical module calculates the heat of formation, wave
function, equilibrium and transition-state geometries and vibrationalfrequencies. MNDO, AM1, RM1, PM3*** and PM6 models are supported.
MNDO/d replaces MNDO for second-row (and heavier) main-groupelements. MNDO has been parameterized for H, He, Li-F, Al-Cl, Ca, Zn,
Ge, Br, Cd, Sn, I, Hg and Pb; AM1 for H, B-F, Al-Cl, Zn, Ge, Br, Sn
and I; RM1 for H, C–F, P, S, Cl, Br and I; PM3 for H, Li-F, Mg-Cl, Ca,
Ti-Br, Zr, Mo-Pd, Cd-I, Hf-Pt and Hg-Bi and Gd; PM6 for H–Bi except for
Ce–Yb. All semi-empirical models involve a minimal valence basis set.
The preset limits for all semi-empirical calculations is 300 atoms.
Hartree-Fock Models
The Hartree-Fock module calculates the energy and wave function,equilibrium and transition-state geometries and vibrational frequencies.
* MMFF is the only method available for generation of conformer libraries.
** The published parameters for MMFF have been extended to all elements in the Periodic Table.
While it can be applied to any molecule, it is likely to perform poorly for molecules incorporatingtransition metals, lanthanides and actinides.
*** The published parameters for PM3 has been extended to transition metals. Except for Zn, Cd andHg, these include d-type orbitals in the basis set.

Appendix B

637

Both closed and open-shell (either restricted, ROHF, or unrestricted, UHF)
calculations are supported. Available basis sets are enumerated later in thisappendix. Hartree-Fock models have been implemented for use on multicore processors.
Preset limits for Hartree-Fock calculations are 200 atoms and 2,000 basis
functions. Calculations on molecules with up to 100 atoms are practical.
Density Functional Models
The density functional module calculates the energy and wave function,equilibrium and transition-state geometries and vibrational frequencies, aswell as provides for conformational searching by means of a multi-step
recipe. Available functional cover a wide range drawn from several
categories: GGA, GH-GGA, RSH-GGA, mGGA, GH-mGGA, RSH-mGGA,
and with Spartan’24 dual hybrid (DH) RSH-mGGA, where the common
denominator is the Generalized Gradient Approximation (GGA), that is,depends on the electron density and its gradient. Three dozen commonly
employed functionals appear in menus, separated by category, and others may
be specified by name. Both closed and open-shell calculations are supported.
Available basis sets are enumerated later in this appendix. Density
functional models have been implemented for use on multi-coreprocessors.
Preset limits for density functional calculations are 200 atoms and 2,000
basis functions. Calculations on molecules with up to 100 atoms arepractical.
MP2 Models
The Møller-Plesset module calculates the energy and wave function andequilibrium and transition-state geometries using either the MP2 or RI-MP2
models. Vibrational frequencies are also available from both models, but
require numerical differentiation of analytical gradients. Both closed andopen-shell calculations are supported. Available basis sets are enumerated
later in this appendix. MP2 and RI-MP2 models have been implemented
for use on multi-core processors.

Appendix B

638

Depending on basis set, practical considerations limit application of thesetechniques to molecules comprising 20-30 heavy (non- hydrogen) atoms,
although program limits are set much larger.
Wave Function-Based Correlated Models
The wave function based correlated module calculates only the energy.
Available from layered menus are the MP3 and MP4 Møller-Plesset
methods, CCSD and CCSD(T) coupled-cluster methods and QCISD and
QCISD(T) quadratic CI methods. In addition, the electronic energy from theG3, G3(MP2), G4 and G4(MP2) thermochemical recipes (see below) isavailable. Other methods may be specified according to their name. Available
basis sets are enumerated later in this appendix.
Depending on the specific model and basis set, practical considerations limit
application of these techniques to molecules comprising 10-20 heavy (nonhydrogen) atoms, although program limits are set much larger.
Thermochemical Recipes
The G3, G3(MP2), G4 and G4(MP2) recipes are available for highly- accurate
heat of formation calculations which in our view represent approximations
to coupled-cluster methods. Practical considerations generally limit
application of the G3 and G4 recipes to molecules comprising less than 10
heavy atoms and the G3(MP2) and G4(MP2) recipes to molecules
comprising less than 15 heavy atoms.
The T1 recipe has been developed to closely reproduce G3(MP2) heats offormation. It makes use of an HF/6-31G* geometry, instead of the MP2/631G* geometry, replaces the large basis set MP2 calculation in G3(MP2) bya dual-basis set RI-MP2 calculation, eliminates both the QCISD(T)calculation and the vibrational frequency calculation (needed to obtain zeropoint energy and to correct the energy for finite temperature) and introduces
an empirical correction based on the atom counts and Mulliken bond orders.
The result is that T1 requires 2-3 orders of magnitude less computation timethan G3(MP2). Calculations on molecules with 30-50 heavy atoms arepractical.

Appendix B639

T1 is limited to closed-shell, uncharged molecules comprising H, C, N, O, F,
Si, P, S, Cl and Br only and, because it incorporates parameters which depend
explicitly on molecular geometry, is in practice limited to molecules that canbe properly described in terms of a conventional valence structure. T1 is likely
to be unsatisfactory for transition states.
Excited-State Models
Two classes of models are available for calculations of excited states:
configuration interaction (CI) models and time-dependent density
functional (TDDFT) models. The former comprises three models: CIS(configuration interaction singles), CISD (configuration interaction singles
with doubles correction) and RI-CIS(D), which are analogous to the HartreeFock model for ground-state calculations. The latter are analogous to density
functional models for ground-state calculations and support the samefunctionals or combinations of functionals available for geometry
optimization and frequency calculations. Available basis sets are
enumerated later in this appendix.
Preset limits for excited-state calculations are 200 atoms and 2,000 basis
functions. Depending on the specific model and basis set, practicalconsiderations limit applications to molecules comprising 20-30 atoms.
Basis Sets and Pseudopotentials
Available basis sets for Hartree-Fock, density functional, MP2 (RI- MP2)and wave function based correlated models for ground states and CIS, CISD
(RI-CIS(D)) and time-dependent density functional (TDDFT) models for
excited states include the full range of Pople basis sets: minimal STO-3G,
split-valence 3-21G, 6-31G, 6-311G and polarization 6-31G*, 6-31G**, 6311G* and 6-311G**. These may be supplemented with additional and/or
higher-order polarization functions and/or with diffuse functions. Also
available are the Dunning cc-pVDZ, cc-pVTZ and cc-pVQZ, and thecorresponding augmented basis sets, the Weigand/Aldrich def 2 series ofbasis set, the G3 Large basis set, and the PCJ-0, PCJ-1 and PCJ-2 basis sets
(developed for the calculation of NMR coupling constants).

Appendix B

640

Dual-basis set techniques (mixing small and large basis sets) are supported
for ground-state energy calculations for Hartree-Fock, density functionaland MP2 models. These can be up to an order of magnitude less costly thansingle-basis set calculations, depending on choice of small and large basis
sets.
Pseudopotentials are available and are automatically invoked for
calculations on molecules incorporating heavy atoms (for which all- electron
basis sets are not available). Starting with Spartan’18, this includes
lanthanides and actinides pseudopotentials for which have been specificallycalibrated to provide good equilibrium geometries for density functionalmodels using the 6-31G* basis set.
Machine Learning and Neural Network Models
Spartan’24 provides five neural net routines. The first (Corrected
MMFF), starts from MMFF geometry and improves the quality of MMFF
energies (in particular conformer energy differences) attempting to
reproduce ωB97X-V/6-311+G(2df,2p)//MMFF. The second (and likely theroutine to see the most utility) provides ωB97X-D/6-31G* equilibriumgeometries starting from MMFF geometries. (Est. Density Functional:
ωB97X-D/6-31G*). And three additional machine learning routines thatthat estimate total Energies from:•••Est. Density Functional: ωB97X-V/6-311+G(2df,2p)//ωB97X-D/6-31G*
Est. Density Functional: ωB97M-V/6-311+G(2df,2p)//ωB97X-D/6-31G*
Est. Density Functional: ωB97M(2)/6-311+G(2df,2p)//ωB97X-D/6-31G*

Input is either ωB97X-D/6-31G* equilibrium geometries and energies(from QM calculations) or equilibrium geometries from the neural (Est.
Density Functional: ωB97X-D/6-31G*) and a single ωB97X-D/6-31G*
energy calculation.
All routines support for closed-shell, uncharged molecules comprising theelements: H, C, N, O, F, S, Cl and Br (only). There are no atom limits for
the MMFF-based routines neural net. With the exception of a single-point
ωB97X-D/6-31G* energy calculation (required for energies, NMR spectra
and wave function related data) there are no atom limits to the second
routine (Est. Density Functional ωB97X-D/6-31G* geometry). When
Appendix B

641

requiring ωB97X-D/6-31G* energy or geometry as input, atom limits (≈200 atoms, ≈ 2000 basis functions) are the same as for standard density
functional calculations. Utilized strategically, the neutral network routines
can save significant computational time (orders of magnitude in somecases).
Solvent Models
Spartan supports the C-PCM and SS(V)PE models for energy, geometry
and frequency calculations with Hartree-Fock and density functional models
with any basis set. C-PCM and SS(V)PE depend only on the dielectric
constant of the solvent. Menus allow for specifying non-polar and polar
solvents as well as water but specific solvents (dielectric constants) may be
specified. Both models alter the wave function in addition to the energy
allowing graphical surfaces and property maps to be calculated in thepresence of solvent.
Two additional solvent models for energy calculations (only) are supported.
The SM5.4 model, which is available for H, C–F, S–Cl, Br and I, uses a
parameterized procedure to estimate the aqueous solution energy. It estimates
only the aqueous solvation energy. This in turn may be added to the gasphase energy obtained from any molecular mechanics or quantum chemical
model.
Q-Chem’s implementation of SM8 and SM12 are available for H, C–F, S–
Cl and Br, and applicable only to Hartree-Fock and density functionalmodels with the 6-31G*, 6-31G**, 6-31+G* and 6-31+G** basis sets. These
affect the wave function, meaning that graphical displays may be obtainedin the presence of solvent. Both models have been parameterized for water
as well as a variety of organic solvents. Common solvents may be specified.

Appendix B

642

Properties and Spectra
The properties module is automatically invoked following completion of amolecular mechanics or quantum chemical calculation. By default, it
provides for text output printing, population analyses and atomic charge
calculation (Mulliken, natural bond orbital and based on fits to electrostatic
potentials), evaluation of thermodynamic quantities (heat capacity, enthalpy,
entropy and free energy) and zero- point energy if vibrational frequencies areavailable, and calculation of the dipole moment.
The entropy comprises four components: translation, rotation, vibration andconformation.

The sum i is over vibrational modes and the sum j is over conformers, n is thenumber of moles, M is the molecular mass, IA, IB, IC are the principal
moments of inertia, s is the symmetry number,  are the vibrationalfrequencies, E are energies relative to the lowest-energy conformer, g are thenumber of times the conformer appears and Me is the number of 3-fold rotors(“methyl groups”). R, k and h are the gas constant, Boltzmann’s constant andPlanck’s constant, respectively and N0 is Avogadro’s number.
The vibrational component of the entropy is problematic as it goes to as the frequency goes to 0. In practice, the contribution is clamped at 1/2 R(the entropy of rotation).

Appendix B

643

Entropies are available for all EDF2/6-31G* (only) entries in SSPD. Notethat these have not been corrected for the conformational contribution,
which may range to several tens of entropy units for large flexible
molecules.
Properties based on graphical displays that are available include the area,
exposed area and volume of an electron density surface, the polar area ofan electrostatic potential map for cutoff values of-75, -100 and -125 kJ/mol, the maximum and minimum values of theelectrostatic potential on an electrostatic potential map and the minimum
value of the local ionization potential on a local ionization potential map.
These require calculation of the respective surfaces and property maps, andneed to be explicitly requested by checking the QSAR box inside theCalculations dialog (Calculations under the Setup menu; Chapter 21).
They are either available from the QSAR tab of the Molecule Properties
dialog (Properties under the Display menu; Chapter 22) or from the
Formula Editor dialog (Formulas under the Display menu; Chapter 22).
The properties module is also responsible for calculating quantities related
to infrared/Raman spectra (vibrational frequencies and infrared/Raman
intensities), NMR spectra (chemical shifts and coupling constants) andUV/visible spectra (excited-state transition energies and intensities). IR
spectra calculations may be carried out with molecular mechanics, semiempirical, Hartree-Fock, density functional and MP2 and RI-MP2 models.
Note, however, that MP2 and RI-MP2 infrared calculations need to be
performed using numerical differentiation and are in practice limited tosmall molecules. NMR and Raman spectra calculations are limited toHartree-Fock and density functional models and UV/visible spectra
calculations are limited to Hartree-Fock models (CIS for excited states) anddensity functional models (TDDFT for excited states).
Graphical Models
The graphics module provides for data preparation associated with the display
as surfaces, property maps and slices of molecular orbitals, electron
densities, spin densities, electrostatic potentials, and local

Appendix B

644

ionization potentials. The sizes of electron density surfaces (and property
maps based on electron density surfaces) may be chosen either using a
specific value of the density or a value that encloses a specific percentageof the total number of electrons. Accessible and inaccessible regions may
be distinguished for electron density surfaces and all property maps basedon electron density surfaces.
In addition to its more general purpose graphics display, Spartan displays
an orbital energy diagram (up to 12 highest-occupied molecular orbitals andthe 2 lowest-unoccupied molecular orbitals). Molecular orbital graphics
may be generated on-the-fly, given that a wave function is available.
Similarity Analysis
The similarity analysis module evaluates and quantifies the extent to whichmolecules are similar based either on selected atomic centers (structure) oron selected chemical function descriptors (CFD’s). In addition, it quantifies
the degree of fit of a molecule into a chemical environment (apharmacophore). Similarity analyses are carried out between one or more
molecules or pharmacophores in a document (the template) and one or more
molecules or pharmacophores in one or more documents (the library).
Molecules in the library (only) may either correspond to single conformers or
to collections of diverse conformers.

Appendix B

645

Appendix C
Menus
Spartan Screen
File

Appendix C

646

Appendix C

647

Appendix C

648

Appendix C

649

Appendix C

650

Appendix C

651

Appendix C

652

Appendix C

653

Appendix C

654

Appendix C

655

Database
Add Columns...

Adds data columns to search results.

Copy

Copies selected molecules or data.

Paste

Pastes text to data column(s).

FormatFormats data column(s).

DeleteDeletes search results or data columns.

Appendix C

656

Appendix E
Units
Geometries
Cartesian coordinates are given in Ångstroms (Å).
Bond distances are given in Å. Bond angles and dihedral angles are given
in degrees (°).
Surface areas, accessible surface areas and polar surface areas areavailable in Å2 and volumes in Å3.
Energies, Heats of Formation and Strain Energies, Zero-Point
Energies, Enthalpies and Gibbs Energies and Entropies
Total energies from Hartree-Fock calculations are available in au, kcal/mol
and kJ/mol.
Experimental heats of formation as well as those from semi-empiricalcalculations and from thermochemical recipes are available in kJ/ mol, au
and kcal/mol.
Strain energies from molecular mechanics calculations are available in
kJ/mol, au and kcal/mol.
Energies, heats of formation and strain energies corrected empirically for theeffects of aqueous media are given in the same units as the corresponding
gas-phase quantities.
Zero-point energies, enthalpies and Gibbs energies available in kJ/ mol,kcal/mol and au/mol. Entropies are available in J/mol •degree,kcal/mol•degree and au/mol•degree.
Orbital Energies
Orbital energies are available in eV.

Appendix D

657

Energy Conversions
au
1 au
1 kcal/mol
1 kJ/mol
1 eV

1.593 (-3)
3.809 (-4)
3.675 (-2)

kcal/molkJ/moleV

2.390 (-1)
23.06

2625
4.184
96.49

27.21
4.337 (-2)
1.036 (-2)
-

627.5

a) exponent follows in parenthesis, e.g., 1.593 (-3) = 1.593 x 10-3

Electron Densities, Spin Densities, Dipole Moments, Charges,
Electrostatic Potentials and Local Ionization Potentials
Electron densities and spin densities are given in electrons/au3. Dipole
moments are given in Debyes.
Atomic charges are given in electrons.
Electrostatic and hydride potentials are given in kJ/mol. Local ionization
potentials are given in eV.
Vibrational Frequencies, Infrared and Raman Intensities
Vibrational frequencies are given in wavenumbers (cm-1). Intensities are
given relative to the most intense peak. The simplified plot display will
renormalize on-the-fly to correspond to the most intense peak that isdisplayed.
Chemical Shifts, Coupling Constants
Chemical shifts are given in parts-per-million (ppm) relative toappropriate standards: hydrogen (tetramethylsilane); carbon(tetramethylsilane);nitrogen(nitromethane);fluorine(fluorotrichloromethane); silicon; (tetramethylsilane); phosphorous(phosphoric acid). Standards have not been calculated for all models, but they
are available for Hartree-Fock and several popular density functionalmodels with the 6-31G* basis set. A full listing is provided in Appendix L.
Chemical shifts for other models need to be adjusted using the appropriate
standards calculated for the same models. Coupling constants are in Hz.
Appendix E

637

UV/visible Spectramax is given in wavenumbers (cm-1). Intensities are given relative to themost intense peak.

Appendix F
Citation
The proper citation for Spartan’24 is as follows:
Spartan’24
Wavefunction, Inc., Irvine, CA
Many people have contributed to Spartan’s interface. The current members
are: Bernard Deppmeier, Andy Driessen, Thomas Hehre, Warren Hehre,
Philip Klunzinger, Sean Ohlinger, and Jurgen Schnitker.
Except for molecular mechanics and semi-empirical models, the calculation
methods used in Spartan have been documented in: Y. Shao, L.F. Molnar,
Y. Jung, J. Kussmann, C. Ochsenfeld, S.T. Brown, A.T.B. Gilbert, L.V.
Slipchenko, S.V. Levchenko, D.P. O’Neill, R.A. DiStasio Jr., R.C. Lochan, T.
Wang, G.J.O. Beran, N.A. Besley, J.M. Herbert, C.Y. Lin, T. Van Voorhis,
S.H. Chien, A. Sodt, R.P. Steele, V.A. Rassolov, P.E. Maslen, P.P.
Korambath, R.D. Adamson, B. Austin, J. Baker, E.F.C. Byrd, H. Dachsel,
R.J. Doerksen, A. Dreuw, B.D. Dunietz, A.D. Dutoi, T.R. Furlani, S.R.
Gwaltney, A. Heyden, S. Hirata, C-P. Hsu, G. Kedziora, R.Z. Khalliulin, P.
Klunzinger, A.M. Lee, M.S. Lee, W.Z. Liang, I. Lotan, N. Nair, B. Peters, E.I.
Proynov, P.A. Pieniazek, Y.M. Rhee, J. Ritchie, E. Rosta, C.D. Sherrill,
A.C. Simmonett, J.E. Subotnik, H.L. Woodcock III, W. Zhang, A.T. Bell,
A.K. Chakraborty, D.M. Chipman, F.J. Keil, A.Warshel, W.J. Hehre,
H.F. Schaefer, J. Kong, A.I. Krylov, P.M.W. Gill and M. Head-Gordon,
Phys. Chem. Chem. Phys., 8, 3172 (2006).
A discussion and assessment of commonly-used calculation methods is foundin: W.J. Hehre, A Guide to Molecular Mechanics and Quantum Chemical
Calculations, Wavefunction, Inc., Irvine, CA, 2003, available as a PDF
under the Help menu. This is somewhat outdated as there have been many
important developments since it was written, but still of some value. A
guide reflecting current developments is in preparation.
Appendix F

639

Appendix G
Configuring theCambridge Structural Database
Spartan can act as an ancillary interface to the Cambridge Structural
Database (CSD). In order to search the CSD, Spartan must be configured
to point to the appropriate location of the CSD data. The CSD uses Python
to facilitate searching, and a specific python path will need to be set.
Instructions vary depending on platform (Windows, Macintosh, of Linux)and follow below:
Windows:(Click on Config near the bottom right of the CSD tab. This brings up the
Configure CSD Interface dialog:

If the current (2023 at the time of this update to the manual) CSD System
has been installed, the correct path for the python.exe will appear (as in theabove image). If this has been overwritten, it can be restored by clicking on
the Reset button at the bottom left of the dialog. The path may be handedited by typing the field, or may be set by using the file system (accessedby clicking on the downward triangle to the right of the path field). A valid
setting is marked with a green check, and invalid setting is marked with a red
X. Once enabled, you may search the CSD from within Spartan.

Note: The ConQuest application must have been opened at least once, inorder to use Spartan to interface the CSD.
Macintosh:
Click on the Config button near the bottom right of the CSD tab. This brings
up the Cambridge Software folder location dialog:

If the field is blank, click the Set… button and locate the CSD
applications folder (typically, this is a folder named CSD_20nn in the/Applications/CCDC folder, where 202n is the current license year). Spartan
will check the CSD applications and Python_API folders to ensure thenecessary interface tools have been installed.
Note: The ConQuest application must have been opened at least once, inorder to use Spartan to interface the CSD.
Linux:At present the link from the Spartan interface to the CSD is not yet
implemented. This will be addressed in a subsequent minor point releaseand this manual will be updated with necessary configuration instructions atthat time.

Appendix G

641

662

Appendix H
Constructing Custom Databases
New in Spartan’24 is the computational task SSPD Compatible. If thistask has been used to generate either an equilibrium geometry, or atransition state geometry, an additional option from the file menu isavailable: Save to Database ( ). If chosen, the resulting calculation isadded to a new collection, parallel to the existing SSPD (but at the same
computational model), which can optionally be searched alongside theprovided SSPD v. 6.1. Results are automatically saved to the Custom
Database Directory (Database tab, the Options menu Preferences dialog;
Chapter 25).
The same approach can be used to generate custom collections utilizing
different computational models than those available in the SSPD. In thiscase, the File menu Save As feature may employed to save the document
as a Spartan Database file. In this way, other theory levels may be addedon top of those provided in the SSPD, SIRD and SRD. These may either
include the geometry, energy (heat of formation, strain energy), HOMO andLUMO energies, dipole moment, atomic charges, chemical shifts andvibrational frequencies obtained from quantum chemical calculations, or(for SSPD and SIRD only) conformer libraries generated from molecularmechanics calculations. Entries for SRD (transition states) need to derivefrom Spartan’s transition state guessing facility (Guess Transition States
under the Search menu; Chapter 23) in order that they include the original
set of reaction arrows. Documents containing one or more molecules thatare to be placed in a user database are first saved using Save As under theFile menu with Save as type set to Spartan Database. This results in two
files, a .spentry and a .spindex file for each molecule (or list). These should
then be put in a single directory, the path to which must be entered into thePaths Preferences dialog under Preferences... in the Options menu
(Chapter 25).
Note that it is important to specify a label (“name”) for each molecule.
Label specification is done either in the Molecule Properties dialog(see Properties under the Display menu in Chapter 22) or in the
spreadsheet (see Spreadsheet under the Display menu in Chapter 22).
663

Appendix I
Pharmacophore Input
The following file format is used for input of a pharmacophore (illustrated
for a pharmacophore with four hydrophobes and one positive ionizable
center):

The lines between BEGINCFD and ENDCFD define the individual
pharmacophore elements (one line/element):
type1|type2… (| separates types for multiple definitions), Cartesian (X,Y,Z)
coordinates (in Angstroms), unique number, radius of element (inAngstroms), weight of element in fit, use the element in fit (1) or ignore theelement (5)The following element types are available:
HPHOBEhydrophobe
RING_AROM aromatic ring
POS
positive ionizable center
NEG
negative ionizable center
HBA_CENTER hydrogen bond acceptor
HBD_CENTER hydrogen bond donor
EXCL_VOL
excluded volume
Appendix I

643

Appendix J
Input of Experimental Spectra
The databases of infrared and UV/visible spectra accessible on- line from
Spartan are in JCAMP format. Specification of both and examples can befound at the NIST website (NIST.gov).
The database of 13C spectra is in CML (Chemical Markup Language) format.
A description may be found at http://www.ch.ic.ac.uk/omf/ cml. A sample
file is provided below.
<?xml version="1.0" encoding="ISO-8859-1"?><cml><spectrum type="NMR"><metadataList><metadata name="nmr:OBSERVENUCLEUS" content="13C"/></metadataList><peakList><peak xValue="125.1399993896484" peakHeight="0.458" /><peak xValue="128.4499969482422" peakHeight="0.558" /><peak xValue="129.0099945068359" peakHeight="0.658" /><peak xValue="21.64999961853027" peakHeight="0.758" /><peak xValue="137.8399963378906" peakHeight="0.858" /></peakList></spectrum></cml>Blank line

This contains five shifts (xValue) and five associated intensities(peakHeight).

Appendix K

665

Appendix K
Platform Dependencies
This appendix covers variations in Spartan across Windows, Macintosh,
and Linux operating systems.
Accessing the Preferences… and About… dialogs
Under Windows and Linux, program Preferences… and the About… dialogs
are accessed from the Options menu at the top right of the Spartan
interface. For Macintosh users, program Preferences… may be accessed
via the Options menu and, by convention, both Preferences… and theAbout… dialog are accessible from the Spartan’24 (program) menu at the
top left of the Mac interface
Accessing Controls for Spartan Server
Under Windows, the server controls are accessed via the Embedded Server
tab under Preferences… from the Options menu. The server functions aspart of the graphical interface and the program must remain open in orderfor users to remotely submit to the server.
Under Linux and Macintosh, the server controls are accessed from theService Control entry under the Options menu. The server functions as anindependent service and the graphical interface does not need to remain
open in order for users to remotely submit to the server. Under Linux (only)
the service control is web based and may be accessed either locally or
remotely via http://machinename:8080. This requires that ports 8080 (forcommunication with the service controls) and 50002 (initial default for remotesubmission) are opened. The default username is admin, the default password
is password. For https communication instructions, contact
support@wavefun.com.
A description of the Embedded Server/Service Control dialog follows:

Appendix K

666

Settings/Options for the Embedded Server:

A

B

C

H

D E

F

G

I

J

K

L
N

M
O

P

Q
R

S

T

A Username. The Username on the account.
B Status. The account status, possible values are pending and activated.
Pending means a remote registration has been received, but not yet
approved by the server administrator.
C E-mail Address. The email address of the account user. At present this is asecondary means of identification of the account, Spartan does not(currently) generate/send emails.
D Key. A security key can be issued for an account. If a security key isissued, it must also be provided when the account is registered (from the
Available Servers tab).
E Privileges. Option to allow an account with the privilege to start a job
irrespective of the Job Queue.
F Job Quota. Sets limits on how many jobs a user can submit.

Appendix K

667

G Device ID/Name. A unique device ID and the name of the device remotesubmission is received from, in the case of other Spartan licenses, the nameis Spartan’24, in the case of iSpartan, the name of the iPad, iPhone, or iPod
Touch is used. A user account can have more than one Device ID/nameassociated with it.
H Remote Registration. Controls the security level for new user
registration, from lowest (Automatic = automatically register any new user)
to intermediate (Sign Off Required = new users can register, but the server
administrator must approve the account before it becomes active) to highest(Disabled = new accounts cannot be remotely registered and must be
generated manually by the server administrator).
I Job Quota. This is the default job quota (see above) that will be provided
to newly registered user accounts.
J New Account. Allows the server administrator to manually create a newuser account (not needed if the Remote Registration is kept in either
Automatic or Sign Off Required mode).
K Refresh. Refreshes the panel, required to see newly applied changes to thispanel.
L Repository Directory (Path). The location (on the server) that remotely
submitted jobs save to.
M Reset. If the server repository path has been changed, reset will revert tothe default path location.
N Port. The default port used for communication between the client(account) and server. If this is changed from 55002, the URL path specified
when client accounts verify with the server, should be modified with theaddition of a colon (:) and the new port number, for example:
If using default port 55002, a Host URL would be: http://opel.
wavefun.com.
If the port is changed on the server from 55002 to 55000, for example, the Host
URL will need to be changed to: http://opel.wavefun. com:55000.

Appendix K

668

O IP Address. Only used if the server has a secondary Ethernet connection
to specify which IP Address the server should listen on.
P Log Verbosity Level. Specifies the amount of communication logging
written when jobs are remotely submitted/returned/monitored/ etc. (0 meansno logging, 5 is maximum logging)
Q Expert. Off, by default, if turned on enables access to more advanced (andtypically lesser required) settings for server functionality.
R OK. Saves changes and releases the Preferences dialog (Windows), Service
Control dialog (Macintosh and Linux).
S Cancel. Cancels any changes and releases the Preferences dialog(Windows), Service Control dialog (Macintosh and Linux).
T Apply. Applies any changes without releasing the Preferences dialog(Windows), Service Control dialog (Macintosh and Linux).
Settings/Options for the Service Control Panel (Macintosh and Linux):

A

B

C

D

H

E

F

I

G

J

K

L

M
O

P

N
R

Appendix K

Q
S T

669

* Server(On/Off). Check box turns the server on or off (checked = on)
A Username. The Username on the account.
B Status. The account status, possible values are pending and activated.
Pending means a remote registration has been received, but not yet
approved by the server administrator.
C E-mail Address. The email address of the account user. At present this is asecondary means of identification of the account, Spartan does not(currently) generate/send emails.
D Key. A security key can be issued for an account. If a security key isissued, it must also be provided when the account is registered (from the
Available Servers tab).
E Privileges. Option to allow an account with the privilege to start a job
irrespective of the Job Queue.
F Job Quota. Sets limits on how many jobs a user can submit.
G Device ID/Name. A unique device ID and the name of the device remotesubmission is received from, in the case of other Spartan licenses, the nameis Spartan’24, in the case of iSpartan, the name of the iPad, iPhone, or iPod
Touch is used. A user account can have more than one Device ID/nameassociated with it.
H Remote Registration. Controls the security level for new user
registration, from lowest (Automatic = automatically register any new user)
to intermediate (Sign Off Required = new users can register, but the server
administrator must approve the account before it becomes active) to highest(Disabled = new accounts cannot be remotely registered and must be
generated manually by the server administrator).
I Job Quota. This is the default job quota (see above), provided to newly
registered user accounts.
J New Account. Allows the server administrator to manually create a newuser account (not needed if the Remote Registration is kept in either
Automatic or Sign Off Required mode).

Appendix K

670

K Refresh. Refreshes the panel, required to see newly applied changes to thispanel.
L Repository Directory (Path). The location (on the server) that remotely
submitted jobs save to.
M Reset. If the server repository path has been changed, reset will revert tothe default path location.
N Port. The default port used for communication between the client(account) and server. If this is changed from 55002, the URL path specified
when client accounts verify with the server, should be modified with theaddition of a colon (:) and the new port number, for example:
If using default port 55002, a Host URL would be: http://opel.
wavefun.com.
If the port is changed on the server from 55002 to 55000, for example, the Host
URL will need to be changed to: http://opel.wavefun. com:55000.
O IP Address. Only used if the server has a secondary Ethernet connection
to specify which IP Address the server should listen on.
P Log Verbosity Level. Specifies the amount of communication logging
written when jobs are remotely submitted/returned/monitored/ etc. (0 meansno logging, 5 is maximum logging)
Q Expert. Off, by default, if turned on, enables access to more advanced(and typically lesser required) settings for server functionality.
R Apply. Saves changes to the Server Tab of the Service Control panel.
S Cancel. Cancels any changes and releases the Service Control panel.
T Close. Applies any changes and releases, Service Control panel.

Appendix K

671

Additional platform dependencies. While in general Windows,
Macintosh, and Linux versions include identical functionality, a few
important differences should be mentioned, in particular, the embedded
server functionality. In order to utilize the server features, the GUI mustremain opened (it can be minimized, but must be open). On both theMacintosh and Linux platforms, the server is a true service/daemon, anddoes not require the Spartan program nor the Service Control Panel toremain open.
Additionally, the Linux panel is a web-based tool that can be accessed both
locally (on the Linux device) or remotely from a web browser on any of theclient machines. A user login and password are required. The default
username is admin, the default password is password. Once initiallylogged in, the password may be changed.

Appendix K

672

Appendix L
NMR 13C Chemical ShiftStandards
Nucleus
H

C

N

F

Si

P

STO-3G
3-21G(*)
6-31G
6-31G*
6-31+G*
6-31G**
6-31+G**
6-311G*
6-311+G*
6-311G**
6-311+G**
6-311++G**
6-311+G(2d,p)
PC-J0
PC-J1

33.7521 249.4284
33.6181 213.1943
33.6747 208.2044
32.9027 201.7207
32.8181 201.1517
32.3367 203.1517
32.2689 203.0758
32.8321 195.9091
32.7799 195.8544
32.4751 196.1543
32.4498 195.8412
32.4412 196.1088
32.4000 194.5000
33.8736 201.0753
32.2196 194.6676-99.3060 368.5390-251.1870 279.7970-276.2000 222.5260-160.1430 269.3660-159.5610 261.0900-160.3110 269.4610-159.7060 261.0800-177.3440 246.9560-184.5910 246.5820-177.7210 247.0910-184.7400 246.5860-184.9250 246.8600-182.2900 246.8690

578.6340 499.2810
509.1390 502.3530
484.5230 373.9520
450.1490 423.6900
446.6710 415.3570
448.3970 423.1850
444.6390 415.3570
395.6350 368.3180
395.6260 366.5100
396.7650 366.8630
396.7780 366.6250
395.3640 365.8180
385.7540 360.0760

EDF2/6-31G*
EDF2/6-31+G*
EDF2/6-31G**
EDF2/6-31+G**EDF2/6-311G*
EDF2/6-311+G*EDF2/6-311G**
EDF2/6-311+G**EDF2/6-311++G**
EDF2/6-311+G(2d,p)
EDF2/PC-J0
EDF2/PC-J1

32.1340 190.3690
32.0120 191.3710
31.7100 192.4450
31.5980 193.1940
32.2410 184.7540
32.2010 184.5320
31.9570 184.9030
31.9310 184.3930
31.9190 184.5420
31.8930 183.7730
32.9634 186.4313
31.6027 181.6027-110.5960 180.7560-112.6650 175.5010-110.4530 180.8260-112.4710 175.3460-136.9780 153.8800-145.1610 155.2890-137.0820 154.0490-145.1760 155.3610-145.2370 155.3650-146.0210 158.3640

412.4700 368.8170
406.8510 360.9880
410.6870 368.0760
404.6300 360.3590
337.3290 294.6500
336.8110 293.2240
338.9200 292.8010
337.7560 291.9270
336.8950 292.1020
326.5240 288.3070

BLYP/6-31G*
BLYP/6-31+G*
BLYP/6-31G**
BLYP/6-31+G**
BLYP/6-311G*
BLYP/6-311+G*
BLYP/6-311G**
BLYP/6-311+G**
BLYP/6-311++G**

31.8898 184.0004
31.7630 185.0810
31.4860 186.2780
31.3780 187.3770
32.0410 179.6600
32.0070 179.0360
31.7760 178.0360
31.7420 178.3800
31.7310 178.7600-108.0000 134.3119-111.5990 130.3580-107.7320 134.3010-111.4030 130.2770-136.0360 104.7670-145.2880 107.8570-136.1390 104.4190-145.3260 107.3890-145.1020 107.9910

402.4730 351.3090
397.7680 344.5740
402.2490 350.9010
392.9890 344.0820
328.6000 270.0880
321.1830 268.6140
331.9530 268.6970
323.1760 267.6970
323.2360 268.8390

Appendix K

673

BLYP/6-311+G(2d,p)BP/6-31G*
BP/6-31+G*
BP/6-31G**
BP/6-31+G**
BP/6-311G*
BP/6-311+G*
BP/6-311G**
BP/6-311+G**
BP/6-311++G**
BP/6-311+G(2d,p)31.713031.7540
31.6280
31.3470
31.2390
31.8560
31.8130
31.581031.5450
31.5330
31.5070

178.2330
188.0611
188.6910
190.0140
190.6410
182.9310
182.5960
182.8640
182.2710
182.7840
181.9580-146.8750-97.0220-98.8150-98.8200-98.6030-121.4130-129.4560-121.4970-129.3250-129.4050-131.0130

110.3870
142.4206
139.9320
142.4720
139.8580
115.7860
116.8670
115.7740
116.8340
116.8490
121.3390316.6360 267.5940
406.3890 354.6710
401.9640 348.6710
405.1030 353.9890
397.9700 347.9100
341.1380 282.1140
339.5860 282.5860
344.6450 280.5890
331.3310 281.4280
335.0130 280.9070
328.7120 278.3140

B3LYP/6-31G*
B3LYP/6-31+G*
B3LYP/6-31G**
B3LYP/6-31+G**
B3LYP/6-311G*
B3LYP/6-311+G*
B3LYP/6-311G**
B3LYP/6-311+G**
B3LYP/6-311++G**
B3LYP/6-311+G(2d,p)B3LYP/6-311G(2d,2p)
B3LYP/PC-J0
B3LYP/PC-J1

32.184232.062232.755031.659032.2872
32.2467
31.9998
31.9852
31.9669
31.9778
31.8149
33.012931.6464

189.6263
190.6658
191.7270
192.5140184.2227
183.9371
184.3793
183.9396
184.0443
183.9092
183.7248
185.8806
180.8468-117.7850-120.1610-117.5850-119.9760-143.7842-152.4219-143.9561-152.4219-152.4773-153.2297

180.1410
173.4960
180.3140
173.4550
152.2110153.8600
152.1760
153.8350
153.8360
156.5940

413.6860 370.9310
408.2430 362.4460
411.8990 369.5210
405.9210 361.8720
338.7460 294.9520
338.3000 293.2580
340.3220 293.0720
339.2570 292.0990
338.2340 292.2340
328.2710 289.0650
329.0500

ΩB97X-D/6-31G*
ΩB97X-D/6-31+G*
ΩB97X-D/6-31G**
ΩB97X-D/6-31+G**ΩB97X-D/6-311G*
ΩB97X-D/6-311+G*ΩB97X-D/6-311G**
ΩB97X-D/6-311+G**ΩB97X-D/6-311++G**ΩB97X-D/6-311+G(2d,p)ΩB97X-D/6-311G(2D,2P)
ΩB97X-D/PC-J0
ΩB97X-D/PC-J1

32.2255
32.1132
31.7943
31.695432.289632.2378
32.004431.9772
31.963931.929731.8051
33.080931.6687

195.0090
195.6450
196.7768
197.2185
189.4991
189.2949
189.6250
189.2128
189.4118
188.3941
188.8165
192.4019
186.1951-115.3090-120.1610-117.5850-119.9760-143.7842-152.4219-143.9561-152.4219-152.4773-153.2297

203.6770
173.4960
180.3140
173.4550
152.2110153.8600
152.1760
153.8350
153.8360
156.5940

419.2400 473.9430
415.1300 362.4460
417.4570 369.5210
412.9630 361.8720
354.7120 294.9520
354.3290 293.2580
356.1450 293.0720
355.5770 292.0990
354.4180 292.2340
344.4360 289.0650
344.8400

ΩB97X-V/6-31G*
ΩB97X-V/6-31+G*
ΩB97X-V/6-31G**
ΩB97X-V/6-31+G**ΩB97X-V/6-311G*
ΩB97X-V/6-311+G*ΩB97X-V/6-311G**
ΩB97X-V/6-311+G**ΩB97X-V/6-311++G**ΩB97X-V/6-311+G(2d,p)ΩB97XV/6-311G(2d,2p)
ΩB97XV/6-311++G(2d,2p)

32.1775
32.022831.7343
31.6065
32.2128
32.1399
31.912231.881231.951031.9778
31.6679
31.6674

197.4313
197.1721
199.4499
198.9342
194.0790
193.8788
194.1445
193.7954
193.4655
183.9092
192.3933
192.0270-117.7850-120.1610-117.5850-119.9760-143.7842-152.4219-143.9561-152.4219-152.4773-153.2297

180.1410
173.4960
180.3140
173.4550
152.2110153.8600
152.1760
153.8350
153.8360
156.5940

424.0790 370.9310
419.2680 362.4460
422.3330 369.5210
417.1200 361.8720
366.9670 294.9520
366.5780 293.2580
368.2830 293.0720
367.8110 292.0990
367.1550 292.2340
328.2710 289.0650
356.5920
356.2930

Appendix L

653

Glossary
This glossary addresses nomenclature (“jargon”) used throughout the manual,and more generally, in applications of molecular modeling. Some of theterms, such as Basis Set, will be familiar to the modeling community but
foreign to the broader community, while other terms, such as Kinetic
Product, may be foreign to the modeling community and familiar to thebroader community. Terms such as Entropy should be familiar to all and are
generally avoided. A number of terms from both categories have been
defined “in the context” of their use in molecular modeling rather than moregenerally. For example, the term NOE has been defined in terms of providing
information about which pairs of (non-bonded) atoms are inside a specified
cutoff distance (information that is useful in restricting the limits of aconformational search) rather than the nature of the phenomenon which
produces this information.
3-21G. A Split-Valence Basis Set in which each Core Basis Function is
written in terms of three Gaussians, and each Valence Basis Function issplit into two parts, written in terms of two and one Gaussians, respectively.
3-21G basis sets have been determined to yield the lowest total HartreeFock Energies for atoms. The nomenclature 3-21G implies use of the 321G(*) basis set on molecules incorporating second-row (and heavier)main-group elements.
3-21G(*). The 3-21G Basis Set supplemented by d-type Gaussians for eachsecond-row and heavier main-group elements only. This is required in orderto get good equilibrium geometries. Without the added functions, the 3-21G
basis set is not recommended for use for molecules incorporating secondrow (and heavier) main-group elements.
6-31G. A Split-Valence Basis Set in which each Core Basis Function is
written in terms of six Gaussians, and each Valence Basis Function is split
into two parts, written in terms of three andGlossary675

one Gaussians, respectively. 6-31G basis sets have been determined to yield
the lowest total Hartree-Fock Energies for atoms. The 6-31G basis set
is rarely used alone but rather is supplemented by one or more sets of
Polarization Functions and/or Diffuse Functions.
6-31G*, 6-31G**. The 6-31G Basis Set in which non-hydrogen atoms aresupplemented by d-type Gaussians and (for 6-31G**) hydrogen atoms aresupplemented by p-type Gaussians (Polarization Functions). 6-31G* and6-31G** are Polarization Basis Sets.
6-31+G*, 6-31+G**. Basis Sets that are identical to 6-31G* and 6-31G**
except that all non-hydrogen atoms are supplemented by diffuse s and ptype Gaussians (Diffuse Functions). 6-31+G* and 6-31+G** aresupplemented Polarization Basis Sets.
6-311G. A Split-Valence Basis Set in which each Core Basis Function is
written in terms of six Gaussians, and each Valence Basis Function is split
into three parts, written in terms of three, one and one Gaussians,
respectively. 6-311G basis sets have been determined to yield the lowest
total MP2 Energies for atoms. The 6-311G basis set is rarely used alone
but rather is supplemented by one or more sets of Polarization Functions
and/or Diffuse Functions.
6-311G*, 6-311G**. The 6-311G Basis Set in which non-hydrogen atoms
are supplemented by d-type Gaussians and (for 6-311G**) hydrogen atoms
are supplemented by p-type Gaussians (Polarization Functions). 6-311G*
and 6-311G** are Polarization Basis Sets.
6-311+G*, 6-311+G**. Basis Sets that are identical to 6-311G* and 6311G** except that non-hydrogen atoms are supplemented by diffuse s andp-type Gaussians (Diffuse Functions). 6-311+G* and 6-311+G** aresupplemented Polarization Basis Sets.
Ab Initio Models. The general term used to describe methods seeking
approximate solutions to the many-electron Schrödinger Equation, butwhich do not involve empirical parameters. Ab initio models include
Hartree-Fock Models, Møller-Plesset Models and Density Functional
Models.

Glossary

676

Acidity. The energy required to break an XH bond into X- and H+, that is,
to undergo Heterolytic Bond Dissociation. Acidities in the gas phase arevery large positive numbers (producing isolated ions is highly unfavorable);they are much smaller (and of either sign) in solution.
Activation Energy. The energy of a Transition State above that ofreactants. Activation energy is related to reaction rate by way of the
Arrhenius Equation.
AM1. Austin Method 1. A Semi-Empirical Model.
Anharmonic Frequency Correction. Non-quadratic contributions to a
Vibrational Frequency. Because calculated frequencies are harmonic,
that is, assume that the potential is quadratic, they are typically ~5% larger
than measured frequencies, which include anharmonic corrections.
Frequencies can be corrected for anharmonicity but, due to highcomputational cost, this is seldom done for any but very small molecules.
Anion. An atom or molecule with a Total Charge of -1.
Antibonding Molecular Orbital. A Molecular Orbital which isantibonding between particular atomic centers. The opposite is a Bonding
Molecular Orbital.
Arrhenius Equation. An equation governing the rate of a chemical reaction
as a function of the Activation Energy and the temperature.
Atomic Orbital. A Basis Function centered on an atom. Atomic orbitals
typically take on the form of the solutions to the hydrogen atom (s, p, d, f...
type orbitals).
Atomic Units. The set of units which remove all of the constants frominside the Schrödinger Equation. The Bohr is the atomic unit of length andthe Hartree is the atomic unit of energy.
Atomization Energy. The energy of dissociation of an atom or molecule
into separated nuclei and electrons. This is another term for Total Energy.
B3LYP Model. A Global Hybrid Generalized Gradient

Glossary677

Approximation (GH-GGA) functional which improves on the Local
Density Model by accounting explicitly for non-uniformity in electron
distributions. It incorporates the Exchange Energy from the Hartree-Fock
Model and involves three adjustable parameters. The B3LYP model isperhaps the most widely used density functional model and provides a solid
account of equilibrium geometries (including the geometries of molecules
incorporating transition metals), vibrational frequencies and reactionenergies.
Basicity. The energy gained from adding a proton to an atom ormolecule. Basicities in the gas phase are very large negative numbers; they
are much smaller (and of either sign) in solution.
Basis Functions. Functions usually centered on atoms which are linearly
combined to make up the set of Molecular Orbitals. Except for SemiEmpirical Models where basis functions are Slater type, basis functions
are Gaussian type.
Basis Set. The entire collection of Basis Functions.
Becke-Lee-Yang-Parr Model. See BLYP Model, B3LYP Model. BeckePerdew Model. See BP Model.
BLYP Model. A Generalized Gradient Approximation (GGA)
functional which improves on the Local Density Model by accounting
explicitly for non-uniformity in electron distributions.
Bohr. The Atomic Unit of length. 1 Bohr = 0.529167Å.
Boltzmann Distribution. The equilibrium distribution of products in a
Thermodynamically-Controlled Reaction. A special (and very important)case involves the equilibrium distribution of Conformers of a flexible
molecule.
Boltzmann Equation. The equation governing the distribution of productsin Thermodynamically-Controlled Reaction.
Bonding Molecular Orbital. A Molecular Orbital which is bonding
between particular atom centers. The opposite is an Antibonding
Molecular Orbital.

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678

Bond Order. A measure of the number of electrons shared between“bonded” atoms.
Bond Separation Reaction. An Isodesmic Reaction in which a molecule
described in terms of a conventional valence structure is broken down
into the simplest (two-heavy-atom) molecules containing the same
component bonds.
Bond Density Surface. A Density Surface used to elucidate the bonding
in molecules. The value of the density is typically taken as
0.1 electrons/bohr.3
Born-Oppenheimer Approximation. An approximation based on theassumption that nuclei are stationary. Applied to the Schrödinger Equation,
it leads to the Electronic Schrödinger Equation.
C-PCM. The Conductor like Polarizable Continuum Model is a solvent
model that depends on the shape and charge distribution of the molecule(solute) and the dielectric constant of the solvent. This is the default solvent
model used in the Spartan'18 version.
Cambridge Structural Database (CSD). A collection of >900,000
experimental structures for organic and organometallic compounds almost
entirely from X-ray crystallography. Structures lacking carbon are excluded
as are biopolymers (the latter are available from the Protein Data Bank).
Cartesian Coordinates. x, y, z spatial coordinates.
CAS Number. Chemical Abstract Service registry number; a uniquesubstance identifier used to a large degree in the chemistry literature, seewww.cas.org for more information.
Cation. An atom or molecule with a Total Charge of +1.
cc-pV5Z. A Polarization Basis Set which has been developed specificallyfor use with Correlated Models. The Valence has been split into five parts,and functions though g have been included. May be supplemented with
Diffuse Functions.
cc-pVDZ. A Polarization Basis Set which has been developed
specifically for use with Correlated Models. The Valence has been

Glossary679

split into two parts. May be supplemented with Diffuse Functions.
cc-pVQZ. A Polarization Basis Set which has been developed specificallyfor use with Correlated Models. The Valence has been split into four parts,and functions though g have been included. May be supplemented with
Diffuse Functions.
cc-pVTZ. A Polarization Basis Set which has been developed specificallyfor use with Correlated Models. The Valence has been split into three parts,and functions though f have been included. May be supplemented with
Diffuse Functions.
13

C Spectrum; see NMR Spectrum

CCSD/CCSD(T) Models. Coupled Cluster Singles and Doubles optionallywith a triples correction. Correlated Models.
Chemical Function Descriptors. A set of locations each indicating specific“chemical behavior”, for example, a location indicating a possible role asa hydrogen-bond donor or acceptor. Chemical function descriptors mayeither be used without reference to atomic centers (the collection being
termed a Pharmacophore) or attached to atoms.
Chemical Shift. The difference in the energies of nuclear spin states for anucleus in a molecule caused by an external magnetic field. This is thefundamental quantity measured in NMR spectroscopy.
Chiral Molecule. A molecule with a non-superimposable mirror image.
Most commonly (but not necessarily) a chiral molecule will incorporate one
or more R/S centers.
CID Model. Configuration Interaction Doubles. A limited Configuration
Interaction scheme in which only double excitations from occupied tounoccupied molecular orbitals are considered.
CIS Model. Configuration Interactions Singles. A limited Configuration
Interaction scheme in which only single excitations from occupied tounoccupied molecular orbitals are considered. This is perhaps the simplest
method available to the description of Excited States of molecules.

Glossary680

CISD Model. Configuration Interaction, Singles and Doubles. A limited
Configuration Interaction scheme in which only single and double
excitations from occupied to unoccupied molecular orbitals are considered.
Closed Shell. An atom or molecule in which all electrons are paired.
Configuration Interaction. Provides an account of Electron Correlation
by way of explicit promotion (excitation) of electrons from occupied
molecular orbitals into unoccupied molecular orbitals. Full configurationinteraction (all possible promotions) is not a practical method and limited
schemes, for example, CIS, CID and CISD Models, need to be employed.
Conformation. The arrangement about single bonds and of flexible
rings.
Conformational Analysis. One of several different procedures to deal withmolecules that are not properly described in terms of a single Conformer.
Determination of Equilibrium Conformer or establishing a Conformer
Distribution or a Similarity Library are examples of conformational
analysis.
Conformer; See Conformation.
Core. Electrons which are primarily associated with individual atoms anddo not participate significantly in chemical bonding (1s electrons for firstrow elements, 1s, 2s, 2px, 2py, 2pz electrons for second-row elements, etc.).
Core Orbital. A Molecular Orbital that is primarily involved with theCore rather than with the Valence.
Correlated Models. Models which take implicit or explicit account of theCorrelation of electron motions. Møller-Plesset Models, Configuration
Interaction Models and Density Functional Models are correlated
models.
Correlation. The coupling of electron motions not explicitly taken
into account in Hartree-Fock Models.

Glossary

681

Correlation Energy. The difference in energy between the Hartree- Fock
Energy and the experimental energy.
Correlation Functional. A function of the Electron Density and perhaps
as well the gradient of the Electron Density. The functional form derives
from “exact” solution of the Schrödinger Equation for an idealized manyelectron problem. Used in Density Functional Models.
COSY Spectrum; See NMR Spectrum.
Coulomb Energy. The electron-electron repulsion energy according to
Coulomb’s law.
Coulombic Interactions. Charge-charge interactions which follow
Coulomb’s law. Stabilizing when charges are of opposite sign anddestabilizing when they are of the same sign.
Coupling Constant. A measure of the extent to which nuclear spins onneighboring atoms interact (couple) with each other, causing splitting of thelines in an NMR spectrum.
CPK Model. A molecular model in which atoms are represented byspheres, the radii of which correspond to van der Waals Radii. Intended
to portray molecular size and shape. Also known as a space-filling model.
CSD; See Cambridge Structural Database.
Curtin-Hammett Principle. The idea that the reactive conformer in a
Kinetically-Controlled Reaction is not necessarily the lowest- energy
conformer. The rationale is that the energy barriers separating conformers are
typically much smaller than barriers to chemical reaction, and that any
reactive conformers will be replenished.
Density; See Electron Density.
Density Functional Models. Methods in which the energy isevaluated as a function of the Electron Density. Electron Correlation istaken into account explicitly by incorporating into the Hamiltonian terms
which derive from exact solutions of idealized many-electron systems.

Glossary

682

DEPT Spectrum; See NMR Spectrum.
Diffuse Functions. Functions added to a Basis Set to allow description ofelectron distributions far away from atomic positions. Important for
descriptions of anions.
Diffusion-Controlled Reactions. Chemical reactions without Transition
States (or energy barriers), the rates of which are determined by the speed
in which molecules encounter each other and how likely these encounters
are to lead to reaction.
Dipole Moment. A vector indicating the magnitude, sign and direction of
the overall distribution of charge in a molecule based on the combination of
nuclear and electron charges. Most commonly only the magnitude of thedipole moment is known experimentally.
Double Hybrid Functional. A class of functionals that take account ofunoccupied molecular orbitals in addition to occupied molecular orbitals(the density) usually by way of an MP2-like procedure.
Doublet. A molecule with one unpaired electron, also known as a radical.
Dual Basis Set. A technique whereby the converged wavefunction resulting
from a calculation using a small basis set is passed on for a single SCF cycle
using a large basis set. This closely approximates the energy andwavefunction that would have resulted from a full calculation using thelarge basis set but with 5-10 times less computation.
EDF2 Model. A Global Hybrid Generalized Gradient Approximation(GH-GGA) functional which improves on the Local Density Model byaccounting explicitly for non-uniformity in electron distributions. EDF2 was
explicitly formulated to reproduce experimental vibrational frequencies(infrared spectra), and it was for this reason (together with practical concerns)
that the EDF2/6-31G* model was chosen for use in the Spartan Spectra
and Properties Database (SSPD).
Electron Affinity. The energy gained as a result of adding anelectron to an atom or molecule. May be calculated as the (negative

Glossary683

of) the difference in energies between the atom/molecule and it
corresponding radical anion. Note that not all atoms/molecules have positiveelectron affinities, that is, bind an electron.
Electron Correlation. See Correlation.
Electron Density. The number of electrons per unit volume at a point inspace. This is the quantity which is measured in an X-ray diffraction
experiment.
Electron Density Surface. A surface of constant Electron Density. May be
used to elucidate bonding (Bond Density Surface) or to characterize
overall molecular size and shape.
Electronic Schrödinger Equation. The equation which results fromincorporation of the Born-Oppenheimer Approximation to the
Schrödinger Equation.
Electrostatic Charges. Atomic charges chosen to best match theElectrostatic Potential at points surrounding a molecule, subject to overallcharge balance.
Electrostatic Potential. A function describing the energy of interaction ofa positive point charge with the nuclei and fixed electron distribution of amolecule.
Electrostatic Potential Map. A graph that shows the value ofElectrostatic Potential on an Electron Density Isosurface corresponding
to a van der Waals Surface.
Electrostatic Potential Surface. It may be used to elucidate regions in amolecule which are particularly electron rich and subject to electrophilic
attack and those which are particularly electron poor, subject tonucleophilic attack.
Energy Profile. A plot of energy vs. change in geometrical coordinate,
for example, change in bond length or in dihedral angle.
Enthalpy. The heat of a chemical reaction. Related to energy by a pressurevolume that is insignificant at normal pressures.
Equilibrium Conformer. The lowest-energy Conformer.

Glossary684

Equilibrium Geometry. A Local Minimum on a Potential Energy
Surface.
Equilibrium Isotope Effect. The effect on the heat of reaction due to achange in nuclear mass of one or more atoms. The most common (and largest)
isotope effects arise from substitution of deuterium for hydrogen.
Exchange Functional. A function of the Electron Density and perhaps aswell the gradient of the Electron Density. The functional form derives from“exact” solution of the Schrödinger Equation for an idealized manyelectron problem. Used in Density Functional Models.
Exchange Energy. An “attractive” (negative) component of the electronelectron interaction energy. Arises due to an overestimation of the“repulsive” (positive) component or Coulomb energy.
Excited State. An electronic state for an atom or molecule which is not thelowest-energy or Ground State.
Force Constant. For a diatomic molecule, the second derivative of theenergy with respect to change in bond length. For a polyatomic molecule,the second derivative of the energy with regard to a change in Normal
Coordinate.
Force Field. The set of rules underlying Molecular Mechanics Models.
Comprises terms which account for distortions from ideal bond distances
and angles and for Non-Bonded van der Waals and Coulombic
Interactions.
Fourier Series. An expansion of a periodic (in 360o rotation) in terms of
powers of the cosine of the torsion angle.
Frontier Molecular Orbitals. The HOMO and LUMO.
Gx Models. “Recipes” which combine a series of Hartree-Fock andCorrelated Models to properly account for Atomization Energies ofatoms and molecules. Useful for providing accurate thermochemical data.

Glossary685

G3(MP2). A “simplified” version of the G3 Model. Reproduces
experimental Heats of Formation with an RMS errors of ~8 kJ/ mol,practical for molecules comprising less than 20 atoms.
Gaussian. A function of the form xlymzn exp (r2) where l, m, n are integers(0, 1, 2 . . .) and  is a constant. Used in the construction of Basis Sets for
Hartree-Fock, Density Functional, MP2 and other Correlated Models.
Gaussian Basis Set. A Basis Set made up of Gaussian Basis Functions.
Global Minimum. The lowest energy Local Minimum on a
Potential Energy Surface.
Ground State. The lowest energy electronic state for an atom or molecule.
Hamiltonian. An operator which accounts for the kinetic and potential
energy of an atom or a molecule.
Hammond Postulate. The idea that the Transition State for an exothermic
reaction will more closely resemble reactants than products. This provides
the basis for “modeling” properties of Transition States in terms of theproperties of reactants.
Harmonic Frequency. A Vibrational Frequency which has beencorrected to remove all non-quadratic (anharmonic) components.
Calculated Vibrational Frequencies correspond to harmonic frequencies.
The corrections require data on isotopically-substituted systems and are
typically available only for small molecules.
Hartree. The Atomic Unit of energy. 1 Hartree = 627.47 kcal/mol.
Hartree-Fock Approximation. Separation of electron motions in manyelectron systems into a product form of the motions of the individual
electrons.
Hartree-Fock Energy. The energy resulting from Hartree-Fock Models.
Hartree-Fock Equations. The set of differential equations resulting fromapplication of the Born-Oppenheimer and Hartree-Fock

Glossary686

Approximations to the many-electron Schrödinger Equation.
Hartree-Fock Models. Methods in which the many-electron wavefunction
in written terms of a product of one-electron wavefunctions. Electrons are
assigned in pairs to functions called Molecular Orbitals.
Hartree-Fock Wavefunction. The simplest quantum-mechanically correct
representation of the many-electron wavefunction. Electrons are treated as
independent particles and are assigned in pairs to functions termed
Molecular Orbitals. Also known as Single- Determinant Wavefunction.
Heat of Formation. The Enthalpy at 298 K of a balanced chemical reactionin which a molecule is converted into the most stable form of each element,
for example, the hydrogen molecule for hydrogen and graphite for carbon.
Hessian. The matrix of second energy derivatives with respect togeometrical coordinates. The Hessian together with the atomic masses leadto the Vibrational Frequencies of molecular systems.
Heterolytic Bond Dissociation. A process in which a bond is broken anda cation and anion result. The number of electron pairs is conserved, but anon-bonding electron pair has been substituted for a bond.
HOMO. Highest Occupied Molecular Orbital.
Homolytic Bond Dissociation. A process in which a bond is broken andtwo radicals result. The number of electron pairs is not conserved.
HOMO-LUMO Gap. The difference in energies between the
HOMO and LUMO.
HOMO Map. A graph of the absolute value of the HOMO on an
Isodensity Surface corresponding to a van der Waals Surface.
Hybrid Density Functional Models. Density Functional Models which
incorporate the Exchange Energy from the Hartree-Fock Model. The
B3LYP Model is a hybrid density functional model.

Glossary687

Hydrogen-Bond Acceptor. An electronegative element (typically,
nitrogen, oxygen or halogen) with one or more lone pairs able to “accept”
a hydrogen from a Hydrogen-Bond Donor.
Hydrogen-Bond Donor. A hydrogen bonded to an electronegative element(typically nitrogen or oxygen) that can be donated to a Hydrogen-Bond
Acceptor.
Hydrophobe. A non-polar region of a molecule.
Hypervalent Molecule. A molecule containing one or more main- groupelements in which the normal valence of eight electrons has been exceeded.
Hypervalent molecules are common for second-row and heavier maingroup elements but are uncommon for first-row elements.
Imaginary Frequency. A frequency which results from a negative elementin the diagonal form of the Hessian. Equilibrium Geometries arecharacterized by all real frequencies while Transition States arecharacterized by one imaginary frequency.
Infrared Spectrum. Spectrum resulting from transitions between
vibrational energy levels. Infrared intensities depend on the change in
dipole moment associated with the vibration.
Internal Coordinates. A set of bond lengths, bond angles and dihedral
angles (among other possible variables) describing molecular geometry.
The Z Matrix is a set of internal coordinates.
Intrinsic Reaction Coordinate. The name given to procedures with seek
to “walk” in a smooth pathway connecting reactant and product.
Ionization Potential. The energy required to completely eject an electronfrom an atom or molecule. May be calculated as the difference in energies
between the atom/molecule and its corresponding radical cation. May beapproximated from Koopman’s Theorem as the negative of the HOMO
Energy.
Isodesmic Reaction. A chemical reaction in which the number of formal
chemical bonds of each type is conserved.

Glossary

688

Isosurface. A three-dimensional surface defined by the set of points
in space where the value (isovalue) of the function is constant.
Kinetically-Controlled Reaction. Refers to a chemical reaction which has
not gone all the way to completion, and the ratio of products is not related
to their thermochemical stabilities, but rather inversely to the heights of theenergy barriers separating reactants to products.
Kinetic Isotope Effect. The effect on the rate of reaction due to a change
in nuclear mass of one or more atoms. The most common (and largest)
isotope effects arise from substitution of deuterium for hydrogen.
Kinetic Product. The product of a Kinetically-Controlled Reaction.
kJ/mol. The unit commonly used to express chemical energy differences,
replacing kcal/mol. 1 kJ/mol = 0.239 kcal/mol = 0.000381 au.
Kohn-Sham Equations. The set of equations obtained by applying the
Local Density Approximation to a general multi-electron system. An
Exchange/Correlation Functional which depends on the electron density
has replaced the Exchange Energy expression used in the Hartree-Fock
Equations. The Kohn-Sham equations become the Roothaan-Hall
Equations if this functional is set equal to the Hartree-Fock Exchange
Energy expression.
Koopman’s Theorem. Relates the Ionization Potential to the negative of
the HOMO Energy.
LCAO Approximation. Linear Combination of Atomic Orbitals
approximation. Approximates the unknown Hartree-Fock Wavefunctions(Molecular Orbitals) by linear combinations of atom-centered functions(Atomic Orbitals) and leads to the Roothaan-Hall Equations.
LACVP*, LACVP**. Pseudopotentials which include not only Valences and p-type orbitals (s, p and d-type for transition metals) but also thehighest set of Core orbitals, and in which non-hydrogen

Glossary689

atoms are supplemented by d-type Gaussians and (for LACVP**)
hydrogen atoms are supplemented by p-type Gaussians.
Ligand. This term has two meanings in the context of molecular modeling.
It denotes a molecular fragment that is (viewed as) non-covalently
bonded to a transition metal in an inorganic or organometallic compound.
For example, both carbon monoxide and benzene are said to be ligands inbenzene chromium tricarbonyl. It also denotes a molecule that is“associated” (non-covalently bonded) to a protein.
Linear Synchronous Transit. The name given to procedures which
estimate the geometries of transition states based on “averages” of thegeometries of reactants and products, sometimes weighted by the overall
thermodynamics of reaction.
LMP2 Model. An MP2 Model in which the Hartree-Fock orbitals
are first localized.
Local Density Models. Density Functional Models which are based on
the assumption that the Electron Density is constant (or slowly varying)throughout all space.
Local Ionization Potential. A function of the relative ease ofelectron removal (ionization) from a molecule.
Local Ionization Potential Map. A graph of the Local Ionization
Potential on an Isodensity Surface corresponding to a van der Waals
Surface.
Local Minimum. Any Stationary Point on a Potential Energy Surface
for which all elements in the diagonal representation of the Hessian are
positive.
LogP. An empirical measure of the extent to which a moleculepartitions between water and octanol.
Lone Pair. A Non-Bonded Molecular Orbital which is typicallyassociated with a single atom.
LUMO. Lowest Unoccupied Molecular Orbital.

Glossary690

LUMO Map. A graph of the absolute value of the LUMO on an
Isodensity Surface corresponding to a van der Waals Surface.
Mechanism. The sequence of steps connecting reactants and products in an
overall chemical reaction. Each step starts from an equilibrium form
(reactant or intermediate) and ends in an equilibrium form (intermediate or
product).
Minimal Basis Set. A Basis Set which contains the fewest functions needed
to hold all the electrons on an atom and still maintain spherical symmetry.
STO-3G is a minimal basis set.
Minimal Valence Basis Set. A Minimal Basis Set from which Core
Orbitals have been removed. Semi-Empirical Models make use of aminimal valence basis set.
MM2, MM3, MM4. A series of Molecular Mechanics Force Fields
developed by the Allinger group at the University of Georgia.
MMFF94. Merck Molecular Force Field. A Molecular Mechanics Force
Field for organic molecules and biopolymers developed by Merck
Pharmaceuticals.
MNDO. Modified Neglect of Differential Overlap. A Semi- Empirical
Model.
MNDO/d. An extension of the MNDO Semi-Empirical Model in which
second-row (and heavier) main-group elements are provided a set of d-typefunctions.
Molecular Mechanics Models. Methods for structure, conformation andstrain energy calculation based on bond stretching, angle bending andtorsional distortions, together with Non-Bonded Interactions, andparameterized to fit experimental data.
Molecular Orbital. A one-electron function made of contributions of Basis
Functions on individual atoms (Atomic Orbitals) and delocalized
throughout the entire molecule.
Molecular Orbital Models. Methods based on writing the many- electron
solution of the Electronic Schrödinger Equation in terms of a product of
one-electron solutions (Molecular Orbitals).
Glossary691

Møller-Plesset Energy. The energy resulting from Møller-Plesset Models
terminated to a given order, e.g., the MP2 energy is the energy of thesecond-order Møller-Plesset Model (or MP2).
Møller-Plesset Models. Methods which partially account for Electron
Correlation by way of the perturbation theory of Møller and Plesset.
Monte-Carlo Conformation Search. A limited search of Conformers
resulting from a random sampling of all torsional angles (including
constrained torsions associated with flexible rings) while satisfying therequirements imposed by the Boltzmann Equation.
MP2 Energy. The energy resulting from MP2 Models.
MP2 Model. A Møller-Plesset Model terminated to be second order in theenergy.
MP3 Model. A Møller-Plesset Model terminated to be third order in theenergy.
MP4 Model. A Møller-Plesset Model terminated to be fourth order in theenergy.
Mulliken Charges. Atomic charges obtained from a Mulliken
Population Analysis.
Mulliken Population Analysis. A partitioning scheme in whichelectrons are shared equally between different Basis Functions.
Multiplicity. The number of unpaired electrons (number of electrons with“down” spin) +1. 1=singlet; 2=doublet; 3=triplet, etc.
Natural Charges. Atomic charges obtained from a Natural
Population Analysis.
Natural Population Analysis.
NDDO Approximation. Neglect of Diatomic Differential Overlap
approximation. The approximation underlying all present generation SemiEmpirical Models. It says that two Atomic Orbitals on different atoms do
not overlap.

Glossary692

Neural Network. Also often call artificial (or simulated) neural network(s).
In the context of Spartan, these refer to a growing number computationalroutines, trained to specific tasks (provide energy, structure, property) as asignificant time improvement over quantum chemical calculations. See
Appendix A for an extended explanation.
NIST Chemistry Web Book (National Institutes of Standards andTechnology). On-line source of experimental Infrared and UV/visible
spectra.
NMR Spectrum. Spectrum resulting from transitions between nuclear spinstates under the influence of an external magnetic field. Both 1D spectra(most important, proton and 13C) and 2D spectra (most important COSY,
HMBC and HSQC) are available.
NOE (Nuclear Overhauser Effect). An NMR experiment that leads toidentifying pairs of (non-bonded) atoms separated by less than a specified
distance (typically 4-5Å).
Non-Bonded Interactions. Interactions between atoms which are notdirectly bonded. van der Waals Interactions and Coulombic Interactions
are non-bonded interactions.
Non-Bonded Molecular Orbital. A molecular orbital which does not show
any significant Bonding or Antibonding characteristics. A Lone Pair is a
non-bonded molecular orbital.
Non-Local Density Functional Models. Density Functional Models suchas the BLYP, BP, EDF1, EDF2 and B3LYP Models which explicitly take
into account electron inhomogeneities.
Normal Coordinates. Coordinates that lead to a diagonal Hessian, andwhich correspond to vibrational motions in molecules.
Normal Mode Analysis. The process for calculating Normal Coordinatesleading to Vibrational Frequencies. This involves diagonalizing the
Hessian and accounting for atomic masses.
Octet Rule. The notion that main-group elements prefer to be “surrounded”
by eight electrons (going into s, px, py, pz orbitals).
OD/OD(T). Correlated Models.
Orbital Energy. The energy of a Molecular Orbital.
Glossary693

Orbital Energy Diagram. A diagram listing Orbital Energies from mostnegative at the bottom. Usually restricted to occupied Valence Orbitals andthe few lowest unoccupied orbitals.
Orbital Symmetry Rules; See Woodward-Hoffmann Rules.
Open Shell. An atom or molecule in which one or more electrons areunpaired.
Pharmacophore. Collection of Chemical Function Descriptors whichcharacterizes a molecular environment. A pharmacophore may serve as atarget for Similarity Analysis.
PM3. Parameterization Method 3. A Semi-Empirical Model. PM6.
Parameterization Method 6. A Semi-Empirical Model.
Polar Area. The area of an Electrostatic Potential Map that is either morepositive or more negative than some preset value (typically between 80-120
kJ/mol).
Polarization Basis Set. A Basis Set which contains functions of higher
angular quantum number (Polarization Functions) than required for the
Ground State of the atom, e.g., d-type functions for main-group elements
and p-type functions for hydrogen. 6-31G*, 6-31G**, 6-311G*, 6-311G**,
cc-pVDZ, cc-pVTZ and cc-pVQZ are polarization basis sets.
Polarization Functions. Functions of higher angular quantum thanrequired for the Ground State atomic description. Added to a Basis Set toallow displacement of Valence Basis Functions away from atomic
positions.
Polarization Potential. A function describing the energy of electronic
relaxation of a molecular charge distribution following interaction with apoint positive charge. The polarization potential may be added to theElectrostatic Potential to provide a more accurate account of the interactionof a point-positive charge and a molecule.
Polar Surface Area. The area of a space-filling (CPK) model due toelectronegative elements (typically, nitrogen and oxygen) and anyhydrogens that are bonded to these elements.
Pople-Nesbet Equations. The set of equations describing the best
Unrestricted Single Determinant Wavefunction within the LCAO
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Approximation. These reduce the Roothaan-Hall Equations for

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Closed Shell (paired electron) systems.
Potential Energy Surface. A function of the energy of a molecule in termsof the geometrical coordinates of the atoms.
Property Map. A representation or “map” of a “property” on top of an
Isosurface, typically an Isodensity Surface. Electrostatic Potential
Maps, and HOMO and LUMO Maps and Spin Density Maps are usefulproperty maps.
Proton Affinity; See Basicity.
Proton Spectrum; see NMR Spectrum
Pseudopotential. A Basis Set which treats only Valence electrons in an
explicit manner, all other electrons being considered as a part of a “Core”.
LAVCP (and extensions including Polarization and/ or Diffuse
Functions) are pseudopotentials.
Pseudorotation. A mechanism for interconversion of equatorial and axial
sites around trigonal bipyramidal centers, e.g., fluorines in phosphorous
pentafluoride.
QCCD/QCCD(T) Models. Correlated Models.
QCISD/QCISD(T) Models. Quadratic CISD Models. Correlated
Models.
QSAR. Quantitative Structure Activity Relationships. The name given toattempts to relate measured or calculated properties to molecular structure.
Quantum Mechanics. Methods based on approximate solution of
the Schrödinger Equation.
Ramachandran Plot. A plot for each α carbon in a polypeptide of the twodihedral angles that define the conformation of the backbone. The points will
typically cluster in two regions denoting helices and sheets.
Raman Spectrum. Spectrum resulting from transitions between
vibrational energy levels. Infrared intensities depend on the change inpolarizability associated with the vibration.

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Rate Limiting Step. The step in an overall chemical reaction (Mechanism)
which proceeds via the highest-energy Transition State.
Reaction Coordinate. The coordinate that connects the Local Minimacorresponding to the reactant and product, and which passes through aTransition State.
Reaction Coordinate Diagram. A plot of energy vs. Reaction
Coordinate.
Restricted SCF. An SCF procedure which restricts electrons to be pairedin orbitals or permits orbitals to be singly occupied.
RM1. A Semi-Empirical Model.
Roothaan-Hall Equations. The set of equations describing the best
Hartree-Fock or Single-Determinant Wavefunction within the LCAOApproximation.
R/S. Atomic chirality markers.
SCF. Self-Consistent Field. An iterative procedure whereby a one- electron
orbital is determined under the influence of a potential made up of all the otherelectrons. Iteration continues until self-consistency. Hartree-Fock, Density
Functional and MP2 Models all employ SCF procedures.
Schrödinger Equation. The quantum mechanical equation which accounts
for the motions of nuclei and electrons in atomic and molecular systems.
SDBS. Database of experimental infrared and NMR spectra from AIST
(Advanced Industrial Science and Technology, Japan). Freely accessible online but automatic access is not permitted limiting its utility.
Self-Consistent Field; See SCF.
Semi-Empirical Models. Quantum Mechanics methods that seek
approximate solutions to the many electron Schrödinger Equation, butwhich involve empirical parameters.

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Similarity Analysis. A procedure to determine the extent to which amolecule is “similar” to either a standard molecule (defined in terms of a setof atoms or a set of Chemical Functional Groups) or by a set of unassociatedChemical Functional Groups (a Pharmacophore).
Similarity Distribution. A selection of Conformers based on theirenergies, with emphasis on maximum diversity.
Size Consistent. Methods for which the total error in the calculated energy
is more or less proportional to the (molecular) size. Hartree- Fock and
Møller-Plesset models are size consistent, while Density Functional
Models, (limited) Configuration Interaction Models and SemiEmpirical Models are not size consistent.
Size Surface. A Density Surface used to establish overall molecular size andshape. The value of the density is typically taken as 0.002 electrons/bohr3.
Slater. A function of the form xlymzn exp (-r) where l, m, n are integers (0,1, 2 . . .) and  is a constant. Related to the exact solutions to the Schrödinger
Equation for the hydrogen atom. Used as Basis Functions in SemiEmpirical Models.
SM5.4. An empirical solvation model for water only. Furnishes only anenergy correction to be added to the (gas-phase) energy obtained from any
quantum chemical model. A lower (computational) cost variation isavailable for use in conjunction with Molecular Mechanics Models.
SM8. An empirical solvation model applicable to Hartree-Fock and density
functional models . Available for water and a variety of organic solvents.
Furnishes a wavefunction in addition to an energy, meaning that solvatedstructures, infrared spectra and properties may be obtained.
SM12. An improvement over SM8 using a more general charge model
which is less sensitive to the particular basis set. The SM12 training set isboth larger and more diverse and SM12 covers the majority of the periodic
table.
Space-Filling Model; See CPK Model.

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Spartan Infrared Database (SIRD). An alternative entry point into the
Spartan Spectra and Properties Database (SSPD) allowing searching by
match to an (unknown) infrared spectrum.
Spartan Molecular Database (SMD). An early collection of molecular
structures and properties for >125,000 molecules obtained from up to ninedifferent quantum chemical models. Searchable by structure, name,formula, molecular weight and isomer. The SMD was the precursor to the
SSPD.
Spartan Reaction Database (SRD). A collection of ~2,500 transition-state
structures for a wide variety of simple organic and organometallic reactions
obtained from up to five different quantum chemical models. Searchable bystructure.
Spartan Spectra and Properties Database (SSPD). A collection ofmolecular structures, infrared and NMR spectra, molecular and atomic
properties and QSAR descriptors for >300,000 organic molecules obtained
from the B97X-D/6-31G* and EDF2/6-31G* density functional models
based on the lowest-energy conformer assigned from the T1 model. The
wavefunction is available, as such, surfaces and property maps may begenerated “on-the-fly”. Searchable by structure, name, formula, molecularweight and isomer.
Spin Density. The difference in the number of electrons per unit volume of“up” spin and “down” spin at a point in space.
Spin Density Map. A graph that shows the value of the Spin Density on
an Isodensity Surface corresponding to a van der Waals Surface.
Spin Orbital. The form of Wavefunction resulting from application of the
Hartree-Fock Approximation to the Electronic Schrödinger Equation.
Comprises a space part (Molecular Orbital) and one of two possible spinparts (“spin-up” and “spin-down”).
Split-Valence Basis Set. A Basis Set in which the Core is represented by asingle set of Basis Functions (a Minimal Basis Set) and the Valence isrepresented by two or more sets of Basis Functions.

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This allows for description of aspherical atomic environments in molecules.
3-21G, 6-31G and 6-311G are split-valence basis sets.
SSPD; see Spartan Spectra and Properties Database. Stationary Point.
A point on a Potential Energy Surface for which
all energy first derivatives with respect to the coordinates are zero.
Local Minima and Transition States are stationary points.
STO-3G. A Minimal Basis Set. Each atomic orbital is written in terms ofa sum of three Gaussian functions taken as best fits to Slater-type(exponential) functions.
SVWN Model. (Slater, Vosko, Wilk, Nusair) A Density Functional Model
which involves the Local Density Approximation.
SYBYL. A Molecular Mechanics Force Field developed by Tripos, Inc.
Systematic Conformation Search. An exhaustive search of Conformers
resulting from stepping through all torsional angles (including constrained
torsions associated with flexible rings). This is the only procedure thatguarantees identification of the Global Minimum.
T1. A combination of quantum chemical models and empirical parameters
formulated to reproduce Heats of Formation obtained from the G3(MP2)Model using 2-3 orders of magnitude less computation. T1 reproduces
experimental heats with an RMS error of~8 kJ/mol (the same error as obtained from the G3(MP2) Model).
Tautomer. An isomer related by rearrangement of hydrogen atoms, forexample vinyl alcohol is a tautomer of acetaldehyde. All tautomers are isomers
but not all isomers are tautomers.
TDDFT (Time Dependent Density Functional Theory).
Theoretical Model. A “recipe” leading from the Schrödinger Equation toa general computational scheme. A theoretical models needs to be uniqueand well defined and, to the maximum extent possible, be unbiased bypreconceived ideas. It should lead to

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Potential Energy Surfaces which are continuous. It is also desirable (but notrequired) that a theoretical model be Size Consistent and Variational.
Finally, a theoretical model will be applicable for the problems of interest.
Theoretical Model Chemistry. The set of results following fromapplication of a particular Theoretical Model.
Thermochemical Recipes. Combinations of quantum chemical models
and (in the case of T1) empirical parameters to reproduce experimental (orin the case of T1) G3(MP2) Heats of Formation. G3(MP2) and T1 arethermochemical recipes.
Thermodynamically-Controlled Reaction. A chemical reaction which
has gone all the way to completion, and the ratio of different possible
products is related to their thermochemical stabilities according to theBoltzmann Equation.
Thermodynamic Product. The product of a reaction which is underThermodynamic Control.
Total Charge. The sum of the nuclear charges minus the total number ofelectrons.
Total Energy. The energy of a balanced chemical reaction in which amolecule is split into single particle fragments, that is, nuclei and electrons.
Total energy is the standard way to report energy data derived fromquantum chemical models (except Semi-Empirical Models andThermochemical Recipes).
Transition State. A Stationary Point on a Potential Energy Surface in which
all but one of the elements in the diagonal representation of the Hessian are
positive, and one element is negative. Corresponds to the highest-energy
point on the Reaction Coordinate.
Transition-State Geometry. The geometry (bond lengths and angles) of aTransition State.
Transition State Theory. The notion that all molecules react througha single well-defined Transition State.
Triplet. A molecule with two unpaired electrons.

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Unrestricted SCF. An SCF procedure which does not restrict electrons to
be paired on orbitals.
UV/visible Spectrum. The spectrum resulting between ground andexcited electronic states.
Valence. Electrons which are delocalized throughout the molecule andparticipate in chemical bonding (2s, 2px, 2py, 2pz for first-row elements, 3s,3px, 3py, 3pz for second-row elements, etc.).
Valence Orbital. A Molecular Orbital that is primarily involved with the
Valence rather than the Core.
van der Waals Interactions. Interactions which account for short- range
repulsion of non-bonded atoms as well as for weak long-range attraction.
van der Waals Radius. The radius of an atom (in a molecule), which isintended to reflect its overall size. van der Waals radii are used to define
space-filling models.
van der Waals Surface. A surface formed by a set of interpreting spheres(atoms) with specific van der Waals radii, and which is intended torepresent overall molecular size and shape.
Variational. Methods for which the calculated energy represents an upperbound to the exact (experimental) energy. Hartree-Fock andConfiguration Interaction Models are variational while Møller- Plesset
Models, Density Functional Models and Semi-Empirical Models are notvariational.
Vibrational Frequencies. The energies at which molecules vibrate.
Vibrational frequencies correspond to the peaks in an infrared and Raman
spectrum.
Wave function. The solution of the Schrödinger Equation. In the caseof the hydrogen atom, a function of the coordinates which describes the
motion of the electron as fully as possible. In the case of a many-electron
system a function which describes the motion of the individual electrons.

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Zero-Point Energy. The energy of molecular vibration at 0K, given as half
the sum of the Vibrational Frequencies times Planck’s constant.
Z Matrix. A set of internal coordinates (bond lengths, bond angles anddihedral angles only) describing molecular geometry. Of historical interest
only. Not supported in Spartan.
Zwitterion. A neutral valence structure which incorporates both a formal
positive charge and a formal negative charge.

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