Teaching with Schrödinger

Updated: 1-23-22

Stereoisomers
Created with: Release 2021-3
Prerequisites: working knowledge of Maestro
Files Supplied: Stereoisomers_worksheet
Categories:
organic chemistry

About this Lesson
In this lesson plan, students will explore compounds called stereoisomers that differ
from each other only in the three-dimensional, spatial arrangement of their atoms, but
not in the connectivity of their atoms. The connection between stereoisomerism anddrug action will also be discussed.
Using Maestro, students will use the 2D Sketcher and 3D Builder tools to learn how todraw different kinds of stereoisomers. Energy minimizations and geometry optimization
calculations will be performed using Jaguar. The tile function will be used to compare
stereoisomeric relationships between pairs of molecules to determine if they areenantiomers or diastereomers.

Learning Objectives
Designate configuration of a stereocenter using the Cahn-Ingold-Prelog (CIP)
system● Determine the stereochemical relationship between a pair of molecules●

1
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Standards●

ACS Guidelines:○●

ETS Chemistry GRE:○●

Understand molecular structure and bonding (Section 5.2)
Structure, Bonding and Nomenclature – Stereochemical Notation (3.A)

AAMC MCAT:○Stereochemistry of covalently bonded molecules (5B)

Assessments
The following types of formative assessments are embedded in this lesson:●●

Assessment of student understanding through discussion of warm-up questions andfilling in any knowledge gaps about constitutional isomers
Visual assessment of student-generated enantiomers and diastereomers

Warm-Up Questions: To be done on their own or at the beginning of class
Watch the Khan Academy videos on stereochemistry.
1) What is the difference between constitutional isomers and stereoisomers?

2) Label the following pair of molecules as either constitutional isomers or stereoisomers.
Both the skeletal structure and bond line structure of each molecule have been provided.

3) How many chiral center(s) does the following molecule have?

2
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Lesson Outline
1.
2.
3.
4.
5.
6.
7.
8.

What you will need for this lesson - p. 3
Introduction to Stereoisomers - p. 5
Assigning Configuration using the Cahn-Ingold-Prelog Rules - p. 7
Enantiomers - p. 17
Diastereomers - p. 22
Individual Exercises - p. 27
Summary, Additional Resources, and References - p. 29
Glossary of Terms - p. 29

1. What you will need for this lesson
1. Go to the ‘Data’ folder and open yourClass Folder found on the virtual
cluster’s desktop.
2. Right-click on the folder called“Stereoisomers” and copy folder to
Desktop● Here, you will find the lesson
plan, worksheet, and any
additional resources
3. Open Maestro
a. See Starting Maestro if you
need help
Figure 1-1. Open Maestro.

3
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

4. Go to File > Change Working
Directory
5. Find your “Stereoisomers” folder thatyou duplicated to your Desktop, andclick Choose

Figure 1-2. Change Working Directory option.

6. Next, go to File > Save Project As
7. Type “Stereoisomers_tutorial” andclick Save
● The project will be titledstereoisomers_tutorial.prj

Figure 1-3. Save Project panel.

8. Finally, check your Mouse Actions● Edit > Customize Mouse
Actions

Figure 1-4. Choose the best mouse option foryour set up.

9. Make sure you have the best option
chosen for your set up. This lesson
was written with a three-button mousewith a scroll wheel. If you do not havea mouse, choose Trackpad.

4
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

2. Introduction to Stereoisomers
Isomers are molecules that have the same molecular formula but have differing
structural arrangements in space. Though they are made up of the same components,
distinct isomers do not necessarily bear resemblance to each other both visually and interms of their properties. Isomers can be broken into two types: constitutional isomers
and stereoisomers.
Constitutional isomers are when two molecules share the same chemical
formula but differ in structural arrangement. For example, butane (or n-butane) and2-methylpropane (or isobutane) both have a molecular formula of C4H10, but they differ
in connectivity. N-butane is more linear whereas isobutane is more branched, yet they
have the same number of carbon and hydrogen atoms in each isomer.

Figure 2-1. Constitutional isomers of C4H10
Stereoisomers have an identical molecular formula and atomic sequence but
differ in how they are spatially arranged. Cis-trans stereoisomerism can be used todenote disubstituted cycloalkanes. For example, cis-1,2,-dimethylcyclohexane andtrans-1,2-dimethylcyclohexane both have the same molecular formula of C8H16 as wellas the same connectivity of atoms, but the spatial arrangement of the methyl groups
differ. The cis stereoisomer shows the two methyl groups on the same side of the ring,
while the trans stereoisomer shows the two groups on opposite sides of the ring.

Figure 2-2. Cis-Trans isomers of C8H16
Furthermore, the terms cis and trans are also used to describe stereoisomerism
in double bonds. For example, cis-2-butene and trans-2-butene both have the same5
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

molecular formula of C4H8 as well as the same connectivity of atoms, but the spatial
arrangement of the methyl groups differ. The cis stereoisomer shows the groups on thesame side of the double bond, while the trans stereoisomer exhibits groups on opposite
sides of the double bond. These two molecules have two different physical properties
because the double bond does not have free rotation like single bonds do at room
temperature.

Figure 2-3. Cis-Trans isomers of C4H8
The last type of stereoisomer delves into a specific property called chirality.
Chiral objects are not superimposable on their mirror images. The most common
source of molecular chirality is the presence of a chiral center which is a carbon atomwith four unique, or different, substituents attached to it. The tetrahedral sp3-hybridized
carbon atom in bromochloroethanol shown below is chiral because it contains four
different substituents: –OH, –Cl, –Br, and –CH3. We will go into much more detail on
how to assign chirality and how to label stereoisomeric relationships of two chiralmolecules later in this lesson.

Figure 2-4. Stereoisomers of C2H4OClBr

6
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

3. Assigning Configuration using the
Cahn-Ingold-Prelog (CIP) Rules
In order to determine the specific configuration of a stereocenter, a system developedby three chemists named Cahn, Ingold, and Prelog, was developed.
Step 1: Identify the chiral center and rank the substituents around the chiral
center. The higher that atomic number, the higher the priority.
○ If priority can’t be assigned by the direct atoms bonded to the chiral center,look to the next set of atoms. Priority is assigned at the first point ofdifference○ Atoms in a double or triple bond are considered to be bonded to an
equivalent number of similar atoms by single bonds● Step 2: Orient or rotate the molecule so the lowest ranked atom or group points
towards the back (on a dashed bond).
● Step 3: Read the 3 highest priority groups.
○ If the 3 groups are read clockwise, the configuration is (R).
○ If the 3 groups are read counterclockwise, the configuration is (S).
●

Example #1. Assign configuration of (R) or (S) to the following chiral molecule.

●

Step 1: After looking at the periodic table, Br has the highest atomic number of35, then Cl has the second highest atomic number of 17, then O has the third
highest atomic number of 8, and C has the lowest atomic number of 6.

●

Step 2: Since C has the lowest atomic number making it the lowest priority group,
we have to rotate the methyl group to the back (on a dashed bond). Then we canrelabel our priority groups.

7
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

●Step 3: The sequence 1 > 2 > 3 follows a clockwise configuration, so we canassign the chiral center as (R).

Computational Exercise #1: Geometry Optimization using Maestro
Even though we draw bonds coming towards us as wedged bonds and bonds
going away from us as dashed bonds, sometimes it is still difficult to visualize thethree-dimensionality of a molecule when it is drawn on a flat piece of paper. Now we aregoing to learn how to build a three-dimensional structure of a chiral molecule, optimize
its geometry using Maestro, and use the CIP rules to assign its stereochemical
configuration. Visualizing the molecular structure can be done in three different ways:
1) Through the 2D Sketcher
2) Through the 3D Builder
3) Or, by importing pre-built molecules

We will be using the 2D Sketcher tool in Maestro.

8
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Part 1. Build (R)-1-bromo-1-chloroethane
using 2D Sketcher
Before optimizing any molecular geometry,
you will need a starting molecule in yourworkspace. Let’s draw the structure of
1-bromo-1-chloroethane using the 2D
sketcher.
1. Go to Edit > 2D Sketcher

Figure 3-1. Opening 2D Sketcher

Figure 3-2. Drawing 1-bromo-1-chloroethane.

2. Draw 1-bromo-1-chloroethane exactly
how it is shown in Figure 3-2.
a. Go to the selection bar on theleftb. Create a methyl group bychoosing the “draw line” andclicking in the 2D Workspacec. Drag rightwards from themethyl group to add anothercarbond. Create a wedge bond bychoosing the wedge bond anddragging down from thecentral carbon
e. Put your cursor over the end of
the wedge and type Cl to add
a chlorine
f. Create a dashed bond bychoosing the dashed bond anddragging to the left from the9

The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 3-3. Saving 1-bromo-1-chloroethane.

central carbon
g. Put your cursor over the end of
the wedge and type Br to add
a bromineh. Once again click on the “drawline” and click on the “H”. Drag
upwards from the centralcarboni. Try to replicate the sketch
shown in the figure as closely
as possible
3. Click on Save as New and for Input
Entry Title write
1-bromo-1-chloroethane. Click OK.
Part 2. Optimize the Geometry using
Quantum Mechanic DFT
Now let’s optimize the molecule at thequantum mechanical level.

Figure 3-4. Clicking the Tasks button in theupper righthand corner.

4. With the 1-bromo-1-chloroethane
entry selected and included, go to
Tasks > Optimization using Jaguar
a. The Jaguar Optimization panel
opens
5. Use structures from Project Table (1selected entry)

Figure 3-5. Opening the Jaguar Optimization
panel.

10
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 3-6. Setting the Jaguar Optimization
panel to optimization.
Various settings can be altered depending on
the specific use case. We will only adjust the
Input tab for this example.
Figure 3-7. Setting the QM parameters for
optimization.

6. For Theory, select B3LYP-D3
7. For Basis set, select 6-31G**

A few additional comments about preparing for an optimization calculation:●

If you hover the mouse over the basis set in the table, you can see the number ofbasis functions associated with the basis set. This is useful to know since the qualityof the basis set usually improves as the number of functions increases, noting again
the trade-off between quality and computational expense●

Always make sure the charge and the spin multiplicity are correct (in this case,1-bromo-1-chloroethane is a neutral, singlet, so charge = 0 and spin multiplicity = 1).
Multiplicity is defined as 2S + 1, where S is the total orbital spin of the molecule. For
instance, a system with one unpaired electron is a doublet (multiplicity = 2), since thetotal orbital spin S = ½.

●

Use the Atom-Level Settings button to define per-atom basis sets●

Constraints can be defined on the Optimization tab●

Properties, such as atomic charges, vibrational frequencies, surfaces and more canbe requested on the Properties tab●

Solvent can be defined via several implicit solvation models on the Solvation tab. Notethat this example is a gas-phase geometry optimization●

Read more about geometry optimization with Jaguar here
8. Change the Job name to
1-bromo-1-chloroethane_opt_B3LY
P-D3_6-31Gss
a. Usually we incorporate stars(*) and pluses (+) into file11
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

names with S and P,
respectively
9. Adjust the job settings () byclicking the gear button to the right of
the Job name
○ Choose CPU (1600) as yourhost with 1 processor
10. Click Run

Figure 3-8. Naming and running the job.

Figure 3-9. Banner that shows the job isfinished – Result has been incorporated.

Figure 3-10. The output molecule of
1-bromo-1-chloroethane.

When the job finishes, a banner will appear
indicating that the result has been
incorporated. At this time, the molecule withthe optimized geometry is now shown in theworkspace
11. A new entry group is added to theentry list titled
1-bromo-1-chloroethane_opt_B3LYPD3_6-31GSS.011 (1). Select andinclude the molecule titled
1-bromo-1-chloroethane in thissubgroup. This is your optimized
structure.
12. Change the representation toball-and-stick by clicking on the Stylemenu and choosing Applyball-and-stick representation
13. Change the color of the atoms byclicking on the Style > Color Atoms >Element + Custom Ligand

Figure 3-11. Viewing and styling
1-bromo-1-chloroethane.

12
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 3-12. Changing atom colors for
1-bromo-1-chloroethane.

14. To display atom labels, click Style >Apply Labels then click the drop
down arrow on the right side
15. Click Edit Custom Labeling
16. Checkbox Element and press OK
17. Go back to Style > Apply Labels >Custom Label and now each atom inyour workspace should be labeled
Note: You can toggle the atom labels on andoff by clicking Annotations label button in theWorkspace toggle on the bottom right corner

Figure 3-13. Labeling atoms.

13
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 3-14. Toggling labels on.

Figure 3-15. Toggling labels off.
Part 3. Assign stereochemical
configuration using CIP rules
Now that we optimized the geometry of
1-bromo-1-chloroethane, let’s go through the
CIP rules to determine its stereochemical
configuration.
18. Determine which carbon atom is thechiral center. Remember that a chiralcarbon has 4 unique, or different,
substituents around it
Figure 3-16. Determining where the chiral
center is.
19. Label the priorities of each atom
surrounding the chiral center basedon atomic number (this can be foundfrom a periodic table). Feel free totake note of these priorities on a
separate piece of paper

Figure 3-17. Labeling priorities of each
substituent around the chiral center.

14
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

20. Rotate the molecule so the lowest
priority group is facing the backFigure 3-18. Rotating the molecule to thelowest priority group is facing the back.
21. Relabel priorities and determine
whether 1 > 2 > 3 is clockwise (R) or
counterclockwise (S)22. Since groups 1 > 2 > 3 are goingclockwise, this particular isomer is(R)-1-bromo-1-chloroethane

Figure 3-19. Assigning configuration basedon either clockwise or counterclockwise
sequence of the first 3 priority groups.

15
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

23. To double-check your answer anddisplay stereochemistry labels, click
Style > Apply Labels then click thedrop down arrow on the right side
24. Click Stereochemistry + Charge andyou will find that indeed, thisstereocenter is (R)
25. Double-click the entry name in theentry list and change the name to
R-1-bromo-1-chloroethane.

Figure 3-20. Applying the Stereochemistry +Charge Label to the molecule.

16
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

4. Enantiomers
A pair of compounds with the same atom connectivity, molecular formula, andonly 1 chiral center can either be identical or enantiomers with one another. If they are
identical, they would have the same exact stereochemical configuration. If they havecompletely opposite configurations (i.e. one molecule is (R) while the other is (S)), thenthey would be enantiomers. Enantiomers are stereoisomers that arenonsuperimposable, mirror images of one another and exhibit identical physicalproperties. When exposed to plane-polarized light, however, enantiomers exhibit
different behavior. An enantiomer that rotates plane-polarized light in the positive
direction is called dextrorotatory [(+), or d-], while the enantiomer that rotates the light in
the negative direction is called levorotatory [(-), or l-]. When both d- and l- isomers arepresent in equal amounts, the mixture is called a racemic mixture. To learn more about
the optical activity of enantiomers, you can read more about it here.
To better understand and visualize a pair of enantiomers, let’s draw theenantiomer of (R)-1-bromo-1-chloroethane in Maestro.

Computational Exercise #2: Compare Multiple Molecules by Tiling
1. Right-click the entry
R-1-bromo-1-chloroethane
2. Click Duplicate > In Place and you
will see a new entry appear in theentry list
Figure 4-1. Duplicating
R-1-bromo-1-chloroethane in the Entry List.
3. Include and select the new entry17
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 4-2. Including and selecting the newentry.
4. Go to Edit > 2D Sketcher
5. Change the wedged C–Br bond to adashed C–Br bondFigure 4-3. Changing the wedged bond to adashed bond.
6. Click Update Entry
7. Change the representation toball-and-stick by clicking on the Stylemenu and choosing Applyball-and-stick representation
8. Change the color of the atoms byclicking on the Style > Color Atoms >Element + Custom Ligand
9. To display stereochemistry labels,
click Style > Apply Labels >Stereochemistry + Charge Number
Figure 4-4. Update Entry.

18
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 4-5. Applying the Stereochemistry +Charge label to the molecule.
10. Change the Entry name to
S-1-bromo-1-chloroethane bydouble-clicking on the name.

Figure 4-6. Changing the Entry Name.

19
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Now let’s view our molecules side by side.
11. Simultaneously include (control +click or command + click) both theR-1-bromo-1-chloroethane and theS-1-bromo-1-chloroethane

Figure 4-7. Including both molecules in the
Entry List.
12. Click the + symbol in the bottom
left-hand corner to show workspace
configuration panel
13. Click Tile under the Workspace
LayoutFigure 4-8. Opening the Workspace
Configuration Panel

20
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 4-9. Tiling the two enantiomers
side-by-side.
14. Change the background color to white
by clicking on the + symbol in thebottom right-hand corner
15. You can take a screenshot of yourmolecules to input into theStereoisomers worksheet.

Figure 4-10. Changing the background color
to white.

21
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

5. Diastereomers
Diastereomers are stereoisomers that are not mirror images of one another. The
difference between enantiomers and diastereomers is more apparent when we compare
compounds with more than one chiral center. For example, let’s take a look at thestructure of 2-methylcyclohexanol.

Figure 5-1. Structure of 2-methylcyclohexanolThis molecule contains two chiral centers where each one can either have the (R)configuration or the (S) configuration. A molecule can have 2n number of possible
stereoisomers where n is the number of chiral centers. Since 2-methylcyclohexanol has
2 chiral centers, it has a total of 22 = 4 possible stereoisomers, as shown below.

Figure 5-2. The possible stereoisomers of 2-methylcyclohexanol

Stereoisomers #1 and #2 are enantiomers because both chiral centers completely
inverted to the opposite configuration. The same goes for stereoisomers #3 and #4
where the two chiral centers in stereoisomer #3 were (1R, 2R) and they both inverted tothe opposite configuration of (1S, 2S) in stereoisomer #4. Now if we compare
stereoisomer #1 to stereoisomer #3, notice that one chiral center stayed the same (1R)
whereas the second chiral center inverted from (2S) to (2R). Since only one chiral
center inverted, these two isomers are no longer mirror images from one another,making them diastereomers. And the same goes for stereoisomers #2 and #4 where
they are both diastereomers as well.

22
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

As previously mentioned, cis-trans isomers of alkenes are also considered to bediastereomers because they too are not mirror images of one another. Let’s build a few
diastereomeric alkenes to visually compare their differences.

Computational Exercise #3: Build Diastereomeric Alkenes
In order to visualize the molecules andcompare isomers in three dimensions, wefirst have to draw models of the molecules.
This can be done either through the 2D
Sketcher, the 3D builder, or by importing
pre-built molecules. We will be using the 2D
Sketcher tool:
1. Go to Edit → 2D Sketcher

Figure 5-3. Open 2D Sketcher.

23
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

Figure 5-4. Drawing cis-2-pentene.

2. Draw cis-2-pentene○ Go to the selection bar on theleft○ Create a methyl group bychoosing the “C” or the draw
line and clicking in the 2D
Workspace○ Drag from the methyl group to
add more○ Click on the bond between
methyl groups to make it adouble bond
○ Try to replicate the sketch
shown in the figure as closely
as possible
3. Click on Save as New and for Input
Entry Title write cis-2-pentene. ClickOK.

Figure 5-5. Saving cis-2-pentene

24
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

4. Draw trans-2-pentene○ Reference the instructions forcis-2-pentene in step 1○ Try to replicate the sketch
shown in the figure as closely
as possible
5. Click on Save as New and for Input
Entry Title write trans-2-pentene.
Click OK.

Figure 5-6. Drawing trans-2-pentene.

Figure 5-7. Saving trans-2-pentene.

Figure 5-8. Including the cis/trans molecules.

Oftentimes, viewing multiple molecules
simultaneously can be important forcomparing and contrasting them. We willshow our cis and trans isomer molecules side
by side so that we can easily see how theydiffer.
1. Simultaneously include (control +click or command + click) both thecis-2-pentene and the trans-2-pentene

25
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

2. Show workspace configuration panel→ Workspace Layout → Tile

Figure 5-9. Tiling the cis/trans entries.
3. Change the representation toball-and-stick by clicking on the Stylemenu and choosing Applyball-and-stick representation

Figure 5-10. Applying ball-and-stick style tocis/trans entries.
4. Feel free to pan around, zoom in, andlook at your molecules
5. Change the background to white andtake a screenshot of your molecules
to put in the Stereoisomers
worksheet.

Figure 5-11. Viewing 2-pentene isomers.

For 2-pentene, notice that the cis
configuration shows the methyl and the ethyl
substituents on the same side of the doublebond. The trans configuration has the methyl
and ethyl on opposite sides of the double
bond.

26
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

6. Individual Exercises
For each pair of molecules:
1) Build the molecules using 2D sketcher in Maestro and Optimize their geometries byrunning Optimization Jaguar calculations. Attach screenshots of your optimized
molecules tiled next to each other in the worksheet2) Determine the stereochemical configuration using CIP rules3) Determine whether the pair of molecules are identical, enantiomers, or diastereomers
Here is an example:
1)2) Molecule A:(1S, 3R)-1-chloro-3-methylcyclopentane
Molecule B:(1R, 2R)-1-chloro-3-methylcyclopentane
3) Diastereomers because one chiral center
inverted while the other chiral center stayed
the same

1)

2)

3)

27
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

1)

2)

3)

1)

2)

3)

28
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

7. Conclusion and References
The overarching objective of this tutorial was to introduce or reinforce concepts about
different types of stereoisomers. To better understand how pairs of stereoisomers differ
from one another, we used Maestro to model the isomers in three dimensions. By using
Maestro’s computational tools, we learned to use the 2D Sketcher to conveniently build
our molecules in 3D and how to optimize a structure’s geometry using quantum
mechanical DFT. Additionally, we changed the style of our molecules, applied labels tothem, and arranged them in a tiled formation to easily compare a set of molecules.
For some related practice, proceed to explore other relevant tutorials:●

Introduction to Geometry Optimizations, Functionals, and Basis Sets

For further reading:
●
●
●
●
●

Exploring potential energy surface for chemical reactions: An overview of some practicalmethods. DOI:10.1002/jcc.10231
Introduction to Computational Chemistry, 3rd Edition
Essentials of Computational Chemistry: Theories and Models, 2nd Edition
Molecular Modelling: Principles and Applications, 2nd Edition
See the Jaguar help documentation

8. Glossary
Entry List - a simplified view of the Project Table that allows you to perform basic operations
such as selection and inclusion
Included - the entry is represented in the Workspace, the circle in the In column is blue
Project Table - displays the contents of a project and is also an interface for performing
operations on selected entries, viewing properties, and organizing structures and data
Recent actions - This is a list of your recent actions, which you can use to reopen a panel,
displayed below the Browse row. (Right-click to delete.)
Scratch Project - a temporary project in which work is not saved. Closing a scratch project
removes all current work and begins a new scratch project
Selected - (1) the atoms are chosen in the Workspace. These atoms are referred to as "theselection" or "the atom selection". Workspace operations are performed on the selected atoms.
29
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.

(2) The entry is chosen in the Entry List (and Project Table) and the row for the entry ishighlighted. Project operations are performed on all selected entries
Working Directory - the location that files are saved
Workspace - the 3D display area in the center of the main window, where molecular structures
are displayed
2D Workspace - the 2D panel that opens from the “edit” dropdown that allows for theconstruction of molecules using a 2D sketcher
Tile - if multiple entries are included, included entries are displayed side by side in individual
boxes rather than being overlaid in the same space30
The recipient shall not use the Schrödinger software, materials and information other than for the purposes for which they were distributed. Schrödinger owns the software and all materials, and retains all related
intellectual property rights. Schrödinger will retain all intellectual property rights relating to any suggestions, ideas, enhancement requests, feedback, recommendations or other information provided by therecipient or any third party. The recipient shall not use Schrödinger’s names or marks without Schrödinger’s prior written consent. THE SOFTWARE AND MATERIALS ARE PROVIDED "AS IS" WITHOUTWARRANTY OF ANY KIND. TO THE MAXIMUM EXTENT PERMITTED BY APPLICABLE LAW, IN NO EVENT SHALL SCHRÖDINGER OR ITS AFFILIATES OR LICENSORS BE LIABLE FOR ANY SPECIAL,INCIDENTAL, INDIRECT, CONSEQUENTIAL, PUNITIVE OR EXEMPLARY DAMAGES.