Teaching with Schrödinger

Updated: 1-23-22

Diels-Alder Reactions
Created with: Release 2021-3
Prerequisites: working knowledge of Maestro
Files Supplied: Diels_Alder_worksheet
Categories:
organic chemistry

About this Lesson
In this lesson plan, students will examine the relationship between a diene and a
dienophile in a Diels-Alder reaction. Transition state theory will be introduced to analyze
the concerted mechanism of a [4+2] cycloaddition. Reaction energy diagrams will be
investigated to determine whether a reaction is exergonic or endergonic.
Using Maestro, students will use Jaguar’s AutoTS panel to calculate the energetics ofthe reactants, product, and transition state. Students will also calculate the HOMO andLUMO of reactants to help with visualizing π molecular orbital overlap.

Learning Objectives
Identify transition state structures of Diels-Alder reaction mechanisms● Plot reaction energy diagrams with activation energy barriers to determine theirchemical reactivity characteristics (i.e. endergonic, exergonic, etc.)● Generate molecular orbitals of the diene and dienophile to analyze favorable
orbital overlap for product formation●

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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○●

Electronic, steric, and orbital interactions in the behavior and properties ofmolecules (Conceptual Topics)

ETS Chemistry GRE○

Organic Chemistry – Diels-Alder Reaction Mechanisms (3.C)

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 substituent effects on Diels-Alder reactions
Visual assessment of student-generated transition state structures, reaction energy
diagrams of Diels-Alder reactions, and molecular orbitals of the reactants

Warm-Up Questions: To be done on their own or at the beginning of class
Watch the Khan Academy videos on the Diels-Alder reaction.
1) Label the following substituents as either electron-withdrawing or electron-donating:a) –COOHb) –Mec) –OHd) –NO2
2) To speed up a Diels–Alder reaction, what types of substituents should be placed on thediene and dienophile?

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

What you will need for this lesson - p. 3
Introduction to Diels-Alder Reactions - p. 5
Generating Molecular Orbitals - p. 6
Locating Transition States with AutoTS - p. 14
Individual Exercises - p. 21
Summary, Additional Resources, and References - p. 23

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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. 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“Diels_Alder” 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

4. Go to File > Change Working
Directory
5. Find your “Diels_Alder” folder that you
duplicated to your Desktop, and click
ChooseFigure 1-1. Change Working Directory option.

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.

6. Next, go to File > Save Project As
7. Type “Diels_Alder_tutorial” and click
Savea. The project will be titledDiels_Alder_tutorial.prj

Figure 1-2. Save Project panel.

Figure 1-3. Choose the best mouse option foryour set up.

8. Finally, check your Mouse Actions
a. PC : Edit > Customize Mouse
Actionsb. Mac : Workspace >Customize Mouse Actions
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, meaning the scroll
wheel is a button as well as a wheel. If
you do not have a mouse, choose
Trackpad.

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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 Diels-Alder Reactions

The Diels-Alder reaction is a [4+2] cycloaddition that is part of a family ofreactions called pericyclic reactions. In a pericyclic reaction, the two reactants are
relatively non-polar and do not generally go through charged intermediates. A
Diels-Alder reaction combines two components: a diene (a 4 π-electron component)
and a dienophile (a 2 π-electron component). A diene is composed of two adjacent π
bonds that are conjugated. A dienophile contains at least one π bond. In a Diels-Alderreaction, there is a pattern where 4 carbon atoms from the diene come together with 2
carbons from the dienophile to form a new 6-membered ring. The mechanism follows
the same pattern where 3 C–C π bonds are broken, 2 new C–C bonds are formed, anda new C–C π bond is formed.
There are two ways to draw the arrow-pushing one-step, concerted mechanismof the Diels-Alder reaction: clockwise and counterclockwise. Both ways to depict theflow of electrons are correct and each way consists of drawing a total of 3 arrows. See
Figure 1 below for details:

Figure 1. Concerted arrow-pushing mechanism for a Diels-Alder reaction.
In a Diels-Alder reaction, the diene must be conjugated and in an s-cis conformation asshown above in Figure 1. Furthermore, substituents on either the diene or the
dienophile do not affect the bond-forming and bond-breaking pattern in the reaction.
Adding substituents to the reactants does however affect the reaction rate. It also
affects the stereochemistry of the product which you can learn more about here. The
rate of reaction is increased by electron-donating groups on the diene andelectron-withdrawing groups on the dienophile.
For the scope of this lesson, it will only focus on normal electron demand
Diels-Alder reactions, with an electron-rich diene and an electron-poor dienophile.
However, there are examples of Diels-Alder reactions that proceed with electron-poor
dienes and electron-rich dienophiles. Read more about inverse-electron demand
Diels-Alder reactions here.

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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.

Example #1. Predict the product and arrow-pushing mechanism of the following
Diels-Alder reaction.

3.

Generating Molecular Orbitals

Here we will show how the Diels-Alder reaction results form the constructive
orbital overlap between the highest occupied molecular orbital (HOMO) of the diene
with the lowest unoccupied molecular orbital (LUMO) of the dienophile. Since
Diels-Alder reactions are concerted, multiple bonds are formed and broken at the sametime, which means that two orbital interactions have to be considered. In order for thereaction to occur in a single step, there must be constructive overlap between each of
the lobes where the bonds are being formed. If the phases are opposite, there isdestructive interference between the orbitals which means there is zero electron density
between the atoms. Visualizing the interactions between molecular orbitals is often
difficult to see on paper, so we will calculate and generate molecular orbitals of theDiels-Alder reaction between butadiene and ethylene using Maestro’s Jaguar.

Computational Exercise: Calculating Molecular Orbitals in Maestro
This exercise involves 3 parts:
Part 1: Build the molecules using 2D sketcher
Part 2: Run a Jaguar optimization job and calculate molecular orbitals
Part 3: Visualize the HOMO of the diene and LUMO of the dienophile

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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 reactants using 2D Sketcher
Let’s draw the structure of the reactants using
the 2D sketcher.
1. Go to Edit > 2D Sketcher

Figure 3-1. Opening 2D Sketcher

Figure 3-2. Drawing and saving butadiene.

2. Draw butadiene exactly how it isshown in Figure 2-2.
○ Go to the selection bar on theleft○ Select the single carbon bondbutton○ Click and drag to add a carbon
single bond. Continue to click
and drag to draw a 4-carbon
chain○ Double click the single bond to
add double bonds○ 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 butadiene. Click OK.
4. Check your structure to ensure it is inan s-cis conformation. If it is in
s-trans, go to Edit > 3D Builder
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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.

○Click the dropdown arrow next
to Move○ Select Rotate Dihedrals○ Adjust the C–C single bonddihedral angle to 0º○ Click OK in the Rotate
Dihedral banner
5. Repeat steps 1-3 to build the structure
for ethylene

Figure 3-3. Changing the dihedral angle ofs-trans butadiene to s-cis butadiene.
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.

6. With both the butadiene and ethylene
entries selected and included, go to
Tasks > Optimization using Jaguar○ The Jaguar Optimization panel
opens
7. Use structures from Project Table (2selected entries)

Figure 3-5. Opening the Jaguar Optimization
panel.

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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.

8. For Theory, select B3LYP-D3
9. 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,biphenyl is a neutral, singlet, so charge = 0 and spin multiplicity = 1). Multiplicity isdefined as 2S + 1, where S is the total orbital spin of the molecule. For instance, asystem with one unpaired electron is a doublet (multiplicity = 2), since the total 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

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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.

10. Go to the Properties Tab
11. Select Surfaces (MO, density,
potential)
12. Check mark Molecular orbitals
13. Leave HOMO-0 and LUMO+0 for thisexercise. If you would like to visualize
more molecular orbitals, you may
increase these values as necessary

Figure 3-8. Selecting MO Surfaces in theProperties Tab.
14. Change the Job name to
MOs_Diels_alder
15. Adjust the job settings () byclicking the gear button to the right of
the Job name
○ Choose localhost as your hostwith 1 processor
16. Click Run

Figure 3-9. Naming and running the job.

Figure 3-10. Banner that shows the job isfinished – Result has been incorporated.

When the job finishes, a banner will appear
indicating that the result has been
incorporated. At this time, the molecules withthe optimized geometries is now shown in theworkspace10
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 3-11. The output molecules.

Figure 3-12. Toggling the surfaces on.

Figure 3-13. Toggling the surfaces off.

17. A new entry group is added to theentry list. Select and include themolecules titled butadiene andethylene in this subgroup. These areyour optimized structures.
18. You can toggle on and off themolecular orbital surfaces at thebottom right-hand corner. Let’s turn it
off for now.
19. Change the representation toball-and-stick by clicking on the Stylemenu and choosing Applyball-and-stick representation

Figure 3-14. Viewing and styling butadiene
and ethylene.

11
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. To display atom labels, click Style >Apply Labels then click the drop
down arrow on the right side
21. Click Edit Custom Labeling
22. Checkbox Element and press OK
23. 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 3-15. Labeling atoms.

Figure 3-16. Toggling labels on.

Figure 3-17. Toggling labels off.
Part 3. Visualize the HOMO and LUMO
Now that we optimized the geometry of
biphenyl, let’s visualize the molecular orbitals.

Figure 3-18. Selecting the Surface ‘S’ buttonin the Entry List

24. Click the S button in the Entry List to
the right of each entry
25. Select either the HOMO or the LUMO
to visualize
26. If you do not see any surfaces appear
onto the molecule, remember to
Toggle On the surfaces button in thebottom right-hand corner

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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.

27. Tile the 2 structures to visualize theMOs of the diene and dienophileside-by-side by selecting the + buttonin the bottom right-hand corner of theinterface
28. Select the Tile by button underWorkspace Layout○ By default, moving the twomolecules will be linked. If you
wish to move only one
molecule at a time, you canunlink their movement bydeselecting the link button

Figure 3-19. Tile the molecules side-by-side.

Example #2. Take screenshots of the HOMO of the diene and the LUMO of the diene.
Where does the orbital overlap occur between the two reactants?

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.

4.

Locating Transition States with AutoTS

Next, we are going to analyze the Diels-Alder reaction between butadiene andethylene by determining the energetics of the reactants, transition state structure, andproducts. To do this, we will be using Maestro, Schrödinger’s molecular modelingsoftware.

Figure 3.1. General potential energy surface.
Used with permission. Created by Professor H. Bernhard Schlegel, Wayne State
University, Detroit, MI.
Locating a transition state is essential for computing the activation energy of areaction, and thereby the reaction rate. As a result, finding transition states is useful inmany applications: predicting reactivity, understanding reaction mechanisms, catalyst
design and optimization, predicting outcomes of various competing reactions and more.
Besides, locating a transition state is unique to computation -- meaning the transition
state cannot be ‘found’ in the lab. Read more about Schrödinger’s work in the space ofCatalysis and Chemical Reactivity.
Searching for a transition state is typically a relatively difficult task in molecularmodeling. Unlike an optimization to a minimum (see: Introduction to Geometry
Optimizations, Functionals and Basis Sets), the search for a transition state highly
depends on the quality of the initial guess, the initial Hessian and the search direction.
Search for transition states is sometimes described as an ‘art’. Experience and practice
are key, as well as maintaining a thorough understanding of the available tools.
There are several alternative approaches to searching for a transition state with
Jaguar (Schrödinger’s Quantum Mechanics Engine). For this lesson, we will be using
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.

the AutoTS panel which is an automated workflow in which reactants and products are
input and interpolation is used to search for the transition state with minimal userintervention. AutoTS is an automated way of finding transition states, particularly forelementary reactions. Its workflow requires only the structures of the reactants and the
products as input, and then automates the rest of the process: it optimizes reactants
and products, determines which bonds are breaking and forming, establishes
correspondence between atoms in the reactants and the products, generates atransition state guess (either from a template or using an interpolated reaction path),launches a transition state search with the DFT engine Jaguar, verifies if the locatedtransition state is trustworthy, runs frequency calculations, connects the transition statewith the reactants and the products using an intrinsic reaction coordinate (IRC)
algorithm and finally prints the potential energy surface diagram showing the transition
state barrier. AutoTS works best on reactions that have only one transition state
between the reactants and the products, such as the Diels-Alder reaction.

Computational Exercise #2: Generating a Transition State, Geometriesof Reactants and Products, and an Energy Diagram using AutoTS
Let’s employ the AutoTS panel for the Diels-Alder reaction between butadiene
and ethylene. When an AutoTS job is submitted, it produces the following results:
1) Optimized geometries of the reactants and products
2) A transition state structure with an animation to show bonds breaking andforming3) A potential energy surface diagram that includes a transition state barrier

Figure 4-1. Opening the AutoTS panel.

We will first perform an AutoTS
calculation on a simple Diels-Alderreaction between chloroethane and abromide ion to learn the mechanics of thepanel.
1. Go to Tasks and type AutoTS.
Click
AutoTS…
Other
Applications (under the AutoTS
category)

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.

Figure 4-2. Sketching the butadiene
reactant in the AutoTS panel.

Figure 4-3. Sketching the Cl – reactant in
the AutoTS panel.

○ The
AutoTS:
Perform
Calculations panel opens
2. Change the Reaction Name toDiels_Alder_AutoTS
3. Under Reactants, click Sketch anddraw butadiene. In the 2D
Sketcher, select the carbon single
bond, then click and drag to form
a C–C single bond, and continue
adding to get a 4-carbon chain.
Under
Molecular
Properties,
ensure the Total Charge is 0, Spin
Multiplicity is 1, and the box to
Add Hydrogens is checked. It’sokay if butadiene appears to be
s-trans in the AutoTS panel – it will
reorient to s-cis during geometry
optimization. Click Save.
4. Under Reactants, click Sketch anddraw ethylene. In the 2D
Sketcher, select the carbon single
bond, then click and drag to formaC–C
singlebond,anddouble-click to form a doublebond. Under Molecular Properties,
ensure the Total Charge is 0, Spin
Multiplicity is 1, and the box to
Add Hydrogens is checked. ClickSave.
5. Under Products, repeat theprocess and draw the products of
the Diels-Alder reaction.

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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.

○ Your inputs should matchthe Figure 6-4.

Figure 4-4. Sketching the products in the
AutoTS panel.
6. Go to the Advanced Settings tab○ We will keep the settings asdefault in this case
○ Level of theory:i. Method: B3LYP-D3
ii. Basis Set: 6-31G**
7. Change the Job name toDiels_Alder_AutoTS

Figure 4-5. Advanced settings andnaming the job.

8. Adjust the job settings () asneeded○ Change host from local hostto CPU host.
○ Change the Maximum # ofProcessors to 12. The job

17
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.

can be completed in about
5 minutes on a 12 CPU host
9. If you would like to run the job
yourself, click Run. Otherwise, we
can import pre-generated outputs
in the analysis stages
10. Close the AutoTS panel
Figure 4-6. Adjusting job settings fromthe gear icon and running the job.

Note: The Preview Reaction Complex tab
can be used to generate reactant andproduct complexes (merged structures)and to see a guess at the reaction path.
Adjustments can be made as needed
When the job is complete, we can viewthe results in the AutoTS: View Results
panel. The AutoTS calculation assesses
various paths without any additional user
input

Figure 4-7. Importing the results of the
AutoTS calculation.

11. Go to File > Import Structures
12. SelecttheDiels_Alder_AutoTS_full_pa
th.mae file and click Open○ If you did not perform thecalculation yourself and
wish
to
open
the
pre-generated
results,
selecttheDiels_Alder_AutoTS_fu
ll_path.mae file and click
Open○ An entry group including thereactant, transition state18
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.

and product structures is
added to the entry list
13. Use the Workflow Action Menu
(WAM) button (Results panel) to access theAlternatively, go to Tasks and type
AutoTS
Results
and
load
the
full_path.mae file via the Import button
The AutoTS: View Results panel contains
the energy diagram associated with thereaction. If you are interested in viewing
the vibration associated with thetransition state, use the vibration viewer () in the entry list and animate in theworkspace
Figure 4-8. AutoTS results.

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.

Example #3. Using the AutoTS results, let’s analyze the Diels-Alder reaction further.
Answer the following questions:a) Take screenshots of the optimized geometries for the reactants, transition state
structure, and products.
b) List the C–C bond distances of each molecule using the Measure button in units ofångstroms.
Reactants

Transition State Structure

Products

Screenshot:

Screenshot:

Screenshot:

Bond distances:

Bond distances:

Bond distances:c) Now let’s analyze the transition state structure. Look at the animation of its vibration.
What is the hybridization of the carbon atoms involved in the bond breaking and formingat the transition state? How does this differ from the reactants’ starting geometry?

d) Take a screenshot of the reaction energy diagram. Is the reaction exergonic orendergonic? What is the activation energy barrier in units of kcal/mol? Would thereaction speed up or slow down if the dienophile included an electron-withdrawing groupsuch as an aldehyde?

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.

5.

Individual Exercise

Part A:For the following Diels-Alder reaction:1) Label which reactant is the diene and which is the dienophile. Then, predict the productand draw the arrow-pushing mechanism.

2) Generate the HOMO and LUMO of the diene and dienophile. Take a screenshot andpaste it below.
HOMO of Diene

LUMO of Dienophile21
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 B:For the following Diels-Alder reaction:1) Label which reactant is the diene and which is the dienophile. Then, predict the productand draw the arrow-pushing mechanism.

2) Look at the pre-generated AutoTS results for this reaction. Take screenshots of the
optimized geometries for the reactants, transition state structure, and products.
Reactants
Screenshot:

Transition State Structure
Screenshot:

Products
Screenshot: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.

3) Take a screenshot of the reaction energy diagram. Is the reaction exergonic orendergonic? What is the activation energy barrier in units of kcal/mol?

Part C:
Compare the two reactions from Part A and Part B. Which reaction do you expect to have afaster reaction rate and why?

6.

Summary, Additional Resources, and References

Using Maestro, students learned how to use Jaguar’s AutoTS panel to performgeometry optimization calculations of the reactants and products of a Diels-Alderreaction, determine which bonds are breaking and forming, establish correspondence
between atoms in the reactants and the products, and generate a transition state
structure.They learned how to render a potential energy surface diagram to show theactivation energy barrier. Lastly, students generated molecular orbitals of the diene anddienophile to better understand that constructive orbital overlap is necessary for new
bond formation.

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.

For further learning:

For introductory content, focused on navigating the Schrödinger Materials Scienceinterface, an Introduction to Maestro for Materials Science tutorial is available.
For some related practice, proceed to explore other relevant tutorials:●

Introduction to Maestro for Materials Science●

Introduction to Multistage Quantum Mechanical Workflows●

Introduction to Geometry Optimizations, Functionals, and Basis Sets●

Locating Transition States

For further reading:
●
●
●
●
●

Exploring potential energy surface for chemical reactions: An overview of some
practical methods. 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

Glossary of Terms:

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 apanel, 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"the selection" or "the atom selection". Workspace operations are performed on the24
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.

selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row
for the entry is highlighted. 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 inindividual boxes rather than being overlaid in the same space25
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.