1. Double-click the Materials Science icon
   • (No icon? See Starting Maestro)

Figure 2-1. Change Working Directory option.

2. Go to File > Change Working Directory
3. Find your directory, and click Choose
4. Pre-generated input and results files are included for running jobs or examining output. Download the zip file here: schrodinger.com/sites/default/files/s3/release/current/Tutorials/zip/transition_states_plus.zip
5. After downloading the zip file, unzip the contents in your Working Directorythe location where files are saved for ease of access throughout the tutorial

Figure 2-2. Save Project panel.

6. Go to File > Save Project As
7. Change the File name to transition_states_plus_tutorial, click Save
   • The project is now named transition_states_plus_tutorial.prj

Figure 2-3. Imported reactant and product structures in the entry list.

8. Go to File > Import Structures
9. Navigate to where you downloaded the tutorial files (presumably in your working directorythe location where files are saved), and select reactants_products_optimized.maegz. Click Open
   • A new entry group titled optimized_reactants_products (3) appears in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion, containing ten entries associated with the reactants and products of our reactions of interest

Note: You can confirm that these molecules have been geometry optimized by opening the Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data. There you can see the level of theory for the optimizations as well as the energies, among other properties.

Figure 3-1. The previous transition state after importing.

To begin, let’s import the previous transition state

1. Go to File > Import Structures
2. Navigate to where you downloaded the tutorial files, and select previous_TS.maegz. Click Open
   • A new entry is added to the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion titled TS.01
3. Duplicate this entry (right-click > Duplicate > Entries Only (In Place)) and rename it modified_TS_DA
4. Select(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 the 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 and includethe entry is represented in the Workspace, the circle in the In column is blue the new entry from the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
   • We will proceed to alter the modified_TS_DA. We will preserve the manual_TS entry for reference and later use (you can always import again if needed.)

Figure 3-2. Selecting the H atom and opening the 3D Builder palette.

We will modify the ethene to change it into furan using the 3D Builder tools while leaving the double bond acting as a dienophile intact:

5. Select one of the upward-facing hydrogen atoms in the ethene molecule
6. In the Toolbar, click on the Build palette
   • The 3D Builder appears in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed

Figure 3-3. Adding fragment groups.

7. Click Add Fragments
8. Click on the CH₄ fragment from the Organic options
   • Choosing the CH₄ fragment will add a methane molecule if nothing is selected in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed. When an atom is selected to be replaced (as in this case), a methyl group is added
9. Select the other upward-facing hydrogen atom and add an H₂O fragment using the same procedure, this will add an -OH group

Figure 3-4. Adding an oxygen atom and closing the ring.

10. Select one of the hydrogens atoms on the newly added methyl group
11. Select one of the hydrogens on the methyl group and add another CH₄ fragment
12. Select both the oxygen and the just-added carbon atoms (via holding cmd or ctrl) and create a bond between them

Figure 3-5. The new TS starting point after 3D Building.

13. Increase the bond order of the carbon-carbon single bond to create furan
14. Delete any extra hydrogen atoms as necessary
15. Use the Minimize selected atoms tool to make the bond lengths and angles more realistic
    • Be sure to only select atoms and bonds not directly involved in the double bond acting as the dienophile in the Diels-Alder reaction
16. Close the 3D Builder and deselect any selected atoms

Note: Immediately after making a substitution with the 3D Builder, the selected atoms can be manipulated while they remain selected (four stacked horizontal lines appear). Here we do not need to rotate the methyl groups and so we simply clear the selection.

Figure 3-6. The QM Multistage Workflow panel.

This starting point is likely already sufficient to use for a manual transition state search. However, with substituents with more degrees of freedom, two more steps may be helpful in ensuring that the ultimate transition state search converges. First, you may wish to perform a conformational search on the new groups. Next, you may wish to pre-optimize the molecule to a minimum with the bond-breaking and bond-forming atoms frozen.

We will explore the conformational search process in Section 4, in this section we will look at pre-optimization:

17. Ensure that modified_TS_DA is 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 the 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 and go to Tasks > Materials > Quantum Mechanics > Molecular Quantum Mechanics > QM Multistage Workflow
    • The QM Multistage Workflow panel opens
18. Change the Stage type to Optimization
19. Change the Basis set to LACVP**
20. Go to the Optimization tab

Figure 3-7. Setting constraints.

We will perform the optimization with the six distances associated with the bond-breaking and bond-forming atoms fixed. This will relax the surrounding atoms, as well as some minor adjustments to the associated angles and dihedrals corresponding to the bonds directly involved in the Diels-Alder reaction. This structure is likely a great guess for the transition state structure.

21. In the Add new constraint section, set Type to Distance
    • Pick is now checked by default
22. In the workspacethe 3D display area in the center of the main window, where molecular structures are displayed, select the bonds that are relevant in the Diels-Alder transition state in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed by picking the atom pairs, see the Figure
    • The panel updates dynamically to indicate that the distances will be fixed, and the spring symbol appears in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed on the bonds

Figure 3-8. Running the job.

We do not need to call for any Properties here. This optimization is simply to generate an input for the transition state calculation. We are ready to run the job.

23. Change the Job name to modified_TS_DA_opt_B3LYP-D3_LACVPss
24. Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in about 20 minutes on a 8 CPU host
25. If you would like to run the job yourself, click Run. Otherwise, import the pregenerated modified_TS_DA_opt_B3LYP-D3_LACVPss.01.mae file
26. Close the QM Multistage Workflow panel

Figure 3-9. The output after renaming.

When the job finishes or after importing, a new entry appears in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion entitled modified_TS_DA

27. Select(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 the 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, includethe entry is represented in the Workspace, the circle in the In column is blue and rename the entry to modified_TS_DA_preopt

Figure 3-10. Selecting the transition state initial structure.

This entry is now an excellent guess to use as an input for a transition state calculation. From here, we will follow analogous steps from Section 3 of the Locating Transition States: Part 1 tutorial, detailed here again:

28. Go to Tasks > Materials > Quantum Mechanics > Molecular Quantum Mechanics > More Molecular QM Tasks > Transition State Search
    • The Jaguar - Transition State Search panel opens
    • Note that you can use the search function in the tasks menu to access the panel
    • Also note that this job can also be prepared using the QM Multistage Workflow panel by choosing Transition State for Stage Type
29. Keep Standard as the Search method
30. Click Load next to Use Structures From
    • The modified transition state structure that you either imported or calculated in the last step should appear next to Transition State in the table. The checkbox under In should automatically be checked.

Figure 3-11. Defining the constraints.

The quality of a transition state search depends on the search direction. We can identify the relevant bonds to break and form as “active constraints” to help guide the search:

31. Go to the Optimization tab
32. Under Add new constraint, change the Type dropdown to Distance
33. Keeping the panel open, return to the workspacethe 3D display area in the center of the main window, where molecular structures are displayed and again, select the six atom pairs associated with the relevant forming and breaking bonds
    • The atom pairs are added to the constraints table in the panel
    • Spring icons appear in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed associated with the selected distances
34. Once the six pairs are in the panel, check Set constraints as active constraints

Figure 3-12. Updating the basis set.

35. Return to the Transition State tab
    • Some of the parameters have been automatically updated, in particular the Search along option is now updated to the Active coordinate eigenvector associated with our active constraints
36. Change the Basis set to LACVP maintaining the ** Polarization

Figure 3-13. Performing a frequency calculation and running the job.

37. Finally, go to the Properties tab
38. Check Vibrational frequencies
39. Change the Job name to modified_TS_DA_ts_search
40. Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in about 10 minutes on a 8 CPU host
41. If you would like to run the job yourself, click Run. Otherwise, import the pregenerated Section_03 > modified_TS_DA_ts_search > jag_modified_TS_DA_ts_search.01.mae file
42. Close the Jaguar - Transition State panel

Figure 3-14. Visualizing the output.

When the job is complete (or after importing) a new entry is incorporated titled modified_TS_DA

43. Change the name of the entry to TS_DA_exo by double-clicking on the entry name

We can verify the transition state by analyzing the frequency calculation

44. Open the Vibrations directly from the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion by clicking on the button ()
    • Notice that there is one negative frequency as expected
    • If you do not see this button next to the entry, make sure you performed step 29.
45. Visualize this vibration by clicking the play button
    • The animation should resemble the expected bond breaking and bond forming processes
46. Close the Vibrations pop up

We will return to this transition state in Section 5.

Figure 3-15. Preparing the endo input.

For additional practice, repeat the procedure for the analogous reaction that creates the endo product. Begin by duplicating the original manual_TS entry again and renaming it as modified_TS_DA_endo.

(modified_TS.mae is available as a starting point if you are having trouble with the 3D Building)

Figure 3-16. Visualizing the endo output.

The final transition state is shown here. You can also import the pregenerated  modified_TS_DA_endo_opt_B3LYP-D3_LACVPss-out.maegz and  modified_TS_DA_endo_ts_search.01.mae files if you prefer not to run the jobs. We will use the transition state output in Section 5.

Figure 4-1. The previous transition state after importing.

To begin, let’s now use the output from the Part 1 tutorial as our transition state to modify:

1. Duplicate the TS_DA_exo entry As Ungrouped Entries and rename it as modified_TS_DA_exo

Figure 4-2. Adding ethyl groups to the diene.

2. Use the 3D Builder as before to replace the hydrogens at each end of the diene with CH₄ fragments. Repeat the process to create ethyl groups, as shown in the Figure.
   • It does not matter which hydrogen you choose in the second round of fragment additions, in the next steps we will perform a conformational search.

Figure 4-3. Deselecting the atoms and selecting and including the entry.

3. Deselect any atoms in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed and select(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 the 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 and includethe entry is represented in the Workspace, the circle in the In column is blue the modified_TS_DA_exo entry
4. Go to Tasks > Browse All > MacroModel > Conformational Search
   • The Conformational Search panel opens

Figure 4-4. Defining the constraints.

This panel allows us to perform a conformational search on our molecule with the bonds involved in the transition state fixed. This will allow us to sample the various possible conformations of the ethyl groups efficiently

5. Go to the Constraints tab
6. Go to the Distances tab
7. Ensure Pick is selected with Atoms selected in the options menu
8. In the workspacethe 3D display area in the center of the main window, where molecular structures are displayed, select the 6 bonds involved in the reaction, as done before for the transition state search
   • The table will automatically populate

Figure 4-5. Running the conformational search.

9. Change the Job name to modified_TS_DA_exo_csearch
10. Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in less than 5 minutes on a 12 CPU host
11. Click Run
12. Close the Conformational Search panel

Figure 4-6. Including the outputs from the conformational search simultaneously.

When the job is complete, a new entry group is incorporated titled modified_TS_DA_exo_csearch-out (28) containing five entries

13. Includethe entry is represented in the Workspace, the circle in the In column is blue the various entries in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed to see the different conformations of the ethyl groups
    • In the Figure, we tile several of the entries for the ease of comparison, you can do this by using the Workspace Configuration panel ()

Figure 4-7. Adding a property to the entry list directly.

We can compare the relative energies of these conformers directly in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion (note, these energies are based on the force field, we have not yet run any quantum mechanical calculations)

14. At the top of the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion, click on the gear icon () and choose Show Property
    • The Show Properties in Table panel opens

Figure 4-8. Choosing a property to add to the entry list directly.

15. Choose Potential Energy-S-OPLS and click OK
    • The Relative Potential energy property is added to the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion

Figure 4-9. Viewing the relative potential energies.

You can view the relative potential energies of the conformers directly in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. The list is automatically sorted by energy.

Figure 4-10. Visualizing the transition state search output.

At this stage, you can select(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 the 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 and includethe entry is represented in the Workspace, the circle in the In column is blue the lowest energy conformer and repeat the steps detailed in Section 3 for finding the transition state.

The final transition state is shown here. You can also import the pregenerated  modified_TS_DA_exo_opt_B3LYP-D3_LACVPss.01.mae and  modified_TS_DA_exo_ts_search.01.mae files if you prefer not to run the jobs. We will use the transition state output in Section 5

Figure 5-1. Importing pre-optimized structures.

In the Calculating Reaction Energetics for Molecular Systems tutorial, the reactant and product structures for the reaction between furan and cyclopentadiene are optimized. Refer to that tutorial if you are interested in running the optimization calculation yourself. To import the structures:

1. Go to File > Import Structures and select Section05 > optimization_DA > optimization_DA-out.mae
2. Go to File > Import Structures and select Section05 > diethylcyclopentadiene_opt > diethylcyclopentadiene_opt-out.maegz
   • This file has the optimized 1,4-diethylcyclopenta-1,3-diene structure along with the optimized exo-product structure from its reaction with furan