Molecular Modeling and Conformational Analysis Lab
(Modified version—F’17)

Pre-lab Assignment

--Read Chapter 6 in Hornback, then define the following terms in your own words and give an example of each. You can use words, drawings, or a combination of the two in your examples.

1. Conformation
2. Strain (torsional, angle, and diaxial)
3. Dihedral angle
4. Axial substituent
5. Equatorial substituent
6. Ring flip

--To familiarize yourself with Gaussian, please “build” and “optimize” a water molecule using the pre-lab instructions from our Chemistry 105 lab manual on Gaussian: https://sites.google.com/a/wellesley.edu/chem-105-online-lab-manual/labs/08-computational-chemistry/preparation

If you have a set of molecular models, please bring them on your lab day.

Introduction

We have seen that an organic molecule can adapt different conformations to minimize the strain of all kinds: torsional, angular, and axial. strain energy. For example, ethane can assume either a staggered or eclipsed conformation. In the staggered conformation, the torsional strain energy is minimized because the hydrogen atoms on the adjacent carbon atoms are as far apart from each other as they can possible get and none of the bonds are eclipsed with each other. We have used Newman projections as a visual tool for the conformational analysis of ethane:

In this lab, we will use molecule modeling as a mathematical tool for conformational analysis. We will use the Gaussian program to do two types of calculations—optimizations and scans. These calculations will enable us to compare the energies of different conformations of the same molecule. In this way, we can determine which conformations have lower energies and are therefore more stable.

We will see that these calculations enable us to predict the most stable conformations, not only for simple molecules such as vinyl alcohol, but also for larger molecules such as cholesterol.  We will be able to compare our results with values of conformational energies in the textbook.

When doing the calculations in this lab, please follow the directions exactly for the best results.  Haste makes waste…☹

Also, please feel free to reference the “Preparations” section of the Chem. 105 online computational lab for basic instructions on building molecules in Gaussian.

Procedure

NOTE: Some parts of this lab may be designated as “optional” by your instructor.  Please check with your instructor before working on this lab.

Please create a folder on the Desktop with your name/initials as the title and store all your work for this lab in this folder.

Part 1. Dihedral angle scan of vinyl alcohol

Question 1. Which of the three possible conformations of vinyl alcohol, a, b, or c, is preferred? What is your prediction?

We can draw this molecule with GaussView, and then scan/rotate the dihedral angle through 360 degrees. The scan will give us the energy for each step of the calculation as we change the C—C—O—H dihedral angle.

Launch the GaussView program from the start menu. Wait for the program to load. Open the Element fragment menu  and build vinyl alcohol, using the carbon trivalent fragment TWICE to create the double-bonded carbons, and the oxygen tetravalent fragment to add the alcohol.  
Clean and symmetrize the molecule using the following two buttons: .

It should look like this when you are done:

Now open the Redundant Coordinate Editor under the Edit menu.
Click Add, then choose Dihedral from the first drop-down menu and Scan Coordinate from the second drop-down menu. Click/select, from left to right, the two carbons in the double bond,  then the oxygen atom, then the hydrogen atom.

This defines the dihedral angle that we will scan/rotate through 360 degrees. To scan through 360 degrees enter 36 steps of 10 degrees each next to “Scan Coordinate”. Click OK to close the editor which should look like this:

We will use the semi-empirical method at the AM1 level to perform our calculations on the molecule and obtain the the total energy of the molecule at each dihedral angle in the scan. We can use these energies to determine the relative energy of each conformation. To do this, go to the menu bar and select: Calculate and Gaussian Calculation Setup…).

The first three tabs in the Calculation Setup should appear as follows when filled in correctly:

Copy the title and click on Submit…  Click on Save and paste the title of your calculation, i.e.-vinylalcoholscanAM1, into the File name: window.  Make sure to save the calculation in your personal folder on the Desktop.  Save the file as a Gaussian Input Files (*.gif*.com) and click on OK in the “Run Gaussian” pop-up window.  It takes about 5-10 minutes for this calculation to run depending on the age and efficiency of your Desktop computer.  You will produce two types of Gaussian calculation files—check (.chk) files and log (.log) files. The two types contain slightly different information.  [To save time, your instructor may opt to supply you with the vinylalcohol-scan-AM1. log file.]  You will get a pop-up message when the calculation is complete.  Click on “Yes” to close the Gaussian window.  A new window will pop up asking if you want to open either the .chk file or the .log file.  Please select the .log file and click OK.  A new .log file window will appear.

Open the Scan… under Results in the menu bar and place the new graph/scan next to the new .log window. To see lowest energy conformation, highest energy conformation, or any other conformation, click on ANY blue dot in the scan to freeze the structure and display the conformation that corresponds to your chosen dihedral angle. Feel free to click and rotate the structure to view the structure in any position. You can also visualize the relative energy as the dihedral angle rotates through 360 degrees by clicking on the green button in the new .log window.

Question 2. Copy and paste your “Scan of Total Energy” for vinyl alcohol below.  Which structure  (a, b, or c) is has the lowest energy conformation and the highest energy conformation?  Hypothesize a possible reason for these energy minima and maxima conformations for vinyl alcohol. Did the results match your predictions?

Part 2. Dihedral angle scan of a cyclohexane chair

Before beginning, Close any open GaussView windows and open a new window for the next calculation. (File…New…Create molecule group)

The objective of this part of the lab is to scan through the dihedral angle in cyclohexane to provide a conformational energy plot as the chair converts to the half-chair and then to the twist boat conformation.

From the Ring fragment menu  choose the cyclohexane-chair ring fragment from the drop-down menu. Bring the cyclohexane chair to the blue View window by clicking there. Clean and symmetrize the molecule. Open the Redundant Coordinate Editor under the Edit menu (or click on the big R.) Click Add, then choose Dihedral from the first drop-down menu. Click, from left to right, on any four consecutive carbon atoms to define the dihedral angle.

From the second drop-down menu, choose Scan Coordinate. Scan through a total of 120 degrees by taking 12 steps of 10 degrees if the currect value of the dihedral is -60 (or -10 if the current value of the dihedral is 60). Why aren’t we scanning through 360 degrees? 

Click OK to close the editor.

Set up the Calculation (Calculate and Gaussian Calculation Setup…). We will again run a scan calculation using a semi-empirical method at the PM3 level.

The first three tabs in the claculation set-up should look like this:

Copy the title and click on Submit…  Click on Save and paste the title of your calculation, i.e.-cyclohexane-chair-scan-PM3, into the File name: window.  Make sure to save the calculation in your personal folder on the Desktop.  Save the file as a Gaussian Input Files (*.gif*.com) and click on OK in the “Run Gaussian” pop-up window.  The calculation should take less than 5 minutes. Open the .log file.  

It’s easier to see the changes in the chair if you alter it’s appearance from “ball and stick” to “tube.”  To do this, go under File and Preferences and select, “Display Format.”  Under the “General” tab, de-select “Show Hydrogens” and under the “Molecule” tab, select “tube” from all the drop-down menus, then click OK to close the window.

To visualize the various energies, open the scan… under Results and click on the energy maxima and energy minima to visualize the conformations of these relative positions.  You can also click on the green button to show the cyclohexane ring cycling through the chair conformation to the half chair to the twist boat.

Question 3.

Tabulate the energies of the chair, half-chair, and twist boat conformations. You can obtain the scan coordinates and scan energies (in Hartrees) from the “Scan of Total Energy” plot. Convert the energy in Hartrees (au) shown for each of these three conformations to kcal/mol. (One hartee is equal to 627.5095 kcal/mol.)

Question 4

What are the energy differences between the chair and half chair, chair and twist boat, and twist boat and half chair forms (in kcal/mol)? How do these compare with the literature values shown in Hornback figure 6.15?

Figure 6.15 (Hornback)

Part 3. Optimization of the boat conformation of cyclohexane.

GaussView does not include a boat ring fragment of cyclohexane (Gaussian’s boat conformation is a twist boat), so if we want to calculate its energy, we will have to build our own.  Before beginning, Close any open GaussView windows and open a new window for the next calculation. (File…New…Create molecule group) [If applicable, please change the display settings back to “Ball and Stick” from “tube” and “Show Hydrogens”.  (File…Preferences…Display Format) while carrying out this part of the lab.]

From the Ring fragment menu, choose the bicyclo[2.2.1.] heptane ring fragment. Orient the molecule so that the bridge carbon is facing up, and use the delete atom option  to remove the bridge carbon and its bonds to the adjacent carbon atoms.  Use the “add valence” option  to add back the hydrogens to the carbons which were adjacent to the bridge carbon. Now you have boat cyclohexane.

Do not clean and minimize the structure!  Go ahead with an optimization at the PM3 level. The first three tabs of the Calculation Setup should look like this:

Submit and save the file as before.  When the calculation is finished, open the .log file and click on Results…Summary.

Question 5. Paste your Results Summary for the boat conformation below. Convert the energy in Hartrees E(RPM3) to kcal/mol. (One hartee is equal to 627.5095 kcal/mol.)  Use this results and your previous results from Part 2 to calculate the chair-boat energy difference, and compare it to that shown in Figure 6.15 in Hornback.

Question 6. What is the energy difference according to Gaussian between the twist-boat and the boat? Which is more stable?

Part 4. Optimizations of cyclohexane with one substituent

Before beginning, close any open GaussView windows and open a new window for the next calculation. (File…New…Create molecule group)

To compare the axial strain energies of axial methylcyclohexane with equatorial methylcyclohexane, build these molecules separately, clean and symmetrize them, and then run a semi-empirical optimization at the PM3 level for each.

 Question 7. Paste the Results Summary for axial and equatorial methylcyclohexane below. Which conformer is lower in energy? Convert the energy in Hartrees E(RPM3) to kcal/mol. (One hartee is equal to 627.5095 kcal/mol.) What is the energy difference in kcal/mol between the two conformers? How does this compare with the literature values for axial strain energy in Hornback’s Table 6.2? 

Part 5. Optimizations of cyclohexane with two substituents.

Before beginning, close any open GaussView windows and open a new window for the next calculation. (File…New…Create molecule group)

During this part of the lab, you will run semi-empirical optimizations at the PM3 level to compare the energies of cyclohexane with two substituents. Build trans-1,2-dichlorocyclohexane, with two chlorines in the equatorial conformation, and run an optimization at the PM3 level. Repeat for the trans-diaxial conformation and then the cis conformation. From these optimizations, we can obtain relative energies of the isomers.

Question 8. Paste your Results Summaries for the three calculations. Comment on the comparative strain energies of the three molecules. Were the results as you expected? 
NOTE: the lower the energy, the more stable that conformer is relative to the other conformers.

Part 6. Examining an optimized structure of cholesterol

Navigate to the web page shown below and right-click on the file to save it to your computer.

http://pubs.acs.org/doi/suppl/10.1021/ed080p641/suppl_file/jce2003p0641fig1.mol

Save the file in your folder on the desktop and open it with GaussView. You will have to select .mol type files from the drop down choice.

Examine the molecule and answer this question:

Question 9. What features about conformational energy have we discussed in this lab that contributes to the stability of this molecule?  Please try to use the vocabulary of our lab (i.e.-staggered, eclipsed, torsional strain, angular strain, & diaxial strain) to describe specific regions of the cholesterol molecule.

Part 7. Propose a problem about conformational energy to study by molecular modeling. 
(Your proposal should be an extension of what we have done in lab today.)

Please feel free to come up with your own idea (upon instructor approval) OR pick one of the ideas below:

1. Scan the dihedral angle in any alkane chain and compare the energies of various conformations of the alkane chain.

2. Scan the dihedral angle in vinyl acetate or 1,3-butadiene and compare the results to Part 1.

3. Scan the dihedral angle in a mono-substituted cyclohexane and compare your results to the results in
Part 1.

4. Chose a substituent other than the methyl group, from Table 6.2, and run an optimization for both the axial and equatorial conformations at the PM3 level. Then calculate the axial strain energy of your molecule and compare the axial strain energy from your calculation to the literature values posted in Table 6.2.

5. Choose another di-substituted cyclohexane (other than 1,2-dichlorocyclohexane) and compare the conformational energy differences for the cis and trans isomers.

6. Compare some of the nine conformers of inositol, a sugar with half the sweetness of sucrose.

7.  Run optimizations at the PM3 level for alpha and beta-D-glucose. Both of these conformations are present in D-glucose. Which is energetically more stable?

8. Run an optimization of planar cyclohexane and compare its energy to that of the chair and boat forms.

The practice problems in Hornback, Chapter 6 (and the additional problems at the end of the chapter) may provide some additional inspiration for a modeling problem to tackle. 

If you want to study and compare two molecules or conformers, work with your partner, so that you are doing one calculation each. So that your problem does not take more than 15 minutes of calculation time, the molecule(s) you will study should be no larger than a cyclohexane ring with two or three substituents.  You can do either an optimization or a scan at the PM3 level.

Question 10: What problem did you study and what was your hypothesis?  What did you discover? In addition to answering this question, paste your Results Summaries and/or Scan Plots below.  If time permits, we will share our results in lab.