Chem 310, Organic Chemistry Lab Molecular Modeling Using Macromodel

Transcription

1 Chem 310, Organic Chemistry Lab Molecular Modeling Using Macromodel This is a molecular modeling experiment, and should be written up in your lab notebook just as if it were a normal "wet-chemistry" experiment. Your write-up should include an introductory section stating the overall purpose of each of the two studies you will perform (this is described below); the methods used (experimental); a description of your observations and results; and an analysis/interpretation of your data. Attach the completed worksheet tables to your lab notebook as part of your results section, and answer the questions that are posed in the detailed procedures below to complete your data analysis section. There are two parts to this molecular modeling experiment. In the first part, you will be directed step-by-step through an analysis of the low-energy conformations of tert-butylcyclohexane. This procedure will require you to: (a) draw (build) the molecule on the screen with the t-butyl group in an axial position, (b) perform a search for the local minimum-energy conformation of this t-butylcyclohexane conformer, (c) perform a molecular dynamics simulation on this molecule to search for alternative lower-energy conformations, (d) perform a new search for the local minimum-energy conformation of the main alternative conformer that you find (t-butyl group equatorial). You will then compare and analyze the energetics of the two conformers that you have identified. In the second part of this experiment, you are asked to perform a similar analysis of the cis- and trans-stereoisomers of 2-methylcyclohexanol, the products obtained in the reduction experiment performed earlier in this course. You should build and analyze these molecules one-at-a-time, performing an energy minimization initially, and then repeatedly using a molecular dynamics simulation followed by an energy minimization to identify and compare other low-energy conformers of each stereoisomer. Review Prior to performing these analyses and writing up your report, you should review the descriptive terms angle strain, torsional strain, conformations and conformers. Also, review the conformations of cyclohexane and substituted cyclohexanes in detail, including the chair, boat, and twisted-boat conformations, and equatorial and axial substituents, and the energetics of these structures. These topics are all covered in the early chapters of all organic chemistry textbooks. Detailed Procedures Selections: Within any one working session, macromodel remembers changes that you make to any default values, so that you only need to make them once. Mouse functions: all selections are made by left clicking. The middle button is used to rotate molecules in 3D, when the cursor is placed in the model screen. Windows: After you have used them, it is a good idea to close the various windows that open up when you perform each function. This will make it easier to see what is going on.

2 1. Login. Use your individual name and password, as given to you. 2. Open Macromodel. Click on the "Red Hat" icon at the bottom of the screen. In the menu, under "System Tools", select "Terminal", the terminal emulation program. In the new window, enter the command "macromodel" to launch the program. 3. Build t-butylcyclohexane. In the Edit menu, select "build". A new window will open up. To build t-butylcyclohexane, use the new build window. Make sure that "place" is selected in that window. From the fragment window, select "cyclohexyl". Then use the mouse to place a cyclohexane ring in the black display window by left clicking with the cursor in the window. Then select "methyl" from the choice of fragments (there is no t-butyl choice). Use the mouse to place a methyl group in an axial position on the cyclohexane ring by clicking on the end of one of the axial bonds. Then build up the t-butyl group by placing a methyl group at the end of each of the three bonds on the first methyl group. (To delete any mistakes, select "atoms" in the delete box at the top of the building window, and then click on your mistake. Don't forget to reset the "place" choice, before proceeding with building your molecule.) Close the "build" window when you are done. Viewing Your molecule: Use the middle mouse button to rotate the molecule in 3D. Try the various molecular representations, as follows: under the display menu, select "molecular representation". Try picking each of the choices to see how they look: wire (default); CPK (space-filling); tube (bonds are tubes); ball-and-stick (my favorite for these experiments). 4. Energy Minimization. Find the local minimum-energy conformation for the axial tert-butyl conformer you have built. Under the macromodel window, select "minimization". In the new window, in the "Potential" folder change the force field to MM3*. Look at the other choices that can be made, in the folders tagged "Potential", "Constraints", "Substructure" and "Mini". Don't change any of these default values. To minimize, select "start" at the bottom of the new minimization window. Then watch for any significant chamges in the shape of your drawn molecule. In the new data window that opens up, make a note of the energy values of your final structure, by filling in the worksheet table for this project. 5. Molecular Dynamics. Search for other low energy conformations by performing molecular dynamics simulations, followed by energy minimizations. Under the macromodel menu, open a molecular dynamics window by selecting "dynamics".

3 Change the dynamics mode from "Stochastic" to "Molecular". In the new window, look at the other default parameters, but don't change them for now: Temp: 300 K; Time step: 1.5 fs; Equilibration Time: 1.0 ps; Simulation Time: 10 ps. Select "start" at the bottom of the window. Watch the motions of your molecule under this simulation. Note the color changes, which track the most mobile molecular components (kinetic energy is being measured on a color scale, with red being the "hottest"). Look at the shape of the final structure. Is the cyclohexane ring still in a chair conformation? Is the tert-butyl group still axial? Is the ring still in a chair conformation? Change the simulation time to 100 ps, and repeat the molecular dynamics simulation. Is the tertbutyl group still axial? Change the temperature to 1000 K. Repeat the simulation and watch the simulated motions of your molecule. Is the tert-butyl group still axial at the end of this simulation? (Repeat the last simulation, if it is not.) If the tert-butyl group is now equatorial, close the extra windows, choose "minimization" from the macromodel menu, and then perform a new energy minimization. In the new data window that opens up, make a note of the energy values of your final structure for the equatorialmethyl conformer, by filling in the worksheet table for this project. Be careful to include the exponential factor! Is the total energy lower? Fill in the E column in the worksheet table. Which energy components have been lowered by the largest amount? From your data, calculate an equilibrium constant for the equilibrium between the two chair conformers of tert-butylcyclohexane. 6. Analysis of cis- and trans-2-methylcyclohexanol. Build and analyze these two molecules, following the procedures described above: (a) First, build a cis-hydroxyl group into your last structure for tert-butylcyclohexane (t-butyl group equatorial, by replacing one of the axial hydrogens on a ring carbon adjacent to the carbon where the t-butyl group is attached. Be careful to choose the hydroxyl group for this, and not hydroxide! Then delete the methyl groups of the t-butyl group and replace each with hydrogen. Perform an energy minimization on the structure you have just drawn. This should give you an energetic analysis of the chair conformer with the methyl group equatorial. Check to make sure, then, record the energy data in the worksheet table. Then perform several (3-4) molecular dynamics simulations at 1000 K for 100 ps, with an energy minimization step after each one. Each time, note the total energies and conformations of the ring and orientations of the substituents (-OH and methyl) after energy minimization. What other ring conformations do you recognize? Do the substituents ever "flip" from axial to equatorial or vice versa. Do any of these conformers have a lower energy than your initial structure? Report these conformers in the second worksheet table. (b) Build the trans stereoisomer by deleting the cis hydroxyl group and then replacing the equatorial hydrogen on the same carbon with a new hydroxyl group.

4 Repeat the above analysis for the newly built trans isomer. Record the energy data for the chair conformer, as before, and fill in the E column in the worksheet table. Which isomer is more stable, cis or trans? By how much? Some components of the energetics change in opposite directions. Can you rationalize the most significant changes? Did you find any other low energy conformers for the trans isomer? Report these.

5 Chem 310: Worksheet Tables for Molecular Modeling (tape or paste this into your lab notebook) Note: all energies are recorded in kj/mol Energy Component Axial t-butylcyclohexane Equatorial t-butylcyclohexane E Cis 2-methylcyclohexanol Trans 2-methyl - cyclohexanol E Stretch Bend Torsion Improper Torsion VDW Electrostatic Explicit H-Bond Cross Terms Molecular Dynamics Analyses of Cis- and Trans-2-methyl-cyclohexanol. Cis Isomer Cis Isomer Conformation* Trans Isomer Trans Isomer Conformation* Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 *Note conformer type (chair, boat, twisted boat). Note axial-equatorial switching of the methyl group.