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					                                       MOLECULAR MODELING
Required prelab readings: McMurry Sections 3.6, 3,7, 4.5 – 4.8
Previous techniques you must understand and be able to perform: None

         Molecular modeling is an important area of chemical research which utilizes both classical and
quantum mechanical approaches coupled with powerful computer graphics and calculating programs to
predict the three dimensional shape (and a variety of other physical properties) of molecules. Molecular
modeling has wide applications in the fields of chemistry and biochemistry both in academic research and
industrial laboratories. In particular the pharmaceutical, agricultural, and biotechnology fields offer
employment in the area of molecular modeling to scientists with backgrounds in both chemistry and
computer science.

         In this so called "dry" laboratory experiment each student will be given a substituted cyclohexane
and, using the department's molecular modeling programs, build structures of the molecule in both chair
forms, and find the minimum energy conformation of each chair form. Since the conformations are in
equilibrium, the relative energies can be used to calculate the percentage of each conformation according
to the equations below. This information in some cases can be used to predict chemical reactivity and
explain molecular properties.

                                            G  RTln K eq
                                    K eq                                                       1
   % low energy conformation                            % high energy conformation     
                                  K eq 1                                                   K eq 1
                                                                           
        Each student will be given a cyclohexane with a distinct substitution pattern.                Relative
stereochemistry (cis/trans) will be shown with solid and dashed lines, as illustrated below.




        Students will be asked to either examine two chair conformations or energies of conformations
about particular bonds. Prior to beginning the experiment you will be required to draw in your lab
notebook the appropriate forms of your molecule, with substituents labeled as being either axial
or equatorial. (NOTE: the use of Newman Projections along with model kits is one of the best ways to
see cis/trans and conformational relationships). If two chair conformations are being examined then the
side chains can be drawn as shown in Figure 1.
         Figure 1. The two chair conformations of trans-2-ethyl-1-methylcyclohexane

                                                       CH2CH3 (ax)                                                   H

                                                             H                                                           CH2CH3 (eq)
                                                                                                                            CH3 (eq)

                                                       Note: All the other hydrogens have been omitted for clarity

If side chain conformations are being examined they must be shown explicitly, as in Figure 2.

        Figure 2. The three side chain conformations of diaxial trans-2-ethyl-1-methylcyclohexane

                                   H                                                             H                                           CH3
                       H                                                           CH3                                               H
                               C       CH3                                                   C       H                                   C      H
                               (ax)                                                          (ax)                                        (ax)
                           H                                                             H                                           H
                                       H                                                             H                                        H

                 CH3                                                               CH3                                        CH3
                (ax)                                                              (ax)                                        (ax)

                                                  Note: All the other hydrogens have been omitted for clarity

         Once the program is opened the main menu will appear. Click on File and drag down to the word
New. This will automatically take you to the entry level builder menu. The entry level builder has a blank
canvas on the left side of the screen and a palette on the right side. The palette contains a number of
atoms and groups commonly found in organic molecules. In the palette, under rings, click and drag
down to cyclohexane. Now move the mouse to the center of the canvas and left mouse click. A
cyclohexane ring will appear. Before you begin to add substituents, it may be advantageous to reorient
your molecule and enlarge the image on the screen. By holding the left mouse button and dragging while
the cursor is over the canvas you can rotate the ring to see it from any perspective you desire. To enlarge
the structure depress both the Shift Key and the right mouse button and drag the cursor "up". If you wish
only to move the molecule within the canvas without rotating it (translate) this can be done by holding
down the right mouse button.

         To add substituents, click on the desired atom in the palette (an sp 3 carbon for example), then
click on the appropriate bond in the cyclohexane group (see figure on following page). A bond will be
formed between the two atoms at this point, as illustrated below. (Note: The program assumes that
hydrogens are attached to any "unfilled" valence. Therefore, you do not have to connect hydrogens to
your molecule). To delete an atom go to build at the top of the screen and drag down to delete, then
click on the atom in the structure you wish to remove. After deleting click on the + sign at the top of the
screen to continue adding atoms. In order to build the molecule correctly, care must be taken to place
substituents around the ring in their proper positions with respect to both regiochemistry and
stereochemistry. As more substituents are added you will most likely need to rotate the molecule in order
to obtain the correct regio/stereochemistry. It will take a little practice before you are able to rotate the
molecule with facility.
                                                                                                   Click again here
                                           Click on an sp3 C in the
                                           palette, then click here

                                             Will produce

              cyclohexane                                                  equatorial conformation of

                                                                                            Will produce
                                                Click on an sp3 O in the
                                                palette, then click here

                                                 Will produce

                                                                            equatorial conformation of

         For some experiments you may be asked to examine dihedral angles. To define a dihedral angle
click the Geometry menu from the top menu bar and select Measure Dihedral. Select the four atoms you
wish to define as your dihedral by clicking on them (they will become highlighted). You can still reorient
your molecule while you are doing this. Once you have selected the four atoms a value for the dihedral
angle will appear in the lower right hand corner. To change the angle, enter a new value into the text box
and press enter (Note: the angles must between ± 180 °).

Minimizing the Structure: Once you have built the molecule, its geometry can be found by clicking on
the E key at the top. The minimization function steps the molecule through a series (iterations) of
possible conformations until the one with the minimum strain energy is obtained. This information will
appear in the lower right hand corner of the screen. When the iterations have stopped click on the E
button again and additional iterations will take place. Record the final Energy.

3-D Viewing: You may view your molecule in three dimensions using 3-D glasses by clicking under
options (top right of screen) and dragging down to preferences. In preferences click on stereo, then
OK. To go back to 2-D go into preferences and click off stereo.

Printing the Structure: Use the Shift Key and right hand key of the mouse (as described above) to
maximize the size of your molecule on the screen. To the right of File is Model. Clicking on Model
allows you to view your molecule in any one of five different ways. Take this opportunity to see how your
molecule looks in each one of these five representations (you can still use the 3-D key if you wish). In
preparation for printing, click on Model and drag down to Ball and Wire. Use the center and right hand
keys on the mouse to position your molecule so that it prints clearly. When you are ready to print go
under File to the Print command. Your structure will now be printed.

        You are now half-way through the experiment.
        Return to File and drag first to Close, then to New. A new blank canvas and palette will appear.
Repeat all the above steps using the other conformation form of your molecule. Save and print this
structure as well.
                                          Molecular Modeling
                                              Data Sheet



PRELAB: Draw the structure of your compound given to you by your instructor, using solid and dashed
lines to indicate relative (cis- / trans-) stereochemistry. Then draw the structure in the two chair

                                        Keq =

           E=                                                     E=

           %=                                                     %=

2. Construct the conformers you’ve drawn above on the computer using the Spartan program. Write the
   calculated Energy values below the corresponding chair above (don’t forget units).

3. Using the energy values from Spartan, calculate the Keq for the ring and the percentage of each
   conformer at 40°C. Place the values in the table above and place equilibrium arrows in the box to
   show in which direction the equilibrium is favored. Show all work for these calculations.

4. Explain what interactions account for the molecule preferring one conformation over the other. Are the
   percentages what you would have predicted? Explain.
5. Analyze the data given in each to answer the questions.

    I.     The cis-2-halomethylcyclohexanes

                  CH3                                            CH3                                                  CH3
                              Cl                                                   Br                                           I
                    Cl                                                Br                       CH3                     I
                                        CH3                                                                                             CH3
         E=7.45           E=5.54                       E=8.74                   E=7.30                      E=10.27            E=9.57
         4%               96%                          8%                       92%                         23%                77%
What general conclusion can be drawn about how the size of the substituents, Cl < Br < I, affects the
equilibrium between the 2 chair conformations?

    II. The trans-2-halomethylcyclohexanes
                              CH3                                    CH3                                    CH3

                                                                                         CH3                                    CH
                  E=6.87            Cl E=5.90         E=7.28               Br                  E=9.03             I
                                       84%                                      E=8.68                                E=8.34
                  16%    Cl                           31%       Br                             24%      I
                                                                                69 %                                  76%

The trans-1,2-isomers have smaller Keq values than the corresponding cis-isomers. Oddly, the trans-
isomer with the diaxial groups, has a greater percentage of molecules than some of the cis-isomers with
only one group axial. What other possible factor could be at work in these molecules?

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