In the Laboratory
Molecular Modeling as an Aid to Understanding Stereoselectivity
W
John B. Klassen,* Kate J. Graham, and William P. Muldoon Department of Chemistry, College of Saint Benedict/Saint John’s University, Saint Joseph, MN 56374; *
[email protected] Rationale One of our goals for the introduction of molecular modeling into the organic chemistry curriculum was to develop connections between the interpretation of data gathered in the laboratory and the use of calculation and molecular modeling to develop a more compelling mechanistic interpretation of the results. The reduction of 2-, 3-, and 4-methylcyclohexanone with sodium borohydride and subsequent calculation and visualization of the LUMO of the starting ketone affords just such an opportunity. With the introduction of hydride reducing agents, organic chemists were able to search for an explanation for the peculiar reducing pattern of substituted cyclohexanones. We have used this experiment as a means of introducing second-semester organic students to the importance of conformational analysis and the power of orbital analysis in explaining experimental results. Procedures Students worked in groups of three. Each student in a group was assigned one of the three ketones, for which was calculated the Boltzmann distribution of conformers using a molecular mechanics program (MM2 basis set) within Spartan (Spartan Molecular Modeling Package, version 5.1, Wavefunction, Inc, Irvine, CA, 1995) that uses the Osawa “corner flapping” algorithm. Students were able to visualize each conformer, seeing the calculated contribution for each and their rapid interconversion. Using the information that each of the ketones exists between 89 and 94% of the time with the methyl group in the equatorial position, the students predicted the products for the sodium borohydride reduction of their ketone on the basis of steric considerations alone. The majority predicted the major product to be cis-2methylcyclohexanol, trans-3-methylcyclohexanol, and cis-4methylcyclohexanol owing to steric hindrance from 1,3 diaxial hydrogens. In lab, the reduction was carried out and the product mixture was analyzed by IR and GC. The experimental conditions for the reduction were taken from Williamson (1) and afforded a mixture of cis/trans methylcyclohexanols, which were analyzed by GC (see retention times in equipment section). The analysis showed a 3:7 cis/trans ratio of 2-methylcyclohexanols, a 3:1 cis/trans ratio of 3-methylcyclohexanols, and a 1:4 cis/trans ratio of 4-methylcyclohexanols. A semiempirical calculation (AM1) was done to optimize the geometry of the starting material and to determine the shape, size, and electrophilicity of the LUMO. After the calculation, the molecule was displayed with the surface of total electron density, colorcoded, and mapped onto the absolute value of the LUMO.
Students were then able to click and point at the surface of the LUMO to obtain the numerical value of the LUMO at any point. In addition, the LUMO was color-coded and both of these methods affirmed that the LUMO is antisymmetric, having a higher value (thus more electrophilic) on the axial face. Thus, students discovered that the major reason why hydride approaches from the axial face is electronic. It is important to state explicitly that this conclusion requires the assumption that the less stable conformer is not significantly more reactive than the more stable equatorial methyl conformer. Why the Experiment Helps Students Learn The interactive sequence of calculation and prediction, experimental and analytical work, followed by calculation and visualization transforms a standard sodium borohydride reduction of a ketone into a fairly sophisticated experiment. Each individual component has its own value, but taken together, they form a cohesive lesson on a current approach to organic chemistry. Students discover the experimental importance of thinking carefully about conformational bias before conducting a reaction. Furthermore, the consideration of steric and electronic effects takes on practical significance in the prediction of major products. The gathering of data includes IR and GC instrumentation, each of which contributes vital information to the identification of products. The experimental results allow for further analysis of the LUMO that leads to an accurate understanding of how the antisymmetry of the LUMO influences the stereoselectivity of the reaction. In brief, this interactive relationship between laboratory work and molecular modeling provides a rich learning opportunity. Evaluation We have found that this experiment is very accessible to our students, who readily grasp the concepts that are involved. Coming late in the second semester, it serves as a nice review of conformational analysis of six-membered rings. In addition, the ideas concerning facial selectivity were also familiar and understandable. Specialized Equipment Analysis of the alcohol product mixture was available with GC (10% OV-210 on Chromsorb WHP 6-foot column; 85 °C isothermal, 2.1 kg/cm2 carrier gas flow). Retention times for compounds are as follows: 2.74 m and 3.09 m for trans- and cis-3-methylcyclohexanol, respectively; 2.56 m and 2.69 m for cis- and trans-3-methylcyclohexanol, respectively; 2.82 m and 3.22 m for cis- and trans-4-methylcyclohexanol,
JChemEd.chem.wisc.edu • Vol. 76 No. 7 July 1999 • Journal of Chemical Education
985
In the Laboratory
respectively. Silicon Graphics workstations were equipped with Spartan 5.1, using the OSAWA algorithm (2) for conformational analysis of the ring system.1 This calculation takes about 2 minutes; and it is easy to resubmit the calculation under semiempirical conditions, which again takes only a few minutes to complete. Spartan 4.0 can be used for this calculation, but the Boltzmann distribution algorithm needs to be requested from Spartan and installed. Spartan was also used for the calculation and visualization of the LUMO. The conformational analysis calculations were also successfully completed with Hyperchem and CAChe molecular modeling packages. The calculation and visualization of the LUMO, however, was not as compelling with these systems. Acknowledgments We wish to thank Frank Rioux (Department of Chemistry, College of Saint Benedict/Saint John’s University) for many helpful discussions and Gary Spessard from St. Olaf College for performing the calculations on the CAChe system. In addition, we thank Harry Johnson and Wayne Huang (Wavefunction, Inc.) for their continuing technical support. The purchase of the SGI workstations and Spartan was supported in part by the National Science Foundation (NSF grant # USE 9251423). Note W Supplementary materials for this article are available on JCE Online at http://jchemed.chem.wisc.edu/Jour nal/issues/1999/Jul/ abs985.html. 1. Spartan is also available in PC and Macintosh versions.
Literature Cited 1. Williamson, K. L. Macroscale and Microscale Organic Experiments, 2nd ed.; Heath: Lexington, MA, 1994; pp 740–744. 2. Goto, H.; Osawa, E. J. Am. Chem. Soc. 1989, 111, 8950–8951.
986
Journal of Chemical Education • Vol. 76 No. 7 July 1999 • JChemEd.chem.wisc.edu
