In the Laboratory
Molecular Modeling to Predict Regioselectivity of Hydration Reactions
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Kate J. Graham,* Kathleen Skoglund, Chris P. Schaller, William P. Muldoon, and John B. Klassen Department of Chemistry, College of Saint Benedict, Saint John’s University, Saint Joseph, MN 56374-2099; *
[email protected] Rationale One of our goals for the introduction of molecular modeling into the introductory organic chemistry curriculum was to develop the students’ understanding of an empirically observed reaction product distribution by calculation of the intermediate or transition state stabilities. In a series of secondsemester sophomore organic chemistry laboratory experiments, students hydrate several alkenes using acid-catalyzed hydration, oxymercuration/demercuration, and hydroboration to compare the regioselectivity of the different synthetic techniques. The product mixtures are subsequently analyzed by gas chromatography. To fully explain the results, the students use semiempirical calculations to predict the product ratios from the relative stabilities of reactive intermediates or transition states. The calculation and visualization of the reaction pathways greatly enhances students’ understanding of the mechanisms of the different hydration reactions. Procedures In the first cycle of lab, the students worked in groups of four. Each student used acid-catalyzed hydration to hydrate one of the following alkenes: 1-hexene, 3,3-dimethyl-1butene, 3-methyl-2-pentene, 2-ethyl-1-butene, or 3-methyl1-pentene. The reaction mixtures were analyzed by gas chromatography and infrared spectroscopy. The experimental conditions for the acid-catalyzed hydration were a modified version of a lab presented in the lab text by Durst and Gokel (1) and affords the Markovnikov product and rearrangement products. A corresponding computational assignment required the students to calculate the stability of all carbocations possible when their alkene underwent acid-catalyzed hydration. To do this they used an AM1 semiempirical calculation with Spartan1 to determine the heat of formation of the reactive intermediates. Using this information, they were able to explain the ratio of products obtained in the laboratory experiment. After examining the LUMO, the students were able to predict not only the regioselectivity but also whether the product should be chiral. The LUMO is most clearly visualized by mapping the value of the LUMO onto the van der Waals surface of the molecule; the LUMO then appears as a blue region on the surface. A greater LUMO value, corresponding to greater electrophilicity, is illustrated by a more intense blue color. The numerical value of the LUMO can also be obtained for any point on the surface; students thus have a qualitative as well as a quantitative measure of electrophilicity. They can assess regioselectivity by determining the location of greatest electrophilicity on the surface, and stereoselectivity can be predicted by comparing electrophilicity on the two faces. 396
In the second cycle of lab, the students used hydroboration to hydrate one of the alkenes listed above to the respective alcohols. The reaction mixtures were analyzed by gas chromatography and infrared spectroscopy. The experimental conditions for the hydroboration were developed from a procedure developed by Brown (2) and affords the antiMarkovnikov product and minimal Markovnikov products. A second modeling assignment had students investigate the regioselectivity of the hydroboration reaction. Each student used MNDO calculations to calculate the heat of formation of the starting alkene, the borane–THF reagent, and both possible transition states for the formation of the monoalkylborane. Students could then determine the activation energy for the formation of either transition state and interpret the differences in terms of steric and electronic effects. A comparison could be made between the experimentally determined product and the most easily formed product according to the predicted kinetics. In addition, an examination of the LUMO in the transition state helped to illustrate the distribution of charge in the transition state, which aids student understanding of electronic contributions to transition-state stability and to the subsequent reactivity of the alkylborane product. In the third cycle of lab, students used oxymercuration/ demercuration to hydrate one of the alkenes listed above to the corresponding alcohol. The reaction mixtures were analyzed by GC and IR. The experimental conditions for the oxymercuration were developed from a procedure developed by Brown and Geoghegan (3, 4) and affords the Markovnikov product and minimal rearrangement products. A third modeling assignment had the students investigate the regioselectivity of the oxymercuration reaction. Each student used semiempirical calculations with a PM3 (tm) basis set to determine the geometry of the mercuronium ion formed when 1-propene undergoes a reaction with Hg(OAc)2. The 1-propene was chosen as a less complicated alkene to simplify the calculations. An examination of bond lengths illustrates which end of the alkene is bound more closely to the mercury; the other end should be more susceptible to nucleophilic attack by water. Additionally, examination of the LUMO clearly shows which end of the coordinated alkene is more electrophilic. Using this information, students were able to explain the ratio of products obtained in the laboratory experiment. Finally, the student groups gathered all of the computational and experimental data for the three methods of hydration of an alkene. The data were presented in a formal report in the style of an article in Journal of Organic Chemistry. Why the Experiment Helps Students Learn The sequence of three hydration methods used on four alkenes generates enough data for students to develop empirical trends for the regioselectivity of different hydration reactions.
Journal of Chemical Education • Vol. 77 No. 3 March 2000 • JChemEd.chem.wisc.edu
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Previously, this type of empirical data was available only in their textbook. The corresponding calculations add depth to the understanding of the regioselectivity of the reactions by allowing the students to mathematically and visually explore the contributions of sterics, electronics, kinetics, and thermodynamics to the determination of major products of the hydration reactions. The final report in the style of a journal article introduces students to the writing technique needed in the professional science atmosphere and, importantly, helps them to develop a cohesive understanding of the different aspects of these reactions. Overall, the combination of laboratory work and molecular modeling provides a unique opportunity to develop student understanding of regioselectivity and mechanisms of hydration reactions.
20% carbowax on Chromsorb WAW at 105 °C isothermal with 1.5 kg/cm2 carrier gas pressure. Silicon Graphics Indy Workstations were equipped with Spartan 5.0. Acknowledgments We wish to thank Harry Johnson, Wayne Huang, and Warren Hehre (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). W
Supplemental Material
Supplemental material for this article is available in this issue of JCE Online.
Evaluation In an evaluation of the second course, 78% of the students felt that the computer assignments helped them to understand the material, especially in terms of visualizing the reaction mechanisms. In an evaluation of these experiments, 70% of the students felt that the computational aspect of the lab increased their understanding of the regioselectivity of hydration reactions. Many specifically commented that the visualization of the transition states was particularly helpful. Specialized Equipment A gas chromatograph and an IR spectrophotometer were used in this experiment. GC data were collected on a 6-ft
Note 1. Spartan Molecular Modeling package, Version 5.0, 1998; Wavefunction, Inc., 18401 Von Karman Ave., Suite 370, Irvine, CA.
Literature Cited 1. Durst, H. D.; Gokel, G. W. Experimental Organic Chemistry, 2nd ed.; McGraw-Hill: New York, 1987; p 247. 2. Brown, H. C. Organic Syntheses via Boranes; Wiley: New York, 1975; pp 21–24. 3. Brown, H. C.; Geoghegan, P. J. Org. Chem. 1972, 37, 1937. 4. Brown, H. C.; Geoghegan, P. J. Org. Chem. 1970, 35, 1844.
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