Asymmetric Reduction of Acetophenone with (−)-β-chlorodiisopinocampheylborane, and Derivatization with (−)-Menthyl Chloroformate. An Undergraduate Organic Synthesis, GC Analysis, and Molecular Modeling Project

Abstract

A set of experiments is described for the sophomore level organic chemistry laboratory in which students investigate an enantioselective reduction both in the wet laboratory and theoretically, using desktop molecular modeling techniques. In the wet laboratory, students carry out an enantioselective reduction of an asymmetric ketone using (−)-β-chlorodiisopinocampheyl-borane. After workup, the chiral alcohol is derivatized with enantiomerically pure (−)-methyl chloroformate to provide a diastereomeric mixture of carbonates derived from the R and S alcohols. The products are isolated, and purified by silica gel column chromatography. Two reference samples are prepared in a similar manner: derivatization of both racemic and enantiomerically pure alcohols. Each of the three products is anlayzed by capillary gas chromatography to determine the absolute stereochemistry of the reduction products and to quantitate the extent of enantioselectivity in the reduction. Students also investigate the reaction using desktop molecular modeling techniques. They construct the model of the chiral borane–ketone complex and search conformational space in two dimensions to determine an overall energy minimum. They they find, or approximate, the transition-state geometries of two possible diastereomers and compare heats of formation. In this manner they can predict the stereochemical outcome of the reaction, at least in a qualitative sense, and compare their results to the laboratory experiment. The complete laboratory exercise can be accomplished in three 4-hour laboratory periods.