Kinetic Isotope Effect: Mechanisms of Asymmetric Reductions and Hydrogen Transfers
Hydrogen transfer is an important process that takes place in nearly all biochemical reactions and in numerous synthetically useful transformations; however, current understanding of tunneling upon hydrogen transfer remains poorly understood. Further understanding of tunneling requires a detailed analysis of quantum mechanical behavior of hydrogen, which remains a mystery in the majority of both hemolytic and heterolytic hydrogen transfer reactions. Research described herein demonstrates that hydrogen tunneling can fundamentally alter reaction pathways. One primary consequence of this work may be the construction of better competitive inhibitors for enzymes recognized at therapeutic targets. Enzyme-catalyzed hydrogen transfer reactions occur within the substrate- or intermediate-enzyme complex and are, therefore, effectively unimolecular. Conventional tools used to understand hydrogen tunneling have demonstrated strange behavior within enzymes: large primary H/D KIEs, temperature independent KIEs, and amplified secondary H/D KIEs. Largely ignored work by Harold Kwart found similar behaviors in intramolecular hydrogen transfers that occur in small molecules. Unfortunately, Kwart's life was cut short by illness, and these systems were not able to be explored thoroughly.
Our interest in intramolecular hydrogen transfer, in general, followed from our work on the Swern oxidation. The Swern oxidation has an isotopically-insensitive rate-limiting step, so we explored this reaction using intramolecular H/D KIEs. We found evidence for substantial influences upon the intramolecular H/D KIE from tunneling, but the reaction exhibited an uncharacteristically low KIE. We decided to expand our scope to reactions for which we could measure both intramolecular and intermolecular H/D KIEs. In total, three hydrogen transfer mechanisms have been studied here - Swern Oxidation, Benzyl nitrate elimination, and Cope elimination - using both experimental measurements of Kinetic Isotope Effect (KIE) and computational calculations of the transition structure to obtain KIE as a point of comparison to the experimental values. Such comparisons show a surprisingly wide range of behaviors for the above pericyclic reactions each of which possesses a five-member ring transition structure.
Hydrogen tunneling is a key determinant of reactivity in most hydrogen transfers. The other principal descriptor of chemical reactions is selectivity. The design of stereoselective catalytic reactions has been one of the most prominent areas of synthetic methodology development. The second part of this dissertation is devoted to the development of a new mechanistic tool to explore reactions that have two simultaneous reaction pathways. This dissertation focuses first on the Corey-Bakshi-Shibata (CBS) reduction. We use highly refined techniques to elucidate the molecular mechanism of symmetry breaking or chirality transfer in the reduction of 2,2-dimethyl-1,3-cyclohexanedione. We use transition structure models to compute expected intramolecular KIEs in these systems and use experimentally-determined 2H and 13C KIEs to validate the transition structure models. We identify steric contacts responsible for stereoselection at the atomic level and explore the innate flexibility of the CBS catalyst - a catalyst once thought to be highly rigid. These observations may explain why the CBS catalyst has such an extensive substrate range. Finally, we also look at the L-Selectride (lithium tri-sec-butylborohydride) reduction of 2,2-dimethyl-1,3-cyclohexanedione. The substantial steric demand of this reductant gives rise to the first example of a steric 13C KIE. Together, these studies begin to explain the types of motions that give rise to steric KIEs and begin to demonstrate how these measurements infer the structural interactions responsible for 2H and 13C steric KIEs.