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Open Access Publications from the University of California

Deuterium Kinetic Isotope Effects as Mechanistic Probes for Synthetically Useful Cyclic Hydrogen Transfers

  • Author(s): LI, XIAO
  • Advisor(s): Meyer, Matthew P
  • et al.
Creative Commons 'BY-NC-ND' version 4.0 license

Hydrogen transfer reactions are among the most fundamental organic reactions. They are involved in nearly all enzyme-catalyzed reactions necessary for the sustenance of life, and they are often involved in key steps in synthetically useful reductions. Notable among synthetically useful reactions are the class of reactions known as C–H bond functionalization. It is surprising, then, that this most fundamental chemical event is so poorly understood. To address this knowledge gap, we have developed new experimental and computational approaches that allow interrogation of the core physical nature of cyclic hydrogen transfer reactions. In general, our laboratory utilizes kinetic isotope effects (KIEs) to probe chemical reactions. This technique involves accurately determining how replacement of atoms with their heavier isotopes affects the reaction rate (or product distribution). In order to extract the most insightful information from KIE studies, suitable experiments and measurement methods need to be well-designed and carefully executed.

This dissertation is composed of four chapters. The first chapter serves as a general introduction that lays out the background of the mechanistic study of cyclic hydrogen transfer, the concepts of kinetic isotope effect and a concise review of traditional and new techniques that utilize KIEs to elucidate reaction mechanisms. The remaining chapters present three unique studies that culminate in a unified view of cyclic hydrogen transfers. Each study is designed to interrogate the key physical aspects of a synthetically useful and mechanistically interesting hydrogen transfer. The first study explores the Chugaev elimination, which is used to transform alcohols into alkenes in a typically regioselective manner. In this study, we have used a combination of intermolecular and intramolecular 2H KIE measurements to demonstrate that this reaction is dominated by quantum mechanical behavior even though it occurs at elevated temperatures. Comparison between the experimental and computational results imply that the observed KIEs are influenced by the location of the bottleneck (or transition state) which is found to be dependent on the isotopic substitution. Chapter 3 explores the Cope elimination, which can be used to install alkenes adjacent to an amine, demonstrated that seemingly simple cyclic hydrogen transfer reactions can proceed simultaneously via multiple mechanisms depending upon driving force and temperatures. Our approaches in the Cope and Chugaev eliminations were then utilized to explore an exciting new C–H functionalization reaction developed by DuBois. This study demonstrates that cyclic H-transfers mediated by a Ru-nitrene species are fundamentally similar to relatively simpler syn- eliminations in terms of the involvement of quantum mechanical phenomena. The reaction models built with prototype reactions can be generalized to more complicated metal catalyzed reactions to facilitate a better understanding of the reaction in terms of both reactivity and selectivity.

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