Mechanistic Understanding of Proton-Coupled Electron Transfer and Deracemization

Abstract

While the synthetic aspects of Multisite proton-coupled electron transfer (MS-PCET) continue to advance, detailed mechanistic studies of MS-PCET activations remain rare. The first chapter presents a detailed kinetic study of MS-PCET activations of aryl ketones using a variety of Brønsted acids and excited-state Ir(III)-based electron donors. Both the hydrogen-bonding equilibrium constants and the rate constants for the PCET event were simultaneously extracted from deconvolution of the luminescence quenching data. These experiments confirm that these activations occur in a concerted fashion, wherein the proton and electron are transferred to the ketone substrate in a single elementary step. The slope of the rate−driving force relationship deviated significantly from expectations based on Marcus theory. A rationalization for this observation is proposed based on the principle of non-perfect synchronization, wherein factors that serve to stabilize the product are only partially realized at the transition state. The second chapter presents the first study sought to elucidate the factors that control chemoselectivity in MS-PCET reactions. We present a kinetic study that provides a quantitative basis for understanding the chemoselectivity in competitive PCET activations of amides and thiols relevant to catalytic olefin hydroamidation reactions. These results demonstrate how the interplay between PCET rate constants, hydrogen-bonding equilibria, and rate-driving force relationships jointly determine PCET chemoselectivity under a given set of conditions. In turn, these findings predict reactivity trends in a model hydroamidation reaction, rationalize the selective activation of amide N−H bonds in the presence of much weaker thiol S−H bonds, and deliver strategies to improve the efficiencies of PCET reactions employing thiol cocatalysts. In the last chapter, a general strategy for assessing C–H homolysis mechanisms is presented. The deracemization of C–H containing stereocenters can be achieved via several C–H activation mechanisms. Knowing the activation mode is crucial for expanding the scope of deracemization. However, determining which of these mechanisms is operative can be challenging as the starting material and the product of a deracemization reaction are indistinguishable. Therefore, we opted to use deuteration as a mechanistic probe. Our method involves determining the isotope fractionation of deuterium between solvent and substrate that provides a readout for the operative mechanism due to isotope effects. The H/D exchange mechanism determined by this fractionation slope method and that predicted by the known properties of substrate, intermediate, and catalysts, are in excellent agreement.