Proton-Coupled Electron Transfer in Organic Synthesis: Amide Functionalization Reactions

Abstract

Proton-coupled electron transfer (PCET) is a general term used to describe the movement of protons and electrons in a single elementary step. Notably, the protons and electrons may travel from one source to multiple destinations and vice versa. PCET reactions are critical in a number of biological processes such as photosynthetic water oxidation, repairing photochemical damage to DNA, and ribonucleotide reduction for DNA synthesis. Accordingly, PCET has been well studied by numerous communities spanning theoreticians, structural biologists, and bioinorganic chemists and has found widespread utility in other fields such as solar energy conversion. Despite a wealth of literature describing the kinetics, thermodynamics, and fundamental reactivity principles of PCET, currently PCET steps are rarely invoked in the design of new chemical reactions for organic synthesis. This work describes efforts to use PCET in the activation of strong amide N–H bonds in the context of hydroamidation reactions, as well as remote C–C bond formation in the context of a Hofmann-Löffler-Freytag type reaction. Mechanistic studies of these reactions demonstrate unique selectivity principles of PCET activation in synthesis, namely the exquisite, contrathermodynamic chemoselectivity imparted by favorable hydrogen bonding. In addition, the nature of PCET to homolytically weaken strong bonds is demonstrated in the context of an aza-enolate conjugate amination protocol. Computational studies outline the degree of bond weakening of amide N–H bonds upon complexation to redox-active Lewis acids. In the last chapter of this thesis, initial studies towards the selective synthesis of secondary amines by hydroamination of primary amines onto unactivated olefins is presented. Preliminary work suggests that despite more facile oxidation of secondary amines, rapid rates of back-electron transfer from the photocatalyst to secondary aminium radical cations outcompetes olefin addition steps, preventing overalkylation of the secondary amine products generated in this reaction.