Proton-Coupled Electron Transfer in Organic Synthesis: New Strategies for Homolytic Bond Activations

Proton--coupled electron transfers (PCET) are well characterized elementary steps in which protons and electrons are simultaneously transferred between donors and acceptors. Many inorganic and biological redox processes are enabled due to both thermodynamic and kinetic advantages associated with PCET mechanisms. Coupling a favorable proton transfer event to electron transfer processes results in increased thermodynamic driving force and diminished activation barriers. Despite the widely recognized mechanistic advantages, PCET remains largely unexplored as a strategy for homolytic bond activations in organic synthesis.;Ketones were catalytically reduced to ketyl radicals by the joint action of Bronsted acids and one--electron reductants through reductive PCET. Nascent ketyl radical intermediates rapidly engaged pendant olefins forging new carbon--carbon bonds and providing access to cyclical products. Excited state luminescence quenching experiments were consistent with concerted PCET as the mechanism of substrate activation.;The mechanistic advantages of PCET were further demonstrated by the activation of strong amide N--H bonds (N--H BDE = 99 kcal mol-1) with a weak H--atom acceptor, TEMPO (O--H BDE = 67 kcal mol-1), through a complexation induced bond weakening strategy. Upon coordination to a redox active Ti(III) catalyst, amides experience substantial homolytic weakening of the N--H bond. This bond weakening event enables facile reduction of TEMPO by the Ti--amide complex through a PCET mechanism, forming closed shell aza--enolate intermediates. Kinetic, computational, and spectroscopic experiments were performed and are consistent with complexation induced bond weakening as the mechanism of substrate activation.