Rob Knowles

Proton-coupled electron transfer in organic synthesis

Proton-coupled electron transfers (PCETs) are unconventional redox processes in which an electron and proton are exchanged together in a concerted elementary step. While PCET is now recognized to play a central a role in biological redox catalysis and inorganic energy conversion technologies, its applications in organic chemistry remain largely unexplored. This talk will highlight our group’s efforts to use PCET as a means to address significant and long-standing synthetic challenges in the areas of free radical chemistry and asymmetric catalysis. In particular we are interested in the ability of PCET to enable catalytic and chemoselective generation of synthetically useful radical intermediates via the direct homolytic activation of common organic functional groups that are energetically inaccessible using conventional HAT transfer catalysts. Our approach makes use of a simple thermodynamic formalism to rationally identify combinations of proton and electron donors that can formally transfer H• to pi systems to form very weak bonds (BDFEs <25 kcal/mol), or combinations of proton and electron acceptors that are competent to formally remove H• form very strong sigma bonds (BDFEs >105 kcal/mol). Moreover, in PCET reactions the radical intermediates are generated as hydrogen-bonded adducts with the conjugate acid or base of the catalytic proton donor/acceptor. We have found that these non-covalent associations can be strongly stabilizing, providing a basis for asymmetric induction in subsequent bond forming events when chiral proton transfer agents are employed. Applications in complex target synthesis will also be presented.