Proton-coupled Electron Transfer (PCET) in Synthesis

Proton-coupled electron transfer (PCET) has emerged as a powerful mechanistic framework for driving challenging bond activations in organic synthesis. By coupling proton and electron transfer in a single kinetic step, PCET allows access to reactive radical intermediates under mild conditions that would otherwise require strongly reducing reagents. This seminar will trace the development of PCET in synthetic chemistry, beginning with the landmark work of Knowles and co-workers on catalytic ketyl–olefin cyclizations, where concerted reductive PCET was first shown to enable ketyl radical formation. From there, the evolution of PCET strategies for C–C bond cleavage and heterocycle construction will be examined, including asymmetric applications that harness chiral Brønsted acids to achieve enantioselective radical transformations. 

Finally, recent advances in PCET-enabled skeletal editing and functionalization, including Alemán’s 2022 enantioselective radical ring expansions of cycloalkanols, Knowles’ 2025 aminative rearrangements of amino cycloalkanols, and Parasram’s use of electronically tuned nitroarenes to achieve selective O–H activation over competing C–H oxidation will be highlighted. Together, these studies illustrate how PCET has expanded the synthetic toolbox by unlocking new radical pathways, enabling skeletal editing, and providing modular control over both thermodynamics and selectivity.

References:

1.  J. M. Mayer, I. J. Rhile, Biochim. Biophys. Acta 2004, 1655, 51–58.
2. K. T. Tarantino, P. Liu, R. R. Knowles, J. Am. Chem. Soc. 2013, 135, 10022–10025.
3. J. Rono, H. G. Yayla, D. Y. Wang, M. F. Armstrong, R. R. Knowles, J. Am. Chem. Soc. 2013, 135, 17735–17738.
4. G. J. Choi, R. R. Knowles, J. Am. Chem. Soc. 2015, 137, 9226–9229.
5. N. Salaverri, B. Carli, S. Díaz-Tendero, L. Marzo, J. Alemán, Org. Lett. 2022, 24, 3123–3127.
6. A. D. Duke, S. Banerjee, A. P. Thupili, D. R. Pradhan, M. J. Vetticatt, M. Parasram, ChemRxiv 2025, DOI: 10.26434/chemrxiv-2025-s55n1.
7. D. Q. Thach, R. R. Knowles, J. Am. Chem. Soc. 2025, 147, 21818–21823