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 solar energy conversion technologies, its applications in organic chemistry remain largely unexplored. This proposal aims to establish concerted PCET as a general mode of substrate activation for organic synthesis, providing novel solutions to significant and long-standing synthetic challenges in the areas of free radical chemistry, asymmetric catalysis, and organometallic chemistry. The central goal of this work is to establish concerted PCET as a general mechanism for homolytic bond activation that is complementary to and broader in scope than conventional hydrogen atom transfer (HAT) chemistry. Specifically, concerted PCET provides a mechanism by which a Bronsted base and a one-electron oxidant can function together as a formal hydrogen-atom acceptor capable of selectively oxidizing bonds that are energetically inaccessible using conventional H-atom transfer catalyst platforms (up to 110 kcal/mol). Similarly, Bronsted acids and one-electron reductants can function jointly as formal H-atom donors, activating p bonds to form radical centers vicinal to extraordinarily weak bonds (<20 kcal/mol). Taken together with a unique kinetic feature of concerted PCET, this remarkable energetic range presents a framework to develop methods for the direct homolytic activation of nearly any organic functional group. In addition, PCET presents unique opportunities for controlling enantioselectivity in radical processes. PCET typically occurs through a hydrogen-bond complex between the substrate and a proton donor/acceptor. These H-bond interfaces often remain intact following the PCET event, resulting in the formation of strongly stabilized non-covalent complexes of neutral radical intermediates. When chiral proton donors/acceptors are employed, this association can provide a basis for asymmetric induction in subsequent bond forming events. Lastly, this proposal describes a novel PCET mechanism for the generation of organometallic intermediates from unfunctionalized substrates. This work exploits the ability of redox active metal centers to homolytically weaken the bonds in coordinated ligands, enabling otherwise strong X-H bonds (BDE ~100 kcal) to be abstracted by weak H-atom acceptors through concomitant oxidation of the metal center. This 'soft homolysis' mechanism provides a method to generate closed-shell organometallic intermediates from unfunctionalized starting materials under completely neutral conditions. Taken together, these technologies have the potential to simplify and improve the synthesis of drugs and other small-molecule probes of biological function, creating a significant benefit for human health and the associated biomedical sciences.

Public Health Relevance

Innovations in synthetic chemistry are essential to the continued development of new pharmaceutical agents and other small molecule probes of biological function. In this proposal, we demonstrate that proton-coupled electron transfer activation addresses significant and long-standing gaps in the synthetic literature by providing a novel means to both catalytically access useful free radical intermediates from unfunctionalized precursors and controlling the absolute stereochemistry of their subsequent reactions. The reactions and processes enabled by these technologies will provide new tools to simplify the discovery, design and manufacture of new drugs, creating a significant benefit for human health and the associated biomedical sciences.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Princeton University
Schools of Arts and Sciences
United States
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Zhu, Qilei; Graff, David E; Knowles, Robert R (2018) Intermolecular Anti-Markovnikov Hydroamination of Unactivated Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer. J Am Chem Soc 140:741-747
Rauch, Martin P; Knowles, Robert R (2018) Applications and Prospects for Triplet-Triplet Annihilation Photon Upconversion. Chimia (Aarau) 72:501-507
Choi, Gilbert J; Zhu, Qilei; Miller, David C et al. (2016) Catalytic alkylation of remote C-H bonds enabled by proton-coupled electron transfer. Nature 539:268-271
Gentry, Emily C; Knowles, Robert R (2016) Synthetic Applications of Proton-Coupled Electron Transfer. Acc Chem Res 49:1546-56
Miller, David C; Tarantino, Kyle T; Knowles, Robert R (2016) Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities. Top Curr Chem (Cham) 374:30
Yayla, Hatice G; Wang, Huaiju; Tarantino, Kyle T et al. (2016) Catalytic Ring-Opening of Cyclic Alcohols Enabled by PCET Activation of Strong O-H Bonds. J Am Chem Soc 138:10794-7
Miller, David C; Choi, Gilbert J; Orbe, Hudson S et al. (2015) Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Transfer. J Am Chem Soc 137:13492-5
Choi, Gilbert J; Knowles, Robert R (2015) Catalytic Alkene Carboaminations Enabled by Oxidative Proton-Coupled Electron Transfer. J Am Chem Soc 137:9226-9
Tarantino, Kyle T; Miller, David C; Callon, Ted A et al. (2015) Bond-weakening catalysis: conjugate aminations enabled by the soft homolysis of strong N-H bonds. J Am Chem Soc 137:6440-3
Tarantino, Kyle T; Liu, Peng; Knowles, Robert R (2013) Catalytic ketyl-olefin cyclizations enabled by proton-coupled electron transfer. J Am Chem Soc 135:10022-5