Frick Laboratory, 191
Our lab is interested in addressing unsolved problems in synthetic organic chemistry and asymmetric catalysis. One area of recent focus has been exploring the synthetic applications of proton-coupled electron transfer (PCET) reactions. PCETs are unconventional redox processes in which an electron and proton are exchanged together in a concerted elementary step. While these mechanisms are recognized to play a central a role in biological redox catalysis and inorganic solar energy conversion technologies, their applications in synthetic organic chemistry remain largely unexplored.
Our lab aims to establish concerted PCET as a general platform for substrate activation, providing new solutions to significant and long-standing synthetic challenges in the areas of free radical chemistry, asymmetric catalysis, and organometallic chemistry.
Among the primary goals 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 Brønsted 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, Brønsted 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 many otherwise energetically inaccessible organic functional groups under unusually mild, catalytic conditions. 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, we have shown that this association can provide a basis for asymmetric induction in subsequent bond forming events. Lastly, our lab is also developing 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 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.
Alfred P. Sloan Foundation Research Fellowship (2014)
Thieme Journal Prize (2012)
Catalytic Alkylation of Remote C-H Bonds Enabled by Proton-Coupled Electron Transfer. Choi, G. C.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Nature, 2016, AOP, doi: 10.1038/nature19811.
Catalytic Ring-Opening of Cyclic Alcohols Enabled by PCET Activation of Strong O-H Bonds. Yayla, H. G.; Wang, H.; Tarantino, K. T.; Orbe, H. S.; Knowles, R. R. J. Am. Chem. Soc. 2016, 138, 10794–10797.
Synthetic Applications of Proton-Coupled Electron Transfer. Gentry, E. C.; Knowles, R. R. Acc. Chem. Res. 2016, 49, 1546–1556.
Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations. Zhu, Q.; Gentry, E. C.; Knowles, R. R. Angew. Chem. Int. Ed. 2016, 55, 9969–9973.
Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Transfer. Miller, D. C.; Choi, G. C.; Orbe, H. S.; Knowles, R. R.; J. Am. Chem. Soc. 2015, 137, 13492–13495.
Catalytic Alkene Carboamination Enabled by Oxidative Proton-Coupled Electron Transfer. Choi, G. C.; Knowles, R. R.; J. Am. Chem. Soc. 2015, 137, 9226–9229.
Bond Weakening Catalysis: Conjugate Aminations Enabled by the Soft Homolysis of Strong N-H Bonds. Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R. R.; J. Am. Chem. Soc. 2015, 137, 6440–6443.
Catalytic Olefin Hydroamination with Aminium Radical Cations: A Photoredox Method for Direct C-N Bond Formation. Musacchio, A. J.; Nguyen, L. Q.; Beard, G. H.; Knowles, R. R.; J. Am. Chem. Soc. 2014, 136, 12217–12220.
Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer. Development of an Asymmetric Aza-Pinacol Cyclization Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.; Knowles, R. R.; J. Am. Chem. Soc. 2013, 135, 17735–17738.
Catalytic Ketyl Olefin Cyclizations Enabled by Proton-Coupled Electron Transfer. Tarantino, K. T.; Liu, P.; Knowles, R. R.; J. Am. Chem. Soc. 2013, 135, 10022–10015.