Contact
Faculty Assistant

Heather Krupinski
heather.krupinski@princeton.edu
Frick Laboratory, 128
609-258-3674

Research Focus

Rob Knowles video interviewOur 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.

Research Areas
Catalysis / Synthesis
Honors
  • 2018 - Arthur C. Cope Scholar Award (American Chemical Society)
  • 2018 - Mitsui Catalysis Science Award of Encouragement
  • 2018 - E. Bright Wilson Prize (Harvard University, Dept. of Chemistry and Chemical Biology)
  • 2017 - Novartis Early Career Award in Organic Chemistry
  • 2017 - Camille Dreyfus Teacher-Scholar Award
  • 2017 - Grammaticakis-Neumann Prize (Swiss Chemical Society)
  • 2016 - Amgen Young Investigator Award
  • 2016 - Eli Lilly Grantee Award
  • 2014 - Alfred P. Sloan Foundation Research Fellow
Selected Recent Publications

Light-driven Deracemization Enabled by Excited-State Electron Transfer. Shin, N. Y.; Ryss, J. M.; Zhang, X.; Miller, S. J.; Knowles, R. R. Science, 2019, 366, 364–369.

Anti-Markovnikov Hydroamination of Unactivated Alkenes with Primary Alkyl Amines. Miller, D. C.; Ganley, J. M.; Musacchio, A. J.; Sherwood, T. C.; Ewing, W. R.; Knowles, R. R. J. Am. Chem. Soc. 2019, 141, 16590–16594.

C-H Alkylation via Multisite Proton-Coupled Electron Transfer of an Aliphatic C-H Bond. Morton, C. M.; Zhu, Q.; Ripberger, H.; Troian-Gauthier, L; Toa, Z. S. D.; Knowles, R. R.; Alexanian, E. J. J. Am. Chem. Soc. 2019, 141, 13253–13260.

N–H Bond Formation in a Manganese(V) Nitride Yields Ammonia by Light-Driven Proton-Coupled Electron Transfer. Wang, D.; Loose, F.; Chirik, P. J.; Knowles, R. R. J. Am. Chem. Soc. 2019, 141, 4795–4799.

Rate-Driving Force Relationships in the Multisite PCET Activation of Ketones. Qui, G.; R.; Knowles, R. R. J. Am. Chem. Soc. 2019, 141, 2721-2730.

A Redox Strategy for Light-Driven, Out-of-Equilibrium Isomerizations and Application to Catalytic C–C Bond Cleavage Reactions. Ota, E.; Wang, H.; Frye, N. L.; R.; Knowles, R. R. J. Am. Chem. Soc. 2019, 141, 1457–1462.

Enantioselective Synthesis of Pyrroloindolines via Non-Covalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products. Gentry, E. C.; Rono, L. J.; Hale, M. E.; Matsuura, R.; Knowles, R. R. J. Am. Chem. Soc. 2018, 140, 3394–3402.

Intermolecular Anti-Markovnikov Hydroamination of Unactivated Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer. Zhu, Q.; Graf, D. E.; Knowles, R. R. J. Am. Chem. Soc. 2018, 140, 741–747.

Catalytic Intermolecular Hydroaminations of Unactivated Olefins with Secondary Alkyl Amines. Musacchio, A. J.; Lainhart, B. C.; Zhang, X.; Naguib, S. G.; Sherwood, T. C.; Knowles, R. R. Science, 2017, 355, 727–730.

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, 539, 268–271.

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.