Nucleophilic Cobalt Photocatalysis and Organic Single-Electron Photoreductants; Two Enabling Approaches for Chemical Synthesis – Project Summary The objectives of this proposal are two-fold and include the development and fundamental advancement of nucleophilic cobalt photocatalysis and organic single-electron photoreductants. The unifying theme of these two distinct proposed research programs is the expansion of the breadth of carbon radical precursors available to practitioners of synthetic organic chemistry. The successful completion of both objectives will positively and fundamentally impact the field of chemical synthesis by giving medicinal chemists new synthetic methods that provide access to new chemical space, thereby benefiting human health. While carbon-centered radicals have become an increasingly important tool in organic synthesis, the breadth of radical precursors available to synthetic chemists remains underdeveloped. One underutilized strategy for radical generation is the use of nucleophilic catalysts to engage electrophiles as radical precursors. We hypothesize that simple cobaloxime complexes can serve as nucleophilic photocatalysts for the visible-light-generation of carbon-centered radicals from non-traditional electrophilic precursors including haloforms, electron-deficient alkenes, iminium ions, vinyl halides and triflates, and primary alcohols. Cobaloximes are among the strongest nucleophiles known when in the Co(I) oxidation state and can undergo classical substitution reactions with electrophiles. The resulting alkyl–cobaloximes can undergo facile homolytic cleavage when irradiated with visible light to generate carbon-centered radicals. This work will advance our understanding of the reactivity of these cobaloxime complexes, allowing for the development of more efficient catalytic processes that can access new classes of radical precursors, enabling new bond disconnection strategies for organic synthesis. To further advance the field of radical chemistry, general approaches that serve to generate radicals directly from readily available alkyl halides and carbonyl compounds which circumvent the use of tin hydrides and ground state metal reductants would be of great value. We hypothesize that organic single-electron photoreductants can serve as a general platform for visible-light-mediated radical generation directly from unactivated precursors. Our approach will be enabled by two distinct strategies: namely, halogen-bonding photocatalysis and 1,4- dihydropyridine (DHP) anion photoreductants. For our halogen-bonding photocatalysis approach, our substituted hydroquinone catalysts directly engage with carbon–halide bonds via a halogen-bonding interaction, leading to a catalytically generated electron donor-acceptor complex that can be activated by visible-light irradiation. This work is expected to lead to a general strategy for radical generation from a broad range of alkyl halide precursors, yielding methods that have unprecedented functional group tolerance. For our second approach, we hypothesize that simple 1,4-DHPs in the presence of a suitable base can serve as potent excited state reductants. Our work on 1,4-DHP anions will lead to a mild and operationally simple method for ketyl radical formation, which has been shown to be valuable synthetic intermediates in the synthesis of complex, highly functionalized compounds.

Project Narrative/Public Health Relevance Statement The ability to rapidly synthesize a diverse array of chemical structures is critical for the discovery and manufacture of new pharmaceuticals. This work aims to provide two enabling technologies, nucleophilic cobalt catalysis and organic single-electron photoreductants, for the rapid and efficient construction of carbon–carbon bonds. The methods enabled by these technologies will provide new tools for practitioners of medicinal chemistry, streamlining drug discovery and development and thereby positively impacting human health.