Catalytic Nitrogen Fixation and C-N Bond Constructions Mediated by Iron and Copper as Models of Biocatalysis and Tools for Organic Synthesis

California Institute Of Technology, Pasadena CA

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Abstract

Project Summary - Catalytic nitrogen fixation and C–N bond constructions mediated by iron and copper as models of biocatalysis and tools for organic synthesis This R35 application requests support to expand research funded via NIGMS in the Peters laboratory during the past five years (JCP as PI: R01-070757; JCP as co-investigator (Greg Fu as PI): R01-109194), where we have focused on multi-electron (e.g., 2e–, 4e–, 6e–) catalytic transformations involving nitrogen-containing species. Continued studies of Fe-mediated nitrogen reduction (N2R) catalysts are proposed as functional models of biocatalytic N2R mediated by nitrogenase enzymes. Well-defined catalytically functional Fe model systems can test the viability of specific Fe–NxHy intermediates and pathways en route to ammonia, constraining mechanistic hypotheses, while also providing spectroscopic signatures that guide spectroscopic assignment of enzymatic intermediates. Our proposed studies address outstanding questions in the field, including the role of protoncoupled electron transfer (PCET) steps that may level the turnover-limiting potential of N2R. Exciting new tools to electrochemically and photochemically initiate PCET steps to Fe–NxHy species are described, as are studies to control catalytic selectivity (NH3 vs N2H4 vs H2) via new reagent and catalyst development motivated by mechanistic data. These varied pursuits promise increasingly efficient models of biocatalytic N2R. New research on photoinduced, Cu-catalyzed C–N (and other C–C and C–heteroatom) couplings is also described. As most all medicines and drug candidates contain at least one carbon–nitrogen bond, the continued development of diverse methods for the formation of C–N bonds is needed. Our discovery of photoinduced, Cu-catalyzed C–X couplings (in partnership with the Fu laboratory) has led to a fascinating range of catalytic N- alkylations and related couplings that include (but are not limited to) secondary alkyl bromides and iodides, and activated tertiary chlorides, as electrophiles, in combination with a range of N–nucleophiles (e.g., anilines, amines, amides, carbazoles). These methods include examples of enantioconvergent couplings. We now describe research towards well-defined copper(I) complexes featuring chelating LX-type ligands that engender favorable photophysical properties (i.e., long-lived and strongly reducing excited states) to engage, via electron transfer, unactivated alkyl chlorides, thus furnishing organic radical R× intermediates key in C–N cross-couplings. This research may lead to more universally applicable copper(I) photoreductants in this coupling chemistry. Finally, oxidative catalytic pathways to C–N bond constructions are also proposed, including C–H aminations and aziridinations, directly from amine (RR’NH) precursors. Such transformations most typically require preoxidized nitrogen sources. Based on our recent ammonia oxidation (AO) catalysis studies, (2 NH3 « N2 + 6H+ + 6 e–), we hypothesize oxidative transformations directly from amine substrates to form C–N bonds mediated by polypyridyl iron complexes.