The overarching goal of the proposed research program is to synthesize and mechanistically investigate new metal reagents for the selective intermolecular amination and alkylation of activated and unactivated C?H bonds, by means of nitrene/nitrenoid and carbene transfer catalysis. The proposed work relies on systematic catalyst design that involves ligand development and redox active first-row transition elements (Mn, Fe, Co, Cu), operating in conjunction with a wide range of N- and C-donor sources to achieve selective, catalyst- controlled C?H bond functionalization. The resulting functionalities are found in abundance in natural and synthetic products, including pharmaceuticals, agrochemicals, catalytic and other solid-state materials. The research program will be targeting three specific aims. First, new members of a growing family of tripodal and bipodal ligands will be synthesized, in order to incorporate novel elements and residues along the axial and equatorial ligand field for the purpose of modulating the electrophilicity and steric characteristics of a presumptive metal-nitrene/nitrenoid and carbene moiety responsible for C?H aminations and alkylations, respectively. A series of tripodal and bipodal metal reagents will be generated with nonprecious elements (MnII, FeII, CoII, CuI), featuring both negative and positive overall charges, along with a wide range of stereoelectronic and stereochemical attributes (including chiral sites), to control reactivity and facilitate discrimination of C?H bonds. Secondly, the metal reagents obtained in the previous task will be engaged in catalytic amination and alkylation reactions with an electronically and sterically diversified panel of nitrene (or nitrenoid) and carbene donor sources, to further influence the reactivity and selectivity of the catalytic reactions. Catalytic C?H aminations and alkylations will be vigorously pursued, with emphasis on differentiation between benzylic and tertiary sites, but also in pursuit of functionalization of challenging tert/sec/prim-C?H bonds, paving the way for future research that aspires to incorporate light hydrocarbon feedstock in synthetic strategies. Thirdly, metal- and substrate-centered events associated with the most promising amination and alkylation catalysts identified in the second task, will be investigated mechanistically and computationally to identify and spectroscopically characterize the active entity, presumably a metal-nitrene or -carbene unit, that is responsible for performing C?H activation. The mode of operation of this active agent vis--vis the substrate will be further explored with an arsenal of stereo-chemical probes and diagnostic techniques, to determine whether C?H bond insertion occurs in a concerted or stepwise fashion, and characterize the nature and lifetime of intermediates.
The proposed research details synthetic and catalytic methodologies, as well as mechanistic analysis relevant to the selective construction of C?N and C?C bonds via nitrene/carbene transfer chemistry, to afford products of amination and alkylation. These functional groups are associated with the beneficial activity of a plethora of natural and synthetic products, chief among which are pharmaceutical and agrochemical agents, as well as products essential to the science of catalysis and solid-state materials. Several synthetic processes associated with catalytic activation of unfunctionalized C?H bonds share fundamental mechanistic steps with those operating in analogous enzymatic processes, including currently emerging amination and alkylation reactions mediated by engineered and artificial biocatalysts.