Development of First-Row Transtion-Metal Reagents for Catalytic C-H Bond Amination via Nitrene-Transfer Chemistry - Project Summary/Abstract: The overarching goal of the proposed research program is to develop and mechanistically understand the operation of a library of transition-metal catalysts for C–H bond amination reactions via nitrene-transfer chemistry. Amines are widely applicable as commodity and fine chemicals, and as functional building blocks in pharmaceuticals, agrochemicals, polymers and natural products. The proposed research advances catalyst-design principles for applications in aminations of activated and non-activated C–H bonds, with particular emphasis on C–H feedstock that is more difficult to functionalize than benzylic sites. The catalyst design includes suitable axial and equatorial ligand-field interventions to guide reactivity and selectivity outcomes, in conjunction with metal sites from the first-row of transition-metal elements (Mn, Fe, Co, Cu) and a variety of nitrene sources. In particular, synthetic and catalytic studies will be informed by mechanistic input (experimental and computational), as catalytic activity and selectivity can be influenced by small modifications in catalyst design and metal employed. More specifically, a family of tripodal and bipodal ligands, currently featuring [N3E] and [N2E] ligand fields (E = N, Sb, Bi), will be suitably modified to introduce weakly coordinating, non-coordinating, and even electron-reversing axial residues, to enhance the electrophilicity of the active metal- nitrene unit for the amination of challenging C–H bonds. In tandem, the equatorial ligand field will be decorated with superbasic cyclic and acyclic guanidinyl residues, to fine-tune the metal-nitrene electrophilicity, rigidify the reaction cavity and enrich it with chemical substituents for guiding chemo- and site-selectivity. Cationic metal catalysts will be largely synthesized with nonprecious elements (MnII, FeII, CoII CuI/II) and employed as nitrene- transfer agents vis-à-vis different types of C–H bonds. A detailed catalytic investigation will be pursued with the newly synthesized reagents, to establish their reactivity and selectivity proclivities in C–H amination reactions in conjunction with a suitably diversified panel of nitrene-donor precursors. This hypothesis-driven exploration will test whether catalyst-tailored modifications could enhance the reactivity and selectivity of the catalyst library for challenging C–H bond amination reactions. Mechanistic studies will be undertaken with the most successful catalytic systems, to examine metal- and substrate-centered events anticipated to operate in catalytic turnover. Stoichiometric reactions will be pursued, targeting the isolation and characterization of the active metal-nitrene moiety with the assistance of physical-inorganic techniques. Substrate-centered events will be investigated in detail with an arsenal of diagnostic techniques and physical-organic probes, to explore the nature and lifetime of intermediates resulting from the operation of the metal-nitrene oxidant and eventually place them on a reliable reaction trajectory with synergism provided by computational methods. In summary, the proposed research program integrates synthetic, catalytic and mechanistic activities, for advancing the reactivity and selectivity outcomes of catalytic C–H bond amination reactions by means of nitrene-transfer chemistry.
