Bioinspired Copper-Promoted C-H Hydroxylations

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Project Summary: The goal of the proposed research is to develop synthetic inorganic copper complexes to understand the fundamental aspects of structure and function in Cu-dependent monooxygenase enzymes. These metalloenzymes contain 1 or 2 Cu ions in their active center and they couple the reduction of O2 with the oxidation of substrates via formation of transient Cun/O2 reactive intermediates. We are particularly interested in inspecting the reactivity of mononuclear Cu/O2 species since they have been proposed as active oxidants in the hydroxylation of C-H bonds (in peptidylglycine α-hydroxylating monooxygenase and lytic polysaccharide monooxygenase). Many questions concerning the identity of the active Cu/O2 species remain unanswered, including: i) oxidation state of Cu (i.e. CuI, CuII, CuIII); ii) reduction/protonation state of O2 (O2−,(H)O22−, (H)O2−) and the pKa and redox potentials associated with these Cu/O2 species; iii) mechanism by which the Cu/O2 intermediates carry out C-H hydroxylations (e.g. O-O cleavage mechanism, possible generation of high- valent Cu-oxyl species before C-H oxidation). In this research project, we tackle this problem in an unprecedented fashion: we utilize ligand scaffolds (L) that contain C-H substrates covalently attached to their structure (imino-pyridine substrate-containing ligands synthesized from condensation of ketones and amines). This will permit us to generate and characterize LCu/O2 species and evaluate their reactivity towards intramolecular C-H hydroxylation of the substrate-ligands. Research subprojects include: (1) Substrate-ligand scaffold modifications will permit us to: i) evaluate the ability of the Cu/O2 species to oxidize sp3 C-H bonds and sp2 C-H bonds; ii) control the stereo-electronic properties of the Cu complexes by the use of different ligand donors (i.e. N2, N3, N4) that will lead to the generation of mononuclear LCuO2 and dinuclear L2Cu2O2 species, and analyze their reactivity towards intramolecular C-H hydroxylation; iii) develop bioinspired synthetic protocols (amine/Cu/oxidant) for the hydroxylation of a wide variety of substrate-ketones. (2) The proposed Cu complexes bearing substrate-ligand scaffolds offer a unique opportunity to study the chemical properties of LCuII(OOR) since their structure can be modified in three ways: by changing the ligand denticity (N2, N3 and N4), substrate (sp3 vs. sp2) and oxidant (H2O2, tBuOOH or CumOOH). The generation of LCuII(OOR) species (metastable at low temperatures) will lead to: i) understanding the mechanism by which LCuII(OOR) oxidize C-H bonds by tracking the decay of LCuII(OOR) and the evolution of the intramolecular hydroxylation yields; ii) analyzing the reactivity of LCuII(OOR) towards H+ and e− sources that could lead to reductive O-O cleavage; iii) studying the reactivity of LCuII(OOR) towards biologically relevant external substrates such as C-H bonds, phenols, and sulfides. Overall, these studies will contribute to a broader understanding of the biochemical role of Cu ions involved in O2 reduction and biologically relevant oxidations.