Using high-valent dinuclear cobalt complexes to understand enzymatic bond activation and bond formation processes

Project Summary Natural metalloenzymes have developed effective strategies to catalyze substrate transformations that invoke diverse bond breaking and bond forming (BBBF) processes. Better understanding these fundamental steps using biomimetic and bio-inspired first-row transition metal complexes can offer valuable insights on how metalloenzymes carry out catalytic reactions in an efficient and selective manner, ultimately leading to the development of new pharmaceutical and therapeutic strategies. A number of first-row transition metal elements such as iron, copper and manganese are commonly employed as cofactors in many metalloenzymes that generate mononuclear or multinuclear high-valent metal-oxo species as reactive intermediates in their catalytic cycles, with a notable exception for cobalt and nickel---an obvious gap between the elements of iron and copper. While examples of cobalt and nickel-based oxygenases are rarely, the high-valent metal-oxo chemistry for synthetic cobalt and nickel complexes is underexplored and poorly understood, likely due to the limited availability of well-characterized high-valent Co and Ni complexes having an oxidation state of +4. Therefore, it presents challenges on how to understand the roles that these late transition metals might play in enzymatic reactions and, more importantly, how they can be better utilized to carry out important but difficult oxidative substrate transformations. Recent advances in the development of artificial metalloenzymes have shown unprecedented opportunities for incorporating these late transition metal complexes supported by non-natural organic ligands into different protein scaffolds for biocatalysis. In this project, we aim to address these challenges by developing highly reactive, bio-inspired high-valent dinuclear cobalt(IV)-oxo complexes to study three fundamental BBBF reactivities, including the activation of inert aliphatic C–H bonds, reversible activation and formation of the O–O bond, and the formation of C–X bonds by radical rebound. We use synthetic approaches with rational modifications of the ligand and the second metal site to generate unprecedented high-valent dinuclear cobalt(IV)-oxo complexes for spectroscopic and computational studies and investigate fundamental BBBF reactivities mentioned above. These approaches allow us to predictably modulate and balance between the stability and reactivity of these complexes in order to serve for different goals (high stability for characterizing high-valent species vs. high reactivity for substrate transformations). Our published and preliminary results have laid a solid groundwork and demonstrated the viability of the proposed work. Our strategies are truly innovative because the dicobalt system is the only known example capable of carrying out all these rich and diverse reactivities among related dinuclear complexes of first-row transition metals. Our research thus represents an innovative leap forward in the field and, once successful, is expected to advance fundamental understandings of enzymatic BBBF processes and shed light on how dicobalt complexes can be further utilized in molecular catalysis and biocatalysis.