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Mid-valent heme-oxygen intermediates are central to a medley of pivotal physiological transformations in humans, and such systems are increasingly becoming more relevant therapeutic targets for challenging disease conditions. Nonetheless, precise... 

Abstract Heme enzymes play a central role in a medley of reactivities within a wide variety of crucial biological systems. Their active sites are highly decorated with pivotal evolutionarily optimized non‐covalent interactions that precisely choreograph their biological functionalities with specific regio‐, stereo‐, and chemo‐selectivities. Gaining a clear comprehension of how such weak interactions within the active sites control reactivity offers powerful information to be implemented into the design of future therapeutic agents that target these heme enzymes. To shed light on such critical details pertaining to tryptophan dioxygenating heme enzymes, this study investigates the indole dioxygenation reactivities of Lewis acid‐activated heme superoxo model systems, wherein an unprecedented kinetic behavior is revealed. In that, the activated heme superoxo adduct is observed to undergo indole dioxygenation with the intermediacy of a non‐covalently organized precursor complex, which forms prior to the rate‐limiting step of the overall reaction landscape. Spectroscopic and theoretical characterization of this precursor complex draws close parallels to the ternary complex of heme dioxygenases, which has been postulated to be of crucial importance for successful 2,3‐dioxygenative cleavage of indole moieties. 

Abstract High‐valent Fe(IV)=O intermediates of metalloenzymes have inspired numerous efforts to generate synthetic analogs to mimic and understand their substrate oxidation reactivities. However, high‐valent M(IV) complexes of late transition metals are rare. We have recently reported a novel Co(IV)−dinitrate complex (1‐NO₃) that activates sp³C−H bonds up to 87 kcal/mol. In this work, we have shown that the nitrate ligands in1‐NO₃can be replaced by azide, a more basic coordinating base, resulting in the formation of a more potent Co(IV)−diazide species (1‐N₃) that reacts with substrates (hydrocarbons and phenols) at faster rate constants and activates stronger C−H bonds than the parent complex1‐NO₃. We have characterized1‐N₃employing a combination of spectroscopic and computational approaches. Our results clearly show that the coordination of azide leads to the modulation of the Co(IV) electronic structure and the Co(IV/III) redox potential. Together with the higher basicity of azide, these thermodynamic parameters contribute to the higher driving forces of1‐N₃than1‐NO₃for C−H bond activation. Our discoveries are thus insightful for designing more reactive bio‐inspired high‐valent late transition metal complexes for activating inert aliphatic hydrocarbons.