Coordination dynamics of iron enables the selective C-N coupling but bypasses unwanted C-H hydroxylation in Fe(Ⅱ)/α-ketoglutarate-dependent non-heme enzymes
Non-heme Fe(Ⅱ)/α-ketoglutarate (αKG)-dependent enzymes catalyze numerous C-H activation and functionalization reactions.However,how αKG-dependent non-heme enzymes catalyzed C-H func-tionalization beyond the hydroxylation is largely unknown.Here,we addressed this issue in Fe(Ⅱ)/αKG-dependent oxygenase TqaLNc,which catalyzes the selective C-H amination but bypasses the thermodynamically favored C-H hydroxylation.Here,the extensive computational studies have shown that the aziridine formation involves the conformational change of the Fe(Ⅳ)=O species from the axial configuration to the equatorial one,the substrate deprotonation of NH3+group to form the NH-ligated intermediate,the C-H activation by the equatorial Fe(Ⅳ)=O species.Such mechanistic scenario has been cross-validated by oxidation of various substrates by TqaLNc and its variants,including the available experiments and our new experiments.While the presence of steric hindrance between the substrate and the second-sphere residues would inhibit the aziridination process,the intrinsic reactivity of aziridination vs.hydroxylation is dictated by the energy splitting between two key redox-active dπ* frontier molecular orbitals:dπ* Fe-N and dπ* Fe-OH.The present findings highlight the key roles of the coordination change and dynamics of iron cofactor in dictating the catalysis of non-heme enzymes and have far-reaching implications for the other non-heme Fe(Ⅱ)/αKG-dependent enzymes catalyzed C-H functionalization beyond the hydroxylation.
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