Mechanistic insights into axial ligation effects on electron transfer and selective C−H activation catalyzed by iron-oxo analogues

Iron(IV)-oxo porphyrin (Cpd I) is the main catalytically active intermediate in the cytochrome P450 enzymatic cycle. During the C(sp³)-H bond activation, the Cpd I abstracts hydrogen atom from substrate, forming a transient Fe(III)-hydroxo (Cpd II) species and substrate radical. In this study, DFT reported the regioselectivity of CH activation and the effect of axial ligand, using experimentally characterized hemes containing L = none, imidazole, SCH₃, OCH₃, Cl, and CN to simulate no axial ligand, His, Cys, Ser, and inorganic ligands for comparison. The results show that axial ligands can affect the spin density of complex and exhibit lower energy barrier for C2H activation compared to C4H in lidocaine. Ligands OCH₃ and SCH₃ demonstrate superior regioselectivity for C2H activation. For Cpd II, the ligands CN, SCH₃ and OCH₃ are advantageous for C1H abstraction. The findings enhance understanding of the ligand effect in Cpd I and provide novel insights into P450 enzyme catalytic mechanisms.