Substrate activation for O₂ reactions by oxidized metal centers in biology

The uncatalyzed reactions of O₂ (S = 1) with organic substrates (S = 0) are thermodynamically favorable but kinetically slow because they are spin-forbidden and the one-electron reduction potential of O₂ is unfavorable. In nature, many of these important O₂ reactions are catalyzed by metalloenzymes. In the case of mononuclear non-heme iron enzymes, either Fe^II or Fe^III can play the catalytic role in these spin-forbidden reactions. Whereas the ferrous enzymes activate O₂ directly for reaction, the ferric enzymes activate the substrate for O ₂ attack. The enzyme-substrate complex of the ferric intradiol dioxygenases exhibits a low-energy catecholate to Fe^III charge transfer transition that provides a mechanism by which both the Fe center and the catecholic substrate are activated for the reaction with O₂. In this Perspective, we evaluate how the coupling between this experimentally observed charge transfer and the change in geometry and ligand field of the oxidized metal center along the reaction coordinate can overcome the spin-forbidden nature of the O₂ reaction.