Theoretical studies on the mechanism of the methane → methanol conversion reaction catalyzed by methane monooxygenase: O-side vs N-side mechanisms

The hybrid density functional method B3LYP was used to study the mechanism of the methane hydroxylation reaction catalyzed by the methane monooxygenase (MMO) enzyme. The key reactive compound Q of MMO was modeled by cis-(H₂O)(NH₂)Fe(μ-O)₂(ν ²-HCOO)₂ Fe(NH₂)(H₂O), I, where the substrate molecule may coordinate to the bridging oxygen atoms, O¹ and O², located on the H₂O and NH₂ sides, leading to two different mechanisms, O-side and N-side pathways, respectively. Previously we have detailed the N-side pathway (Basch, H.; Mogi, K.; Musaev, D. G.; Morokuma, K. J. Am. Chem. Soc. 1999, 121, 7249); here we discuss the O-side pathway, and compare the two. Calculations show that, like the N-side pathway, the O-side pathway of the reaction of I with CH₄ proceeds via a bound-radical mechanism. It starts from the bis(μ-oxo) compound I and goes over the rate-determining transition state III_O for H abstraction from methane to . form a weak complex IV_O between the Fe(μ-O)(μ-OH)Fe moiety and a methyl radical. This bound-radical intermediate IV_O converts to the oxo-methanol complex VI_O via a low barrier at transition state V_O for the addition of the methyl radical to the μ-OH ligand. Complex VI_O easily (with about 7-8 kcal/mol barrier) eliminates the methanol molecule and produces the Fe(μ-O)Fe, VII_O, complex. During the entire process, the oxidation state of the Fe core changes from Fe^IV-Fe^IV in I to a mixed-valence Fe^III-Fe^IV in the short-lived intermediate IV_O, and finally to Fe^III-Fe^III in VI_O and VII_O. A comparison of the O-side and N-side pathways shows that both include similar intermediates, transition states, and products. The rate-determining step of both pathways is the H-atom abstraction from the methane molecule, which occurs by 23.2 and 19.5 kcal/mol barrier for the O-side and N-side pathways, respectively, in the ground ⁹A states of the systems. Thus, the N-side pathway is intrinsically more favorable kinetically than the O-side pathway by about 4 kcal/mol. However, experimentally in the enzyme the N side is blocked by unfavorable steric hindrance and the actual reaction has to take place on the O side.