Theoretical studies on the mechanism of the methane -> methanol conversionreaction 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 monooxygenas e (MMO) enzyme. The key reactive compound Q of MMO was modeled by cis-(H2O) (NH2)Fe(mu -O)(2)(eta (2)-HCOO)(2) Fe(NH2)(H2O). I, where the substrate mol ecule may coordinate to the bridging oxygen atoms, O-1 and O-2, located on the H2O and NH2 sides, leading to two different mechanisms, O-side and N-si de pathways, respectively. Previously we have detailed the N-side pathway ( Basch, H.; Mogi, K.; Musaev, D. G.; Morokuma, K. J. Am. Chem. Sec. 1999. 12 1, 7249); here we discuss the O-side pathway, and compare the two. Calculat ions 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 b is(mu -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 th e Fe(mu -O)(mu -OH)Fe moiety and a methyl radical. This bound-radical inter mediate 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 mu -OH ligand. Complex VI_O easily (with about 7--8 kcal/mol barrier) eliminates t he methanol molecule and produces the Fe(mu -O)Fe, VII_O, complex. During t he 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-s ide and N-side pathways shows that both include similar intermediates, tran sition 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 (9)A states of the systems. Thus, the N-side pathway is intrinsi cally more favorable kinetically than the O-side pathway by about 4 kcal/mo l. However, experimentally in the enzyme the N side is blocked by unfavorab le steric hindrance and the actual reaction has to take place on the O side .