Theoretical Studies on the Mechanism of the Methane → Methanol Conversion Reaction Catalyzed by Methane Monooxygenase:  O-Side vs N-Side Mechanisms

Abstract

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-(H 2 O)(NH 2 )Fe(µ-O) 2 (η 2 -HCOO) 2 Fe(NH 2 )(H 2 O), I, where the substrate molecule may coordinate to the bridging oxygen atoms, O 1 and O 2 , located on the H 2 O and NH 2 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 CH 4 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 ratedetermining 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 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.

Mechanistic Studies on the Hydroxylation of Methane by Methane Monooxygenase

“…Thus, we limit the following discussion to the O-side attack. 224,226 The structures and energies computed by Morokuma and co-workers are shown in Figure 9. The proposed structure of Q is significantly different from the Yoshizawa model and contains two six-coordinate iron centers with two bridging carboxylate ligands in addition to the two bridging oxo groups.…”

“…Mulliken Spin Densities of the Structures Involved in the Methane Hydroxylation MechanismProposed by Morokuma et al224 …”

THEORETICAL STUDY ON METHANE HYDROXYLATION BY MIMIC METHANE MONOOXYGENASE WITH bis(μ-OXO)DIMANGANESE CORE

“…According to the experimentally available structure information of enzyme with bis(µ-oxo) dimanganese core and the MMO with bis(µ-oxo) diiron core, 5,12,[18][19][20][21][22][23][24] the working model should satisfy the following conditions: (1) It should include two Mn-Mn bridging oxo ligands, two bridging carboxylates of glutamic acid residue coordinated to the two Mn centers, and one histidine acid residue and one monodentate terminal carboxylate of glutamic acid residue coordinated ligands for each Mn center. (2) Net charge of the system should be "zero." (3) For treating each Mn center as the same electronic environment, histidine acid residues are located trans to each other, i.e.…”

“…1 A key compound Q, as an oxidizing species for MMO, has been proposed to be responsible for the direct reactivity toward methane, which is a chemically challenging reaction. 2 The understanding of the reaction mechanism, in which the enzyme catalyzes the hydroxylation of C-H bond, is not only of great academic interest but also of possible practical value for the biomimetic design of new catalysts for industrial conversion of methane to methanol. 3 Over the past decade, extensive experimental and theoretical studies of MMO have been carried out, thereby contributing substantially toward the elucidation of various steps in the catalytic cycle at an atomic level of detail.…”

Theoretical Studies for Large Tunneling and the Hydrogen‐Transfer Mechanism in the CH Activation of CH3CN by a Di(μ‐oxo)diiron(IV) Complex: A Model for Intermediate Q in Soluble Methane Monooxygenase

“…The M06 level of theory was used because this functional produced good benchmark results for various metal complexes. [16] The "small" Morokuma-Basch model [17] of intermediate Q was used to mimic the hydroxylation in sMMO, and a full range of QM calculations were carried out to determine the IRC of hydrogen transfer with CH 3 CN. Intermediate Q was shown to be diamagnetic and contain two antiferromagnetically coupled high-spin Fe IV atoms.…”