Reductive Cleavage Mechanism of Methylcobalamin:  Elementary Steps of Co−C Bond Breaking

Density functional theory has been applied to the investigation of the reductive cleavage mechanism of methylcobalamin (MeCbl). In the reductive cleavage of MeCbl, the Co−C bond is cleaved homolytically, and formation of the anion radical ([MeCbl]<sup>•-</sup>) reduces the dissociation energy by ∼50%. Such dissociation energy lowering in [MeCbl]<sup>•-</sup> arises from the involvement of two electronic states:  the initial state, which is formed upon electron addition, has dominant π*<sub>corrin</sub> character, but when the Co−C bond is stretched the unpaired electron moves to the σ*<sub>Co</sub><sub>-</sub><sub>C</sub> state, and the final cleavage involves the three-electron (σ)<sup>2</sup>(σ*) bond. The π*<sub>corrin</sub>−σ*<sub>Co</sub><sub>-</sub><sub>C</sub> states crossing does not take place at the equilibrium geometry of [MeCbl]<sup>•-</sup> but only when the Co−C bond is stretched to 2.3 Å. In contrast to the neutral cofactor, the most energetically efficient cleavage of the Co−C bond is from the base-off form. The analysis of thermodynamic and kinetic data provides a rationale as to why Co−C cleavage in reduced form requires prior departure of the axial base. Finally, the possible connection of present work to B<sub>12</sub> enzymatic catalysis and the involvement of anion−radical-like [MeCbl]<sup>•-</sup> species in relevant methyl transfer reactions is discussed.