Elucidating the mechanism of cob(I)alamin mediated methylation reactions by alkyl halides: SN2 or radical mechanism?

Abstract

Methyl transfer reactions mediated by cobalamins (Cbls) have been considered as one of the most important biologically relevant molecular transformations for many enzymatic reactions catalyzed by Cbl-dependent enzymes. The exact mechanism of methyl transfer reactions involving Cbls is still poorly understood. To investigate the mechanistic details of Cbl mediated methylations by alkyl halides, density functional theory (DFT) along with the polarizable continuum model (PCM/water) for solvation has been applied. Two different mechanisms have been examined, namely SN2 and radical-based electron transfer (ET) to elucidate the methyl transfer reaction. The calculations have suggested that the methyl transfer from methyl halides proceeds through SN2 nucleophilic displacement. However, with more bulky alkyl substrate, namely isopropyl and tert-butyl halides the reaction followed the ET-based radical pathway which is associated with an ET from diradical form of cob(I)alamin to alkyl halides. Our proposed mechanism for alkyl transfer reaction corroborates with the experimental findings, which reported a mechanistic switch from a two-electron (SN2-type) to a one-electron mechanism for sterically demanding alkyl halides. The present theoretical contribution provides more in-depth insight into the methyl transfer reaction catalyzed by corrinoid-dependent methyltransferases.