Mechanism of Cobalamin-Mediated Reductive Dehalogenation of Chloroethylenes

Reductive dehalogenation involving cobalamin has been proved to be a promising strategy for decontamination of the polluted environment. However, cob(I)alamin can act both as a strong reductant and a powerful nucleophile, and thus, several competing dehalogenation pathways may be involved. This work uses experimentally calibrated density functional theory on a realistic cobalamin model to resolve controversies of cobalamin-mediated reduction of chloroethylenes by exploring mechanisms of electron transfer, nucleophilic substitution, and nucleophilic addition. The computational results provide molecular-level insight into the competing pathways for chloroethylenes reacting with cob(I)alamin: the computed ratios of inner sphere to outer-sphere pathways for perchloroethylene and trichloroethylene are 17:1 and 3.5:1, respectively, in accord with the corresponding experimental ratios of >10:1 and >2.3:1, while the computed outer-sphere pathway for other less-chlorinated ethylenes is hampered by high barriers (>25 kcal/mol). Thus, a new mechanistic picture has been obtained in which the highly chlorinated ethylenes primarily react via an inner-sphere nucleophilic-substitution pathway, whereas the less-chlorinated ethylenes mainly react through an inner-sphere nucleophilic-addition pathway. Especially, the quantitative comparison of standard reduction potentials between the formed chlorinated-cobalamin and cob(II)alamin/cob(I)alamin couple can be used to distinguish whether the inner-sphere pathway can proceed or not, and linear free-energy relationships have been developed to predict the reductive dehalogenation reactivity within a given mechanism. Finally, we propose new dual-isotope analyses for distinguishing the various environmental dehalogenation mechanisms.