Dithiols such as
British anti-lewisite (BAL, rac-2,3-dimercaptopropanol) are an important class of antidotes for the
blister agent
lewisite (trans-2-chlorovinyldichloroarsine) and, more generally, are
chelating agents for
arsenic and other toxic metals. The reaction of the vicinal
thiols of BAL with
lewisite through the chelation of the As(III) center has been modeled using density functional theory (DFT) and
solvent-assisted
proton exchange (SAPE), a microsolvation method that uses a network of water molecules to mimic the role of bulk
solvent in models of aqueous phase chemical reactions. The small activation barriers for the stepwise SN2-type nucleophilic attack of BAL on
lewisite (0.7-4.9kcal/mol) are consistent with the favorable leaving group properties of the
chloride and the affinity of As(III) for soft
sulfur nucleophiles. Small, but insignificant, differences in activation barriers were found for the initial attack of the primary versus secondary
thiol of BAL and the R vs S enantiomer. An examination of the relative stability of various
dithiol-
lewisite complexes shows that ethanedithiols like BAL form the most favorable chelation complexes because the angles formed in five-membered ring are most consistent with the hybridization of As(III). More obtuse S-As-S angles are required for larger chelate rings, but internal As⋯N or As⋯O interactions can enhance the stability of moderate-sized rings. The low barriers for
lewisite detoxification by BAL and the greater stability of the chelation complexes of small dithiols are consistent with the rapid reversal of toxicity demonstrated in previously reported animal models.