Comparative Sulfhydryl Reaction Pathways of Chlorooxirane and Chloroacetaldehyde

Article abstract of DOI:10.1021/jo00289a018

Two bifunctional alkylating agents, chlorooxirane (1) and chloroacetaldehyde (2), which are putative metabolites of vinyl chloride (VC), are expected to be detoxified via S-(formylmethyl)glutathione as the common intermediate.This paper compares the behavior of 1 and 2 in their reactions with to model thiols in aqueous and chloroform media to evaluate the above hypothesis.In aqueous media, 1 and 2 react with N-acetylcysteine (3a) or its methyl ester 3b to form the same S-acetaldehyde 4a or 4b, which, upon standing, cyclized to the dihydro-1,4-2H-thiazine derivatives6a and 6b.In chloroform, the above products were obtained for both 1 and 2 via different pathways: the reaction of 3b and 2 formed initially the thiohemiacetal 7 at 0 deg C, which rearranged to the aldehyde 4b after warming or treatment with triethylamine.Another thiol, 3,4-dichlorobenzenethiol (8), used for trapping alkylating metabolites from VC as the S-acetaldehyde 9, was found to react with 1 but not 2 in aqueous solution to produce 9, whose identity was verified by an independently synthesized sample.The reaction of the thiol 8 and 1 in chloroform yielded 9 sluggishly; the reaction of 8 and 2 gave the thiohemiacetal 11, which rearranged to the aldehyde 9 when heated at 50 deg C or treated with pyridine.