Thietanium ion formation from the food mutagen 2-chloro-4-(methylthio)butanoic acid

2-Chloro-4-(methylthio)butanoic acid (1) is a direct-acting mutagen and suspected gastric carcinogen isolated from fish preserved with salt and nitrite. The reactive intermediates formed from acid 1 that may be associated with its mutagenicity have not been identified. A candidate reactive intermediate is proposed in this work. 1-Methyl-2-thietaniumcarboxylic acid may result from internal displacement of chloride by neighboring-group participation of sulfide sulfur in the solvolysis of acid 1. Evidence for the formation of 1-methyl-2-thietaniumcarboxylic acid was derived from experiments in which 4-chlorophenol and aniline were included to react with electrophilic intermediates formed from acid 1. Incubation of acid 1 in the absence of the aniline or 4-chlorophenol resulted in the formation of 2,4-bis(methylthio)butanoic acid. Incubation of acid 1 with 4-chlorophenol or aniline gave adducts that were identified by 1H NMR spectroscopy and GC/MS as 2-(4-chlorophenoxy)-4-(methylthio)butanoic acid and 4-(4-chlorophenoxy)-2-(methylthio)butanoic acid or 2-anilino-4-(methylthio)butanoic acid and 4-anilino-2-(methylthio)butanoic acid, respectively. The structures of these adducts indicate the intermediate formation of 1-methyl-2-thietaniumcarboxylic acid as a reactive intermediate derived from acid 1 that may be associated with its observed mutagenicity.