Studies of chemical selectivity of hapten, reactivity, and skin sensitization potency. 3. Synthesis and studies on the reactivity toward model nucleophiles of the 13C-labeled skin sensitizers, 5-chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI).

The skin sensitizers, 5-chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI), have been synthesized isotopically labeled with 13C at all carbon positions. The reactivity of 3-[13C]-, 4-[13C]-, and 5-[13C]MCI and MI toward a series of model nucleophiles for protein amino acid residues, i.e., butylamine, imidazole, sodium propanethiolate, and sodium phenoxide, was followed by 13C and 1H{13C} NMR spectroscopy. While MCI was found to react quantitatively with sodium propanethiolate and butylamine and significantly with imidazole and sodium phenoxide, MI reacted only with sodium propanethiolate. Reaction of MCI with nonthiol nucleophiles proceeded through an initial addition−elimination at position 5, leading to stable substitution adducts in the case of imidazole and sodium phenoxide. In the case of butylamine, the initial adduct was subjected to extra reactions at the sulfur atom through a cleavage of the S−N bond, leading to open adducts of the thioamide or amide type. Experiments carried...