Electrophilic reactions of skin-sensitizing sultones

Reactions of the strong skin sensitizer hexadec-1-ene-1,3-sultone with sodium hydroxide, sodium methoxide, sodium metabisulfite, sodium butanethiolate, n-butylamine, and aniline have been investigated, and the reaction products have been identified. Most of the nucleophiles studied react by nucleophilic addition (Michael type addition) to the double bond at the 2-position, although in most cases the final products result from further reactions of the initital adducts. The findings are considered together with those reported by Meschkat, Barratt, and Lepoittevin for reactions of hex-1-ene-1,3-sultone and hexane-1,3-sultone, and the implications of the two sets of findings for the mechanism of skin-sensitizing action are discussed. It is concluded that nucleophilic attack at the 3-position of the alk-1-ene-1,3-sultones occurs only with those nucleophiles, which either have very low reactivity in nucleophilic addition or are unable to give rise to thermodynamically stable products via initial reaction at the 2-position. It is further concluded that the observed differences in electrophilic reactivity between alk-1-ene-1,3-sultones and alkane-1,3-sultones are not large enough to rationalize the differences in skin sensitization properties between the two types of sultone. It is suggested that the differences in specificity arise because the alk-1-ene-1,3-sultones act as Michael type electrophiles whereas the alkane sultones act as S(N)2 electrophiles. It is suggested that the reason for the greater potency of the alk-1-ene-1,3-sultones may be the ability of the initial C2 adducts with protein to undergo further reactions by substitution at C3, leading to cross-linking and consequent perturbation to the protein tertiary structure.