Linear Free Energy Relationships for Reactions of Electrophilic Halo- and Pseudohalobenzenes, and Their Application in Prediction of Skin Sensitization Potential for SNAr Electrophiles

Abstract

Published kinetic data and linear free energy relationships for nucleophilic aromatic substitution reactions (SNAr reactions) are analyzed so as to derive a reactivity parameter (RP), defined as sigma sigma-(o,m,p) + 0.45 sigma*(ipso), quantifying the relative reactivities of SNAr electrophiles toward aniline in ethanol. It is shown that the dataset of Landsteiner and Jacobs, in which 20 SNAr electrophiles were classified on the basis of experimental evidence as either skin sensitizing and reactive to aniline or nonsensitizers and unreactive to aniline, can be equivalently classified on the basis of RP values and that predictive criteria can be defined as follows: sensitizing/aniline reactive: RP > 3.80; nonsensitizing/unreactive to aniline: RP < 3.65. These predictive criteria based on calculated RP values are applied to seven further SNAr electrophiles to predict which are sensitizers and which are not. There is close agreement between the predictions and the biological data. This validates the applicability of the reactivity parameter RP, derived from linear free energy relationships, to prediction of skin sensitization potential for SNAr electrophiles. More generally, the applicability of physical organic chemistry principles to structure-activity relationships in contact allergy is further demonstrated.