Experiment and Computational Study on the Regioselectivity of Nucleophilic Addition to Unsymmetrical p-Benzynes Derived from Bergman Cyclization of Enediynes

Abstract

The regioselectivity in addition of nucleophiles to the p-benzyne intermediates derived from unsymmetrical aza- substituted enediynes via Bergman Cyclization was studied. Computational studies [using UB3LYP/6-31G(d,p) level of theory] suggest that the p-benzyne intermediate retains its similar electrophilic character at the two radical centres even under unsymmetrical electronic perturbation, thus supporting the predicted model of nucleophilic addition to p- benzyne proposed by Perrin and O’Connor (JACS 2007) and later by Alabugin et al. (EJOC 2013). However, observed experimental results suggest that there was small but definite regioselectivity (~5–25%), the extent varying with the electronic nature of the substituents. Differential solvated halide ion concentrations around the vicinity of two radical centres arising due to surrounding surface electrostatic potential (computationally calculated) may be one of the possible factors for such selectivity in some of the examined p-benzynes. However, other complicated dynamical issues like the trajectory of the attacking nucleophile to the radical centre which can be influenced by electronic and/or steric perturbation of starting enediyne conformation cannot be ruled out. The overall yield of the anionic addition was in the range of 80–99%.