Ab Initio Study of the Bergman Reaction: The Autoaromatization of Hex-3-ene-1,5-diyne

Abstract

The Bergman reaction of the hex-3-ene-1,5-diyne molecule (enediyne) to form the singlet biradical p-benzyne structure under ring closure has been studied by ab initio methods. The complete active space (CAS) SCF method was used for geometry optimizations at five points along the reaction path of the Bergman reaction. Subsequent calculations using the multireference second-order perturbation theory based on a CASSCF reference (CASPT2) established the energetics along the reaction path, especially for the reactant, transition state, and product. The energetics were further corrected for zero point vibrational energy at the CASSCF level of theory. The study incorporated four different basis sets: a double-zeta plus polarization (DZP), a triple-zeta plus double polarization (TZ2P), and two different average atomic natural orbital (ANO) basis sets. The study predicts the energy barrier to ring closure to be 25.0 +/- 3.1 kcal/mol and the enthalpy of reaction to be 4.9 +/- 3.2 kcal/mol. The latter value deviates significantly from the value estimated on the basis of group additivity and the Born-Haber cycle. The enediyne moiety is the main functional group of a new class of anticancer agents. The activation of the Bergman reaction in these drugs has been argued to be due to a small structural change in the terminal-terminal carbon distance of about -0.5 Angstrom originating from an epoxide conversion in the rest of the drug. The present study indicates that such a structural change is not sufficient for the Bergman autoaromatization to proceed at an appreciable rate. A new reaction path involving no biradical formation, resulting in the same products, is suggested.