How to promote sluggish electrocyclization of 1,3,5-hexatrienes by captodative substitution

Hexatriene electrocyclization, if not disfavored by its harsh reaction conditions, can be highly useful for the synthesis of complex organic molecules. Herein we developed a two-layer ONIOM method which could predict the activation free energy of hexatriene electrocyclization with an accuracy of about 1.0 kcal/mol. Using this carefully benchmarked method, we calculated the activation free energies for a variety of substituted hexatrienes. It was found that extraordinarily rapid electrocyclization could occur for certain patterns of captodative substituted hexatrienes, including 2-acceptor-3-donor hexatrienes, 2-acceptor-5-donor hexatrienes, and 3-acceptor-5-donor hexatrienes. The activation free energies for these systems could be up to 10 kcal/mol lower than that of the unsubstituted hexatriene, and therefore, their electrocyclization could proceed smoothly even at room temperature. The mechanism for the captodative effect on hexatriene electrocyclization could be understood by calculating the affinity between the donor and acceptor group in the reactant state and transition state of the reaction. If the affinity was stronger in the transition state, captodative substitution would produce an extra acceleration effect. It was shown that our theoretical results were in excellent agreement with the experimental data from the recent synthetic studies of hexatriene electrocyclizations. Thus, the theoretical tools developed in the present study could be used to predict not only how to accelerate the hexatriene electrocyclization via substituent manipulation but also under what conditions each particular electrocyclization could be accomplished in the real experiment.