Transition state of the base-promoted ring-opening of isoxazoles. Theoretical prediction of catalytic functionalities and design of haptens for antibody production

In previous research, Hilvert and co-workers developed an antibody which catalyzes the decomposition of a nitrobenzisoxazole with a rate > 10(8) times faster than the acetate-catalyzed reaction in water. Quantum mechanical calculations were carried out on a model system, the reaction of isoxazole with formate. The orientation of the carboxylate group has a significant effect on the rate, Complexation of the formate base by one water retards the reaction by approximately 5 kcal/mol; hence desolvation of the catalytic base could account for as much as four orders of magnitude in reaction rate. It was also determined that hydrogen-bonding to the forming oxide could potentially lead to greater rate acceleration. The gas phase activation barriers predict that water is the most effective general acid, lowering the activation energy by 9.5 kcal/mol. Methanol and formic acid are also effective, lowering the activation energy by 7.5 and 7.8 kcal/mol, respectively. Our calculations suggest that the combined effects of proper base orientation and acid catalysis could lead to an additional factor of 10(5)-10(6) increase in rate acceleration. Based on these results, various new haptens were proposed. Each was quantitatively assessed for similarity with the located transition states to predict their potential as successful haptens.