Comparison of Experimental and Theoretical Structures of a Transition State Analogue Used for the Induction of Anti-Cocaine Catalytic Antibodies

Comparison of the crystal structure of a transition state analogue that was used to raise catalytic antibodies for the benzoyl ester hydrolysis of cocaine with structures calculated by ab initio, semiempirical, and solvation semiempirical methods reveals that modeling of solvation is crucial for replicating the crystal structure geometry. Both SM3 and SM2 calculations, starting from the crystal structure TSA I, converged on structures similar to the crystal structure. The 3-21G(*)/HF, 6-31G*/HF, PM3, and AM1 calculations converged on structures similar to each other, but these gas-phase structures were significantly extended relative to the condensed phase structures. Two transition states for the hydrolysis of the benzoyl ester of cocaine were located with the SM3 method. The gas phase calculations failed to locate reasonable transition state structures for this reaction. These results imply that accurate modeling of the potential energy surfaces for the hydrolysis of cocaine requires solvation methods.

Investigation of the Potential Energy Surface for the First Step in the Alkaline Hydrolysis of Methyl Acetate

The potential energy surface for the first step of the alkaline hydrolysis of methyl acetate was explored by a variety of methods. The conformational search routine within SPARTAN was used to determine the lowest energy am1 and pm3 structures for the anionic tetrahedral intermediate. Ab initio single point and geometry optimization calculations were performed to determine the lowest energy conformer, and the linear synchronous transition (lst) method was used to provide an initial structure for transition state optimization. Transition states were obtained at the am1, pm3, 3-21G, and 3-21 + G levels of theory. These transition states were compared with the anionic tetrahedral intermediates to examine the assumption that the intermediate is a good model for the transition state. In addition, the Cramer/Truhlar sm3 solvation model was used at the semiempirical level to compare gas phase and aqueous alkaline hydrolysis of methyl acetate.

A Computationally Efficient Procedure for Modeling the First Step in the Alkaline Hydrolysis of Esters

A computationally efficient procedure for modeling the alkaline hydrolysis of esters is proposed based on calculations performed on methyl acetate and methyl benzoate systems. Extensive geometry and energy comparisons were performed on the simple ester methyl acetate. The effectiveness of performing high level single point ab initio energy calculations on the geometries obtained from semiempirical and ab initio methods was determined. The AM1 and PM3 semiempirical methods are evaluated for their ability to model the transition states and intermediates for ester hydrolysis. The Cramer/Truhlar SM3 solvation method was used to determine activation energies. The most computationally efficient way to model the transition states of large esters is to use the PM3 method. The PM3 transition structure can then be used as a template for the design of haptens capable of inducing catalytic antibodies.