We report a first-principles study on ethyl acetate neutral hydrolysis in which we focus on the activation energy variation resulting from the conformational effect in the transition state. We use the conformers of ethyl formate, ethyl acetate, ethyl fluoroacetate, and ethyl chloroacetate as the ester models and one water molecule with a one-step reaction mechanism. We also consider the long-range interaction and the surrounding water in the form of PCM. Our results show that the various conformers yield a significant range of activation energy. Moreover, the gauche conformer has lower activation energy than the trans conformer. The activation energy in its own right is lowered by the halogen atoms. Finally, we remark that the long-range correction and PCM stabilize the transition state geometry but raise the activation energy.

Acetylcholine, which is associated with Alzheimer’s disease, is widely known to have conformers. The preference of each conformer to undergo neutral hydrolysis is yet to be considered. In this study, we employed density-functional calculations to build the conformers and investigated their preference in one-step neutral hydrolysis. The results showed the preference in ten possible hydrolysis pathways involving seven acetylcholine conformers (reactant), four transition state structures, and two choline conformers (product). Three out of the seven acetylcholine conformers predicted from the results confirmed experimental findings on the conformers stability. We suggested that two out of ten possible pathways were observed in the experimental results based on agreement in reaction energy. Eventually, this study will emphasize the importance of considering acetylcholine conformers in its hydrolysis study.

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