COMPUTER MODELING OF PHENYL ACETATE HYDROLYSIS IN WATER AND IN REACTION WITH BETA-CYCLODEXTRIN - MOLECULAR-ORBITAL CALCULATIONS WITH THE SEMIEMPIRICAL AM1 METHOD AND THE LANGEVIN DIPOLE SOLVENT MODEL

The Langevin dipole (LD) solvent model is used with the AM1 semiempiri cal quantum mechanical method to compare reaction pathways in the gas phase and in polar solution for phenyl acetate cleavage by hydroxide i on and by beta-cyclodextrin. The gas-phase results show that nucleophi lic substitution at the acyl carbon atom of phenyl acetate by the hydr oxide ion exhibits a downhill potential profile. The introduction of s olvent effects using the LD model results in correct reproduction of t he experimental values for the activation barrier and the heat of hydr olysis. The reaction of the alkoxide ion of cyclodextrin with bound ph enyl acetate in the gas phase is found to have a positive energy of ac tivation, which is further increased in the presence of polar solvent. The results show that acylation at the S'-hydroxyl of cyclodextrin is favored over the 2'-position by about 15 kcal/mol due to less structu ral reorganization of the macrocycle during hydrolysis at the S'-site. The results also show that attack at the 3'-hydroxyl lowers the activ ation energy barrier by about 10 kcal/mol compared to attack by hydrox ide ion in solution. The results are discussed in terms of the known p hysicochemical properties of cyclodextrins and their inclusion complex es.