On the origin of the regioselective hydrolysis of a naphthoquinone diacetate: A molecular orbital study

The regioselectivity found in the mild basic hydrolysis of the 2,5-dimethyl -1,4-naphthohydroquinone diacetate (Nunes, R. L.; Bieber, L. W.; Longo, R. L. J. Nat. Prod. 1999, 62, 1600) has been studied with ab initio and semiem pirical molecular orbital methods. In the gas phase (isolated systems), the se methods were not able to provide results that could explain the observed selectivity. However, when the solvent effects were included in the AM1 me thod using the discrete solvation model it was possible to establish that t his selectivity is due to the relative stability of the tetrahedral interme diates and their transitions states. The origin of this relative stability and thus of the observed selectivity is due to the repulsive interactions b etween the 2-methyl substituent in the naphthalene ring and the methyl grou p in the 4-acetate substituent, as well as their hindrance towards the hydr ation of the ionic group in the tetrahedral intermediates.