Aspirin. An ab Initio Quantum-Mechanical Study of Conformational Preferences and of Neighboring Group Interactions

2001-01-12T00:00:00Z (GMT) by Rainer Glaser
The potential energy surface of acetylsalicylic acid, aspirin, has been explored at the RHF/6-31G* and B3LYP/6-31G* levels, and single-point calculations were performed at levels up to B3LYP/ 6-311G**//B3LYP/6-31G*. All conformational isomers have been located, the thermochemical functions have been computed, and relative energies and free enthalpies were determined. The conformational space of aspirin is spanned by three internal coordinates, and these are the carboxylic acid C−O conformation (<i>s</i>-<i>trans</i> preferred by about 7 kcal/mol), the C−COOH conformation (<i>Z</i> preferred unless there are H-bonding opportunities), and the ester C−O conformation (<i>s</i>-<i>trans</i> preferred by about 4 kcal/mol). There are nine aspirin isomers since one of the conformers realizes hydrogen-bonding structure isomerism as well. Neighboring group interactions are discussed with reference to the intrinsic properties of benzoic acid and phenyl acetate. The intrinsic conformational preference energies for benzoic acid and phenyl acetate are not additive. The acid <i>s</i>-<i>trans</i> preference energies differ by as much as 9 kcal/mol depending on the Ph−COOH and ester conformations. Similarly, the <i>E</i>-preference energies about the Ph−COOH bond vary by as much as 6 kcal/mol depending on the ester conformation. The structural discussion suggests an overall <i>ortho</i> repulsion between the functional groups in <i>all</i> aspirin isomers including the intramolecularly hydrogen-bonded isomers. The isodesmic reaction between the most stable conformers of benzoic acid and phenyl acetate to form aspirin and benzene is found to be endothermic by 2.7 kcal/mol and provides compelling evidence for and a quantitative measure of <i>ortho</i> repulsion. The <i>ortho</i> repulsion of 2.7 kcal/mol is a lower limit, and the <i>ortho</i> repulsion can increase to as much as 6 kcal/mol in some aspirin isomers.