| Abstract
| - 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 thermochemicalfunctions have been computed, and relative energies and free enthalpies were determined. Theconformational space of aspirin is spanned by three internal coordinates, and these are the carboxylicacid C−O conformation (s-trans preferred by about 7 kcal/mol), the C−COOH conformation (Zpreferred unless there are H-bonding opportunities), and the ester C−O conformation (s-transpreferred by about 4 kcal/mol). There are nine aspirin isomers since one of the conformers realizeshydrogen-bonding structure isomerism as well. Neighboring group interactions are discussed withreference to the intrinsic properties of benzoic acid and phenyl acetate. The intrinsic conformationalpreference energies for benzoic acid and phenyl acetate are not additive. The acid s-trans preferenceenergies differ by as much as 9 kcal/mol depending on the Ph−COOH and ester conformations.Similarly, the E-preference energies about the Ph−COOH bond vary by as much as 6 kcal/moldepending on the ester conformation. The structural discussion suggests an overall ortho repulsionbetween the functional groups in all aspirin isomers including the intramolecularly hydrogen-bonded isomers. The isodesmic reaction between the most stable conformers of benzoic acid andphenyl acetate to form aspirin and benzene is found to be endothermic by 2.7 kcal/mol and providescompelling evidence for and a quantitative measure of ortho repulsion. The ortho repulsion of 2.7kcal/mol is a lower limit, and the ortho repulsion can increase to as much as 6 kcal/mol in someaspirin isomers.
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