jo001241s_si_011.pdb (1.63 kB)
Aspirin. An ab Initio Quantum-Mechanical Study of Conformational Preferences and of Neighboring Group Interactions
dataset
posted on 2001-01-12, 00:00 authored by Rainer GlaserThe 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 (s-trans preferred by about 7 kcal/mol), the C−COOH conformation (Z
preferred unless there are H-bonding opportunities), and the ester C−O conformation (s-trans
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 s-trans preference
energies 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/mol
depending on the ester conformation. The structural discussion suggests an overall ortho repulsion
between the functional groups in all 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 ortho repulsion. The ortho repulsion of 2.7
kcal/mol is a lower limit, and the ortho repulsion can increase to as much as 6 kcal/mol in some
aspirin isomers.