• absolute configuration;
  • Density Functional Theory;
  • optical rotation


The absolute configuration (AC) of a chiral molecule can be determined via calculation of its specific rotation. Currently, the latter is most accurately carried out using the TDDFT/GIAO methodology. Here we examine the reliability of this methodology in determining ACs of molecules with small specific rotations. We report TDDFT/GIAO B3LYP/aug-cc-pVDZ//B3LYP/6-31G* calculations of the sodium D line specific rotations, [α]D, of 65 conformationally rigid chiral molecules whose experimental [α]D values are small (<100). The RMS deviations, σ, of calculated and experimental [α]D values is 28.9. The distribution of deviations is approximately Gaussian, i.e., random. For eight molecules, more than 10% of the set, the sign of the predicted [α]D is incorrect. In determining an AC of a rigid molecule from [α]D with 95% confidence, the calculated [α]D value must lie within ±2σ of the experimental [α]D for one, but not both, of the possible ACs. For the 65 molecules of this study ±2σ is 57.8. For conformationally flexible molecules, the error bar is ±>57.8. Chirality 17:S52–S64, 2005. © 2005 Wiley-Liss, Inc.