Determination of absolute configurations of chiral molecules using ab initio time-dependent density functional theory calculations of optical rotation: How reliable are absolute configurations obtained for molecules with small rotations?

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, [alpha](D), of 65 conformationally rigid chiral molecules whose experimental [alpha](D) values are small (< 100). The RMS deviations, sigma, of calculated and experimental [alpha](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 [alpha](D) is incorrect. In determining an AC of a rigid molecule from [alpha](D) with 95% confidence, the calculated [alpha](D) value must lie within +/- 2 sigma of the experimental [alpha](D) for one, but not both, of the possible ACs. For the 65 molecules of this study +/- 2 sigma is 57.8. For conformationally flexible molecules, the error bar is +/-> 57.8. Chirality 17:S52-S64, 2005. (c) 2005 Wiley-Liss, Inc.