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, [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.