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?

Abstract

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 +/-2sigma of the experimental [alpha]D for one, but not both, of the possible ACs. For the 65 molecules of this study +/-2sigma is 57.8. For conformationally flexible molecules, the error bar is +/- >57.8.

Bijvoet in Solution Reveals Unexpected Stereoselectivity in a Michael Addition

“…For molecules with greater than four rotatable bonds, the magnitude of the resulting conformational space is immense rendering the required calculations computationally infeasible. [7][8][9][10] In this contribution, a new fundamental methodology overcoming the flexibility issue to resolve the absolute configuration will be presented. Rather than sampling the entirety of the conformational space, ensembles of ten structures derived by NMR spectroscopy, which reproduce the experimental NMR spectroAbstract: The absolute configuration of small crystallizable molecules can be determined with anomalous X-ray diffraction as shown by Bijvoet in 1951. For the majority of compounds that can neither be crystallized nor easily be converted into crystallizable derivatives, stereocontrolled organic synthesis is still required to establish their absolute configuration.…”

Determination of absolute configuration of conformationally flexible cis‐dihydrodiol metabolites: Effect of diene substitution pattern on the circular dichroism spectra and optical rotations

“…In many cases, the accordance of experimental and theoretical data was found satisfactory. 14 The calculations of OR, as well as ECD, are very sensitive to inaccuracy in determining the equilibrium of participating conformers. Thus, carefully carried out conformational analysis of the molecule is the first and the most important step of the calculations.…”

Gas phase optical rotation calculated from coupled cluster theory with zero‐point vibrational corrections from density functional theory

“…[1][2][3][4][5][6][7][8][9][10] The conceptually simplest approach is to compare theoretically calculated and experimentally measured specific optical rotations to deduce the absolute stereochemistry. This procedure relies first and foremost on the accuracy of the theoretical model used to compute the optical rotation.…”

“…Stephens and coworkers 7,9,10,[12][13][14][15] have assessed the accuracy of the B3LYP exchange-correlation functional 16,17 in optical rotation calculations at the molecular equilibrium geometry. For a test set of 30 chiral molecules with absolute values of experimental sodium D-line specific optical rotations ranging from $10-12008 (dm g/cm 3 ) 21 a mean absolute deviation of 208 (dm g/cm 3 ) 21 was found.…”

“…13 For smallangle rotations [absolute value <1008 (dm g/cm 3 ) 21 ], the wrong sign was predicted for about 12% of 65 molecules at the sodium D-line. 10 Recently, Crawford and Stephens 15 compared B3LYP and coupled cluster singles and doubles (CCSD) 18 calculations of sodium D-line optical rotations to experimental results for 13 molecules and found that the accuracies of the two models are almost identical (excluding the problematic case of norbornenone) when comparing with liquid-phase experimental data. However, a number of other studies have demonstrated that, at shorter wavelengths than the sodium D-line (589.3 nm), B3LYP and CCSD often differ substantially due to the generally more accurate prediction of excitation energies and rotatory strengths by the latter.…”