Determination of Absolute Configuration Using Density Functional Theory Calculations of Optical Rotation and Electronic Circular Dichroism:  Chiral Alkenes

Abstract

In principle, the absolute configuration (AC) of a chiral molecule can be deduced from its optical rotation (OR) and/or its electronic circular dichroism (ECD). In practice, this requires reliable methodologies for predicting OR and ECD. The recent application of ab initio time-dependent density functional theory (TDDFT) to the calculation of transparent spectral region OR and ECD has greatly enhanced the reliability with which these phenomena can be predicted. TDDFT calculations of OR and ECD are being increasingly utilized in determining ACs. Nevertheless, such calculations are not perfect, and as a result, ACs determined are not 100% reliable. In this paper, we examine the reliability of the TDDFT methods in the case of chiral alkenes. Sodium d line specific rotations, [alpha]D, are predicted for 26 conformationally rigid alkenes of known AC, ranging in size from 5 to 20 C atoms, and with [alpha]D values in the range of 0-500. The mean absolute deviation of predicted [alpha]D values from experimental values is 28.7. With one exception, beta-pinene, the signs of [alpha]D are correctly predicted. Errors in calculated [alpha]D values are approximately random. Our results define a "zone of indeterminacy" within which calculated [alpha]D values cannot be used to determine ACs with >95% confidence. TDDFT ECD spectra are predicted for eight of the alkenes and compared to experimental spectra. Agreement ranges from modestly good to poor, leading to the conclusion that TDDFT calculations of ECD spectra are not yet of sufficient accuracy to routinely provide highly reliable ACs. TDDFT OR calculations for two conformationally flexible alkenes, 3-tert-butylcyclohexene and trans-4-carene, are also reported. For the former, predicted rotations are incorrect in sign over the range 589-365 nm. It is possible that the AC of this molecule has been incorrectly assigned.

First-principles investigation of the vibrational properties of 3-tert-butylcyclohexene

“…Conformer A is energetically more stable than conformer B which is in agreement with the results of McCann and Stephens [6]. The energy difference is very similar in LDA and GGA: 4.88 mRy for LDA and 5.42 mRy for GGA.…”

“…The two conformers have an oppositely buckled cyclohexene ring, which is in accordance with theoretical reference data [6]. Furthermore, I have found the same relative instability of the two conformers as McCann and Stevens [6]. Concerning the vibrational density of states, I have been able to trace back the differences between LDA and GGA results to a difference in the bond-length obtained by the two approaches as well as to the difference in the description of the electronic contribution to the inter-atomic force constants.…”

“…The bond-lengths are in agreement with results for carbon compounds. The two conformers have an oppositely buckled cyclohexene ring, which is in accordance with theoretical reference data [6]. Furthermore, I have found the same relative instability of the two conformers as McCann and Stevens [6].…”

Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue

“…Molecules 2015, 20, page-page cannot reflect all of the actual molecular properties in the solvent [30]. Therefore, the above results need to be corroborated.…”

“…In spite of the agreement achieved between the computational and experimental ECD spectra, the ECD method is not 100% accurate because the calculated ECD spectra is only a simulation and cannot reflect all of the actual molecular properties in the solvent [30]. Therefore, the above results need to be corroborated.…”