Abstract
Determination of the absolute handedness, known as absolute configuration
(AC), of chiral molecules is an important step in any field related to chirality,
especially in the pharmaceutical industry. Vibrational optical activity (VOA) has
become a powerful tool for the determination of the AC of chiral molecules in the
solution state after nearly forty years of evolution. VOA offers a novel
alternative, or supplement, to X-ray crystallography, permitting AC determinations
on neat liquid, oil, and solution samples without the need to grow single crystals
of the pure chiral sample molecules as required for X-ray analysis. By comparing the
sign and intensity of the measured VOA spectrum with the corresponding ab initio
density functional theory (DFT) calculated VOA spectrum of a chosen configuration,
one can unambiguously assign the AC of a chiral molecule. Comparing measured VOA
spectra with calculated VOA spectra of all the conformers can also provide
solution-state conformational populations. VOA consists of infrared vibrational
circular dichroism (VCD) and vibrational Raman optical activity (ROA). Currently,
VCD is used routinely by researchers in a variety of backgrounds, including
molecular chirality, asymmetric synthesis, chiral catalysis, drug screening,
pharmacology, and natural products. Although the application of ROA in AC
determination lags behind that of VCD, with the recent implementation of ROA
subroutines in commercial quantum chemistry software, ROA will in the future
complement VCD for AC determination. In this review, the basic principles of the
application of VCD to the determination of absolute configuration in chiral
molecules are described. The steps required for VCD spectral measurement and
calculation are outlined, followed by brief descriptions of recently published
papers reporting the determination of AC in small organic, pharmaceutical, and
natural product molecules.
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