Vibrational CD, Theory and Application to Determination of Absolute Configuration

Abstract

The vibrational circular dichroism (VCD) spectra of the two enantiomers of a chiral molecule are of equal magnitude and opposite sign: i.e., mirror-image enantiomers give mirror-image VCD spectra. In principle, the absolute configuration (AC) of a chiral molecule can therefore be determined from its VCD spectrum. In practice, the determination of the AC of a chiral molecule from its experimental VCD spectrum requires a methodology that reliably predicts the VCD spectra of its enantiomers. The only reliable methodology developed to date uses the Stephens quantum-mechanical theory of the rotational strengths of fundamental transitions, developed in the early 1980s, implemented using ab initio density functional theory in the GAUSSIAN program in the mid-1990s. This methodology has by now been widely used in determining ACs from experimental VCD spectra. This article discusses the protocol for determining the ACs of chiral molecules with optimum reliability and its implementation for a variety of molecules, including the D3 symmetry perhydrotriphenylene; a thiazino-oxadiazolone recently shown to be a highly active calcium channel blocker; the alkaloid natural products schizozygine, isoschizogaline, and isoschizogamine; and the iridoid natural products plumericin, isoplumericin, and prismatomerin. The power of VCD spectroscopy in determining ACs, even for large organic molecules and for confomationally flexible organic molecules, is clearly documented.