Chirality is a chemical property that is very important to current pharmaceutical development processes. In the past, manufacturing processes for drugs ignored chirality, and whatever mixture of enantiomers was produced synthetically was used. However, the effects of the different enantiomers are often not equivalent. In some cases, they have very different physiological effects; sometimes, two enantiomers of the same compound can be used to treat separate medical conditions. Sometimes, the less active enantiomer is responsible for most of the side effects in the racemic drug version.

In some cases, where the beneficial medical effects come solely or primarily from one enantiomer, creating a single enantiomer version of the drug can provide effective treatment with fewer side effects. Thus the search for single enantiomer drugs is an important area of pharmaceutical research.

Chirality can be studied using the vibrational optical activity (VOA) of molecules. The IR form of VOA is known as vibrational circular dichroism (VCD), which has significant advantages over other methods for determining absolute configurations of molecules. For example, in contrast to other techniques, VCD requires no foreign additive to the sample, nor any physical separation of the enantiomers. It is also relatively insensitive to temperature and to density changes arising from long path lengths.

The use of such tools as the ChiralIR VCD spectrometer from BioTools to measure VCD spectra, and a workstation running Gaussian ® to generate electronic structure calculations, has made VCD generally available beyond the laboratory. The VCD spectrum of a chiral molecule is dependent on its three-dimensional structure; VCD results provided by electronic structure calculations can be used to identify the absolute configuration of a chiral molecule, by comparing calculated with experimental spectra. Currently, DFT calculations provide the best tradeoff between accuracy and computational cost.

VCD can not only determine the absolute configuration, but can also determine solution conformation. Sometimes, a VCD spectrum exhibits features from more than one conformation. Consider the following diagram, which displays the predicted VCD spectra for two conformations of the (+)-(R) enantiomer of 3-methylcyclohexanone. Comparing the calculated and experimental spectra indicates that the latter is dominated by the second conformation (the middle spectrum). However, some of its features are clearly attributable to the first conformation (upper spectrum), as indicated by the stars in the experimental spectrum.

The combination of IR and VCD measurement and theoretical calculation enables the determination of solution-state stereochemical structural information in chiral molecules that, in some cases, is unavailable from any other method. This information includes absolute configuration and solution-state conformation for single-conformer molecules or principal conformational populations for multiple-conformation molecules. The inclusion of additional solvent modeling options, such as the polarizable continuum model (PCM) and ONIOM in Gaussian 03 will make possible new, more detailed studies of the effects of solvent environments on the conformations of chiral molecules and biomolecules in solution through the calculation of their IR and VCD spectra.

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