Vibrational Optical Activity of Pharmaceuticals and Biomolecules

Abstract

Abstract This article describes recent progress in the field of vibrational optical activity (VOA) as a probe of the structural properties of pharmaceutical and biological molecules. A strong emphasis is placed on vibrational circular dichroism (VCD) owing to its more advanced state of development. Raman optical activity (ROA) is included in the first two sections for completeness; other reviews give additional information about ROA. 1–3,8 The article focuses on the practical aspects of VCD spectral measurement and interpretation. This is supplemented by examples that serve to illustrate the principal areas of VOA application. VCD is defined as the difference in the absorbance of the left circularly polarized (LCP) versus right circularly polarized (RCP) infrared (IR) radiation for a chiral molecule undergoing a vibrational transition. A pair of enantiomers will produce VCD spectra that are equal and opposite in sign and a racemic mixture will have a null VCD signal. VCD can be measured for all kinds of chiral molecules, irrespective of their size. In practice, measurements are often carried out in solution but, with the new advances in instrumentation, it is now possible to measure spectra of solids and mulls. Compared to other optical techniques such as electronic circular dichroism (CD) and IR absorption, VCD is unique because it combines the optical activity property of CD with the rich structural fingerprint region of IR. The discovery and first measurements of VCD occurred in the early 1970s. Although over a dozen practitioners have published close to a 1000 papers since then, it is only recently that VCD instrumentation has become available commercially for nonspecialists. Applications span a variety of fields from chemical and pharmaceutical to biological. The VCD technique can be used for the determination of absolute configuration of small chiral molecules or larger natural products. It can also be used to follow a chiral synthesis both for stereochemistry and for optical purity, and to study the secondary structure of large proteins and small peptides, and the conformation of nucleic acids and sugars. Some recent reports have also shown the unique sensitivity of ROA in the study of viruses and in protein‐folding experiments. VOA is now fulfilling its promise of becoming a technique that is broadly used for stereochemical and conformational studies of all varieties of chiral molecules, both natural and synthetic.