The sections in this article are Introduction Definitions of Vibrational Optical Activity Measurement and Calculation of Vibrational Optical Activity Determination of Absolute Configuration Real‐Time Monitoring of Reactions of Chiral Molecules Vibrational Optical Activity of Proteins and Protein Therapeutics Vibrational Circular Dichroism of Solids and Formulated Products Conclusions and Future Applications

A brief history of the development of the experimental and theoretical aspects of infrared and Raman vibrational optical activity (VOA) is provided as an introduction. The infrared form of VOA is known as vibrational circular dichroism (VCD) and the Raman form is known as vibrational Raman optical activity (ROA). VCD is defined as the difference in the absorbance of a chiral molecule for left versus right circularly polarized radiation during a vibrational transition. The principal areas of coverage of VCD include the theory of VCD and its relation to measured spectra, instrumentation used for the measurement of VCD including intensity standards and commercially available instruments, methods used for the ab initio calculation of VCD spectra, and advanced instrumental techniques. The principal applications of VCD include determination of absolute configuration, enantiomeric purity, and solution‐state conformational populations. A concluding section predicts substantial growth in the application of VCD as theoretical and instrumental methods improve in the future.

Formulas for the transition probabilities and hence the absolute intensities of molecular vibrational spectra are obtained from a unified quantum field treatment. The theory of infrared, Raman, and hyper-Raman spectroscopy of molecular vibrations is developed by assuming these processes occur as time-ordered steps involving the creation or destruction of one quantum of vibrational energy and changes in the occupation number of one, two, or three photons, respectively. The formulas obtained by this method for ir transitions become equivalent to the earlier treatment of Jones and Simpson if the energy difference of the ground and first excited electronic energy levels are very large relative to that of the vibrational quantum. The formulas obtained for Raman transitions are very similar to those obtained by the method originated by Albrecht and developed further by Savin; we get not only the original terms of Albrecht but also the trace terms obtained by Savin. Furthermore by using third-order time-dependent equations from the start we avoid many of the difficulties of the earlier treatments; our equations predict different conditions for the resonant Raman effect than do the earlier equations, and experiments are suggested for testing the new equations. The formula which we give for the absolute intensity of the hyper-Raman effect appears to be the first ever given.

. 69, 1619 (1991).Vibrational circular dichroism (VCD) spectra of an exceptionally simple chiral three-membered ring molecule, (S,S)-[2,3-'H2]oxirane, have been obtained for samples in the gas phase and in C2C14 and CS2 solution. The VCD band contours for the gas phase samples of this molecule with C2 symmetry follow those of the absorption spectra, with the modes of A symmetry species giving rise to bands with two sharp Q-branch maxima on either side of adistinct minimum, and the modes of B symmetry species giving rise to bands with a strong central Q-branch. The signs and relative intensities of the VCD bands can be understood in terms of chiral perturbation by the deuterium substitution of the vibrational modes of the parent oxirane molecule, which mixes modes of Al and A2 symmetry, and modes of BI and B2 symmetry, thus introducing angular charge oscillation about the direction of linear charge oscillation.Key words: vibrational circular dichroism, oxirane, chiral perturbation. IntroductionThe evaluation of theoretical formulations (1 -8) and calculational approaches (9-16) for determining vibrational circular dichroism (VCD) intensities (17-21) requires small rigid molecules for which testing of methodological variables is practical. Simple three-membered ring molecules that are chiral due to isotopic substitution are ideal for this purpose. Calculations on such species (9-15, 22) have outpaced the generation of experimental data (23-26) with which theoretical results can be compared and evaluated. In addition, these simple chiral molecules provide the opportunity to investigate mechanisms for generating VCD intensity that can be applied to the interpretation of VCD spectra of complex molecules, in order to obtain information on solution conformations when calculations are not practical or desirable.The smallest chiral molecule in this category, (S,S)-[2,3-2~2]-oxirane, 1, has been the focus of recent theoretical investi-

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.

We report the first vibrational circular dichroism (VCD) measurement of spatial heterogeneity in a sample using infrared (IR) microsampling. Vibrational circular dichroism spectra are typically measured using a standard IR cell with an IR beam diameter of 10 mm or greater making it impossible to investigate the spatial heterogeneity of a solid film sample. We have constructed a VCD sampling assembly with either 3 mm or 1 mm spatial resolution. An XY-translation stage was used to measure spectra at different spatial locations producing IR and VCD maps of the sample. In addition, a rotating sample stage was employed using a dual photoelastic modulator (PEM) setup to suppress artifacts due to linear birefringence in solid-phase or film samples. Infrared and VCD mapping of an insulin fibril film has been carried out at both 3 and 1 mm spatial resolution, and lysozyme films were mapped at 1 mm resolution. The IR spectra of different spots vary in intensity due primarily to sample thickness. The changes in the VCD intensity across the map largely correlate to corresponding changes in the IR map. Closer inspection of the insulin map revealed changes in the relative intensities of the VCD spectra not present in the parent IR spectra, which indicated differences in the degree of supramolecular chirality of the fibrils in the various spatial regions. For lysozyme films, in addition to different degrees of supramolecular chirality, reversal of the net fibril chirality was observed. The large signal-to-noise ratio observed at 1 mm resolution implies the feasibility of further increasing the spatial resolution by one or two orders of magnitude for protein fibril film samples.

In agreement with predictions from the stereochemical outcome of pyruvate hydrogenation with chiral 1-(9-phenanthryl)ethylamine (1), the (+) isomer (as measured in CHCl 3 ) was assigned the (R) configuration by use of the Zn−porphyrin host-guest CD exciton chirality method after derivatization with 4-[(Boc-amino)methyl]pyridine-2-carboxylic acid, and also directly on the amine by use of the VCD method. Attempts to use the bis(chromophoric) CD exciton

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