New Spectrometer Sheds Light on Chemical Mystery

Susanna Contini Hennink

GLASGOW, UK -- Determining the absolute configuration of molecules is a prerequisite to developing new medicines. So-called chiral molecules are common and yet complex entities, existing in two forms that are mirror images of one another. Among the simplest of them is bromochlorofluoromethane (CHFClBr), which has hidden the relationship between its three-dimensional structure and the sign of its optical rotation -- until now.
A collaboration among scientists in France, Scotland and the US has established the absolute configuration of CHFClBr, thanks in part to a Raman optical activity spectrometer developed by a team of researchers led by Laurence Barron, a professor at the University of Glasgow.
The endeavor began with the identification of CHFClBr's enantiomer by studying the substrate molecule's capture by a larger receptor molecule, cryptophane. These experiments, performed in Andre Collet's laboratory at the Centre National de la Rechèrche Scientifique in Lyon, France, provided enough information about the spatial structure of each enantiomer to carry out a numeric simulation to reproduce the behavior of the model substrate-receptor system. The method of calculation used was developed and applied to the CHFClBr/cryptophane interaction by Andrew McCammon, a professor at the University of California at San Diego.
According to Barron, the Raman optical activity spectrometer measures a tiny difference (down to one part in 100,000) in the intensity of Raman scattering from chiral molecules in right and left circularly polarized incident laser light. This circular intensity difference is shown only by chiral molecules, and it is a measure of optical activity associated with molecular vibrational transitions rather than ultraviolet electronic transitions, as in conventional optical rotation and circular dichroism techniques. Conventional Raman spectrometers measure only Raman spectra in fixed linearly polarized incident light and so are blind to chirality.
"[Raman optical activity] gives much more detailed information about the three-dimensional structure" of a chiral molecule, Barron said.
For CHFClBr, the conventional method does not work, Barron said, because the molecule's first absorption band is too far into the ultraviolet to be accessible.
Thanks to back-thinned charge-coupled device cameras from Wright Instruments Ltd. of Enfield, Scotland, and holographic Raman notch filters from Kaiser Optical Systems Inc. of Ann Arbor, Mich., Barron and his colleagues have been able to measure Raman optical activity rapidly and routinely. Barron reported that the group has used the technique not only on small chiral molecules such as CHFClBr, but also on biomolecules such as peptides, proteins, carbohydrates and nucleic acids. This gives a new perspective on their 3-D solution structure and dynamics.
The work on CHFClBr/cryptophane interactions is a step toward what Collet describes as "the ultimate goal, which is clearly to describe and reproduce from basic physical principles and statistical thermodynamics the real behavior of a complex multimolecular system and its time dependence." The ability to predict the relative affinity of different substrates to a given bioreceptor will aid in the design of medicines.