Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy

University Of Virginia Main Campus, Charlottesville VA

Investigators

Abstract

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Brooks Pate and his research group at the University of Virginia are addressing challenges associated with the quantitative analysis of samples containing molecules not superimposable on their mirror image: i.e. "chiral" molecules, analogous to a person's right and left hand. The chemistry and interactions of chiral molecules - including many pharmaceuticals and most natural biomolecules - can depend sensitively on their chirality or "handedness." For example, the different chiral forms of a drug can have radically different efficacy and side reactions, despite their otherwise similar structure and properties. As a result, analysis of chirality is critically important, although it is generally a difficult, time-consuming, and often costly part of drug development and manufacture. The Pate group is pioneering new methods for rapid chiral analysis. The work exposes undergraduate and graduate students to state-of-the-art analysis methods. A specific focus of this work is to develop a chemical measurement technique that can perform quantitative analysis of the stereoisomers of a molecule with multiple chiral centers. The problem is challenging because it entails both diastereomers (isomers with distinct molecular geometries) and the non-superimposable mirror images of each diastereomer (enantiomers). Conventionally, different spectroscopic and/or chromatographic techniques are needed to perform both diastereomer and enantiomer analysis. The Pate group is developing a much simpler approach based on rotational spectroscopy using chiral tags - small molecules with chiral centers attached non-covalently to the target analyte(s). Accurate quantum chemistry calculations make it possible to determine the base enantiomer responsible for each spectrum recorded in the measurement. The ratio of enantiomers is determined by changes in spectral intensity observed when the measurement is performed using racemic and enantiopure samples of the chiral tag. In addition to proof-of-principle measurements to validate the concept, the team is exploring chemical ideas for designing chiral tag molecules that can improve analysis speed, reliability, and scope of application. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.