Analysing Vibrational Circular Dichroism: Confidence Levels for Absolute Chirality Assignment
The application of chiroptical methods such as vibrational circular dichroism (VCD) spectroscopy is valuable in the assignment of absolute chirality. Assignment of chirality traditionally involves visual comparison of calculated and experimental spectra which can be subjective and time consuming. Experimental VCD spectra for 40 compounds were acquired on different VCD spectrometers over the course of this work. To these data were added several compounds from published literature for which VCD data was already available. By successive trials over a dataset containing 60 compounds and their VCD spectra, various automated methods for interpretation of VCD spectra are developed and investigated, with the aim of achieving a confidence level assignment algorithm for absolute chirality. The algorithm functions by comparing baseline-corrected VCD spectra of a compound with theoretically predicted spectra for each enantiomeric form. The prediction method for VCD spectra involves conformational searching at the molecular mechanics level to find stable conformational minima, followed by quantum calculations using density functional theory (DFT) to find the vibrational modes. DFT calculations are performed using the B3LYP and B3PW91 functionals, in conjunction with the 6-31G(d,p) and cc-pVTZ basis sets. Comparison between calculated and observed data is performed using a novel multiplicative percentage scoring method, scanning through a range of scale factors between 0.95 and 1.00. The degree of similarity is given a score ranging from -100% to +100%, with percentage values given such that uncertain cases need not be ignored or overconfidently assigned, but can be realistically evaluated according to existing spectral data. This analysis is optimised using a database of 30 pairs of small-molecule organic compounds, including many drug-like and drug precursor molecules. Through these and further computational methods we present a reliable and time-efficient method for determination of absolute chirality, with the aim of developing into a standardized procedure for small-molecule organic compounds.