26 chromatography • spectroscopy


VCD offers a novel route to absolute chirality determination


Hiroshi Izumi, Atsushi Ogata, Laurence A Nafie and Rina K Dukor look at determination of absolute configuration of chiral molecules by vibrational circular dichroism.


D


etermination of absolute configuration (AC) of chiral molecules is an important


Fig. 1. Comparison of the measured VCD (∆ε) and IR (ε) spectra of (+)-malathion (thin line) with the calculated spectra of Boltzmann-weighted sum of eight energetically preferred conformations for (R)-malathion (bold line).


step in any field related to chirality, but nowhere is it as critical as in the pharmaceutical industry. Te phenomenon of ‘chiral recognition’ – in which the enantiomers of a chiral drug may exhibit differences in biological activity or other processes such as distribution, uptake, and metabolism – makes it a necessity (or requirement) to know the AC not only of the final drug molecule but also of any intermediate in as early in the process of drug discovery and development as possible. Within the past decades, it has been conclusively demonstrated that vibrational circular dichroism (VCD) is a reliable method for AC determination1


and the technique


is now routinely used. VCD offers a novel alternative to X-ray


crystallography, permitting AC determinations on neat liquid, oil, and solution samples. VCD requires no derivatisation of the sample or growth of a pure single crystal. VCD is defined as the differential absorption of a chiral molecule for left circularly polarised infrared (IR) light versus the right during a vibrational transition. VCD combines the structural specificity of vibrational IR absorption spectroscopy with the stereochemical sensitivity of chiroptical spectroscopy such as CD2


. Te absolute


stereochemistry is established by comparing the solution -phase VCD spectrum to the results of an ab initio quantum chemistry calculation.


Te calculations are carried out in commercial packages such as Gaussian03/09 (Gaussian Inc, Wallingford, CT). Here we show an example of determination of AC for the (+)-malathion, a widely used pesticides for suppression of harmful insects such as mosquito3


.


VCD spectra are typically measured in the mid-IR region from 800 to 2000 cm-1


. In the example shown,


spectra were collected on the commercially available ChiralIR FT- VCD spectrometer. Te optimum sampling conditions achieve an average IR absorbance intensity of ~0.5 for the bands of interest; here the concentration used was 0.11 M


in CCl4, 0.72-mm-pathlength BaF2 cell. Collection times vary from four to five hours at 4 cm-1


resolution.


Spectra presented were measured for four hours at a resolution of 4 cm-1 and are solvent subtracted. Calculations were carried out with Gaussian03 at the DFT level (B3LYP functional/6-31G(d) basis set). Te theoretical absorbance and VCD spectra were simulated with Lorentzian band shapes and 6 cm-1 full width at half-height.


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Fig. 1 shows a comparison between spectra of Boltzmann– population weighted composite of the calculated spectra of eight lowest-energy conformers for the (R)- configuration and the observed spectra of (+)-malathion3


(+)-malathion has a flexible liquid-state conformation at room temperature3


.


Te absolute configuration and solution conformation of (+)-malathion were determined by using VCD spectroscopy and a fragment-conformational search3


.


As a result of the close agreement between calculated and measured VCD spectra, the absolute configuration is unambiguously determined to be (R)-(+)-malathion. Te availability of VCD commercial instruments and computational technology has opened the door for the routine use of VCD in studies of many stereochemical problems.


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Hiroshi Izuεmi, Atsushi Ogata are with AIST, Tsukuba, Japan. Laurence A Nafie is affiliated with Syracuse University, NY, USA.Rina K Dukor is with BioTools Inc, Jupiter, FL , USA. www.btools.com


References: 1


.


T B Freedman, X Cao, R K Dukor, and L A Nafie,


Chirality 15, 743-758 (2003). 2


R K Dukor and L A Nafie,


“Vibrational Optical Activity of Pharmaceuticals and Biomolecules” in Encyclopedia of Analytical Chemistry, R A Meyers, Ed, 662-676 (John Wiley & Sons: Hoboken,


NJ, 2000). 3


H. Izumi, A. Ogata, L. A. Nafie and R. K. Dukor, Chrality 21, S172-S180 (2009).


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