Conformational Spaces and Absolute Configurations of Chiral Fluorinated Inhalation Anaesthetics. A Theoretical Study

The results of an ab initio DFT study of the conformational spaces of the chiral fluorinated inhalation anaesthetics Isoflurane and Desflurane and their theoretical VCD spectra using the hybrid density functional B3LYP and 6-311++G** GIAO basis functions are reported. In each case six conformers were characterized by analytical frequencies. At room temperature conformers 1 and 2 of Isoflurane account for 71% and 27% of the population, respectively, and conformers 1 and 2 of Desflurane account for 82% and 16% of the population, respectively. Each of the six conformers of (R)-Isoflurane and (R)-Desflurane gives rise to a clearly distinct VCD spectrum with different vibrational frequencies and rotatory strengths. The less populated conformers 2 of (R)-Isoflurane and of (R)-Desflurane give rise to vibrational modes with much higher rotational strength than the corresponding conformers 1. In studies of conformational equilibria and absolute configurations based on VCD spectroscopy, Boltzmann weights rather than arbitrarily selected relative weights are recommended. In view of the ambiguities and shortcomings of the previous calculated and experimental VCD spectra of Isoflurane and Desflurane, the results of the present theoretical VCD study may serve together with future independent experimental VCD spectra as a basis for an unequivocal determination of the absolute configurations of Isoflurane and Desflurane.