Theoretical and Experimental Studies of Enflurane. Infrared Spectra in Solution, in Low-Temperature Argon Matrix and Blue Shifts Resulting from Dimerization

Abstract

Theoretical studies are performed on enflurane (CHFCl-CF 2 -O-CHF 2 ) to investigate the conformational properties and vibrational spectra. Calculations are carried out at the B3LYP/6-31G(d) level along with a natural bond orbital (NBO) analysis. Experimental infrared spectra are investigated in carbon tetrachloride solution at room temperature and in argon matrix at 12 K. In agreement with previously reported data (Pfeiffer, A.; Mack, H.-G.; Oberhammer, H. J. Am. Chem. Soc. 1998, 120, 6384), it is shown that the four most stable conformers possess a trans configuration of the C-C-O-C skeleton and a gauche orientation of the CHF 2 group (with respect to the central C-O bond). These conformations are favored by electrostatic interaction between the H atom of the CHF 2 group and the F atoms of the central CF 2 group. Hyperconjugation effects from the O lone pairs to the antibonding orbitals of the neighboring C-H and C-F bonds also contribute to the stability of the four conformers. The vibrational frequencies, infrared intensities, and potential energy distributions are calculated at the same level of theory for the most stable conformers. On the basis of the theoretical results, these conformers are identified in an argon matrix. The influence of the concentration on the ν(CH) vibrations suggests the formations of higher aggregates in solution. Theoretical calculations are carried out on the enflurane dimer. The results show that the dimer is formed between two enflurane conformers having the largest stability. The dimer has an asymmetric cyclic structure, the two enflurane molecules being held together by two nonequivalent C-H‚‚‚F hydrogen bonds, the C-H bond of the CHFCl group acting as a proton donor, and one of the F atoms of the CHF 2 groups acting as a proton acceptor. The theory predicts a contraction of 0.0014-0.0025 Å of the two CH bonds involved in the interaction along with a blue shift of 30-38 cm -1 of the corresponding ν(C-H) bands, in good agreement with the blue shifts of 35-39 cm -1 observed in an argon matrix.

Theoretical studies of the interaction between enflurane and water

“…Conformers I and II differ in energy by only 0.07 kcal mol −1 . It should be mentioned that the stability order of the conformers is slightly different from that obtained at the MP2/6–311G(2d) level in our earlier studies [9]. Conformers I and II of the present work correspond to the B and C conformers of ref [9].…”

“…It should be mentioned that the stability order of the conformers is slightly different from that obtained at the MP2/6–311G(2d) level in our earlier studies [9]. Conformers I and II of the present work correspond to the B and C conformers of ref [9]. Let us notice that in I, the two CH bonds are in a trans position, and in II, the two CH groups adopt the cis position.…”

“…It is worth mentioning that in the enflurane dimer, the O 3 atoms do not participate in the interaction. The two enflurane molecules having the trans conformation are held together by CH…F hydrogen bonds [9].

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“…Enflurane (CHClF-CF 2 -O-CHF 2 ), a volatile anaesthetic, is characterized by two CH bonds which can interact with neighboring molecules. The structures of the stable conformers of this molecule have been reported in earlier works [7–9]. The basicity of enflurane and its interaction with guest molecules have been investigated as well [10–13].…”

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

“…It has been proposed that intramolecular CH∙∙∙FC hydrogen bond drives the conformational preference of enflurane [18]. In order to check if such an interaction operates in isoflurane, QTAIM (Quantum Theory of Atoms in Molecules) calculations were performed for 1–5 .…”