Structural evidence of anomeric effects in the anesthetic isoflurane

Abstract

The conformational and structural properties of the inhalational anesthetic isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) have been probed in a supersonic jet expansion using Fourier-transform microwave (FT-MW) spectroscopy. Two conformers of the isolated molecule were identified from the rotational spectrum of the parent and several 37 Cl and 13 C isotopologues detected in natural abundance. The two most stable structures of isoflurane are characterized by an anti carbon skeleton (t(C 1 -C 2 -O-C 3 ) = 137.8(11)1 or 167.4(19)1), differing in the trans (AT) or gauche (AG) orientation of the difluoromethyl group. The conformational abundances in the jet were estimated from relative intensity measurements as (AT)/(AG) E 3 : 1. The structural preferences of the molecule have been rationalized with supporting ab initio calculations and natural-bond-orbital (NBO) analysis, which suggest that the molecule is stabilized by hyperconjugative effects. The NBO analysis of donor-acceptor (LP -s*) interactions showed that these stereoelectronic effects decrease from the AT to AG conformations, so the conformational preferences can be accounted for in terms of the generalized anomeric effect.

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

“…The results for the gas phase are in agreement with previous calculations [14] and microwave experiments [15], where five conformations were found, but only three could be experimentally detected, due to their lower energies. These correspond to conformers 1 , 2 and 3 of Table 1, the most stable ones in the gas phase and implicit solution.…”

“…It is worth mentioning that, according to our calculations, the solvent has a little effect on the conformer populations, such as in enflurane [16], suggesting that intramolecular interactions govern the conformational equilibrium in a biological-free environment. Indeed, Lesarri et al [15] pointed out that anomeric effects owing to donor–acceptor (LP → σ*) interactions are responsible for the conformational preference of isoflurane. Despite the contribution from specific hyperconjugative interactions representing the anomeric effects (mainly LP O → σ* CF , Table 2), our natural bond orbital (NBO) analysis indicates that the main conformers 1 and 2 are less favored by electronic delocalization than 3 , 4 and 5 .…”

Complete basis set, hybrid-DFT study and NBO interpretation of conformational analysis of 2-methoxytetrahydropyran and its thiopyran and selenopyran analogues in relation to the anomeric effect

“…Several explanations have been proposed for the validity of the AE [12][13][14][15][16][17][18][19][20][21][22]. The simplest justification is through the repulsive interaction between the ring dipole (generated by the LP of the endocyclic heteroatom) and the nearly parallel polar bonds in the equatorial conformation (see Scheme 1).…”

“…The stereoelectronic interactions are expected to play an important role in the conformational properties of heterocyclic compounds [10,11]. The most dominant conformation-controlling factor in carbohydrate compounds is known as the anomeric effect (AE) [12][13][14][15][16][17][18][19][20][21][22]. The AE describes the tendency of polar substituents to prefer the axial orientation in a six-membered saturated ring instead of the less hindered equatorial orientation that would be expected from steric considerations.…”

The origin of the anomeric effect: probing the impacts of stereoelectronic interactions

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] It should be noted that the anomeric effect is defined as the preference of an electronegative substituent to be axially rather than equatorially oriented in opposition to the steric effect which normally leads to a preference for the equatorial conformation. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] It should be noted that the anomeric effect is defined as the preference of an electronegative substituent to be axially rather than equatorially oriented in opposition to the steric effect which normally leads to a preference for the equatorial conformation.…”