Stereoelectronic Interactions and the One-Bond C-F Coupling Constant in Sevoflurane Matheus P. Freitas,* ,† Michael Bü hl, ‡ David O’Hagan, ‡ Rodrigo A. Cormanich, § and Cla ́ udio F. Tormena § † Department of Chemistry, Federal University of Lavras, P.O. Box 3037, 37200-000, Lavras, MG, Brazil ‡ EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, U.K. § Chemistry Institute, State University of Campinas, P.O. Box 6154, 13083-971, Campinas, SP, Brazil * S Supporting Information ABSTRACT: The conformational preference of the widely utilized anesthetic fluoromethyl-1,1,1,3,3,3-hexafluoro-2-propyl ether (sevoflurane) has been investigated computationally and by NMR spectroscopy. Three conformational minima were located at the B3LYP/aug-cc-pVDZ level, but one is significantly more stable (by ca. 4 kcal/mol) than the other two. This is the case both for gas phase calculations and for solution NMR data. Although the main conformer is stabilized by electron delocalization (n O → σ* C-F ), this type of hyperconjugation was not found to be the main driver for the conformer stabilization in the gas phase and, consequently, for the apparent anomeric effect in sevoflurane. Instead, more classical steric and electrostatic interactions appear to be responsible for the conformational energies. Also the 1 J CF coupling constants do not appear to be dominated by hyperconjugation; again, dipolar interactions are invoked instead. 1. INTRODUCTION The anomeric effect is a key concept in carbohydrate chemistry and the prototype for stereoelectronic control of molecular conformations. It can be defined as the preference of electronegative substituents (X) attached to the anomeric carbon (C-1) to occupy an axial orientation (α-anomer) instead of the less hindered equatorial orientation (β-anomer) that would be expected from steric considerations of a chair conformation. 1 The origin of this effect, which was observed for the first time by Edward in 1955, 2 has been attributed to antiperiplanar hyperconjugation (n O → σ* CX ), which can operate simultaneously in both exo- and endo-directions in cyclic sugars. 3-5 However, interpretations based on repulsive dipole-dipole interactions have also been used to explain the anomeric effect for both isolated molecules and ones in solu- tion (Figure 1), and a consensus on the relative contributions of these effects remains unresolved. 5-9 The anomeric concept has been extended to acyclic and other heterocyclic systems. Because fluorine is the most electronegative atom in organic chemistry with a low-lying σ* CX LUMO, a fluorine atom bonded to the anomeric carbon offers the best prospects of observing the (n O → σ* CX ) hyperconjugative interaction. The anomeric effect has been investigated in a variety of acyclic compounds such as pnictogens 10 and isoflurane. 11 In these cases, hyperconjugation has been invoked as contributing to the minimum energy conformers. Hyperconjugative interactions have been used to explain some NMR observations too; for example, in cyclohexane, the 1 J CH ax spin-spin coupling constant is generally smaller than the corresponding 1 J CH eq . The assumption is that axial C-H bonds are longer and therefore weaker than equatorial bonds as a result of σ CH → σ* CH hyperconjugative interactions from the more electron-rich antiperiplanar C-H bonds, relative to antiperiplanar C-C bonds. Thus, the Fermi contact (FC) term is reduced for axial C-H bonds and, therefore, the coupling decreases. 12 This phenomenon has been referred to as the “Perlin effect”, 13,14 and it has also been described in sugars. 12,15 However, recently in tetrahydropyran, the Perlin effect has been attributed to dipolar interactions between the axial C-H bond with both the oxygen lone pairs and the polar C-O bond, Received: December 12, 2011 Revised: January 10, 2012 Published: January 10, 2012 Figure 1. Possible explanations for the anomeric effect in substituted tetrahydropyrans: hyperconjugation (a) endo- and (b) exo-anomeric effect and (c) dipolar repulsion in the equatorial conformer. Article pubs.acs.org/JPCA © 2012 American Chemical Society 1677 dx.doi.org/10.1021/jp211949m | J. Phys. Chem. A 2012, 116, 1677-1682