Structural evidence of anomeric effects in the anesthetic isoflurane

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 Cl-37 and C-13 isotopologues detected in natural abundance. The two most stable structures of isoflurane are characterized by an anti carbon skeleton (tau(C-1-C-2-O-C-3) = 137.8(11)degrees or 167.4(19)degrees), 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) approximate to 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 -> sigma*) 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.