Ab Initio Molecular Orbital Calculation of Carbohydrate Model Compounds. 5. Anomeric, Exo-Anomeric, and Reverse Anomeric Effects in C-, N-, and S-Glycosyl Compounds Igor Tvaros ˇka* Institute of Chemistry, SloVak Academy of Sciences, SK-842 38 BratislaVa, SloVak Republic Jeremy P. Carver* Department of Molecular and Medical Genetics, Faculty of Medicine, UniVersity of Toronto, Toronto, Ontario M5S1A8, Canada ReceiVed: April 8, 1996 X An ab initio study of the conformational behavior of R- and -anomeric linkages in C-, N-, and S-glycosyl compounds has been carried out on axially and equatorially 2-substituted derivatives (2-ethyl, 2-methylamino, 2-thiomethyl, and 2-methylammonio) of tetrahydropyran as models. The geometry of the conformers about the anomeric C-X bond was determined by gradient optimization at the SCF level using the 6-31G* basis set. The potential of rotation has been calculated using the 6-31G* and 6-31+G* basis sets. Vibrational frequencies were calculated at the 6-31G* level and used to evaluate zero-point energies, thermal energies, and entropies for minima. Variations in calculated valence geometries for the compounds, display structural changes distinctive for the anomeric and exo-anomeric effects. Differences between bond lengths and bond angles for different conformers correlate with the importance of the lone pair delocalization interactions. The calculated conformational equilibria have been used to estimate the magnitudes of the anomeric, reverse anomeric, and exo-anomeric effects. It was found that the anomeric effect decreases in the following order: chlorine > methoxy ∼ fluorine > thiomethyl > methylamino > ethyl > methylammonio, with the methylamino, ethyl, and methylammonio groups exhibiting reverse anomeric effects. The sc preference of the methyl group over the ap orientation around the C1-C bond in 2-ethyltetrahydropyran is assumed to be entirely on basis of steric interactions. The exo-anomeric effect is expected to be present when the preference for the sc conformation is larger than that for the ethyl group. Thus, the exo-anomeric effect decreases in the order methoxy ∼ methylamino > thiomethyl. The methylammonio group does not show an exo-anomeric effect. Introduction The empirical observation of the preference for a polar exocyclic substituent to occupy the axial over the equatorial position at the anomeric carbon of a pyranose ring led to the introduction of the anomeric effect. 1,2 The terms exo-anomeric effect 3 and reverse anomeric effect 4 were later introduced for the orientational preference of the aglycon around the glycosidic C-O bond and for the enhanced trend of the quaternary nitrogen atom to adopt an equatorial position, respectively. First identified in carbohydrate chemistry, the anomeric effect is now recognized as being of a more general importance for all molecules having two (or more) heteroatoms linked to a tetrahedral center and was denoted as the generalized anomeric effect. 5 The generalized anomeric effect describes the prefer- ence for synclinal (sc, gauche) over antiperiplanar (ap, trans) conformations in a class of compounds containing the R-X- T-Y moiety, where X ) N, O, or S, Y ) Br, Cl, F, N, O, or S. Atoms R and T are of intermediate electronegativity, and T is usually C, P, Si, or S. The anomeric and related stereoelec- tronic effects have received very extensive experimental and theoretical examination 6-17 (and references therein). From these studies, it has become increasingly apparent that the anomeric effect is a complex phenomenon characterized, apart from the conformational preferences, by unique variations of valence geometry, reactivity, and other properties that have far-reaching consequences. However, in spite of clear progress in this area, our understanding of these effects still does not provide a totally integrated rationalization of this phenomenon. Recently we have undertaken an ab initio analysis of the stereoelectronic effects on the geometry and the conformational behavior of cyclic model compounds of carbohydrates. In the first papers of this series 18-20 we have investigated the fluorine, chlorine, and methoxy derivatives of tetrahydropyran. In this paper, as a continuation of this effort, we present the results of a conformational analysis of 2-substituted tetrahydropyrans (XTHP) in both the axial and equatorial forms, namely the 2-ethyltetrahydropyran (CTHP), the 2-methylaminotetrahydro- pyran (NTHP), the 2-methylammoniotetrahydropyranyl cation (NHTHP), and the 2-methylthiotetrahydropyran (STHP). These compounds have been chosen to model the linkages in C-, N-, and S-glycosyl compounds. For the 2-methylaminotetrahydro- pyran, the nitrogen atom is a chiral center. Therefore, two different configurations, S-(S-NTHP) and R-(R-NTHP), were assumed. Although the anomeric effect has been studied extensively by theoretical methods, 6-17 a study of the potential energy curves for internal rotation around the C-X bonds in these molecules, using ab initio methods with an extended basis set, has not been carried out. In this paper, we have performed such calculations to ascertain the energy differences between conformers and also the rotational barriers. The conformational properties of these molecules are of considerable interest since they span the whole * Corresponding authors. Present address: GlycoDesign Inc., 480 University Avenue, Suite 900, Toronto, Ontario, Canada, M5G 1V2. Fax: (416) 593-8988. X Abstract published in AdVance ACS Abstracts, June 15, 1996. 11305 J. Phys. Chem. 1996, 100, 11305-11313 S0022-3654(96)01042-8 CCC: $12.00 © 1996 American Chemical Society