Nature of the Anomeric Effect

The electrostatic concept predicts the stability of conformers in qualitative agreement with experimental observation, but quantitative accord cannot 

Some insight into these interactions may be obtained from the distribution of oxygen lone-pair electrons calculated by the ab initio method with 

4-3IG basis for methanol, fluoromethanol, and methanediol. In methanol itself, the t-type lone-pair electrons are subjected to back-donation into antibonding-type orbitals of suitable symmetry on the methyl group. This leads to a decrease of the n-orbital population from the value of 2.00, appropriate to water, 1.97. A comparable electron displacement occurs in fluoromethanol when the C-F bond is in the nodal plane of the oxygen lone-pair orbital. If, however, the C-F bond and lone-pair orbital are in the same plane (in the og orientation), the back-donation lowers the population to 

and leads to additional stabilization. Similarly, the back-donation from the oxygen lone-pair orbital to the C-O antibonding orbital in the (sc, sc) conformation of methanediol is O.OS, which is significantly larger than the 

—Orientation of Two Non-equivalent Lone-pairs of the (rand it Type in the a and e Forms of 2-Substituted Oxane Derivatives. 

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The nature of the anomeric effect in the bicyclic /ra r-fused octahydro-l-methyl-l//-2,l-benzothiazine 2,2-dioxide 37 has been examined by single crystal X-ray structure analysis (Figure 5) <1998CJC164>. The crystal structure of 37 shows that the A -Me group assumes an axial position in the solid state. The authors suggest that this conformation is also the most stable in solution and propose that this hyperconjugation effect is >2.0 kcal mol . ... 

A number of fundamental studies of the nature of the anomeric effect have been undertaken, probed via kinetics and exo-/endo-regioselectivities. 

Mikolajczyk, M.. Graczyk, P. and Wieczorek, M.W., Conformational preference in L3-dithianes containing 2-phosphoryl. -(thiophosphoryl), and -(selenophosphoryl) groups. Chemical and crystallographic implications of the nature of the anomeric effect, J. Org. Chem., 59. 1672, 1994. 

There have also been a number of computational investigations into the nature of the anomeric effect. The axial-equatorial conformational equilibria for 2-fluoro and 2-chlorotetrahydropyran have been investigated with several MO calculations, including the MP2/6-31G level. The MP2/6-31G calculations give values of 3.47 and 2.84 kcal/mol, respectively, for the energy favoring the axial conformer. Solvent effects were also explored computationally and show the usual trend of reduced stability for the axial conformation as solvent polarity increases. Salzner and Schleyer applied... 

The nature of the anomeric effect operative in the S—C—P system will be considered taking into account (1) thermodynamic, (2) MM- and MO-based, (3) X-ray crystallographic, (4) spectroscopic, and (5) kinetic implications. It must be added that solvent studies were shown to be not useful to reveal... 

The complex nature of the anomeric effect has motivated researchers to propose alternative models to explain it. Thus, Doboszewski et al. justify the pseudoaxial conformational preference of purine and p5rrimidinic bases in analogs of nucleotides as the result of a combination of axial-stabilizing n —> (T c N interaction originated by the presence of a double bond in the tetrahydropyran ring, and steric repulsions present in the equatorial conformers (Scheme 21) (95JOC7909). 

The magnitude of the anomeric effect depends on the nature of the substituent and decreases with increasing dielectric constant of the medium. The effect of the substituent can be seen by comparing the related 2-chloro- and 2-methoxy-substituted tetrahydropy-rans in entries 2 apd 3. The 2-chloro compound exhibits a significantly greater preference for the axial orientation than the 2-methoxy compound. Entry 3 also provides data relative to the effect of solvent polarity it is observed that the equilibrium constant is larger in carbon tetrachloride (e = 2.2) than in acetonitrile (e = 37.5). 

An unambiguous success of the n-a overlap model of the anomeric effect is its ability to rationalise 35C1 nuclear quadrupole resonance frequencies in axial and equatorial glycopyranosyl chlorides (David, 1979). The axial chlorides invariably resonate at lower frequency, in accord with the more ionic nature of the C—Cl bond and hence the more spherically symmetrical distribution of electrons around the chlorine nucleus. 

Although the origin and nature of the anomeric and exo-anomeric effects appear well appreciated, the importance of these effects on conformational equilibria, especially with regard to the influence of the exo-anomeric effect on the conformational preferences about glycosidic linkages, is not well appreciated. This paper is concerned with experimental investigations which were designed to help clarify this situation. 

A significant contribution in this area was presented by Cuevas from his theoretical analysis of the anomeric effect in S—C—P units. Thus, using computational resources and 2-dimethylphosphinoyl-l,3-dithiane as a model system the author argues that the polar nature of the P—O bond... 

Thus, the magnitude of the anomeric effect determined in this way depends uptm other factors such as the nature and the configuration of substituent at the C2 carbon atom. In the case of p-o-mannopyranose, the C2-oxygen bond bisects the torsional angle between the Cl-Ol and the C1-05 bonds (Fig. 2.5), and this dipolar interaction seems to introduce an additional electronic destabilization which is evident fi-om the increased value of the anomeric effect (1.0 kcal/mol). This interaction was considered as a separate electronic interaction and was named by Reeves [19-21] A2 effect. It is now regarded as simpler to take as the base value for the anomeric effect the value of 0.85 kcal/mol, which is the value for the 2-deoxy-i> araWno-hexopyranose 14, and then when an electronegative substituent at the C2 carbon is axial, as in 13, to increase this value by 0.15 kcal/mol, and when the C2 substituent is equatorial to decrease it by 0.30 kcal/mol (Fig. 2.5). 

Abstract. The subject paper presented the first conformational analysis of the anomeric effect within the context of molecular orbital theory, discussed the utility of Fourier decomposition of a torsional coordinate as a method for analyzing disparate electronic influences on that coordinate, and helped settle debate on the nature of anomeric stabilization. 

Assessment of the anomeric effect natural orbital analysis... 

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