Magnitude of anomeric effect

B. Classical Approach to Evaluation of Magnitude of Anomeric Effect... 

Early experimental studies have shown qualitatively how the anomeric and gauche effect control the conformational equilibria of pentofuranoses in nucleofs) tides. Chattopadhyaya et al. [8 0] made accurate estimates of the magnitude of stereoelectronic effects driving the two-state North South pseudorotational equilibrium in nucleos(t)ides (Fig. 6.1). 

The interplay between TS- and product-stabilizing effects is illustrated by the evolution of the anomeric effect along the reaction coordinate for the C-Cl bond ionization shown in Figure 10.4. Importantly, the magnitude of this effect increases as an axial C-X bond at the anomeric position starts to break and thus this effect has the necessary qualities to provide TS stabilization for bond breaking. 

It IS not possible to tell by inspection whether the a or p pyranose form of a par ticular carbohydrate predominates at equilibrium As just described the p pyranose form IS the major species present m an aqueous solution of d glucose whereas the a pyranose form predominates m a solution of d mannose (Problem 25 8) The relative abundance of a and p pyranose forms m solution depends on two factors The first is solvation of the anomeric hydroxyl group An equatorial OH is less crowded and better solvated by water than an axial one This effect stabilizes the p pyranose form m aqueous solution The other factor called the anomeric effect, involves an electronic interaction between the nng oxygen and the anomeric substituent and preferentially stabilizes the axial OH of the a pyranose form Because the two effects operate m different directions but are com parable m magnitude m aqueous solution the a pyranose form is more abundant for some carbohydrates and the p pyranose form for others... 

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). 

In the case of 2-hydroxytetrahydropyran, the axial conformer 22 is calculated to be more stable than its equatorial conformer 23 in vacuum (Fig. 12). Solvent effects change the equilibrium constant and the equatorial form 23 is favored in aqueous solution, in agreement with data. The magnitude of the conformational endo-anomeric effect in 22 is estimated to 2.0 kcal/mol (gas phase stereoelectronic effects overwhelming the steric... 

OH group in an axial alignment which, assuming that the anomeric effect in keto-hexoses is of the same magnitude as in aldoses (5), supplements the conformational impact of the equatorial 1-carbinol group.)... 

In an extensive, comparative study of a range of glycosyl halide derivatives in their thermodynamically more-stable forms, it was uniformly found that the conformation adopted in solution is the one having the halogen group axial, suggesting that the anomeric effect must be of considerable magnitude (29, 30). 

On the basis of the above results and discussion, the glycosides can now be considered. Efforts have been made previously to evaluate the magnitude of the anomeric effect by undertaking equilibration studies between equatorial and axial isomers at the anomeric center in carbohydrates (48), in monosubstituted 2-alkoxytetrahydropyrans (49, 50) and in more rigid systems (51). The anomeric effect has been evaluated to be of the order of 1.2 to 1.8 kcal/mol from these studies. In these evaluations, the conformation of the OR group in the axial and in the equatorial isomer was not considered the influence of the exo-anomeric effect was therefore neglected (3). Nevertheless, these studies demonstrated the importance of the anomeric effect. 

The magnitude of the anomeric effect depends on the substituent with the effect decreasing with increasing dielectric constant of the environment. 

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