Anomeric effect solvent dependence

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). 

Several structural factors have been considered as possible causes of the anomeric effect. In localized valence bond terminology, it can be recognized that there will be a dipole-dipole repulsion between the polar bonds at the anomeric carbon in the equatorial conformation. This dipole-dipole interaction is reduced in the axial conformation, and this factor probably contributes to the solvent dependence of the anomeric effect. 

The decrease of the anomeric effect in polar solvents was also supported by quantum mechanics calculations.13 Nevertheless further studies on the anomeric effect demonstrated the limitations of the electrostatic model. In particular, Juaristi et al.14 demonstrated that, at low temperature, the dependence of conformational equilibria of 2-carbomethoxy-l,3-dithiane upon solvent shows an opposite trend to the stronger anomeric effect in less polar media observed at 25 °C (Table 4). 

Based simply on steric effects, this proportion appears somewhat low, whereas in view of the anomeric effect just described the proportion now seems rather high. Anomeric effects are observed to be solvent dependent, and hydroxy componnds experience considerable solvation with water throngh hydrogen bonding. This significantly increases the steric size of the substituent, and reinforces the steric effects. 

The exo anomeric effect was described as being more dependent on the solvent for a P-anomer than for an a-anomer [72]. A solvent which can donate hydrogen bonds to the ring oxygen like water will strengthen the exo anomeric effect. 

The strength of an electrostatic effect will depend on the dielectric constant of the medium, and results from a number of laboratories (summarised in Kirby, 1983, p. 9) indicate that the strength of the anomeric effect does indeed decrease in polar solvents. 

The so-called anomeric effect, ie. that polar substituents X attached to a carbon a to a heteroatom Y (Y = O, N) in a six-membered ring preferentially reside in the axial position, has been shown to be solvent-dependent [82, 83, 217, 282-286], In general, the position of an anomeric equilibrium shifts in favour of the equatorial anomer with increasing solvent polarity. The anomeric effect is thought to be the result of either molecular orbital interactions, which stabilize the axial conformer, or electrostatic interactions, which destabilize the equatorial conformer [82, 282],... 

The MO explanation for the anomeric effect considers the n-a overlap between the lone-pair of Y and the vacant a orbital of the C—X bond. This stabilizing interaction is more effective when X is axial and thus the axial conformer is favoured. The electrostatic explanation invokes the destabilizing interaction between the dipole moment of the C—X bond and the dipole moment resulting from the C—Y bond and the lone-pairs of Y. Such dipole/dipole interactions are minimized when X is axial and again the axial conformer is preferred in the gas phase or in nonpolar solvents. It is not so easy to distinguish between the relative importance of each interaction. However, the observation that the axial preference is diminished by increasing solvent polarity is best explained by the electrostatic interaction model [82, 282-284], The unfavourable electrostatic dipole/dipole repulsion in the equatorial anomer decreases with increasing solvent polarity, and hence the equilibrium shifts towards the equatorial conformer in polar solvents. This solvent-dependent anomeric effect has been particularly well studied with 4,6-dimethyl-2-methoxytetrahydropyran [283, 284] and 2-methoxy-1,3 -dimethylhexahydropyrimidine [282]. 

The anomeric effect is solvent and substituent dependent and decreases in the following order Cl > OAc > OMe > OH, as exemplified by the equilibrium concentrations of the a and (3 anomers of substituted D-glucose in various protic solvents at 25... 

When the substituent in 54 or 55 is axial, and also in the case of the a-anomer of a sugar, it is clear that the destabilizing C-O dipole effects, present when oxygen of OMe is equatorial, are minimized when this oxygen becomes axial. The absence of any significant dipolar repulsions in the latter case has been proposed as the cause of the anomeric effect (see Perrin et al.1). Though its cause is still uncertain the anomeric effect is well documented and it commonly has a magnitude of ca. 8-10 kJ mol, and is solvent dependent. 

The term A parameter is also used in the literature for the Gibbs energy —AGg. According to the definition in Eq. 7, the anomeric effect AG(AEl) depends on the A value of the substituent, and on the temperature and solvent used in measurement of equilibria in Eq. 7. This definition can be extended to multisubstituted pyran derivatives, and simple, additivity schemes of steric interactions of substituents are used for the estimation ofAG(AEl). 

Furthermore, a questionable approximation of the same entropy and volume of a and e isomers is usually assumed. Obviously, the energy of the anomeric effect, AE(AE2), depends on the quality of the method used for determination of AEpp. The extra function AE(AE2) may differ, depending on whether AG or AE° has to be matched. Furthermore, if Eq. 3 applies for an equilibrium in a solvent, the extra term AE(AE2) also includes a contribution of the solvent effect due to its neglect or an incomplete representation in energy AEpp. 

In summary, experimental data on the isomeric abundances at anomeric equilibrium reveal that the preference for the axial position depends on several, interconnected factors which were clarified in surveys on carbohydrate stereochemistry, and these provided a background for ensuing theoretical studies. The elucidation of this relationship in complex carbohydrates is greatly facilitated by measurements on the simple derivatives of oxane, and qualitative trends have already been established. Table II illustrates sever possibilities of the quantification of the energetic aspect of the anomeric effect. The procedure most frequently used, based on Eq. 7, suffers from the ambiguity of the A values for the oxane ring and by their presumed variation with solvent. 

Solvent Dependence of the Anomeric Effect, AG(AE,), Recaknlated from AE(AEjX of the Chlorine, FInorine, Methoxyl, and Hydroxyl Groups ... 

A reversed dependence of the axial preference on solvent polarity, which is sometimes regarded as a proof for the reverse anomeric effect, is discussed together with our results on phosphonio-l,3-dithianes in Section II.I. 

The presence of a reverse anomeric effect was suggested (29) for chlo-romethyl, CICH2—, and bromomethyl, BrCHj—, groups located at the anomeric carbon atom of a 1,3-dioxane ring. This claim was based on the observed reversed dependence of axial preference on solvent polarity, that is, more polar solvents increased the population of axial conformers. This observation is in line with the fact that a-glucopyranosylimidazoles in water (very polar solvent) do not change conformation on protonation (162). 

Xylose and arabinose must be analyzed more carefully. In principle, xylose should exist in the chair with all the substituents equatorial but there exist examples where the anomeric effect forces them all in axial positions. Arabinose should always be discussed in terms of chairs equilibrium and the first thorough examination of arabinose in saponins is due to Tori et al. (81). values range from 90.6 to 95.8 ppm, in esters Jh1-H2 froi 2.3 Hz to 5 Hz and Jch fro 165 to 177 Hz. Of course these values depend on temperature and solvent. 

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