Electrostatic interactions, anomeric effect

The first interpretation of the conformational anomeric effect, given by Edward,2 invoked more favorable electrostatic interactions in the axial anomers than in the equatorial anomers of carbohydrates (Fig. 8). 

The rationalization of the conformational anomeric effect solely based on electrostatic interactions fails to account for these solvent effects. Another interpretation based on bond polarizability in 1,1-dialkoxyalkyl systems calls electronic transfer from a non bonding electron pair of one oxygen atom to the empty cr c 0 orbital from the other alkoxy substituent (Fig. 10).16... 

Product or reactant stabilizing factors that have been studied thus far include resonance/charge delocalization, solvation, hyperconjugation, intramolecular hydrogen bonding, aromaticity, inductive, jr-donor, polarizability, steric, anomeric, and electrostatic effects, as well as ring strain and soft-soft interactions. Product or reactant destabilization factors are mainly represented by anti-aromaticity, steric effects in some types of reactions, and, occasionally, electrostatic effects. What makes the PNS particularly useful is that it is completely general, mathematically provable,4 and knows no exception. 

FIGURE 1.10 The anomeric effect, (a) The n-o interaction stabilizes the a anomer. (b) The P anomer experiences unfavorable dipole-dipole interaction that is reduced in the a anomer. (c) Greater electrostatic repulsion between the lone-pair electrons of the endocyclic oxygen and the electronegative anomeric substituent in the (1 anomer. 

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]. 

Quantum-mechanical discussions of the ngauche effect and the "anomeric and exo-anomeric effect have been published ( 10-13 ) which provide a more complete description of these electronic interactions, and the electrostatic repulsions between the vicinal lone-pair electrons. 

The balance of electrostatic and delocalization interactions in an isolated molecule may be perturbed by the influence of the solvent. In calculations based on Eq. 7, the analysis of solvation-energy terms suggested that the electrostatic contribution stabilizing the ap orientation of the acetal s ment is the conformationally dominant term. For example, in 2-methoxyoxane, the difference in energy of the (ap, ap) and (ap, sc) conformers in water, compared to that in the isolated molecule, caused by solute-solvent electrostatic interactions alone, amounts to 4 kJ.mor. Accordingly, the inter-and intra-molecular, electrostatic interactions operate in reverse directions in acetals. Whereas the intramolecular, electrostatic interactions are responsible, together with delocalization interactions, for the aiq)earance of the anomeric, reverse anomeric, and exo-anomeric effects, the solute-solvent electrostatic interactions lessen their im nitude, and may even cancel them. Of course, the solvent may also influence the electron distribution and energy of MO s in a molecule. In this way, the orbital interactions of lone-pairs and delocalization contributions to the anomeric effect may be scaled by the solvent, but this mechanism of the environmental effect is, in most cases, of only minor importance. 

The key piece of evidence for the rationalisation of the anomeric effect in terms of classical electrostatic dipole interactions has been the apparent existence of a reverse anomeric effect. Reversal of the sense of the dipole of the C-X bond, so that X now carries a net positive rather than negative charge, should, on the electrostatic picture, result in X having a more than ordinary tendency to be equatorial. The effect was first observed in glycosyl pyridinium salts and, in what at first sight seemed to be an elegant experiment, the steric demand of the bulky pyridinium salt was apparently eliminated as the source of the effect by the observation that tri-O-acetyl-ot-D-xylopyranosylimidazole changed from 65% to > 95% equatorial on addition of excess acid. Protonation of imidazole will have only a minor effect on its steric requirements, since protonation takes place at a remote site . ... 

It is widely observed that preferred conformations of glycosides with equatorial glycosidic C-O bonds have values of (pn in the general range 45-25° ((p=-15 to -95°) and those of axial glycosides around -30° (cp = 90°). The electronic or electrostatic interactions that determine these preferences are the same as those governing the anomeric effect and were termed the exo-anomeric effect by Lemieux and co-workers.Whereas the no-bond resonance explanation for... 

As with equatorial pyranosides, the (pu x 180° rotamer is disfavoured by ordinary steric interactions, as the group R is right under the a face of the pyranose ring. As with equatorial pyranosides also, the electrostatic explanation of the anomeric effect indicates the same two rotamers are favoured as the non-bond resonance explanation in the rotamer with (pnx - 60°, in the Newman projection the resultant of the R Ol and Cl Ol dipoles is aligned exactly with the C1 05 dipole. 

In general, electrostatic interactions alone do not seem to be sufficient to account for the magnitude of the anomeric effect and do not directly explain the bond length changes that are observed. These factors led to the proposal that the anomeric effect is, at least in part, due to a a hyperconjugation effects. From the molecular orbital viewpoint, the anomeric effect is expressed as resulting from an interaction... 

Electrostatic interactions with the oxygen lone-pair electrons are not, exclusively, the sole cause of the anomeric effect. Increasing the positive charge on C5 by substitution with electronegative groups increases the strength of the dipole and hence the anomeric effect (Fig. 3) [18]. 

The reverse anomeric effect was initially explained on the basis of electrostatic interactions by Lemieux (27). The enhanced equatorial preference... 

The main advantage of this rationalization relates to solvent effects. In polar media electrostatic interactions are reduced, and hence destabilization of the equatorial conformer (in Figure 13a) or stabilization of the axial one (in Figure 13b) is attenuated. The same conclusion may be drawn if the polarity (representd by dipole moments) of the two conformers is scrutinized (cf. Section II.G). Such solvent trends have generally been assumed to be indicative of the electrostatic etiology of the anomeric effect. 

The electrostatic interpretation of the anomeric effect has generally been regarded as incomplete because it does not lead to quantitative agreement with experiment (188) and does not account for the observed geometries. In particular, dipole-dipole repulsive interactions have been criticized from the theoretical point of view on the basis of ab initio (189) and semiempirical EHMO and CNDO/2 calculations (190) and recently (191) based on the decreased barrier to ring inversion in 2,2-dimethoxyoxane (98, see Section... 

The anomeric effect seems to be not solely due to the interplay of simple van der Waals repulsions and electrostatic interactions. Therefore, molecular mechanics (MM) force field calculations are not expected to reproduce it unless the effect is deliberately included. Hence it has long been recognized that considerable difficulties may appear in proper description of a molecule by the MM method when two heteroatoms are geminally bonded (48, 205, 206). 

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