Anomeric effect electrostatic effects

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. 

The mechanical, nonbonded, and electrostatic expressions described above are not sufficient to describe some structural and spectroscopic effects. Three specific structural and spectroscopic phenomena have been incorporated into MM3. They are the electronegativity, anomeric, and Bohlmann effects, which essentially can be traced to molecular orbital origins. These chemical effects are a part of the MM3 program.74,75... 

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 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). 

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... 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

Electrons, orbitals and epiphenomena 145 The electrostatic explanation of the anomeric effect successes and failures 146... 

The hypothesis gained considerable plausibility by appearing to be a simple extension of what was already accepted. Thus, an antiperiplanar lone pair of electrons can be considered to play essentially the same role as the pair of electrons in the breaking C—H bond in an E2 elimination, and the strong preference for anti-stereochemistry in such reactions had long been known. Moreover, the frontier-orbital explanation of the anomeric effect was receiving support at the expense of the antecedent electrostatic explanation, and the ALPH merely applied the same ideas to transition states. 

THE ELECTROSTATIC EXPLANATION OF THE ANOMERIC EFFECT SUCCESSES AND FAILURES... 

As originally put forward by Edward (1955), the electrostatic explanation of the anomeric effect envisaged repulsion between the negative end of the C(l)—X dipole of an electronegative substituent at C(l) of a pyranose ring... 

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 main factor leading to the recent unpopularity of the electrostatic explanation is the failure to account for perceived patterns of bond length changes, even though with more data now available, it is clear that these are not simple. A further weakness of the electrostatic explanation was highlighted by Romers et al. (1969) who showed there were quantitative discrepancies between experiment and the strength of the anomeric effect... 

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. 

Trioxolanes (molozonides) 232 are highly unstable species but because of their involvement in ozonolysis they have been the subject of many MO calculations. There is general agreement that the envelope conformation with 0(2) out of plane is the most stable. For the 4-halo derivatives 232 (R = F, Cl) the yy/z-conformation is calculated to be the most stable ( 2kcalmol-1) due to electrostatic repulsion and an anomeric effect <2002JPCA4745, CHEC-III(6.05.4.2)150>. 

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. 

Two effects whose relative importance is uncertain cause the anomeric effect. These are (1) an n->c effect (Scheme 6.2) and (2) electrostatic repulsion,... 

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