Heterocycles anomeric effects

In a previous section we have discussed the importance of n—a conjugative interactions in dictating the axial-equatorial preference of an electronegative substituent at C—1 of a pyranose ring, i. e. the anomeric effect . Here, we shall extend the discussion of n—a conjugative interactions to other saturated heterocyclic molecules. 

The anomeric effect is rather complex and will not be considered in any detail. It occurs when we have a heterocyclic ring (O, N, or S), with an electronegative substituent (halogen, OH, OR, OCOR, etc.) adjacent to the heteroatom, and favours the isomer in which the substituent is axial. Thus, with the first of the... 

Although the conformations of heterocycles are governed by the same principles that apply to carbocycles, where appropriate, additional factors, such as the anomeric effect, can have a significant influence upon the energies of the isomers in equilibrium. 

An anomeric effect is observed in 3,4-dihydro-2H- pyrans. For example, a 2-alkoxy group preferentially occupies an axial position (71DOKd96)367>. Indeed, a study of the NMR spectra of some 2-alkoxy-3,4-dihydro-2//-pyrans and their 4-methyl derivatives established that the anomeric effect was more important in the unsaturated heterocycles than in the corresponding tetrahydropyrans (72BSF1077). The axial preference of an alkoxy group is even more accentuated when the double bond is associated with a fused benzenoid ring, as in the 2-alkoxychromans. It is also of interest to note that the role of the polarity of the solvent on the conformational equilibrium is less important than for the saturated analogues. 

It was also observed that an electropositive group, particularly nitrogen-containing heterocycles, at the anomeric center tends to be oriented equatorially. This phenomenon is referred to as reverse anomeric effect. However, it is accepted that the reverse anomeric effect is not generalized [1,2]. 

Some substituents of saturated heterocycles prefer to be axial the anomeric effect... 

AHC(36)1] and also involve differences in nonbonded interactions and ring fusion strain. Thus, comparison of the equilibrium positions for indolizidine with that for 466 shows a relative stabilization of the 0-inside cis-conformer (469) (Scheme 5) of the 1,3-heterocycle. This stabilization is due to the favorable anomeric effect in 469 and the smaller oxygen/C-5... 

As you now know (p. 1134) aU esters and lartones prefer to be in the conformation shown for the first compound so that they can enjoy stabilization by the anomeric effect. The second ester would also prefer o be like this too (first diagram below) but in this conformation it cannot cyclize at all. Even in the less favourable conformation it uses for reaction, it prefers conjugate to dirert substitution as the latter would give a strained truns-cycloheptene. The first compound can enjoy both the anomeric effert and conjugate addition as a frans-alkene in a ten-membered ring is fine. It is better than fine in the heterocyclic product as the lactone also enjoys the anomeric effect... 

Hphe term anomeric effect was introduced by Lemieux in 1958 as a result of a detailed study of the anomerization of acetylated pento-and hexo-pyranoses. The effect is well known to carbohydrate chemists, and refers to the tendency of an electronegative substituent at C-l of a pyranoid ring to assume the axial rather than equatorial orientation, in contrast to predictions based solely on steric grounds. However, the phenomenon is not restricted to carbohydrate systems, but is displayed in many types of heterocyclic compounds. Thus, the investigation of the anomeric effect has been of considerable interest to a variety of chemists, namely, theoreticians, structural chemists, physical organic chemists, and synthetic chemists. Chemists from all of these areas participated in the Symposium on The Origin and Consequences of the Anomeric Effect. This symposium was the first symposium devoted exclusively to a discussion of the anomeric effect, and it provided a mechanism for interactions between the diverse types of chemists. The chapters in this volume are not merely the texts as presented at the symposium, but they also incorporate some new interpretations by the authors resulting from these interactions. 

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