Equatorial conformer, destabilization

Figure 6.57 Electrostatic explanation for the axial preference of electronegative substituents in the anomeric effect. C-Y and C-X bond dipoles point to the same direction in the equatorial conformer, destabilizing the molecule.

For instance, in structure 12-e, the C-X and C-0 dipole moments are additive, leading to a destabilization of the molecule by increasing the energy. In structure 12-a, offset of the C-X and C-0 dipole moments minimizes electrostatic interactions, thus leading to a more stable conformation. This electrostatic model was supported by the observed increase of the percentage of the equatorial conformation of 2-methoxy tetrahydropyran (14) when moving from a non-polar to a polar solvent (Table 3).12 In this model, the polar groups are not polarizable and lead to dipole/dipole (hard/hard) interactions. 

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]. 

According to Stoddart (1), the unexpected preference for an electronegative substituent on C-l of a pyranoid ring to assume the axial orientation, first discussed by Edward (2) and later termed "the anomeric effect" by Lemieux (3), is now a generally recognized phenomenon in the conformational analysis of heterocyclic compounds. The preference for axial orientation is related to destabilization of the equatorial conformer in which a polar bond lies between two electron pairs on a vicinal oxygen atom. 

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. 

For methylene cyclohexanes and C-X o-acceptors (Figure 6.86), the dominant interaction pattern is reminiscent of the anomeric effect. Experimental NMR conformational measurements and detailed dissection of NBO interactions in these systems has been provided by Tormena and coworkers. The 1,3 allylic strain can serve as an additional destabilizing effect that disfavors equatorial conformers for substituted alkenes. 

When X is more electronegative than carbon, the equatorial form is destabilized by repulsive dipole-dipole interactions. In polar solvents, such interactions are alleviated and, except for the iodo-derivative, the equatorial conformer becomes predominant. 

A group larger than methyl would result in an even greater dominance of the equatorial conformation over the less stable axial conformation. The 1,3-diaxial bumpings responsible for the destabilizing gauche interactions will be magnified, and reflected in the equilibrium constant (Fig. 5.30 Table 5.3). 

Apparently, the torsional and steric effects resulting from equatorial isopropyl groups destabilize the all-equatorial conformation to a greater degree than axial isopropyl groups destabilize the all-axial conformation. The fully axial structure assigned on the basis of X-ray studies is also supported by calculations. 

Spherical polar coordinates are used for conformational representation of pyranose rings in the C-P system. Unlike the free pseudorotation of cyclopentane, the stable conformations of cyclohexane conformers are in deeper energy wells. Even simong the (less stable) equatorial (6 = 90 ) forms, pseudorotation is somewhat hindered. Substitutions of heteroatoms in the ring and additions of hydroxylic or other exocyclic substituents further stabilize or destabilize other conformers compared to cyclohexane. A conformational analysis of an iduronate ring has been reported based on variation of < ) and 0 (28), and a study of the glucopyranose ring... 

The conformational energies of monosubstituted oxanes studied to date are collected in Table I. In position 2, polar substituents (except NR2) prefer the axial position other substituents prefer the equatorial orientation, which is generally the case for groups in positions 3 and 4. Destabilizing 1,3-diaxial interactions cause the equatorial geometry to be usually favored in the 2-position, the anomeric effect stabilizes the axial conformation. A large purine moiety in position 2 of oxane, for example, prefers the equatorial position because the 1,3-diaxial interactions overcome the anomeric effect (75TL1553). 

Indolo or benzo fusion at the 5,6-position in perhydropyrido[l,2-c]pyrim-idine (335-340) (Fig. 13), as in 360 and 361 shifts the equilibrium in favor of the cis-fused conformer 364 and the axial JV-methyl trans-fused con-former 362, with 54% of the equatorial iV-methyl trans-fused conformer 363 present at room temperature (CDC13 solution).284 285 The shift in equilibrium (compare corresponding shift for 192-194 compared to quinolizidine 179-181, Section III,B,3) is presumably a result of a destabilization of 362 and 363 by the peri-type interaction involving the C-l-H and either the... 

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