2-Methoxytetrahydropyran anomeric effect

Anomeric effects are cumulative, and can cause a potentially flexible ring to adjust to a more rigid conformation in order to maximize the overlap of suitable lone pair and a orbitals. It has been particularly instructive in explaining anomalous preferences for substituent orientations in tetrahydropyrans and related compounds. In the case of 2-methoxytetrahydropyran, for example, the axial conformer is three times more populated than the equatorial form (Scheme 1.2). 

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 approach originated by Booth is becoming increasingly accepted (12,18,113). Booth et al. have recently presented an estimation of the enthalpic anomeric effect in 2-methoxytetrahydropyran (39) (p. 186), 2-(2, 2, 2 -trifluoro-ethoxy)tetrahydropyran (24) (112) (Table 3), and carbomethoxy (COOMe) and cyano (CN) derivatives of tetrahydropyran (30 and 33, respectively. Table 4) and piperidine (31 and 34, respectively) (42). Unfortunately Franck s suggestion (Section II.C) has been overlooked in this endeavor, and AH values have been evaluated (42, 50,71, 112) according to Eq. [17]. 

Rather than fit the torsional energy term for the anomeric effect to ah initio data, the approach used in MM2 and MM3 has been to reproduce the experimental conformational energies in molecules containing the C—O— C—O—C atomic sequence, such as 2-methoxytetrahydropyran.22.86 Based on a very limited data set, it appears that MM3 is slightly superior to MM2. 

The conformational equilibrium in 2-methoxytetrahydropyran has been studied experimentally, with ab initio calculations, and with MM2, MM3, and MM4. It is important to fit this equilibrium well with molecular mechanics, if one is to have a good foree field for carbohydrates. For a study of the anomeric effect what we really need is information regarding the axial/equatorial equilibrium. This is a little more complicated than it sounds because the methoxyl group can rotate to give three equatorial conformations and three axial conformations. Their relative MM4 energies are shown in Table 7.5. 

Computation of the conformational energies of 2-methoxytetrahydropyran, a model for the methyl aldopyranosides, gave results in agreement with experimental observations. A preference for the axial conformer was apparent, but the nature of the stabilizing factor (anomeric effect) was not resolved. Force-field calculations have been extended to include alcohols, ethers, simple acetals, and 2-methoxytetrahydropyran. 2 The preference of 2-methoxytetrahydropyran for the axial conformer was attributed to interaction of the axial lone-pair orbital on the ring-oxygen atom with the axial C—O bond of the methoxy-group, which can be represented by the resonance structure (501) (see also, Vol. 6, p. 163). 

The origin of the anomeric effect has been the subject of considerable controversy. Experimentally, it is known that the gas-phase eneigy difference for 2-methoxytetrahydropyran, 5.0 kJ mol , is reduced to 1.7 kJ mol in a polar aprotic solvent such as acetonitrile, and that the conformational preference is reversed in water. The experimental results have been reproduced by calculations that take the. solvent effect into account. " Similar observations have been made for related compounds. In the absence of the anomeric effect, it has been estimated that the equatorial conformer would be favored over axial by about 5 kJ mol. This strongly suggests that about half of the anomeric effect in this case is due to the unfavorable dipole-dipole interaction between the C-0 bonds in the equatorial methoxy isomer. There remains about 5 kJ mol to be accounted for in some other way. One hypothesis is that the axial methoxy isomer is stabilized by a... 

In another recent example, the effect of hydration on the anomeric equilibrium between axial and equatorial 2-methoxytetrahydropyran was computed. The sc, sc con-fontier for the axial form was converted to the t, —sc equatorial conformer by epimerization with MC-FEP calculations ... 

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