Dipole moments, anomeric effects

The greater stability of the axial conformer of 2-alkoxytetrahydropyrans, ascribed to the anomeric effect, has been confirmed by a combined NMR and dipole moment investigation (69T3365). Additionally, out of the six conformers which in principle can arise from rotational isomerism about the exocyclic C—OR bond, two were shown to predominate in the equilibrium mixture. 

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]. 

Let us focus on molecules I4a and 14b (Scheme 8) in which an anomeric effect (in AG° or AH° terms) is possible in the vapor phase. Usually, the dipole moment of 14a is less than that of 14b (125-128). Since the more polar form is stabilized in solution (114, 128) [as a rule, with several exceptions (29, 129) vide infra] it may happen that the anomeric effect (i.e., increased preference for 14a) disappears in solution or may even change its sense (from AG g > 0 to AG g < 0). Such a possibility has been supported by quantum chemical calculations for dimethoxymethane (128). It was shown that, while in CCI4 solution dimethoxymethane (11) exists almost exclusively as the most stable sc, sc conformer, in aqueous solution almost exclusive occurrence of the ap, ap conformation may be expected. Hence, all considerations regarding the presence, magnitude, or origin of the anomeric effect must take... 

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. 

A second major rationalization of the anomeric effect is based on anticipated dipole-dipole repulsion between the two electronegative atoms (one part of the ring, the other exocyclic) and their associated lone electron pairs in the equatorial isomer, with the consequent preference for the axial conformation with the smallest dipole moment (Scheme 3) (55C1L1102, 93M14,95M15,95M17, 99M18). 

The initially proposed explanation for the anomeric effect as a simple dipole-dipole interaction [12] therefore accounts for only a part of the effect, but it does not represent the whole story. If one calculates the electrostatic interaction energy in frans-2,5-dichloro-l,4-dioxane (Fig. 2.9) (the molecular geometry is known from X-ray analysis) using the values of ji = 2.2 and 1.4 D for the dipole moments of C-Cl and C-0 bonds and e = 2.3 for the dielectric constant, one arrives at the energy difference of about 1 kcal/mol in favor of the diaxial form [36]. This difference is clearly too small to account for a strong preference for the diaxial conformation [37]. 

The axial conformation in MM4 is stabilized by the anomeric effect, which is represented largely by substantial (-1.85) and V2 (-1.30) torsion potentials (Fig. 7.1). The bond dipoles in the equatorial conformation add up to give a greater dipole moment, and a higher dipole-dipole repulsion energy than in the axial conformation. Thus, increasing the dielectric constant tends to stabilize the equatorial conformation more than it stabilizes the axial, as shown in Table 7.5. The anomeric effect in MM4 is the summation of the electronic delocalization effect included in the torsion potential, plus contributions from torsion-stretch and torsion-bend interactions, plus the electrostatic effect from the interaction of the bond dipoles. 

Detailed information about the anomeric effect has generally come from ab initio MO calculations. The principal rotamers of dimethoxymethane and their relative energies calculated at the HF/6-31G level are shown in Figure 2. The -l-sc,- -sc conformation is the global minimum, and it is interesting to note that it has the smallest dipole moment. The next to lowest energy conformer is +sc,trans, with a relative energy of 10.0 kJ mol" and a dipole moment of 2D. The -Hsc,- -sc conformer corresponds to axial 2-methoxytetra-hydropyran, and +sc,trans corresponds to the equatorial methoxy counterpart. 

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