Anomeric effect interactions

Figure 1.11 The anomeric effect interaction of the endocyclic oxygen electron lone pair with the nonbonding orbital in an axially substituted compound.

It is clear that a combination of a-a and n—a, i.e. the anomeric efFect interactions favor the aa conformation. 

It IS not possible to tell by inspection whether the a or p pyranose form of a par ticular carbohydrate predominates at equilibrium As just described the p pyranose form IS the major species present m an aqueous solution of d glucose whereas the a pyranose form predominates m a solution of d mannose (Problem 25 8) The relative abundance of a and p pyranose forms m solution depends on two factors The first is solvation of the anomeric hydroxyl group An equatorial OH is less crowded and better solvated by water than an axial one This effect stabilizes the p pyranose form m aqueous solution The other factor called the anomeric effect, involves an electronic interaction between the nng oxygen and the anomeric substituent and preferentially stabilizes the axial OH of the a pyranose form Because the two effects operate m different directions but are com parable m magnitude m aqueous solution the a pyranose form is more abundant for some carbohydrates and the p pyranose form for others... 

Several structural factors have been considered as possible causes of the anomeric effect. In localized valence bond terminology, it can be recognized that there will be a dipole-dipole repulsion between the polar bonds at the anomeric carbon in the equatorial conformation. This dipole-dipole interaction is reduced in the axial conformation, and this factor probably contributes to the solvent dependence of the anomeric effect. 

In cyclic systems such as 1, the dominant conformation is the one with the maximum anomeric effect. In the case of 1, only conformation lA provides the preferred antiperiplanar geometry for both oxygens. Antiperiplanar relationships are indicated by including lone pairs in the oxygen orbitals. Other effects, such as torsional strain and nonbonded repulsion, contribute to the conformational equilibrium, of course. Normally, a value of about 1.5 kcal/mol is assigned to the stabilization due to an optimum anomeric interaction in an acetal. 

For oxathiane 1, lone pair selectivity is controlled by steric interactions of the gem-dimethyl group and an anomeric effect, which renders the equatorial lone pair less nucleophilic than the axial lone pair. Of the resulting ylide conformations, 25a will be strongly preferred and will react on the more open Re face, since the Si face is blocked by the gem-dimethyl group (Scheme 1.9) [3, 15]. 

Hall et al.1 s estimated the conformational equilibrium for the structural units in the polymer of 2 using the numerical parameters determined for carbohydrates16. For a frans-l,3-tetrahydropyranoside, conformer 8 is calculated to be more stable than 7 by 9.2 kJmol-1 and would therefore occur almost exclusively (ca. 98%) at equilibrium. For a m-1,3-tetrahydropyranoside unit, the anomeric effect favors con-former 9, but its severe syn-axial interaction between alkoxy and alkyl groups would highly favor 10 (ca. 99%). 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

On account of the more favorable anomeric effect,12 as well as of the larger nonbonding interactions of vicinal, synclinal substituents in furanoses as compared to pyranoses, jS-D-glucofuranose,13 /3-D-glucofuranurono-6,3-lactone, and their derivatives are of higher thermodynamic stability than their respective a-D anomers. 

The role of steric effects is unclear but the anomeric effect could also contribute to an increase in electron density at nitrogen. X-ray data for the two TV-acyloxy-TV-alkoxyamides, a urea and a carbamate outlined above show clear evidence, both from bond lengths and conformations, of an anomeric interaction RO-N bonds are short when compared to alkoxyamines. This interaction is responsible for SN1, SN2, homolytic and rearrangement reactions of /V-acyloxy-TV-alkoxyamides (vide infra) and has also been supported computationally. Acyloxylation of the hydroxamic esters results in both pyramidalisation as well as anomeric donation from the... 

These results clearly indicate that barriers to all isomerisation processes are at least less than about 8kcalmol 1. In /V-benzyloxy-7V-chlorobenzamide 44 the amide isomerisation was not observable but the anomeric overlap resulted in diastereotopic benzylic hydrogens, which at coalescence afforded a barrier for rotation about the N-OBn bond of around 10.3 kcalmol-1.32 Like its /V-chloro analogue, the amide isomerisation barrier in 43 is too low to be observed by 3H NMR and even though there is definitive X-ray and theoretical evidence for anomeric effects in /V-acyloxy-/Y-alkoxyamidcs, the barrier to isomerisation about the N-OBn bond must be lower than 10.3 kcalmol-1. The n0-CN ci anomeric interaction in 44 is predicted to be stronger than the n0-CN OAc interaction in 43 on purturbation arguments.32... 

While the lone pair on the hydroxyl oxygen of hydroxamic acid 77 would be tightly bound resulting in a weak noH-cr N Qr interaction, the anion 78 would possess a high energy pair of electrons that would enhance the anomeric effect and drive the rearrangement. 

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). 

Fig. 8 Interpretation of the conformational endo-anomeric effect according to Edwards (hard/hard interactions).

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 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. 

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