Anomeric equilibria ring substituent effects

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],... 

If most of the ring substituents are removed from a sugar, a 2-X-sub-stituted tetrahydropyran remains and the enhanced population of the conformation in which X is axial is observed here also, and is shown for the case of 49 and 50. The anomeric effect is now expressed as a free-energy difference, which is derived from the equilibrium axiakequatori-al ratios of X in, for example, tetrahydropyrans (THPs) 49 and 50. Tetrahydropyrans are used in preference to cyclohexanes because the C-O bond (ca. 0.14 nm) in a THP is shorter than its C-C counterpart (0.154 nm) in a cyclohexane. 

Effects of Ring Substituents on the Anomeric Equilibrium of Aldopyranoses and Derivatives... 

It is not possible to tell by inspection whether the a- or P-pyranose form of a particular carbohydrate predominates at equilibrium. As just described, the P-pyranose form is the major species present in an aqueous solution of D-glucose, whereas the a-pyranose form predominates in a solution of D-mannose (Problem 25.8). The relative abundance of a- and p-pyranose forms in 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 in aqueous solution. The other factor, called the anomeric effect, involves an electronic interaction between the ring oxygen and the anomeric substituent and preferentially stabilizes the axial OH of the a-pyranose form. Because the two effects operate in different directions but are comparable in magnitude in aqueous solution, the a-pyranose form is more abundant for some carbohydrates and the P-pyranose form for others. 

The stereoselective formation of spiroketals 242 can be explained in terms of the thermodynamic stability of the three possible products. Oxonium cation 245, formed by the condensation of ortholactone 244b and allylsilyl ether 106a, is in equilibrium with the starting materials. Spiroketal 242 also equilibrates under the reaction conditions with the other anomers. The thermodynamically more stable product 242b, stabilized by a double anomeric effect, is obtained as the only product of the reaction (Scheme 13.89) as the substituents attempt to occupy equatorial positions in the newly generated tetrahydropyran ring. 

Until the present we have become accustomed to the idea that a bulky substituent imposes a six-membered ring conformation where this substituent is equatorial. The tendency is thus opposite in the a-position of an ether. This phenomenon can be observed on sugar derivatives with a halogen or, more generally, an oxygen atom at C-1. We will try to evaluate the anomeric effect starting from an equilibrium such as (2.5), relative, this time, to the most common pyranose. 

We saw in Chapter 2 that glucose can cyclize to form either the a ox hemiacetal. All of the substituents on the tetrahydropyran ring of glucose are equatorial except for the hemiacetal hydroxyl group, which may be either axial (for the a anomer) or equatorial (for the 6 anomer). If the conformational preferences of the tetrahydropyran ring are similar to those of cyclohexane, then an A value for OH of 0.87 in a protic solvent would predict that the axial anomer should comprise no more than 10% of the mixture. Experimentally, it has been determined that the a anomer is present to the extent of 34% of the equilibrium population of conformers. In the case of o-marmose, the a anomer (10) is the major isomer, and the )3 anomer (11) comprises only 32% of the equilibrium mixture. This preference for axial conformer in carbohydrates has been termed the anomeric effect. This term is also used for any system R-Y-C-X, where X is an electronegative atom and Y is an atom with at least one lone pair. 

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