Does the “C₃ effect” offset the Δ2 effect, as regards the solution flexibility of aldoses?

Abstract

The solution flexibility of carbohydrates influences a variety of molecular recognition and regulatory processes. For aldoses and other monosaccharides, this flexibility is dictated by the orientations of the various hydroxyl (OH) groups present, which influences conformer and anomer ratios, interactions among these OH groups, and interactions between them and the surrounding solvent. Depending on the number and position of axial OH groups, a variety of structures can coexist in solutions at equilibrium. In 1950, as part of his pioneering studies on the shape of pyranoside rings, Reeves described the Δ2 effect, the greater destabilization of the pyranose ring conformation when the OH group on carbon 2 (C2 ) is in the axial position. It was later proposed by Angyal that the Δ2 effect could be cancelled by the presence of an axial OH on C3 , termed here the "C3 effect." Employing size-exclusion chromatography, an entropically-controlled separation technique, we have investigated whether or not the C3 and Δ2 effects indeed do compensate for one another with respect to their influence on the solution flexibility of select aldohexoses and aldopentoses. As will be seen, while qualitatively and semiquantitatively this mutual cancellation of effects does occur in aldohexoses, it does not appear to do so in aldopentoses. An explanation for the latter appears to lie in the variety of anomers and conformers present in equilibrium solutions of those aldopentoses studied and in the relative entropic contribution of individual conformers or anomers to the total solution flexibility.

Entropic-Based Separation of Diastereomers: Size-Exclusion Chromatography with Online Viscometry and Refractometry Detection for Analysis of Blends of Mannose and Galactose Methyl-α-pyranosides at “Ideal” Size-Exclusion Conditions

“…4 in [4] purportedly shows the baseline-level SEC separation of galactose and talose. However, the peak for talose is actually the peak for at least four major conformers in equilibrium with each other at the experimental conditions, because at 30 °C an aqueous solution of this monosaccharide is composed of 28.7% 4 C 1 β-pyranose conformer, 42.1% 4 C 1 α-pyranose, 17.9% 3 E α-furanose, and 11.1% 3 E β-furanose [6,18]. Likewise, hidden under the galactose peak in that same figure is an equilibrium solution composed of 64% 4 C 1 β-pyranose conformer, 30% 4 C 1 α-pyranose, 2.5% 3 E α-furanose, and 3.5% 3 E βfuranose [19].…”

“…In reality, of course, there will always be some enthalpic contributions to the separation. Consequently, we speak of "near-ideal" SEC separations, generally understanding these to be SEC separations in which K SEC shows little dependence on temperature, with changes in K SEC on the order of less than 10% as a result of a 10 °C or more change in temperature [3][4][5][6].…”

“…Because of the direct relationship between ΔS and the flexibility of analytes in solution, SEC provides a direct route for comparing to each other the flexibilities of monodisperse analytes, at identical solution conditions, when separation proceeds by an ideal, or near-ideal sizeexclusion mechanism. A principal application of SEC to the above effect, first introduced over a decade-and-a-half ago [1], has been to study how various parameters-such as anomeric configuration, glycosidic linkage, degree of polymerization, linearity versus cyclicity, and intramolecular hydrogen bonding-quantitatively affect the solution flexibility of mono-, di-, and oligosaccharides, both at aqueous, quasi-physiological conditions of temperature and pH and in select organic solvents [2][3][4][5][6][7][8].…”

“…Monosaccharide diastereomers can be viewed as providing one of the grand challenges in SEC separation, i.e., can SEC separate two analytes of the same molar mass, same chemical formula, and essentially the same structure save for the axial versus equatorial orientation of a single hydroxy group on the sugar ring, and can it do so with minimal enthalpic contribution to the separation? While separation of sugar diastereomers by SEC and other liquid chromatography techniques has been shown for various aldohexoses and aldopentoses in aqueous solution [4,6,17], mutarotation (i.e., interconversion between α and β anomeric forms) in aqueous solutions and, even, in many organic solvents, means that each peak in a chromatogram generally corresponds to a heterogeneity of conformers in tautomeric and anomeric equilibrium with each other at the given solvent and temperature conditions. For example, Fig.…”

“…Here, we examine the methyl glycosides of α-dgalactose and α-d-mannose, the structures of which are shown in Scheme 1. (The equilibrium composition of galactose in water is given above; for mannose, non-glycosylated 30 °C aqueous solutions are composed of 32.8% 4 C 1 β-pyranose, 66.2% 4 C 1 α-pyranose, and a < 1% combination of α-and β-furanose isomers [6,18].) As can be observed from Scheme 1, these two monosaccharides constitute a diastereomeric pair, the only difference between them being that in α-MeMan the axial hydroxy group is located on carbon 2 (C 2 ), whereas on α-MeGal the axial OH is located at C 4 .…”