Anomeric effect measures

Reduction of aldonolactones and their derivatives with isotopically modified reducing agents leads to sugars labeled at the anomeric center. Glycosides substituted with deuterium or labeled with tritium are widely employed for kinetic isotope-effect measurements, mechanistic studies, isotope-tracing experiments, and so on. 

Eliel et al. (82JA3635) examined the conformational equilibria of a number of disubstituted oxanes (Table III) by low-temperature C NMR spectroscopy (830MR94) and estimated the AG° values of 3-Me and 2-C=CH substituents (see Table I). The concentration of the axial 2-Me and 4-Me conformers, however, was so small and difficult to detect by NMR spectroscopy that they were forced to employ the use of counterpoised di-2-C=CH and ds-2-CH = CH2 groups to generate equilibria that were sufficiently balanced to measure accurately (AG° values in Table I). Eliel et al. (82JA3635) also discussed the conformational energies in terms of 1,3-diaxial interactions and the anomeric effect. 

J. M. Berry, L. D. Hall, D. G. Welder, and K. F. Wong, Proton spin lattice relaxation A new quantitative measure of aglycon sugar interactions, in W. A. Szarek and D. Horton, (Eds.), Anomeric Effect, Origin and Consequences, No. 87, American Chemical Society, Washington, DC, 1979, pp. 30-49, (Chapter 3). 

HCl in Et0H/H20 (1 1, reflux, 30 h). In agreement with X-ray and NOE measurements of (451) and consistent with the assumed operation of an exo anomeric effect, reactive diene conformations (Q) and (R) were proposed. It was therefore inferred that the major cycloaddition pathway involves attack of the dienophile (452) at the least-hindered top face of conformer (Q). 

Clearly though, even a purely qualitative evaluation of the geometric influences of the anomeric and exo-anomeric effects based on a new independent measurement tool, has some considerable relevance and further studies on this topic are being actively pursued at this time. And to leave the more sceptical readers of this article with some positive food-for-thought, we summarise below in Table V the interproton distances, determined (22.) by proton relaxation measurement, for an organic molecule, the bicycloheptene portion of XII which is, according to all presently available criteria, tumbling isotropically. 

Durette and Horton (18) have also measured conformational equilibria for a series of mixed acetylated and benzoylated pentopyranoses. Our calculations of the conformer distribution corresponds largely to their results. It is quite obvious that there is only a minor difference in the anomeric effect of an acetoxy and a benzoyloxy group. This problem cannot be discussed in detail in the present context. 

As just mentioned, a more significant value for the anomeric effect of a polar substituent could be calculated if the A value at position 2 of oxane were known. But this can be measured only for weakly polar substituents such as methyl, hydroxymethyl, vinyl, and ethynyl, which are supposed to exhibit no anomeric effect. For such substituents, the A value at position 2 of oxane correlates fairly well with the conformational free energy in cyclohexane. 

The theory also explains the increase in the effect of the order of chlorine, bromine, and iodine as well the atomic polarizabilities of halogens are as follows fluorine, 0.557 chlorine, 2.18 bromine, 3.05 iodine, 4.7. The anomeric effect of fluorine should be the weakest because of the compact nature of its orbitals. It has not been measured but it is unquestionable. It imposes 85% of the tetraaxial conformation on derivative 2.6 in solution. The comparison of the solid structures 2.5 and 2.27 is indicative. The length of the axial C-F bond is 1.386 A and that of the equatorial C-F bond, 1.367 A. The length of the C-1-0 bonds in derivatives 2.5 and 2.27 are 1.406 A and 1.339 A, respectively. A calculation (Tvarosvka 1989) leads to an anomeric effect of 1.85 kcal mol" , indeed lower than that of chlorine. 

Take note that this effect would stabilize the equatorial anomers, hence diminishes the anomeric effect of oxygenated substituents. However, there are other physical indications of the favoured delocalization of the cyclic oxygen towards the exocyclic oxygen as furnished by the direct coupling constant value Vch between the anomeric carbon and hydrogen. A comparison of the 7ch values, measured on about 20 anomeric pairs having various configurations and substitutions, shows that for each pair we observe... 

Unfortunately, Aj at position 2 of an oxane is not measurable for a substituent with an anomeric effect because steric repulsion cannot be separated experimentally from this effect. Let us look at the CFE in cyclohexane. The example of the methyl group, without the anomeric effect (see Section 2.5), leads us to suppose that the repulsion is greater at this position. We obtain values lower than they are in reality. There are other definitions, but none can escape criticism. 

The most frequently used measure of the anomeric effect is based on the comparison of the stabihty of 2-substituted oxane (tetrahydropyran THP) and cyclohexane. In general, conformational properties of the oxane ring are similar to those of cyclohexane, with dominance of a chair conformation. It is further presumed that steric interactions in oxane are the same as in cyclohexane, with preference for equatorial positions of bulky substituents. The Gibbs energy of the anomeric effect, AG(AEl), can be expressed as the... 

The term A parameter is also used in the literature for the Gibbs energy —AGg. According to the definition in Eq. 7, the anomeric effect AG(AEl) depends on the A value of the substituent, and on the temperature and solvent used in measurement of equilibria in Eq. 7. This definition can be extended to multisubstituted pyran derivatives, and simple, additivity schemes of steric interactions of substituents are used for the estimation ofAG(AEl). 

Examples of variation of the anomeric effect AG(AEl) with the substituents are shown in Tables II and III for oxane derivatives. The application of Eq. 1 to the results of the measurements of anomeric and conformational equilibria have established that the anomeric effect decreases in approximately the following order halogen > PhC02 > AcO > AcS > RO > RS > HO > NH2 > Me02C0 > imidazolium > pyridinium. 

The measures of the anomeric effect, based on Eqs. 7-i are of relative character, because they are expressed in reference to a standard compound or a computational method. Some absolute measure is needed for theoretical considerations, and it could be simply the positive difference of the energy of the a and e isomers or of the sc and ap conformation in model compounds. ... 

In summary, experimental data on the isomeric abundances at anomeric equilibrium reveal that the preference for the axial position depends on several, interconnected factors which were clarified in surveys on carbohydrate stereochemistry, and these provided a background for ensuing theoretical studies. The elucidation of this relationship in complex carbohydrates is greatly facilitated by measurements on the simple derivatives of oxane, and qualitative trends have already been established. Table II illustrates sever possibilities of the quantification of the energetic aspect of the anomeric effect. The procedure most frequently used, based on Eq. 7, suffers from the ambiguity of the A values for the oxane ring and by their presumed variation with solvent. 

Finally, a less conventional explanation of the origin of the anomeric effect may be mentioned. In a communication, " it was stated that, contrary to the results from measurements and theoretical calculations, the equilibrium coitstant for axial-equatorial equilibrium in... 

Glycosylamines (NH2 on Cl) are configurationally unstable, but it is possible to measure the of the mixture and the difference between a- and (3-anomers by the technique described by eqn (2.8). The marginally stronger basicity of equatorial glycosylamines is attributed to the more ready solvation of their conjugate acids, but the anomeric effect makes the difference smaller than in carbocyclic systems. 

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