Cyclohexanes anomeric effect

NMR has been used to show that the anomeric effect operates in 2-bromo- and 2-chloro-tetrahydropyrans, which exist predominantly with the halogen atom axial (66JOC544), whilst the equatorial preference of a 4-halogen atom is less pronounced than in cyclohexane and decreases with decreasing electronegativity (78SA(A)297). 

Quantitatively, the anomeric effect is defined as the difference in conformational free energy for the process shown in Scheme 28 and the corresponding process in cyclohexane. Conformational energies for a range of substituents are available (82JA3635). 

Also, the steric interactions might be greater (30) in a substituted tetra-hydropyran ring than those of a simple cyclohexane system. For those reasons, the value of 1.4 kcal/mol for an anomeric effect must be considered only as a reasonable minimum value. 

The first precise evaluation of the anomeric effect was realized by Descotes and co-workers in 1968 (22). These authors have studied the acid catalyzed isomerization of the cis and trans bicyclic acetals 6 and 6 and found that, at equilibrium, the mixture contains 57% ci s and 43% trans at 80°C. The cis isomer is therefore more stable than the trans by 0.17 kcal/mol. The cis isomer 5 has one (stabilizing) anomeric effect whereas the trans isomer 6 has none. Steric interactions in cis acetal 5 were estimated tobel.65 kcal/mol (one gauche form of ri-butane, 0.85 kcal/mol and an OR group axial to cyclohexane, 0.8 kcal/mol). By subtracting an entropy factor (0.42 kcal/ mol at 80°C) caused by the fact that the cis acetal S exists as a mixture of two conformations (cis decalin system), they arrived at a value of 1.4 kcal/mol for the anomeric effect. 

Recently, Crabb, Turner, and Newton (68) have observed that perhydropyrido-[1.3]oxazine exists as a =9 1 mixture of the trans and the cis forms 97 and 98. The cis form 98 has two anomeric effects (-2.8 kcal/mol), two gauche forms of butane (1.8 kcal/mol) and one gauche form of -propyl ether (0.4 kcal/mol) whereas the trans form 97 has only one anomeric effect (-1.4 kcal/ mol). On that basis, the trans form 97 should be more stable than the cis form 98 by about 0.8 kcal/mol, in agreement with the experimental result. Katritzky and co-workers (69) have also shown that 1-oxa-3,5-diaza and 1,3-dioxa-5-aza cyclohexane derivatives exist respectively in the conformations 99 and 100. With an alkyl group in the axial orientation, both conformations gain two anomeric effects. 

Substituents in cyclohexanes prefer an equatorial orientation. Nonetheless, an electronegative substituent X situated a to the oxygen in a tetrahydropyran will prefer an axial position. This is the anomeric effect. 

The equilibrium constants derived from the 31P NMR spectra at temperatures below coalescence show that there is a considerable predominance of the axial conformer of 2-diphenylphosphinoyltetrahydrothiopyran (Table 26) which contrasts with the equatorial preference in the corresponding cyclohexane derivative. This result indicates a strong anomeric effect, estimated at 2.40 kcal mol-1. The corresponding data for the anancomeric cis and trans 4-/-butyl derivative at chemical equilibration are presented in Table 26. The large difference in AG° at 173 and 323 K is compatible with a significant entropy effect, calculated AS° = +4.8 0.7 cal K.mol-1, with... 

The conformational analysis of monosaccharides, disaccharides, and ohgosaccharides is reviewed. Conformational terms are introduced through examination of the conformations of cyclohexane and cyclopentane then applied to the pyranose, furanose, and septanose rings. Concepts such as the anomeric effect are discussed. Topics of current interest, such as hydroxymethyl group and hydroxyl group rotation and disaccharide conformations are summarized. Physical methods for studying conformation are outlined. 

Solvents which are poor donors are commonly used in glycoside synthesis, for instance dichlorometh-ane, cyclohexane or petroleum ether. These solvents favor SN2-type reactions. Solvents which are better donors, for instance ethers (diethyl ether, THF, etc.), acetonitrile, pyridine, nitromethane etc., each result in a typical change in the reaction course due to their different participation in the stabilization of the reaction intermediates. With ethers, acetonitrile and pyridine participation leads to onium-type intermediates (Scheme 5 8 and 9), which eventually provide, via fast equilibration, mainly the -anomer (8), due to their higher thermodynamic stability, based on the inverse anomeric effect .Thus a-product formation is often favored in these solvents (see Section 1.2.3.2.5). Solvents with even higher dielectric constants commonly result in lower diastereocontrol in glycoside synthesis. 

As one of a number of such examples, the a-form of d-glucose (36%) is more abundant with respect to the fi-form (64%) than expectations based on substituents in cyclohexane would indicate. This unexpected abundance of the a-form is known as the anomeric effect,... 

The anomeric effect is quoted as a free energy difference between axial and equatorial forms in tetrahydropyrans fTHPs) with account taken of the greater steric preference of a substituent to be equatorial in a THP with respect to a cyclohexane. 

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. 

In some sugars, e.g. D-glucose, and 2-alkoxytetrahydropyrans, the axial form is populated to a greater extent than the axial population of the corresponding cyclohexane would suggest. This is known as the anomeric effect and two possible contributory factors were discussed. 

A. J. Weldon, T. L. Vickrey, and G. S. Tschumper, Intrinsic conformational preferences of substituted cyclohexanes and tetrahydropyrans evaluated at the CCSD(T) complete basis set limit Implications for the anomeric effect, J. Phys. Chem. A, 109 (2005) 11073—11079. 

The coplanar effect did not create as much excitement with the theoreticians as did the anomeric effect and its cause is not known with certainty. The simplest explanation is that the 1,3-diaxial interaction of a methyl group at position 2 of the oxane with the C-H bond at position 6 is increased because these two substituents are closer than if they were separated by -CH2- instead of -O-. The calculation for the crystalline a-o-glucopyranose, with carbon-oxygen bonds of 1.439 and 1.427 A making an angle of 113.7° between them, gives 2.400 A for the C-l-C-5 distance, whereas the corresponding value for cyclohexane is at least equal to 2.5 A. It is a well-known fact that steric strain increases rapidly as the intemuclear distance decreases. 

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 relationship, A(oxane) = 1.53 A(cyclohexane) + 0.02, should also be valid for polar substituents if it expresses only an effect of bulkiness, due to the greater steric constraints at position 2 of oxane. It may be used to calculate their correct A value at this position and therefore derive a more significant value for the anomeric effect. Thus the minimum value of (9-methyl is recalculated as 2.1 kcal mol, a figure 60% higher than that in Table 2.3 (Franck 1983). 

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... 

Fig. 5.—The Standard Equilibrium in (a) Substituted Oxanes and (b) Substituted Cyclohexanes Used in the Definition of the Anomeric Effect by Eq. I.

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