Tetrahydropyranes, anomeric effect

H. Booth, K. A. Khedhair, and S. A. Readshaw, Experimental studies of the anomeric effect Part I. 2-substituted tetrahydropyrans, Tetrahedron, 43 (1987) 4699-4723. 

H. Booth, J. Mark Dixon, and R. Simon, Experimental studies of the anomeric effect. Part V. The influence of some solvents on die conformational equilibria in 2-methoxy- and 2-(2/,2,2 -trifluoroethoxy)-tetrahydropyran, Tetrahedron, 48 (1992) 6151-6160. 

U. Salzner and P.v.R. Schleyer, Ah initio examination of anomeric effects in tetrahydropyrans,... 

Anomeric effects are cumulative, and can cause a potentially flexible ring to adjust to a more rigid conformation in order to maximize the overlap of suitable lone pair and a orbitals. It has been particularly instructive in explaining anomalous preferences for substituent orientations in tetrahydropyrans and related compounds. In the case of 2-methoxytetrahydropyran, for example, the axial conformer is three times more populated than the equatorial form (Scheme 1.2). 

Recall that in the latter, certain types of substituents adjacent to oxygen in the ring actually prefer axial arrangements. This observation has been codified in what is commonly referred to as the anomeric effect and is responsible in part for the conformations of carbohydrates. Is it possible that conformational preferences seen in substituted tetrahydropyrans will carry over into preferences in transition-state geometries for Claisen rearrangements ... 

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). 

An anomeric effect is observed in 3,4-dihydro-2H- pyrans. For example, a 2-alkoxy group preferentially occupies an axial position (71DOKd96)367>. Indeed, a study of the NMR spectra of some 2-alkoxy-3,4-dihydro-2//-pyrans and their 4-methyl derivatives established that the anomeric effect was more important in the unsaturated heterocycles than in the corresponding tetrahydropyrans (72BSF1077). The axial preference of an alkoxy group is even more accentuated when the double bond is associated with a fused benzenoid ring, as in the 2-alkoxychromans. It is also of interest to note that the role of the polarity of the solvent on the conformational equilibrium is less important than for the saturated analogues. 

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. 

The SM2/AM1 model was used to examine anomeric and reverse anomeric effects and allowed to state that aqueous solvation tends to reduce anomeric stabilization [58]. Moreover, SM2/AM1 and SM3/PM3 models were accounted for in calculations of the aqueous solvation effects on the anomeric and conformational equilibria of D-glucopy-ranose. The solvation models put the relative ordering of the hydroxymethyl conformers in line with the experimentally determined ordering of populations. The calculations indicated that the anomeric equilibrium is controlled primarily by effects that the gauche/trans 0-C6-C5-0 hydroxymethyl conformational equilibrium is dominated by favorable solute-solvent hydrogen bonding interactions, and that the rotameric equilibria were controlled mainly by dielectric polarization of the solvent [59]. On the other hand, Monte Carlo results for the effects of solvation on the anomeric equilibrium for 2-methoxy-tetrahydropyran indicated that the AM1/SM2 method tends to underestimate the hydration effects for this compound [60]. 

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. 

In general, any tetrahydropyran bearing an electronegative substituent in the 2-position will prefer that substituent to be axial. This is is known as the anomeric effect. 

Anomeric effect - The stabilization ( x—>ocz ) of a ring conformation by interaction of a lone pair of electrons ( x)on a ring heteroatom with an antibonding c orbital (oCz ) of an adjacent electron-withdrawing substituent Z is known as the anomeric effect. This type of stabilization (i.e., o >°cz ) was first invoked to explain the preference for the axial orientation of electronegative substituents Z at the 2-position (anomeric position) of tetrahydropyrans. For examples see Sections 2.2.3.1, 2.2.4.3, and 2.4.4.4. 

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. 

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 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... 

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