Anomeric effect calculated

For solutions, the data for the various ring-forms of the axial 2-methoxyoxane given in Table XVII show that AG(EAEl) for the exo-anomeric effect is minimal in water, and higher in less-polar media. The results for the model of o ,a-trehalose, namely, the a, a) form of 2-(oxan-2-yloxy)oxane, indicate a different behavior.The magnitude of the exo-anomeric effect calculated for this compound is 15 kJ.moC, and is not sensitive to solva-... 

The anomeric effect is also present in acyclic systems and stabilizes conformations that allow antiperiplanar (ap) alignment of the C—X bond with a lone-pair orbital of the heteroatom. Anomeric effects are prominent in determining the conformation of acetals and a-alkoxyamines, as well as a-haloethers. MO calculations (4-3IG) have found 4kcal/mol as the difference between the two conformations shown below for methoxy-methyl chloride. ... 

Hall et al.1 s estimated the conformational equilibrium for the structural units in the polymer of 2 using the numerical parameters determined for carbohydrates16. For a frans-l,3-tetrahydropyranoside, conformer 8 is calculated to be more stable than 7 by 9.2 kJmol-1 and would therefore occur almost exclusively (ca. 98%) at equilibrium. For a m-1,3-tetrahydropyranoside unit, the anomeric effect favors con-former 9, but its severe syn-axial interaction between alkoxy and alkyl groups would highly favor 10 (ca. 99%). 

The decrease of the anomeric effect in polar solvents was also supported by quantum mechanics calculations.13 Nevertheless further studies on the anomeric effect demonstrated the limitations of the electrostatic model. In particular, Juaristi et al.14 demonstrated that, at low temperature, the dependence of conformational equilibria of 2-carbomethoxy-l,3-dithiane upon solvent shows an opposite trend to the stronger anomeric effect in less polar media observed at 25 °C (Table 4). 

In the case of 2-hydroxytetrahydropyran, the axial conformer 22 is calculated to be more stable than its equatorial conformer 23 in vacuum (Fig. 12). Solvent effects change the equilibrium constant and the equatorial form 23 is favored in aqueous solution, in agreement with data. The magnitude of the conformational endo-anomeric effect in 22 is estimated to 2.0 kcal/mol (gas phase stereoelectronic effects overwhelming the steric... 

Theoretical studies have been done in order to understand this behavior difference. Semiempirical calculations (AMI, MNDO) of formation energy (of the hemithio-ketal-hemiketal interconversion) have shown that hemithioketals are less stable than the corresponding hemiketal (from 10 to 15 kcal/mol). This difference can be due to steric factors, connected to the respective sizes of sulfur and oxygen. Stereoelectronic factors can also be evoked stabilization that is brought about by the anomeric effect is a priori more important for a gem-dihydroxylated compound than for the hemi-thioketal. Moreover, at the kinetic level, displacement of the water molecule of the inhibitor (under aqueous conditions, the inhibitor is hydrated) by the thiol of the enzyme is a slow and disfavored reaction. In contrast, the same reaction is favored with the hydroxyl of a serine. Experimentally, equilibrium occurs very slowly with the enzyme as well as with model molecules. ... 

Simple calculations (MM2 and HF/6-31G ), supported by a low-temperature NMR study, reveal that 2-NMc2-l,3-dioxane and the 5,5-dimethyl derivative exist exclusively in the conformation with the dimethylamino group in axial position <2001ARK(xii)58>, and DFT calculations at the B3LYP/6-31G(d,p) level of theory show that the anomeric effect of 2-Cl in 1,3-dioxane is of stereoelectronic origin while 2-F, 2-OMe, and 2-NH2 substituents on the same molecule are not <2000MI42>. 

The reaction field theory is used96 to simulate the effect of the water environment the results on how couplings are affected by this medium effect are compatible with the known inhibition of the anomeric effect due to solvent dielectric influence. In this way, it is calculated that in methanol and methylamine only one-bond and 2J(H,H) and 2J(N,H) couplings are affected by the water environment. Changes in such couplings are dominated by the FC term. 

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