Conformations, anomeric effect gauche

The conformational anomeric effects design the contrasteric effects observed in acetals which render the more sterically encumbered gauche/ gauche conformers more stable than their anti/gauche and anti/anti conformers. Such effects were first evidenced by Jungins in 1905 and rediscovered by Edward in 1955 and by Lemieux and Chiu in 1958. They observed the higher stability of alkyl a-D-glucopyranosides in comparison with their (3-anomers (Fig. 5).8... 

The preference for the gauche arrangement is an example of the anomeric effect. An oxygen lone pair is anti to fluorine in the stable conformation but not in the unstable conformation. 

Second-row heteroatoms are known to show a substantial anomeric effect. There appears to be evidence for a reverse anomeric effect in 2-aminotetrahydro-pyrans. ° It has been called into question whether a reverse anomeric effect exists at all. ° In 94, the lone-pair electrons assume an axial conformation and there is an anomeric effect. In 95, however, the lone-pair electron orbitals are oriented gauche to both the axial and equatorial oc-CH bond and there is no anomeric effect. ... 

Stereoelectronic factors are also important in the conformational dynamics of acyclic acetals [6] (Cosse-Barbi and Dubois, 1986). Here the usual preference for staggered conformations is supplemented by the anomeric effect (Kirby, 1983), which favours the gauche stereochemistry ( = 60°) about both central C-O bonds, mainly because this allows optimal n-rr overlap between an oxygen lone pair and the antibonding (cr ) orbital of the C-0 bond. Thus the pathway for conformational isomerization suggested by... 

The gauche effect — which has the same electronic origin as that of the anomeric effect—is able to stabilize a conformation that should, a priori, be disfavored by steric factors. Thus, the gauche effect prevents the trans antiperiplanar conformation of two electronegative substituents borne by two vicinal carbon atoms (Figure 3.2). ° ... 

Anet and Yavari (44) have studied chloromethyl methyl ether by low temperature proton nmr spectroscopy. Their results show that this compound exists in the gauche conformation 38 and they observed a barrier of 4.2 kcal/mol for the rotation of the O-CHjCl bond. This barrier is appreciably higher than that expected on the basis of steric repulsion alone. A rough estimate of the steric barrier is 2 kcal/mol, and they concluded that the anomeric effect increases the barrier to rotation of the O-CHgCl bond by approximately 2 kcal/mol. 

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. 

This last study is quite interesting because it permits an evaluation of the anomeric effect for the nitrogen atom. Conformer 91 with the axial N-methyl group should be less stable than conformer 92 by approximately 1.3 kcal/mol on the basis of steric effects (one gauche form of n-butane, =0.9 kcal/mol and one gauche form of CHj — N - CHj-0, =0.4 kcal/mol). The second anomeric effect caused by the equatorial orientation of the nitrogen electron pair in 91 must compensate for the steric effect. An approximate value of 1.3 kcal/mol must therefore be taken for that electronic effect, a value close to that estimated for the oxygen atom of the acetal function. 

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. 

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]. 

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