The Anomeric Effects

FIGURE 13. The geometry of 9-methylamino-lf/-phenalen-l-one (l,4-dioxan-2-yl hydroperoxide) solvate (29) in the solid state °  

The second largest number of hydrogen bonds in crystal structures of alkyl hydroperoxides refers to interactions of the type OO—H OR R, where R is an alkyl group and R denotes H, alkyl or R O. The OO OR R distances vary between 2.67-2.91 A and the associated O—H O angles range from 152 to 177°. In some compounds, formation of intramolecular hydrogen bonds of the type OO—H 0=X would in principle have been feasible. The number of examples documented in the literature so far is clearly in favor of the intermolecular type of H bonding. 

TABLE 7. Parameters associated with hydrogen bonds of the type 0 0 —H A in the solid state 

FIGURE 14. Intramolecular hydrogen bonds the carbonyl, sulfoxide and phosphine oxide group as acceptor for the hydroperoxide proton  

A rare example of H-bond formation between the OOH proton and the proximal O atom of a hydroperoxide group as acceptor is observed in 5,6,7,8-tetrahydro-6-hydroxy-8-hydroperoxy-2,2,6,8-tetramethyl-7-methylenechroman-5-one (25) (PI, O O = 2.96 A, O H = 2.12 A, O H—O = 160°) . This mode of binding is reminiscent of the self-aggregation of cumene hydroperoxide molecules in the liquid phase . The distal O atom of the OOH group is the accepting unit in the crystal structure of 3,4-dihydro-3-trifluoroethoxy-4-(tert-butyl)-2(l//)-benzopyranyl hydroperoxide (31) (P2i/a, O O = 2.76 A, O H = 2.13 A, O H—O = 152°) . In a similar way hydrogen bonds between the OOH functionality and an endoperoxide O atom have been observed, such as in the crystal structure of the antunalaria active compound 4-methoxy-4-methyl-2,3-dioxabicyclo[3.3.1]nonyl hydroperoxide (P2i /c, O O = 2.86 A, O H = 2.02 A, O H-O = 176°, Table 6, entry 39) . 

In general, the stability of a particular conformer can be explained solely by steric factors, and a basic rule for the conformational analysis of 

The tendency of an electronegative substituent to adopt an axial orientation was first described by Edward26 and named by Lemieux and Chii27 the anomeric effect . This orientational effect is observed in many other types of compounds that have the general feature of two heteroatoms linked to a tetrahedral centre i.e. C—X—C—Y, in which X = N, O, S, and Y = Br, Cl, F, N, O or S, and is termed the generalised anomeric effect.28,29 

Solvent Dielectric constant (s) Percentage axially substituted conformer 

The conformational effects arising from the endoanomeric effect are for furanoses much less profound and as a result relatively little research has been performed in this area. The puckering of the furanose ring of an a and a P anomer usually adjusts the anomeric substituent in a quasi-axial orientation and hence both anomers experience a similar stereoelectronic effect. On the other hand, the conformational preference of the exocyclic C—O bond is controlled by the exoanomeric effect in the usual way. 

In solution, the a and p forms of D-glucose have a characteristic optical rotation that changes with time until a constant value is reached. This change in optical rotation is called mutarotation and is indicative of an anomeric equilibration occurring in solution. 

The anomeric effect is simply negative hyperconjugation under another name. It is best known as the effect that stabilises the normally less stable axial position of oxygen substituents on sugars and can be demonstrated using the axial and equatorial hydroxypyranes in Fig. 3.24. 

In the axial conformation, negative hyperconjugation between the higher lying of the two lone pairs on the ring oxygen and the exocyclic o qq-orbital leads to a stabilisation that is not possible in the equatorial conformation, as shown on Fig. 3.25. 

In the alternative equatorial conformation, only a much weaker interaction between the -orbital and the lower of the two ring oxygen lone 

Many carbohydrate conformations follow simply from the same considerations that govern alicyclic conformations, that bulky substituents prefer equatorial 

Proton-proton coupling constants in a-D-xylopyranosyl-4-methyl-pyridinium ion and methyl-P-D-galactopyranoside. Note the differences between coupling constants associated with very similar dihedral angles and the lower couplings experienced when the proton-attached carbon atoms have multiple electron-withdrawing groups. 

The frontier orbital explanation is that there is overlap between a lone pair on oxygen and the a orbital of the C-X bond, which is efficient (in the case of a pyranose ring) when the C-X substituent is axial, but not when it is equatorial. 

Most of the features of the effect can also be rationalised by classical electrostatic considerations. The C-X bond will be associated with a dipole, usually with its negative end towards X. The ring oxygen atom will be 

Overlap of p-type lone pair with o orbital of an axial substituent. This corresponds to no-bond resonance in the sense shown 

FIGURE 12. Geometries of alkyl hydroperoxides 23, 28 and 33 in the solid state (ball and stick 

FIGURE 15. Intramolecular hydrogen bonds of the type OO H -OR R2 (R1 — alkyl, R2 = H, alkyl, RO)75-76109. 

The preference of electronegative substituents at Cl of pyranose rings for the axial orientation has been known for 30 years [13]. This preference is the reverse of what would be expected in cyclohexane chemistry, and is termed the anomeric effect. It is responsible for the exclusive production of a-glycopyranosyl halides when these are equilibrated under strongly acidic conditions (Fig. 3, I). 

If i8-glyeopyranosyl halides are made by other routes they can be shown in a number of cases to adopt normally disfavoured conformations (Fig. 3, II). 

In the case where the electronegative substituent at Cl is not torsionally symmetrical - as with pyranoses and pyranosides - an exactly similar effect is observed with respect to rotation about the 01—Cl bond. This is termed the exo-anomeric effect [15], and ensures that the preferred conformation of an a-glycoside is as shown the other rotamer not disfavoured by the exo-anomeric effect has R exactly under the pyranose ring, where there are severe non-bonded interactions (Fig. 4). 

In the case of /8-glycosides there are again two rotamers which are not disfavoured by the anomeric effect (Fig. 4), the rotamer involving fewer ordinary steric interactions being the one that is exclusively observed. 

As might be anticipated, positively charged substituents at Cl of a pyranose ring have a more than ordinary preference for the equatorial orientation, or other orientation in which the positive charge can eclipse the concentration of negative charge on oxygen. This reverse anomeric effect is so powerful that 2,3,4,6-tetra- 

Equilibrium constant not known in solution ctystalline form has all chlorines axial. TH-O-acetyl-p-D-xylopyranosyl chloride 

The NMR spectrum in CDCI3 indicates that the all axial form is strongly favored. The equilibrium constant is not known. 

The magnitude of the anomeric effect depends on the nature of the substituent and decreases with increasing dielectric constant of the medium. The effect of the substituent can be seen by comparing the related 2-chloro- and 2-methoxy-substituted tetrahydropy-rans in entries 2 apd 3. The 2-chloro compound exhibits a significantly greater preference for the axial orientation than the 2-methoxy compound. Entry 3 also provides data relative to the effect of solvent polarity it is observed that the equilibrium constant is larger in carbon tetrachloride (e = 2.2) than in acetonitrile (e = 37.5). 

Compounds in which conformational, rather than configurational, equilibria are influenced by the anomeric effect are depicted in entries 4—6. Single-crystal X-ray dilfiaction studies have unambiguously established that all the chlorine atoms of trans, cis, ira j-2,3,5,6-tetrachloro-l,4-dioxane occupy axial sites in the crystal. Each chlorine in die molecule is bonded to an anomeric carbon and is subject to the anomeric effect. Equally striking is the observation that all the substituents of the tri-0-acetyl-/ -D-xylopyranosyl chloride shown in entry 5 are in the axial orientation in solution. Here, no special crystal packing forces can be invoked to rationalize the preferred conformation. The anomeric effect of a single chlorine is sufficient to drive the equilibrium in favor of the conformation that puts the three acetoxy groups in axial positions. 

Several structural factors have been considered as possible causes of the anomeric effect. In localized valence bond terminology, it can be recognized that there will be a dipole-dipole repulsion between the polar bonds at the anomeric carbon in the equatorial conformation. This dipole-dipole interaction is reduced in the axial conformation, and this factor probably contributes to the solvent dependence of the anomeric effect. 

Studies of the temperature dependence of the C-NMR chemical shifts of 2-methoxytelrahydropyran have determined AG values ranging from 0.5 to 0.8kcal/mol, 

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The anomeric effect is best explained by a molecular or bital analysis that is beyond the scope of this text... 

It IS not possible to tell by inspection whether the a or p pyranose form of a par ticular carbohydrate predominates at equilibrium As just described the p pyranose form IS the major species present m an aqueous solution of d glucose whereas the a pyranose form predominates m a solution of d mannose (Problem 25 8) The relative abundance of a and p pyranose forms m solution depends on two factors The first is solvation of the anomeric hydroxyl group An equatorial OH is less crowded and better solvated by water than an axial one This effect stabilizes the p pyranose form m aqueous solution The other factor called the anomeric effect, involves an electronic interaction between the nng oxygen and the anomeric substituent and preferentially stabilizes the axial OH of the a pyranose form Because the two effects operate m different directions but are com parable m magnitude m aqueous solution the a pyranose form is more abundant for some carbohydrates and the p pyranose form for others... 

An electronegative substituent adjacent to a ring oxygen atom also shows a preference for an axial orientation. This is known as the anomeric effect , and is particularly significant to the conformations of carbohydrates (B-71MI20100, B-83MI20100). 

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. ... 

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. 

Many examples of reactivity effects that are due to the anomeric effect have been identified. For example, Cr03 can oxidize some pyranose acetals, leading eventually to ketoesters. 

Gluconolactone shows no exchange. The reason is that the tetrahedral intermediate is formed and breaks down stereoselectively. Even though proton exchange can occur in the tetrahedral intermediate, the anomeric effect leads to preferential loss of the axial oxygen. 

E. Juaristi and G. Cuevas, The Anomeric Effect, CRC Press, Boca Raton, Florida, 1995. 

A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects at Oxygen, Springer-Verlag, New %rk, 1983. 

The six-membered rings 8.12a and 8.12b adopt chair conformations with all three halogen atoms in axial positions. This arrangement is stabilized by the delocalization of the nitrogen lone pair into an S-X a bond (the anomeric effect) All the S-N distances are equal within experimental error [ld(S-N)l = 1.60 (8.12a)/ 1.59 A (8.12b) ]. 

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%). 

Polymerization of 4-bromo-6,8-dioxabicyclo[3.2.1 ]octane 2 7 in dichloromethane solution at —78 °C with phosphorus pentafluoride as initiator gave a 60% yield of polymer having an inherent viscosity of 0.10 dl/g1. Although it is not described explicitly, the monomer used seems to be a mixture of the stereoisomers, 7 7a and 17b, in which the bromine atom is oriented trans and cis, respectively, to the five-membered ring of the bicyclic structure. Recently, the present authors found that pure 17b was very reluctant to polymerize under similar conditions. This is understandable in terms of a smaller enthalpy change from 17b to its polymer compared with that for 17a. In the monomeric states, 17b is less strained than 17a on account of the equatorial orientation of the bromine atom in the former, whereas in the polymeric states, the polymer from 17b is energetically less stable than that from 17a, because the former takes a conformation in which the bromine atom occupies the axial positioa Its flipped conformation would be even more unstable, because the stabilization by the anomeric effect is lost, in addition to the axial orientation of the methylene group. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

A number of explanations have been offered for the anomeric effect. The one ° that has received the most acceptance is that one of the lone pairs of the polar atom connected to the carbon (an oxygen atom in the case of 93)... 

Cameron DR, Thatcher GRJ (1993) In Thatcher GRJ (ed) The anomeric effect. ACS Symposium 539, American Chemical Society, Washington DC, pp 256-276... 

A detailed spectroscopic and theoretical study of the conformation of dioxolanes 1 has appeared <96T8275>, and a theoretical study has shown that the anomeric effect explains the non-planarity of 1,3-dioxole <96JA9850>. The tetraalkynyldioxolanone 2 has been prepared and its structure and reactivity studied <96HCA634>. Both enantiomers of the chiral glycolic acid equivalent 3 can be prepared from D-mannitol <96HCA1696>, and lipase-mediated kinetic... 

Deslongschamps P (1993) In Thatcher GJ (ed), The Anomeric Effect and Associated Stereoelectronic Effects. American Chemical Society, Washington, DC, p 26 Recent reviews on C-glycoside synthesis (a) Du Y, Linhardt RJ, Vlahov IR (1998) Tetrahedron 54 9913 (b) Levy DE, Tang C (1995) The Chemistry of C-Glycosides. Elsevier Science, Oxford... 

In an attempt to isolate the anomeric effects, analogous phosphonites have been studied. Equilibration of cis- (109) and /ra 5-2-methyl-5-t-butyl-l,3,2-dioxaphosphorinanes(l 10) demonstrated the thermodynamic preference for cis over trans (72% and 28% respectively at 40 °C). This surprising result must mean that axial P-methyl is more stable than equatorial even when no anomeric effects are present, and the authors interpret their n.m.r. results in terms of two equilibrating conformers for trans- 10)... 

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