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CHAPTER 2

Conformations of Monosaccharides
2.1 DIFFERENCES BETWEEN CONFORMATIONAL ANALYSIS OF CARBOHYDRATES AND OTHER ORGANIC MOLECULES

The gas-phase conformations of small molecules can now be computed with some accuracy by ab initio methods. In the case of non-polar molecules, whose conformations are unlikely to alter much in solution in non-polar solvents, computational calculations are often the method of rst choice in determining conformation. Carbohydrates, however, are very polar molecules. This means that their gasphase conformations, which can be computed, are likely to be largely determined by electrostatic and intramolecular hydrogen bonding interactions. They are therefore likely to be of questionable relevance to the conformation of the same molecules in polar solvents, particularly water. At the time of writing (early 2007) there does not appear to be a force eld which can accurately predict the conformations of carbohydrates in water; by contrast, Angyals instability factors, a purely empirical way of estimating carbohydrate conformations, are still used.1 The major problem with computational approaches appears to be nearly free rotation about the CO bonds of hydroxyl groups, which gives rise to a very asymmetric potential which is dicult to handle with computational economy. In addition to steric eects and electrostatic eects, the conformational analysis of carbohydrates requires two stereoelectronic eects to be taken into consideration: the gauche eect and the anomeric eect, in its various manifestations. Both of these eects can be considered as aspects of no-bond resonance.

2.2

THE GAUCHE EFFECT

As is well known, trans-butane has about 4 kJ mol1 less internal energy than gauche-butane and is therefore favoured in the gas phase at ordinary temperatures. However, 1,2-diuoroethane prefers the gauche conformation, with an internal energy dierence of 7.3 kJ mol1 between it and the trans conformation.2 The eect is seen in other, less clear-cut cases with oxygen substituents. The origin of the eect is considered to lie in the same phenomena that are 41

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Chapter 2

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Figure 2.1

Preferred conformations of butane and 1,2-diuoroethane, illustrating the gauche eect. In the gauche conformation each CF s* orbital can overlap with a CH s orbital on the vicinal carbon, corresponding to no-bond resonance as shown. Such no-bond resonance would be disfavoured if the CF bonds were trans, since it would remove electron density from an electronegative element. The eect is strong enough in this case to overcome the electrostatic repulsion between the two CF dipoles, which favours the trans form.

responsible for the great stabilisation of carbenium ions b-substituted with silyl groups,3 namely overlap of s orbitals with vicinal s* orbitals, as shown in Figure 2.1.4,5 2.3 CONFORMATIONS OF ACYCLIC SUGARS

In general, the conformations of alditol chains are determined by the tendency of the carbon backbone to adopt the extended zig-zag conformation of polyethylene, with all the four-carbon units being in the conformation of transbutane. Because of the gauche eect, there is no large preference for OH groups to be trans or gauche and this zig-zag conformation is adopted by mannitol and galactitol. However, such a conformation involves a 1,3-parallel interaction between the OH groups of glucitol (Figure 2.2). This is strongly disfavoured by electrostatics, so that glucitol adopts a so-called sickle conformation.6,7

2.4

DESCRIPTION OF THE CONFORMATIONS OF SUGAR RINGS

The currently used terms for describing sugar conformations in general derive from a mathematical study of Cremer and Pople,8 who built on the treatment of furanose rings of Altona and Sundaralingam.9 Cremer and Pople showed rigorously that the conformation of a ring with x atoms could be described rigorously by x 3 spatial coordinates (this, of course, neglects any substituents

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Conformations of Monosaccharides
OH HO HO OH OH HO 6 D-mannitol
1

43
OH OH
4

HO HO

OH OH
2

OH OH

OH

OH zig-zag

OH

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OH

1,3-syn interaction OH OH HO OH OH OH D-glucitol HO HO 6


1

HO

OH OH OH

OH
6

OH
4

OH
2

OH OH
6

OH
4

OH
2 OH

OH

OH

OH sickle

OH

Figure 2.2

Conformations of D-glucitol and D-mannitol. Note the apparent toleration of vicinal hydroxyl groups being either gauche or trans, but the prohibition on 1,3-syn interactions of hydroxyl groups.

Figure 2.3

CremerPople treatment of ring conformations. Left, cyclobutane conformations are completely dened by degree of pucker; centre, cyclopentane conformations require specication of the degree of pucker and a pseudorotational angle; right, cyclohexane conformations require specication of the degree of pucker and two angles; for conformations on the equator (y 901) j becomes a pseudorotational angle similar to that for cyclopentane.

on the x atoms). They realised that if these coordinates were polar rather than Cartesian, then ring conformations could be described in ways which corresponded to chemical intuition. They accordingly dened a puckering parameter Q, essentially the degree to which the atoms departed from the mean plane of the ring, as the radius, and x 4 angles which described the position on a multi-dimensional surface of this radius. Although four-membered rings are rare in carbohydrate chemistry, they represent the simplest case for the CremerPople treatment, x 4, so that their conformation is described uniquely by the puckering amplitude, i.e. the amount by which the fourth atom is displaced from the plane dened by the remaining three (Figure 2.3).

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Chapter 2

For ve-membered rings (x 5), only two parameters, the puckering parameter and an angle, are required. The internal angle of a pentagon (1081) is very close to the tetrahedral angle (109.51), but in the planar forms of ve-membered rings all the substituents are eclipsed. Puckering of the ring results in two lowenergy forms, the envelope, in which one ring atom lies out of a plane containing the remaining four, and the twist, in which two adjacent atoms lie above and below the plane dened by the remaining three. There are 10 envelope conformations and 10 twist conformations, which can be interconverted by rotations about single bonds. This gives the appearance of the outof-plane atoms rotating round the ring, and, in the case of cyclopentane itself, looks equivalent to the ring rotating about its vertical axis. The origin of the term pseudorotation for the interconversions of twist and envelope conformations lies in this feature of the geometry of cyclopentane itself, but is extended to systems where the ring atoms are not equivalent and the ring does not appear to rotate. In the case of six-membered rings, a puckering parameter and two angles are required; therefore, all conformations at a given degree of pucker can be described by their position on a sphere. The chair conformations are located at the poles, and the twist and classical boat conformations round the equator. The conformations round the equator form a pseudorotational itinerary similar to that seen with ve-membered rings: rotations about single bonds can give the appearance of a cyclohexane molecule on the skew/boat itinerary rotating, and the term is extended to systems where ring atoms are non-equivalent. In middle latitudes on the sphere of six-membered ring conformations are found the halfchair and envelope conformations that are transition states for cyclohexane, but the half-chair (like the boat conformer on the equator) is a stable conformer for cyclohexene. In addition to an envelope conformation similar to that seen with vemembered rings, but with ve, rather than four, contiguous atoms coplanar, six-membered ring conformations are discussed in terms of chair, boat, skew and half-chair conformations. The half-chair conformation has four contiguous ring atoms coplanar, with the remaining two above and below the plane so dened. The well-known chair conformation of cyclohexane has a six-fold axis of rotationinversion and perfectly staggered substituents about each CC bond, although since the CO bond is somewhat shorter than the CC bond, this perfect geometry is not fully transferred to pyranosides. Also well known is the boat conformation, with two orthogonal mirror planes, despite its being at a local energy maximum for saturated systems. The skew conformation, with a two-fold axis of symmetry, is at a local energy minimum. The conformations of furanose and pyranose rings are described qualitatively by italicised letters T, E, C, H, S and B for twist, envelope, chair, halfchair, skew and boat, respectively; T refers only to furanose rings and C, H, S and B only to pyranose rings, but E, describing conformations with just one ring atom out of the plane of the remainder, can refer to both pyranoses and furanoses. The particular conformation is specied by superscripts and subscripts referring to atoms above and below a dened plane; thus 4C1 (the

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Conformations of Monosaccharides

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commonest preferred conformation of hexopyranose derivatives) refers to a chair conformation with carbon 4 above the plane and carbon 1 below. The reference planes in the case of E and H dene themselves. The reference plane in B is dened not by either of the planes containing four contiguous atoms, but by the plane dening the bottom of the boat. Above the plane is dened as the direction from which the numbered carbon atoms increase in a clockwise direction and thus corresponds to the commonest representation of D-sugars in Haworth or conformational representations. Several planes containing three ring atoms can be drawn through T conformers and containing four ring atoms through C and S conformers. Where there is a choice of planes, that plane which gives the lowest superscripts and subscripts is chosen as the reference. Thus, the 4C1 conformation (reference plane C2, C3, C5, O) is called such, rather than 2C5 (reference plane C3, C4, O5, C1). Unfortunately, the rule that above the denition plane of a particular conformer is the direction from which the carbon atom numbers increase round the ring has the eect of reversing conformational designations between enantiomers the mirror image of a-D-glucopyranose in the 4C1 conformation is a-L-glucopyranose in the 1C4 conformation. In the case of furanosides, especially nucleosides, Altona and Sundaralingams original symbols for the pseudorotational angle P and pucker tm (or sometimes jm) are used; P 01 is dened as the 3T2 conformation. Figure 2.4 shows the pseudorotational itinerary, with a nucleoside (sugar D-ribose) as an example. Nucleoside chemists refer to conformations with 0 r P r 361 as N

Figure 2.4

Conformational itinerary of a furanose ring.

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-D-Glucopyranose in the 4C conformation 1 Downloaded by Universidad del Valle - Colombia on 18 November 2012 Published on 31 December 2007 on http://pubs.rsc.org | doi:10.1039/9781847558015-00041

Chapter 2

Methyl N-acetyl -D-neuraminide 2 in the C5 conformation

Tri-O-acetyl -D-xylopyranosyl fluoride in the 1C4 conformation

D-mannono--lactone in the B2,5 conformation

-D-glucopyranosyl pyridinium ion in the 1S3 conformation: the reference plane goes through C4, C5, O and C2

Figure 2.5

Preferred conformations of some pyranose derivatives, showing the reference plane.

(for Northern, although more properly NNE) and with 144 r P r 1801 as S (for Southern, really SSE), as these are the two commonest conformations adopted by the ribose ring. Replacement of a nucleoside base with an OMe group did not alter conformational preferences.10 Figure 2.5 shows the preferred conformations of some pyranosyl derivatives. The examples are chosen both to illustrate the principles by which the conformations are named and also to illustrate the operation of various eects which determine the conformations. The conformations are all necessarily found on the surface of the CremerPople sphere; the inter-relations of the various conformations in the northern and southern hemispheres are set out in Figure 2.6.

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Figure 2.6

Conformations on the surface of the CremerPople sphere for a pyranose ring: (a) Northern hemisphere; (b) Southern hemisphere.

In addition to the familiar axial and equatorial description of substituents in chair conformations, substituents in non-chair conformers of six-membered rings also have their descriptors: there are four isoclinal, four pseudoaxial and four pseudoequatorial bonds in skew cyclohexane and four pseudoaxial, four

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pseudoaxial axial equatorial

Chapter 2

pseudoequatorial isoclinal

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flagstaff

bowsprit pseudoequatorial

pseudoaxial

Figure 2.7

Designations of bonds in chair and non-chair six-membered rings.

pseudoequatorial, two bowsprit and two agsta bonds in boat cyclohexane (Figure 2.7).

2.5

ANALYSIS OF CARBOHYDRATE CONFORMATION AND CONFIGURATION BY NMR THE KEY ROLE OF THE KARPLUS EQUATION

Most of our knowledge of the conformation of sugar rings in solution has come from NMR, in particular from spinspin coupling constants. The coupling is a through-bond eect that can be envisaged as a minute unpairing of the electrons in the bond to pair up with a nucleus with a spin. The unpairing is transmitted through valence electrons, depending on the symmetries of their overlaps, to another nucleus. Coupling falls o sharply with the number of bonds through which it has to be transmitted, 1H1H coupling through four bonds only being detectable with particular favourable geometries (W coupling). Three-bond coupling constants 3J are particularly informative, as their magnitude depends sinusoidally on dihedral angles, with, in general, maxima at dihedral angles of 01 and 1801 (i.e. synperiplanar and antiperiplanar disposition). Karplus11 derived eqn (2.1) for three-bond coupling of protons. This is illustrated in Figure 2.8.
3

J A Bcosj C cos2j

2:1

It is often forgotten that the magnitudes of A, B and C depend not only on the nuclei coupled, but also on the particular system. In particular, coupling

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Conformations of Monosaccharides
3

49

J1,2 /Hz

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180

360

Dihedral angle (radians) (degrees)

Figure 2.8

Three-bond protonproton coupling constants as a function of dihedral angle, according to eqn (2.1), illustrated with Karpluss original values of A 4.22, B 0.5 and C 4.5, applicable to hydrocarbons.

constants are reduced by electron-withdrawing substituents: there have been many attempts to correct for this explicitly. The most successful is a veparameter approach for three-bond protonproton coupling constants by Altona and colleagues.12 In practice, coupling constants usually are interpreted empirically, by reference to other closely related molecules. Some caution must be exercised before a peak splitting is identied with a coupling constant. This is in general only the case where the chemical shift dierence (Ds) between the coupled nuclei, expressed in Hz rather than ppm, is signicantly (say, 10-fold) larger than the coupling constant, J, so that the spectra are rst order. As Ds approaches the value of the coupling constant, the inner lines of multiplets increase at the expense of the outer lines. Thus, a socalled AX two-proton system, where the chemical shift dierence is large compared with the coupling constant, appears as two clean doublets (i.e. four equal-intensity lines). However, as Ds approaches J, the two inner lines increase in intensity relative to the two outer ones, so that in a one-dimensional spectrum, a so-called AB system with Ds B J can be mistaken for the 1:4:4:1 methylene quartet of an ethyl group. Since the important parameter is Ds in Hz, increase of eld strength, which increases while J remains constant, can simplify spectra. At 60 MHz, although anomeric protons can often be distinguished, other ring protons form an unanalysable complex multiplet, whereas

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Chapter 2

at 600 MHz most splitting systems of the ring protons of sugars are rst order, although even at this eld (14.1 T) there are exceptions. Although many pyranoid systems adopt one conformation predominately, and coupling constants can be assigned to this conformation, furanoid systems are generally mobile, and more than one conformation is adopted. In systems in the fast exchange region, chemical shifts and coupling constants are weighted averages. The requirement for fast exchange is that the rate constant for interconversion of observed molecules is much greater than chemical shift dierences (in Hz) between them. This is generally true of furanosyl systems at accessible temperatures, because the energy barriers to interconversion of conformers are so low. The signicant barriers to interconversion of chair sixmembered rings, however, mean that pyranosyl systems which signicantly occupy both chair conformers may exhibit broadened spectra as the temperature is lowered and the intermediate exchange region approached. In CS2 solution, the single CH3 proton resonance of the axial and equatorial methoxyl groups of 2,2-dimethoxytetrahydropyran begins to broaden at 80 1C; a barrier to chair chair interconversion of 36 kJ mol1 can be calculated [interestingly, this is less than the barriers for chairchair interconversion of cyclohexane (44 kJ mol1) and 1,1-dimethoxycyclohexane (45 kJ mol1), indicating that the anomeric eect (Section 2.6), while it aects preferences, if anything reduces conformational barriers13]. In the slow exchange regime, two distinct spectra of the dierent conformers are observed, in the same way as dierent anomers, etc. Pyranosyl derivatives in chair conformations are the most amenable to analysis of three-bond protonproton coupling by the Karplus equation, eqn (2.1) and Figure 2.8. It is seen that a dihedral angle of B601, (1.047 radians) corresponding to axialequatorial or equatorialequatorial coupling, gives rises to a fairly low coupling constant, whereas axialaxial couplings, corresponding to a dihedral angle of 1801, give rise to a maximum coupling constant. In general, the anomeric protons of sugar derivatives resonate at the lowest eld of all the ring protons, since they are attached to carbons with two electronwithdrawing oxygen substituents. Axial hydrogens resonate at higher eld than equatorial hydrogens, but even axial anomeric hydrogens can usually be readily identied. More troublesome in the case of water-soluble materials is that the proton resonance from residual HOD in D2O commonly comes between the expected resonances of axial and equatorial anomeric protons and if care is not taken to exclude moisture during sample preparation, may obscure them. The 3JH1,H2 coupling alone can unambiguously identify anomeric conguration, if the conformation can be predicted with condence. Thus, in the D-gluco series, all the substituents except the anomeric are equatorial in the 4C1 conformation, so that the preference for this conformation can only be overcome by bulky, charged aglycones (Figure 2.5); for ordinary oxygen aglycones, therefore, a 12 Hz splitting of the H1 resonance indicates an a conguration and a 78 Hz splitting a b conguration; as discussed above, the axial H1 of b-congured glycoside resonates at higher eld (lower d). The technique can be applied to galactopyranosides and xylopyranosides, but not to mannopyranosides, since H2 is now equatorial in the 4C1 conformation, so that 601 dihedral angles, and

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Figure 2.9

Predicted H1H2 dihedral angles for b- and a-glucopyranosides (top) and b- and a-mannopyranosides (bottom).

attendant low splittings, are observed with both mannopyranoside anomers (Figure 2.9). Anomeric assignments of mannopyranosides may be based on the chemical shift of the anomeric proton if both anomers are available, but otherwise are uncertain; one-bond 13C1H couplings at the anomeric centre are more reliable (1 J13 C;H 1J13CH for a glycosides is around 170 Hz, compared to 160 Hz for their anomers14). If the anomeric conguration of a glycosyl derivative is known with condence, then three-bond proton coupling constants can enable the conformation to be determined. Thus, the bulk of the pyridinium ring in a-D-xylopyranosylpyridinium ions, and the necessity for extensive solvation of the positive charge, constrain the ring in the 1C4 conformation, as shown by the protonproton coupling constants displayed in Figure 2.10. Note the four-bond (or W) coupling observed between H3 and H1. Also displayed are the couplings from methyl b-D-galactopyranoside; note how they are all lower than would be predicted for a perfect chair and from Figure 2.8 and also that very similar dihedral angles can give appreciably dierent couplings. 2.6 THE ANOMERIC EFFECT

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

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OH OH H 1.1 H H HO H H 13.4 0.9 H 1.8 2.5 H OH H OH 2.7 H 1.5 N+ OH O 1.4 H 9.9 OH H 7.9 OCH3 O

Chapter 2

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3.4

CH3

Figure 2.10

Protonproton coupling constants in a-D-xylopyranosyl-4-methylpyridinium ion15 and methyl-b-D-galactopyranoside. Note the dierences 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.

and pseudo-equatorial orientations and that aligned electrostatic dipoles involve large energetic cost. Many, but not all: b-D-xylopyranosyl uoride adopts the 1C4 conformation in which all four ring substituents are axial, as does its tri-O-acetyl derivative. In preparative carbohydrate chemistry, it is common to make protected glycopyranosyl halides by reaction of the protected sugar with a highly acidic solution of the appropriate hydrogen halide the axial halide is the major thermodynamic product.i In the case of cellobiosyl uoride, 12% only of the b-compound appears to be present at equilibrium.19 The tendency of electronegative substituents at C1 of a pyranose ring to adopt an axial orientation is termed the anomeric eect.20 The name has been extended to the tendency of the CO dihedral angle of XCOR fragments to adopt a conformation in which X is antiperiplanar to a lone pair on the oxygen, when X is an electron-withdrawing group. There have been two explanations of the origin of the anomeric eect, one based on classical (pre-quantum) electrostatics and the other on frontier orbital theory. The consensus that appears
i

The classic way of making per-O-acetylglycopyranosyl bromides (acetobromo sugars) is acetylation of glucose, galactose, mannose, xylose, etc., with acetic anhydride and perchloric acid, followed by reaction of the products with HBr generated in situ from red phosphorus, bromine and water16; chlorides are made similarly, with the acetylation solution saturated with HCl; uorides can be made from the anomeric mixture of fully acetylated sugars in liquid HF or, less hazardously, pyridinium poly(hydrogenuoride).17 Per-O-acetylglycosyl iodides can be made with anhydrous HI in dichloromethane at low temperature.18

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to have emerged is that frontier orbital interactions are the main origin of the eect, but that classical electrostatics plays some role. The frontier orbital explanation is that there is overlap between a lone pair on oxygen and the s* orbital of the CX bond, which is ecient (in the case of a pyranose ring) when the CX substituent is axial, but not when it is equatorial. To understand this, it is necessary to be clear about what the conventional representations of the lone pair electrons on oxygen do and do not represent. In a fragment ROR, if the ROR angle is 109.51, then the lone pairs can be represented as being in two orthogonal sp3 orbitals, drawn in the conventional skittle shape; however, the outline of the skittle represents a contour of c, not electron density; the small and large lobes of the skittle in fact have opposite signs. If these two sp3 orbitals are both doubly occupied, then the resulting electron distribution has the shape of a large, blunt sp3 orbital, with a maximum in charge density between the two individual sp3 orbitals.21 The same electron density, however, results from considering the lone pairs as occupying an sp and a p orbital; in fact, the lone pairs on oxygen can be represented as two sp3 orbitals, one p and one sp orbital or anything in between: the same electron density, which is the experimentally measurable quantity, results (Figure 2.11). The s* orbital of a CX bond, is, like the p-type lone pair on oxygen, composed of two approximately equal lobes. The overlap between the p-type lone pair and the s* orbital of an axial CX bond in a pyranose ring is relatively ecient [the dihedral angle about C1O5 bond described by the axis of the p-type lone pair and the s* orbital will be about 301; pp overlap of this type varies approximately as the square of the cosine of the dihedral angle and cos2(301) 0.75]. While the overlap of the sp lone pair with an equatorial CX bond is geometrically optimal, the electrons in an sp orbital are held very much closer to the nucleus than those of a p orbital and are much less readily available for donation. The anomeric eect, on the frontier orbital model, thus corresponds to no bond resonance in the sense shown, but only in the axial position (Figure 2.12). Most of the features of the eect can also be rationalised by classical electrostatic considerations. The CX bond will be associated with a dipole, usually with its negative end towards X. The ring oxygen atom will be

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R R

R R

R O R
2)

(two sp3 orbitals)

Electron density (

(one p and one sp orbital)

Figure 2.11

Cartoons of contours of c for the equivalent representations of oxygen lone pairs in an ether as in two sp3 orbitals or one p and one sp orbital and an electron density contour. Note that hybrid spn orbitals do not have a node at the nucleus, as a pure p orbital does, but rather one behind the nucleus, between it and the small lobe.

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Chapter 2

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

O X

Overlap of sp-type lone pair with the orbital of an equatorial substituent. The sp lone pair is much closer to the nucleus, so the overlap is much less important, even though the sp lone pair and the C-X orbital are exactly eclipsed.

Figure 2.12

Frontier orbital rationalisation of the anomeric eect.

associated with a region of negative charge, both by virtue of the lone pairs on oxygenii (Figure 2.11) and also by virtue of the dipoles associated with the C1O5 and C5O5 bonds, which have a resultant in the plane dened by C5, O5 and C1 and approximately bisecting the C5O5C1 angle. This resultant dipole will exactly eclipse the CX dipole if the CX bond is equatorial, but not if it is axial (Figure 2.13). The no-bond resonance picture of the anomeric eect predicts that the proportion of axial conformer in mobile 2-aryloxytetrahydropyrans should increase as electron-withdrawing substituents are introduced into the aryl group and the electron demand of the CX bond increases This will have the eect, however, of decreasing the negative charge on the exocyclic oxygen and according to the electrostatic model the anomeric eect should decrease. In fact,

ii

If the two lone pair sp3 orbitals on oxygen are drawn in the customary skittle shapes, the major lobes in a Newman projection look like two rabbits ears. The direct electrostatic eect of lone pair electrons was therefore dubbed the rabbits ears eect, but failed to nd acceptance, as much from the overtones of Beatrix Potter as from the fact that the shape of electron density resembled not two, but one ear (Figure 2.11).

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Figure 2.13

Electrostatic explanation of the anomeric eect.


X O O O O X

X = NO2 CN, Cl,

78 78 71

X = H, 68 CH3, 69 OCH3, 69

Figure 2.14

Proportions of axial conformer of 2-aryloxytetrahydropyrans in deuterochloroform solution.22 The conformational equilibrium is invariant with X in cyclohexane (8487% axial).

as is shown in Figure 2.14, there is a small eect in CDCl3 solution, which disappears in cyclohexane. Since CDCl3 is a weakly hydrogen-bonding solvent, it could be that hydrogen-bonding reduces the charge on the exocyclic oxygen atom, allowing the frontier orbital eect to be experienced unmasked by the electrostatic eect, as it is in cyclohexane solution. The no-bond resonance model of the anomeric eect predicts that, in a series of axial aryloxytetrahydropyran derivatives, the intracyclic bond should shorten and the extracyclic bond should lengthen as the parent phenol becomes more acidic and the ion-paired canonical form; any eect should be much smaller in the equatorial case. Careful X-ray crystallographic studies23 of a series of tetrahydropyranyl ethers (structures in Figure 2.15) indeed showed that for seven such axial compounds, with the pKa of ROH spanning 8 pK units, the ) of the extracyclic bond (x) and the intracyclic bond (n) were given lengths (A by eqns (2.2) and (2.3), respectively: x 1:493 0:006495pKa r 0:985 n 1:364 0:003639pKa r 0:939 2:2 2:3

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O n x R O

Chapter 2

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O
O OR O

O X
R O

Figure 2.15

Tetrahydropyranyl structures used in the investigation of the anomeric eect by X-ray crystallography.

However, similar, but not as pronounced, trends were also seen with seven equatorial tetrahydropyranyl ethers, with a pKa range of 13 units: x 1:456 0:00476pKa r 0:945 n 1:394 0:00214pKa r 0:911 2:4 2:5

The picture was made yet more ambiguous by the fact that the equivalent bond lengths in seven a-D-glucopyranosides (over an aglycone acidity range of 12 pK units) showed no such correlation for n and only a weak one for x: x 1:427 0:00102pKa r 0:636 2:6

Such a correlation is to be expected in the absence of the frontier orbital interactions of Figure 2.12, since the COR bond in a variety of structures lengthens with increasing acidity of ROH in a wide variety of structures, with a sensitivity comparable to that seen in the tetrahydropyranyl systems.24 The key piece of evidence for the rationalisation of the anomeric eect in terms of classical electrostatic dipole interactions has been the apparent existence of a reverse anomeric eect. Reversal of the sense of the dipole of the CX bond, so that X now carries a net positive rather than negative charge, should, on the electrostatic picture, result in X having a more than ordinary tendency to be equatorial. The eect was rst observed in glycosyl pyridinium salts25 and, in what at rst sight seemed to be an elegant experiment, the steric demand of the bulky pyridinium salt was apparently eliminated as the source of the eect by the observation that tri-O-acetyl-a-D-xylopyranosylimidazole changed from 65% to >95% equatorial on addition of excess acid.26 Protonation of imidazole will have only a minor eect on its steric requirements, since protonation takes place at a remote siteiii.27

iii

The A values for imidazole and imidazolium in cyclohexyl systems, measured directly, are both 9.2 0.4 kJ mol 1, but measurement of the dierence in Ka directly indicates that the imidazolium A value is about 0.4 kJ mol1 higher.

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Conformations of Monosaccharides

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However, NMR titration of a mixture of the anomeric glucopyranosylimidazoles in a variety of solvents established conclusively that the a-anomer was more basic than the b-anomer by around 0.3 pK units in D2O, but less in less polar solvents.28 This is exactly the opposite of what is predicted by any reverse anomeric eect, but is what would be predicted on the frontier orbital picture of the normal anomeric eect of Figure 2.12, since protonation would increase the electron demand of the anomeric substituent. The additional hydroxymethyl group of glucopyranosylimidazoles, ensures that they, unlike xylopyranosylimidazoles, remain in the 4C1 conformation on protonation. On the electrostatic model, therefore, the protonated a-anomer is expected to be destabilised and the protonated b-anomer stabilised, which should make the b-anomer more basic. The elegant NMR approach by Perrin et al.28 enables the ratio to be measured without any absolute measurement of pH. Equation (2.7) follows from the thermodynamic box of Figure 2.16, where Ka refers to an acid dissociation constant and Ke to an anomeric equilibrium constant ( [b]/[a]):
b a 0 Ka Ke Ka Ke

2:7

The dierence in anomeric equilibrium between protonated and neutral glucosylimidazoles can thus be measured as an acid dissociation constant ratio (i.e. pKa dierence). Proton transfers are normally rapid on the NMR time-scale at ordinary temperatures. Therefore, the chemical shift of all the nuclei in part-protonated glucosylimidazoles will be a weighted average of the chemical shifts for protonated and unprotonated species. If both anomers are present in the same solution, then, irrespective of the absolute value of [H1], Kaa/Kab will be

OH HO HO O N OH + NH Ka HO HO

OH O N OH N

Ke +

Ke 0

OH HO HO O OH K a HO HO

OH O OH

N + NH

N N

Figure 2.16

Thermodynamic box for protonation and equilibration of glucopyranosylimidazoles.

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58

Chapter 2

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[aH1][b]/[a][bH1]. The method thus permits measurement of ratios of acid dissociation constants (dierences in pKa values) in any medium, without the necessity for measuring any absolute pH and thus can be used in all solvents, provided that proton transfer is fast in them. Equation (2.8) holds, where an unsubscripted d refers to the observed chemical shift of a reporter nucleus, d0 and d1 to its value when the substrate is fully deprotonated and fully protonated, respectively, and the superscripts to the anomer. The acid dissociation constant can thus be obtain from the gradient of a linear plot obtained from chemical shifts obtained during an NMR titration.
a a a a b b a b db db 0 d d Ka =Ka d d0 d d

2:8

The ratio Kaa/Kab is, however, solvent dependent, increasing from 0.52 in D2O to 0.80 in CD3OD and to 0.97 in (CD3)2SO, consistent with a small solventdependent, electrostatic interaction favouring protonation of the b-anomer, which becomes more important as the solvent becomes less polar. Similar experiments with tetra-O-methylglucosylanilines in acetonitrile indicated that here the protonation of the b-anomer was slightly favoured, with Kaa/Kab varying29 from 1.6 to 2.1, depending on the aniline substituents. However, measurements of the analogous parameter for the corresponding axial and equatorial 4-tert-butylcyclohexylanilines revealed that protonation of the equatorial isomer was favoured by a slightly larger factor (3.53.1), indicating the existence of steric hindrance to solvation of the axial epimers and a small normal anomeric eect in the protonated glucosylanilines.30 The greater basicity of b- compared with a-glucosylamines is likewise attributed to such steric hindrance of solvation. Glucosylanilines, like most glycosylamines, are not congurationally stable, but the NMR titration method requires only that the interconversion be slow on the NMR time-scale. The anomeric eect appears to be particularly strong when there is an axial substituent on position C2 (this was at one stage called the D2 eect). This would appear to be an electrostatic eect, the C2O dipole opposing the CX dipole of an equatorial substituent and thus reinforcing the anomeric eect (Figure 2.17).

HO OH OH HO O OH

HO OH OH O OH OH

Figure 2.17

Enhancement of the anomeric eect in D-mannopyranose. The D-mannopyranose ring is rotated by 1801 about a vertical axis from the normal viewpoint.

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Conformations of Monosaccharides 2.7 CONFORMATIONAL FREE ENERGIES IN PYRANOSES

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,24 whereas the The length of the CO bond in ethers is generally taken as 1.43 A 31 . This makes tetrahydrolength of an unstrained CC bond is around 1.53 A pyran slightly less puckered than cyclohexane. In cyclohexane chemistry, conformational preferences are discussed in terms of A values for substituents (the free energy dierence between the axial and equatorial chair conformers of a monosubstituted cyclohexane). These A values for cyclohexane32,33 cannot be applied directly to tetrahydropyran,34,35 even in the absence of an anomeric eect, not least because they vary with the position of substitution, even with non-polar substituents which do not exert an anomeric eect (Table 2.1). For 2-aryloxysubstituents, which do exert an anomeric eect, Kirby and Williams36 combined their own data for cyclohexane37 with that of Ouedrago and Lessard for aryloxytetrahydropyrans38 to derive eqn (2.9) for the strength of the anomeric eect of a 2-phenoxysubstituent: Anomeric effect=kJ mol1 7:1 0:8 0:22 0:08pKa 2:9

A values, however, which refer to non-polar solvents such as CS2 or CDCl3, are not particularly useful for the medium to which most carbohydrate research applies, water. In the 1960s, by measurement of conformational energy dierences of a wide range of substances, Angyal and co-workers produced a series of empirical instability factors which could predict the conformations of pyranose rings.1,39 These interaction energies are set out in Table 2.2; they are destabilisation energies, so the anomeric eect factor is added to the equatorial conformer or epimer. The existence of a destabilising interaction between gauche vicinal oxygen substituents seems at variance with the results from studies of acyclic sugars, but may be a solvation eect. An example of the power of these instability factors is their prediction that epimerisation of b-D-mannopyranose at C5 to give a-L-gulose will change the conformational preference of the ring from 4C1 to 1C4. A closely analogous epimerisation occurs during biosynthesis of alginate (Chapter 4), whose Table 2.1
Substituent 2-CH3 3-CH3 4-CH3 2-COOCH3 3-COOCH3 2-CH2OH 3-CH2OH 2-Cl 3-Cl 4-Cl

A values (kJ mol1) for cyclohexane and tetrahydropyran.


Cyclohexane32,33 7 5.5 Tetrahydropyran34,35 12 6 8 5.8 2.5 12 3.3 o7.5 2.8 1.3

2.2

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60 Table 2.2 Interaction energies (kJ mol1) in carbohydrate systems.


1.9 3.8 6.3 10.5 1.5 1.9 2.1 4.2

Chapter 2

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Axial Haxial O (OH, OAc, etc.) Axial Haxial C (CH3 or CH2OH) Axial Oaxial O Axial Oaxial C Vicinal Ovicinal O (ee or ae only, not aa) Vicinal Ovicinal C (ea or ee only, not aa) Anomeric eect, O1 and O2 equatorial Anomeric eect, O1 equatorial, O2 axial

-D-mannopyranose, C1 3 OOvic 1 OCvic 1 OaxHax 1 anomeric, O2ax Total 4.5 1.9 1.9 4.2

-D-mannopyranose, C4 2 OOvic 1 OaxHax 2 CaxOax 1 OaxOax Total 3.0 1.9 21.0 6.3

-L-gulopyranose, C1 3 OOvic 1 OaxHax 1 OCvic 2 CaxHax 1 anomeric, O2ax Total 4.5 1.9 1.9 7.6 4.2 20.1

-L-gulopyranose, C4 2 OaxHax 2 OOvic 1 OCvic 3.8 3.0 1.9

12.5

32.2

Total

8.7

OH HO HO HO O OH

HO OH O

OH HO HO

HO O OH OH

HO

OH O

OH

OH OH

OH OH

Figure 2.18

Use of instability factors to predict the conformation of b-D-mannopyranose and a-L-gulopyranose.

properties are critically dependent on alternating sequences of poly b(1-4)mannuronic acid and poly-a(1-4)-guluronic acid, in which the pyranose rings of the latter adopt the alternative chair conformation (Figure 2.18).

2.8

RATIONALISATION OF THE COMPOSITION OF AQUEOUS SOLUTIONS OF REDUCING SUGARS (SEE TABLE 1.1)

Easiest to understand is that those sugars which have all substituents except the anomeric OH equatorial in the pyranose form (glucose, xylose) have few if any furanoses at equilibrium: ve-membered rings are generally less stable than six-membered rings (though they are formed faster). Glucofuranose and xylofuranose additionally have a cis interaction between the 3OH and the 4-substituent, which further destabilises furanose forms. Pyranose forms of galactose and arabinose are destabilised by a single axial OH at position 4, whereas the furanose forms have all the substituents trans to each other; furanose forms are therefore more abundant than with glucose and xylose. There is a single axial OH at position 3 in ribopyranose and allopyranose and accordingly furanose forms of these sugars are also more abundant, although it

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Conformations of Monosaccharides
R HO HO O OH OH HO OH -D-xylopyranose and -xylofuranose (R = H) and -D-glucopyranose and -glucofuranose (R = CH2OH) H R OH O OH HO OH OH R O OH R HO H HO OH O OH

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-L-arabinopyranose and -arabinofuranose (R = H) and -D-galactopyranose and -galactofuranose (R= CH2OH) H OH O OH

H HO HO HO HO O OH HO HO

R OH O OH OH OH HO

R O OH

OH

HO

OH

-D-mannopyranose and -mannofuranose

-D-ribopyranose and -ribofuranose (R = H) and -D-allopyranose and -allofuranose (R = CH2OH)

OH HO O OH HO OH

HO HO HO

O OH

OH

HO HO AcNH

OH O HO

OH COOH

-D-fructopyranose and -fructofuranose

-D-N-acetylneuraminic acid

Figure 2.19

Conformations of representative pyranose and furanose forms of common reducing sugars.

is not clear why they should be more abundant than in arabinose and galactose. Mannofuranose has the substituents at C2, C3 and C4 all cis, so that despite the axial 2OH in mannopyranose, furanose forms are present in only trace amounts. D-Fructose is D-arabinose with the anomeric hydrogen replaced by a hydroxymethyl group; furanose forms are therefore present for the same reason as with arabinose. The approximately 60:40 ratio of equatorial to axial pyranose anomers of glucose, xylose, galactose and arabinoseiv illustrates the operation of the anomeric eect: the A value for hydroxyl (Table 2.1) predicts an equatorial/ axial preference in cyclohexane of about 5.4:1. The enhancement of the anomeric eect by an axial 2OH in mannopyranoses results in a-mannopyranose becoming the predominant tautomer. By contrast, an axial 3-OH, as in ribose and allose, results in 1,3-diaxial clashes with an axial anomeric OH group and an equatorial anomeric OH group being favoured more than in, say, glucose. In ketopyranoses, the reluctance of carbon substituents to become axial acts in the same direction as the anomeric eect, so that the OH-axial pyranose anomer is overwhelmingly predominant, as in fructopyranose and N-acetylneuraminic acid (Figure 2.19).

iv

Because of the change of bottom reference asymmetric carbon, a- not b-arabinopyranose has the anomeric OH equatorial (formal removal of the C5 CH2OH from b-D-galactopyranose gives a-L-arabinopyranose).

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62 2.9 CONFORMATIONS OF HYDROXYMETHYL GROUPS

Chapter 2

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The conformations about the C5C6 bond in hexopyranoses can be dealt with in several ways. In crystal structures of small molecules, the C4C5C6O6 dihedral angle, w, can be determined reasonably exactly and is often quoted (see Section 4.1). In some polymers w can be determined, but in others (most notably some forms of cellulose) there is disorder about the C5C6 bond. In solution, it is fairly easy to obtain vicinal coupling constants between H5 and both H6R and H6S. However, rotation about C5C6 is suciently fast that the system is in the fast-exchange region and an average value of w comes out of the Karplus equation, with the nature of the averaging that produced it not clear. Some authors consider the system in terms of a rapid equilibrium between three perfectly staggered conformers, termed gg (O6 gauche to both O5 and C4), gt (O6 gauche to O5 and trans to C4) and tg (O6 trans to O5 and gauche to C4).v These are illustrated in Figure 2.20. Other authors consider the equilibrium in terms of a continuum of rotamers of smoothly varying energy.40 In the gg and gt conformations, the two oxygens are gauche to each other and are thus stabilised relative to the tg conformation by the gauche eect; additionally, there is the possibility of weak hydrogen bonding by OH6 to the lone pairs on the ring oxygen. It is therefore unsurprising that (on the three perfect conformer model), the tg conformation is relatively uncommon.
(a) Viewed C6 O6 O5 H6s H5 gg C4 H6R C5 H6R H6s C4 H6s H5 gt O5 H6R H5 tg C4 O6

O5

O6

(b) Viewed C5-C6 O6 O5 HS HR O5 O6 H5 gt HS O5 HR

C4 HR

C4 HS

C4 O6

H5 gg

H5 tg

Figure 2.20

Three perfectly staggered rotamers about the exocyclic C5C6 of aldohexopyranoses.

Note that the relationship of O6 to O5 is described before its relationship to C4.

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Conformations of Monosaccharides 2.10 CONFORMATIONS OF SEPTANOSIDES

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Septanosides are rarely, if ever, encountered in Nature, but the ability of hydroxylated azepanes (azacycloheptanes) to inhibit glycosyl-transferring enzymes prompted an investigation of the conformational preferences of some septanosides.41 The CremerPople treatment of a seven-membered ring requires three angles in addition to the puckering parameter and loses its visual usefulness. It appears, nonetheless, that low-energy conformers are conned to positions on a pseudorotational itinerary involving twist-chair and chair conformers. Chair conformers are described by the one atom above and the two below the seat of the chair, as in the 5C12 conformation sketched in Figure 2.21. As might be expected from the fully eclipsed C1C2 bond in such a conformation, it is at a local energy maximum and distorts to the twist-chair (TC ) conformation. The reference plane in TC conformations is dened by three contiguous ring atoms, with the ring atoms above and below the reference plane, superscripts or subscripts. Substitution patterns can enforce the occupancy of a single conformer, as in the 5,6TC3,4 conformation adopted exclusively by methyl a-D-glycero-D-idoseptanoside, in which the anomeric eect is fully expressed. It appears that methyl b-D-glycero-D-guloseptanoside, whilst occupying the 5,6TC3,4 conformation predominantly, can also occupy the 6,OTC4,5 conformation to a signicant extent (Figure 2.21).

methyl -D-glycero-D-idoseptanoside OH HO HO O H OH OH H
5C 1,2

OH HO HO O OH H H

OCH3

OH

OCH3

(energy maximum)

3,4TC 5,6

methyl -D-glycero-D-guloseptanoside OH O H OCH3 HO HO O H OCH3 H OH

OH HO HO

OH HO
3,4TC 5,6

OH
6,OTC 4,5

Figure 2.21

Some conformations of glucose-derived septanosides.

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64 REFERENCES

Chapter 2

1. S. J. Angyal, Angew. Chem. Int. Ed. Engl., 1969, 8, 157. 2. D. Friesen and K. Hedberg, J. Am. Chem. Soc., 1980, 102, 3987. 3. J. B. Lambert, Y. Zhao, R. W. Emblidge, L. A. Salvador, X. Y. Liu and E. C. Chelius, Acc. Chem. Res., 1999, 32, 183. 4. A. J. Kirby and A. H. Williams, ACS Symp. Ser., 1993, 539, 53. 5. B. M. Pinto and R. M. Y. Leung, ACS Symp. Ser., 1993, 539, 126. 6. Y. Israeli and C. Detellier, Carbohydr. Res., 1997, 297, 201. 7. A. Schouten, J. A. Kanters, J. Kroon, S. Comini, P. Looten and M. Mathouthli, Carbohydr. Res., 1998, 312, 131. 8. D. Cremer and J. A. Pople, J. Am. Chem. Soc., 1975, 97, 1354. 9. C. Altona and M. Sundaralingam, J. Am. Chem. Soc., 1972, 94, 8205. 10. J. B. Houseknecht, C. Altona, C. M. Hadad and T. L. Lowary, J. Org. Chem., 2002, 67, 4647. 11. M. Karplus, J. Chem. Phys., 1959, 30, 11. 12. C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona, Tetrahedron, 1980, 36, 2783. 13. C. L. Perrin and O. Nun ez, J. Chem. Soc., Chem. Commun., 1984, 333. 14. K. Bock and C. Pedersen, J. Chem. Soc., Perkin Trans. 2., 1974, 293. 15. L. Hosie, P. J. Marshall and M. L. Sinnott, J. Chem. Soc., Perkin Trans. 2., 1984, 1121. + sy, Nature, 1950, 165, 359. rczai-Marcos and F. Koro 16. M. Ba 17. J. Ju nnemann, J. Thiem and C. Pedersen, Carbohydr. Res., 1993, 249, 91. 18. S. M. Chervin, P. Abado and M. Koreeda, Organic Letters, 2000, 2, 369. 19. D. Becker, K. S. H. Johnson, A. Koivula, M. Schu lein and M. L. Sinnott, Biochem. J., 2000, 345, 315. 20. The effect was rst proposed by J. T. Edward, whose account of the historical background is published in ACS Symp. Ser., 1993, 539, 1. 21. A. Streitweiser and P. H. Owens, Orbital and Electron Density Diagrams, Macmillan, New York, 1973, p. 120. 22. M. J. Cook, T. J. Howe and A. Woodhouse, Tetrahedron Lett., 1988, 29, 471. 23. A. J. Briggs, R. Glenn, P. G. Jones, A. J. Kirby and P. Ramaswamy, J. Am. Chem. Soc., 1984, 106, 6200. 24. F. H. Allen and A. J. Kirby, J. Am. Chem. Soc., 1984, 106, 6197. 25. R. U. Lemieux and A. R. Morgan, Can. J. Chem., 1965, 43, 2205. k and M. Friedemann, Chem. Ber., 1974, 107, 26. H. Paulsen, Z. Gyo rgydea 1590. 27. C. L. Perrin, M. A. Fabian and K. B. Armstrong, J. Org. Chem., 1994, 59, 5246. 28. C. L. Perrin, M. A. Fabian, J. Brunckova and B. K. Ohta, J. Am. Chem. Soc., 1999, 121, 6911. 29. C. L. Perrin and K. B. Armstrong, J. Am. Chem. Soc., 1993, 115, 6825. 30. C. L. Perrin and J. Kuperman, J. Am. Chem. Soc., 2003, 125, 8846. 31. L. S. Bartell and J. K. Higginbotham, J. Chem. Phys., 1965, 42, 851.

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32. A. Streitweiser, C. H. Heathcock and E. M. Kosower, Introduction to Organic Chemistry, Macmillan, New York, 4th edn, 1992. 33. E. L. Eliel, K. D. Hargrave, K. M. Pietrusiewicz and M. Manoharan, J. Am. Chem. Soc., 1982, 104, 3635. 34. H. Booth, K. A. Khedhair and S. A. Readshaw, Tetrahedron, 1987, 43, 4699. 35. T. H. Lowry and K. S. Richardson, Mechanism and Theory in Organic Chemistry, HarperCollins, New York, 3rd edn, 1987, p. 139. 36. A. J. Kirby and N. H. Williams, J. Chem. Soc., Chem. Commun., 1992, 1286. 37. A. J. Kirby and N. H. Williams, J. Chem. Soc., Chem. Commun., 1992, 1285. 38. A. Ouedrago and J. Lessard, Can. J. Chem., 1991, 69, 474. 39. S. J. Angyal, Aust. J. Chem., 1968, 21, 2737. 40. K. Bock and J. . Duus, J. Carbohydr. Chem., 1994, 13, 513. 41. M. P. DeMatteo, S. Mei, R. Fenton, M. Morton, D. M. Baldisseri, C. M. Hadad and M. W. Peczuh, Carbohydr. Res., 2006, 341, 2927.