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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 first choice in determining

conformation.

Carbohydrates, however, are very polar molecules. This means that their gas-

phase conformations, which can be computed, are likely to be largely deter-

mined by electrostatic and intramolecular hydrogen bonding interactions. They

are therefore likely to be of questionable relevance to the conformation of thesame molecules in polar solvents, particularly water. At the time of writing

(early 2007) there does not appear to be a force field which can accurately

predict the conformations of carbohydrates in water; by contrast, Angyals

instability factors, a purely empirical way of estimating carbohydrate confor-

mations, 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 difficult to handle with

computational economy.

In addition to steric effects and electrostatic effects, the conformational

analysis of carbohydrates requires two stereoelectronic effects to be taken into

consideration: the gauche effect and the anomeric effect, in its various mani-

festations. Both of these effects can be considered as aspects of no-bond

resonance.

2.2 THE GAUCHEEFFECT

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 temper-atures. However, 1,2-difluoroethane prefers the gauche conformation, with an

internal energy difference of 7.3 kJ mol1 between it and the trans conform-

ation.2 The effect is seen in other, less clear-cut cases with oxygen substituents.

The origin of the effect is considered to lie in the same phenomena that are

41

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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 poly-

ethylene, with all the four-carbon units being in the conformation of trans-butane. Because of the gauche effect, 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 derivefrom 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

Figure 2.1 Preferred conformations of butane and 1,2-difluoroethane, illustrating thegauche effect. In the gauche conformation each CF s* orbital canoverlap with a CH s orbital on the vicinal carbon, corresponding tono-bond resonance as shown. Such no-bond resonance would be dis-favoured if the CF bonds were trans, since it would remove electrondensity from an electronegative element. The effect is strong enough inthis case to overcome the electrostatic repulsion between the two CFdipoles, which favours the trans form.

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on the x atoms). They realised that if these coordinates were polar rather than

Cartesian, then ring conformations could be described in ways which corre-

sponded to chemical intuition. They accordingly defined 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, theyrepresent the simplest case for the CremerPople treatment, x 4, so that theirconformation is described uniquely by the puckering amplitude, i.e. the amount

by which the fourth atom is displaced from the plane defined by the remaining

three (Figure 2.3).

OH

HO

HO

OH

OH

OH

HO OH

OH

OHHO

HOOH

OH

OH

OH

OH

OH

OH

HO

OH

OH

OH

OH

HO OH

OHHO

HO OH OH

OH

OH

OH

OH

OH

D-mannitol

D-glucitol

zig-zag

1,3-syn interaction

sickle

6 1

61

64 2

6 4 2

OH

OH

OH

OH

OH

OH

64 2

Figure 2.2 Conformations of D-glucitol and D-mannitol. Note the apparent tolera-tion of vicinal hydroxyl groups being either gauche or trans, but theprohibition on 1,3-syn interactions of hydroxyl groups.

Figure 2.3 CremerPople treatment of ring conformations. Left, cyclobutane con-formations are completely defined by degree of pucker; centre, cyclopen-tane conformations require specification of the degree of pucker and apseudorotational angle; right, cyclohexane conformations require speci-fication of the degree of pucker and two angles; for conformations on the

equator (y 901) j becomes a pseudorotational angle similar to that forcyclopentane.

43Conformations of Monosaccharides

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For five-membered rings (x 5), only two parameters, the puckering para-meter 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 five-membered

rings all the substituents are eclipsed. Puckering of the ring results in two low-

energy forms, the envelope, in which one ring atom lies out of a planecontaining the remaining four, and the twist, in which two adjacent atoms lie

above and below the plane defined by the remaining three. There are 10

envelope conformations and 10 twist conformations, which can be intercon-

verted by rotations about single bonds. This gives the appearance of the out-

of-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 confor-

mations 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 doesnot 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 five-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 half-

chair 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 five-

membered rings, but with five, 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 conti-

guous ring atoms coplanar, with the remaining two above and below the plane

so defined. The well-known chair conformation of cyclohexane has a six-foldaxis 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 qualita-

tively by italicised letters T, E, C, H, S and B for twist, envelope, chair, half-

chair, skew and boat, respectively; T refers only to furanose rings and C, H, Sand 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 specified by superscripts and sub-

scripts referring to atoms above and below a defined plane; thus 4C1 (the

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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 Eand Hdefine themselves. The reference

plane in B is defined not by either of the planes containing four contiguous

atoms, but by the plane defining the bottom of the boat. Above the plane isdefined 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 con-

taining three ring atoms can be drawn through T conformers and containing

four ring atoms through Cand Sconformers. 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 definition plane of a particularconformer is the direction from which the carbon atom numbers increase round

the ring has the effect of reversing conformational designations between

enantiomers the mirror image ofa-D-glucopyranose in the 4C1 conformation

is a-L-glucopyranose in the 1C4 conformation.

In the case of furanosides, especially nucleosides, Altona and Sundara-

lingams original symbols for the pseudorotational angle P and pucker tm (or

sometimes jm) are used; P 01 is defined as the3T2 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 Pr 361 as N

Figure 2.4 Conformational itinerary of a furanose ring.


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(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 conform-

ations 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 confor-mations are named and also to illustrate the operation of various effects which

determine the conformations. The conformations are all necessarily found on the

surface of the CremerPople sphere; the inter-relations of the various confor-

mations in the northern and southern hemispheres are set out in Figure 2.6.

-D-Glucopyranose in the4C1 conformation

Methyl N-acetyl -D-neuraminide

in the2C

5conformation

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

-D-glucopyranosyl pyridiniumion in the 1S3 conformation:

the reference plane goes through

C4, C5, O and C2

Tri-O-acetyl -D-xylopyranosylfluoride in the 1C4 conformation

Figure 2.5 Preferred conformations of some pyranose derivatives, showing the

reference plane.

46 Chapter 2

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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

Figure 2.6 Conformations on the surface of the CremerPople sphere for a pyranosering: (a) Northern hemisphere; (b) Southern hemisphere.


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at 600 MHz most splitting systems of the ring protons of sugars are first order,

although even at this field (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 inthe 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

differences (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 significant barriers to interconversion of chair six-

membered rings, however, mean that pyranosyl systems which significantly

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 effect

(Section 2.6), while it affects preferences, if anything reduces conformational

barriers13]. In the slow exchange regime, two distinct spectra of the different

conformers are observed, in the same way as different 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 ofB601, (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

field of all the ring protons, since they are attached to carbons with two electron-

withdrawing oxygen substituents. Axial hydrogens resonate at higher field than

equatorial hydrogens, but even axial anomeric hydrogens can usually be readily

identified. More troublesome in the case of water-soluble materials is that theproton 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 configur-

ation, if the conformation can be predicted with confidence. Thus, in the D-gluco

series, all the substituents except the anomeric are equatorial in the 4C1 confor-

mation, 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 configuration and a 78 Hzsplitting a b configuration; as discussed above, the axial H1 of b-configured

glycoside resonates at higher field (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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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 (1J13C;H1J13CH for a glycosides is around 170 Hz, compared to

160 Hz for their anomers14).

If the anomeric configuration of a glycosyl derivative is known with confi-

dence, then three-bond proton coupling constants can enable the conformationto be determined. Thus, the bulk of the pyridinium ring in a-D-xylopyranosyl-

pyridinium 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 different couplings.

2.6 THE ANOMERIC EFFECT

Many carbohydrate conformations follow simply from the same considerations

that govern alicyclic conformations, that bulky substituents prefer equatorial

Figure 2.9 Predicted H1H2 dihedral angles for b- and a-glucopyranosides (top) andb- and a-mannopyranosides (bottom).


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and pseudo-equatorial orientations and that aligned electrostatic dipoles in-

volve large energetic cost. Many, but not all: b-D-xylopyranosyl fluoride 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 fluoride, 12%

only of the b-compound appears to be present at equilibrium.19

The tendency of electronegative substituents at C1 of a pyranose ring toadopt an axial orientation is termed the anomeric effect.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 effect, one based on classical (pre-quantum) elec-

trostatics and the other on frontier orbital theory. The consensus that appears

1.1

3.4

9.9

7.9

O

OH

H

H

HO

H

OH

H

OCH3

H

OH

O

H

OH

OH

H

OH

H

N+

H

CH3

H

H

1.4

0.9

2.72.5

1.5

1.8

13.4

Figure 2.10 Protonproton coupling constants in a-D-xylopyranosyl-4-methyl-pyridinium ion15 and methyl-b-D-galactopyranoside. Note the differ-ences between coupling constants associated with very similar dihedralangles and the lower couplings experienced when the proton-attachedcarbon atoms have multiple electron-withdrawing groups.

iThe classic way of making per-O-acetylglycopyranosyl bromides (acetobromo sugars) is ace-tylation 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 andwater16; chlorides are made similarly, with the acetylation solution saturated with HCl; fluoridescan be made from the anomeric mixture of fully acetylated sugars in liquid HF or, less hazardously,pyridinium poly(hydrogenfluoride).17 Per-O-acetylglycosyl iodides can be made with anhydrousHI in dichloromethane at low temperature.18

52 Chapter 2

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to have emerged is that frontier orbital interactions are the main origin of the

effect, 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 efficient (in the case of

a pyranose ring) when the CX substituent is axial, but not when it isequatorial.

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 ofc, 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 maximumin 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 sp 3

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 efficient [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 CXbond 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 effect, 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 effect 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

R

OR

(two sp3 orbitals)

R

OR

(one p and one sp orbital)

R

OR

Electron density (2)

Figure 2.11 Cartoons of contours ofc for the equivalent representations of oxygenlone pairs in an ether as in two sp3 orbitals or one p and one sp orbitaland an electron density contour. Note that hybrid spn orbitals do nothave a node at the nucleus, as a pure p orbital does, but rather onebehind the nucleus, between it and the small lobe.


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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 defined 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 effect 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

effect, however, of decreasing the negative charge on the exocyclic oxygen and

according to the electrostatic model the anomeric effect should decrease. In fact,

O

X

O

X

O

X

O+

X-

Overlap of p-type lone pair with orbital of an axial substituent.

This corresponds to no-bond resonance in the sense shown

Overlap of sp-type lone pair with the

orbital of an equatorial substituent. The splone 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 effect.

iiIf the two lone pair sp3 orbitals on oxygen are drawn in the customary skittle shapes, the majorlobes in a Newman projection look like two rabbits ears. The direct electrostatic effect of lone pairelectrons was therefore dubbed the rabbits ears effect, but failed to find acceptance, as muchfrom the overtones of Beatrix Potter as from the fact that the shape of electron density resemblednot two, but one ear (Figure 2.11).

54 Chapter 2

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as is shown in Figure 2.14, there is a small effect 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 effect to be experienced unmasked by the

electrostatic effect, as it is in cyclohexane solution.The no-bond resonance model of the anomeric effect predicts that, in a series

of axial aryloxytetrahydropyran derivatives, the intracyclic bond should short-

en and the extracyclic bond should lengthen as the parent phenol becomes more

acidic and the ion-paired canonical form; any effect 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

lengths (A ) of the extracyclic bond (x) and the intracyclic bond (n) were given

by eqns (2.2) and (2.3), respectively:

x 1:493 0:006495pKar 0:985 2:2

n 1:364 0:003639pKar 0:939 2:3

Figure 2.13 Electrostatic explanation of the anomeric effect.

O

O

X

O

O

X

X = NO2CN,

Cl,

X = H, 68CH3, 69

OCH3, 69

7878

71

Figure 2.14 Proportions of axial conformer of 2-aryloxytetrahydropyrans in deutero-chloroform solution.22 The conformational equilibrium is invariant withX in cyclohexane (8487% axial).


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However, similar, but not as pronounced, trends were also seen with sevenequatorial tetrahydropyranyl ethers, with a pKa range of 13 units:

x 1:456 0:00476pKar 0:945 2:4

n 1:394 0:00214pKar 0:911 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 effect in

terms of classical electrostatic dipole interactions has been the apparent exist-

ence of a reverse anomeric effect. 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 effect was first observed in glycosyl pyridinium salts25 and, in

what at first sight seemed to be an elegant experiment, the steric demand of the

bulky pyridinium salt was apparently eliminated as the source of the effect 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 effect on its steric requirements, since

protonation takes place at a remote siteiii.27

O R

On

x

O OR O

X

O

OR

O

Figure 2.15 Tetrahydropyranyl structures used in the investigation of the anomericeffect by X-ray crystallography.

iiiThe A values for imidazole and imidazolium in cyclohexyl systems, measured directly, are both 9.2 0.4 kJ mol1, but measurement of the difference in Ka directly indicates that the imidazolium Avalue is about 0.4 kJ mol1 higher.

56 Chapter 2

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However, NMR titration of a mixture of the anomeric glucopyranosylimi-

dazoles 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 effect, but is what would be predicted on the frontier orbital picture ofthe normal anomeric effect 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 xylopyranosyl-

imidazoles, remain in the 4C1 conformation on protonation. On the electro-

static 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) followsfrom the thermodynamic box of Figure 2.16, where Ka refers to an acid

dissociation constant and Ke to an anomeric equilibrium constant ( [b]/[a]):

Kba K

e Kaa K

0e 2:7

The difference in anomeric equilibrium between protonated and neutral

glucosylimidazoles can thus be measured as an acid dissociation constant ratio

(i.e. pKa difference).

Proton transfers are normally rapid on the NMR time-scale at ordinary

temperatures. Therefore, the chemical shift of all the nuclei in part-protonatedglucosylimidazoles 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/Ka

b will be

OHO

OH

HO

OH

NNH

+ OHO

OH

HO

OH

N N

OHO

OH

HO

OH N

NH+

OHO

OH

HO

OHN

N

Ka

Ka

Ke+ Ke0

Figure 2.16 Thermodynamic box for protonation and equilibration of glucopyrano-sylimidazoles.


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2.7 CONFORMATIONAL FREE ENERGIES IN PYRANOSES

The length of the CO bond in ethers is generally taken as 1.43 A ,24 whereas the

length of an unstrained CC bond is around 1.53 A .31 This makes tetrahydro-

pyran slightly less puckered than cyclohexane. In cyclohexane chemistry,

conformational preferences are discussed in terms of A values for substituents

(the free energy difference 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

effect, not least because they vary with the position of substitution, even with

non-polar substituents which do not exert an anomeric effect (Table 2.1).

For 2-aryloxysubstituents, which do exert an anomeric effect, 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 effect 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 differ-

ences 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 effect 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 effect.

An example of the power of these instability factors is their prediction that

epimerisation ofb-D-mannopyranose at C5 to give a-L-gulose will change the

conformational preference of the ring from 4C1 to1C4. A closely analogous

epimerisation occurs during biosynthesis of alginate (Chapter 4), whose

Table 2.1 A values (kJ mol1) for cyclohexane and

tetrahydropyran.

Substituent Cyclohexane32,33 Tetrahydropyran34,35

2-CH3 7 123-CH3 64-CH3 82-COOCH3 5.5 5.83-COOCH3 2.52-CH2OH 123-CH2OH 3.32-Cl 2.2 o7.53-Cl 2.84-Cl 1.3


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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: five-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

Table 2.2 Interaction energies (kJ mol1) in carbohy-

drate systems.

Axial Haxial O (OH, OAc, etc.) 1.9Axial Haxial C (CH3 or CH2OH) 3.8Axial Oaxial O 6.3Axial Oaxial C 10.5Vicinal Ovicinal O (ee or ae only, not aa) 1.5Vicinal Ovicinal C (ea or ee only, not aa) 1.9Anomeric effect, O1 and O2 equatorial 2.1Anomeric effect, O1 equatorial, O2 axial 4.2

-D-mannopyranose,4C1

-D-mannopyranose,1C4 -L-gulopyranose,

4C1 -L-gulopyranose,

1C

4

3 OOvic

4.5 2 OOvic 3.0 3 OOvic 4.5 2 OaxHax

1 OCvic 1.9 1 OaxHax 1 OaxHax 2 OOvic 3.01 O

axH

ax2 C

axO

ax21.0 1 OC

vic1 OC

vic1.9

1 anomeric, O2ax 4.2 1 OaxOax 2 CaxHax 7.6

1 anomeric, O2ax

Total Total Total Total 8.7

OHO

HO

HO

OH

OH

O

OH

OH

OH

OHHO

OHO

HO

HO

OH

OH

O

OH

OH

OH

OH

HO

1.9

12.5

1.9

32.2

6.3

1.91.9

20.1

4.2

3.8

Figure 2.18 Use of instability factors to predict the conformation ofb-D-mannopyra-nose and a-L-gulopyranose.

60 Chapter 2

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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 despitethe axial 2OH in mannopyranose, furanose forms are present in only trace

amounts.

D-Fructose is D-arabinose with the anomeric hydrogen replaced by a hydro-

xymethyl 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 effect: the A value for hydroxyl (Table 2.1) predicts an equatorial/

axial preference in cyclohexane of about 5.4:1. The enhancement of the ano-meric effect 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 effect, so that the OH-axial pyranose

anomer is overwhelmingly predominant, as in fructopyranose and N-acetyl-

neuraminic acid (Figure 2.19).

OR

HO

HO

OH

OHO

R

HO

OH

OHOH

H

-D-xylopyranose and -xylofuranose (R = H)

and -D-glucopyranose and -glucofuranose (R = CH2OH)

OR

HOOH

OH

OH

R

HO

OH

OH

HO

O

H

-L-arabinopyranose and -arabinofuranose (R = H)

and -D-galactopyranose and -galactofuranose (R= CH2OH)

-D-mannopyranose and -mannofuranose

OOH

OHH

HO OH

HOOHO

HO OH

HOHO

-D-ribopyranose and -ribofuranose (R = H)

and -D-allopyranose and -allofuranose (R = CH2OH)

OR

OH

OHH

HO

OH

OR

HO

OHOH OH

OH

O

OH

HO

HOOH

O

OH

HO

HO

OH

HO

-D-fructopyranose and -fructofuranose

O

OH

COOH

HO

HO

HO

OH

AcNH

-D-N-acetylneuraminic acid

Figure 2.19 Conformations of representative pyranose and furanose forms of com-mon reducing sugars.

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


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2.9 CONFORMATIONS OF HYDROXYMETHYL GROUPS

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 H6Rand H6S. However, rotation about C5C6 is sufficiently fast that the system is

in the fast-exchange region and an average value ofw 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 interms 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 effect; addi-

tionally, 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 C5

O5

H5

C4

O6

H6s H6R

gg

C4

H5

O5H6R

O6 H6s

gt

C4

H5

O5

H6s

H6R

O6

tg

(b) Viewed C5-C6

O5C4

H5HR HS

O6

gg

HRC4 O5

H5O6

HS

gt

HS

HRO6

C4 O5

H5

tg

Figure 2.20 Three perfectly staggered rotamers about the exocyclic C5C6 of al-dohexopyranoses.

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

62 Chapter 2

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2.10 CONFORMATIONS OF SEPTANOSIDES

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

confined 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 conforma-

tions is defined by three contiguous ring atoms, with the ring atoms aboveand below the reference plane, superscripts or subscripts. Substitution pat-

terns can enforce the occupancy of a single conformer, as in the 5,6TC3,4conformation adopted exclusively by methyl a-D-glycero-D-idoseptanoside,

in which the anomeric effect 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 significant

extent (Figure 2.21).

OH

HO

OH

HO O H

OCH3

OH

H

methyl -D-glycero-D-idoseptanoside

5C1,2 (energy maximum)3,4TC5,6

3,4TC5,6

OHO

OH

HO

OH

H

OCH3

H

OH

OHO

OH

HO

OH

OCH3

HH

HO

methyl -D-glycero-D-guloseptanoside

6,OTC4,5

H

OCH3OHO

OH

HO

OHOH

H

Figure 2.21 Some conformations of glucose-derived septanosides.


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