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Chapter 5 - The Shape of Things to Come, Pages 27-35


Chapter 5

The Shape of Things to Come

A century of investigation had unlocked the stereochemical secrets of D-()glucose, depicted as either a Fischer projection or, more accurately as we have seen, a cyclic molecule in a Haworth formula:a
CHO OH HO OH OH CH2OH D-(+)-glucose OH OH β-D-glucopyranose CH2OH O OH OH

In the early 1900s, most chemists believed that the pyranose ring was nonplanar. However, it took the work of Hassel,b using electron diffraction studies in the gas phase, to put some substance into these notions; the cyclohexane ring was shown to have a non-planar shape (conformation), actually that of a chair:1

He Ha

Some years later, Bartonb recognized the importance of the two different types of bonds present in cyclohexane (equatorial and axial) and used this information to explain the conformation and reactivity in molecules such as the steroids.2,3 The beauty of this result was that, in the chair conformation for cyclohexane, each carbon was almost exactly tetrahedral in shape ± cyclohexane, as predicted and shown, exhibited no Baeyer ``angle strain''.
a b

From now on, hydrogen atoms bound to carbon will generally not be shown.

Odd Hassel (1897 ± 1981, PhD from the University of Berlin), a Norwegian, shared a Nobel Prize (1969) with Derek Harold Richard Barton (1918 ± 1998), British.

28

Carbohydrates: The Sweet Molecules of Life

A further advance by Hassel was to predict that the conformation of the pyranose ring would also be non-planar and, probably, again a chair:
O

For b-D-glucopyranose, the most common monosaccharide in the free form on our planet, all of the hydroxyl substituents on the pyranose ring had to be equatorially disposed (otherwise the molecule is no longer b-D-glucose!), the most stable arrangement possible:
OH O HO HO OH OH

It is well known that cyclohexane, as the neat liquid or in solution, is in rapid equilibrium, via the boat conformation, with another, but degenerate, chair conformation; a result of this equilibrium is that there is a general interchange of equatorial and axial bonds on each carbon atom:
H H H H H H

What would be the consequences, if any, of such a process applied to b-Dglucopyranose?
OH HO O HO HO OH OH HO HO O OH HO OH OH O HO OH

OH

Again an equilibrium is possible, and again via a boat conformation, but the new chair conformation is obviously different here from the original with only axial substituents, the energy of the new conformation is significantly higher (some 25 kJ mol1).

The Shape of Things to Come 29

How, then, do we actually establish the preferred conformation for a molecule such as b-D-glucopyranose?
OH O HO HO OH OH

When the molecule in question is crystalline, then a single crystal, X-ray structure determination will yield both the molecular structure and the conformation. When the molecule is a liquid, or in solution, 1H nuclear magnetic resonance spectroscopy will often give the answer. For a conformation such as the one just above, the value of the coupling constant between H1 and H2 (J1,2) will normally be ``large'' (7± 8 Hz) and so indicative of a trans-diaxial relationship:
OH H HO HO O 2 1 H

OH

HO

It goes almost without saying that the other, higher energy, all axial conformation will have a ``small'' (1 ± 2 Hz) value for J1,2:c
OH OH O HO 2 HO OH 1 H H

A final word of caution is necessary here the conformation of a molecule in the solid state is not necessarily the same as that in the liquid or in solution. As we saw earlier, the D-aldopentoses and D-aldohexoses exist in aqueous solution primarily as a mixture of the a- and b-pyranose forms; occasionally, as with D-ribose, -altrose, -idose and -talose, significant amounts of the furanose forms can also be found.6 In all of these pyranose forms, it is the ``normal'' chair conformation that is almost always preferred; however, a- and b-D-ribose, b-Darabinose and a-D-lyxose, -altrose and -idose all show contributions from the
These values in carbohydrates are in general agreement with the early observations by Lemieux4 and, a little later, with the rule enunciated by Karplus,5 as applied to the relationship between the magnitude of the coupling constant and the size of the torsional angle between vicinal protons.
c

30

Carbohydrates: The Sweet Molecules of Life

``inverted'' chair conformation and, indeed, a-D-arabinose even shows a preference for it.7 Apart from these chair conformations for the D-aldopyranoses, there exist other, higher energy conformations, namely the boat and the skew. It must be stressed that, although these higher energy forms are not present to any extent in aqueous solution, they are discrete conformational intermediates in the conversion of one chair into the other. The half-chair is a common conformation for some carbohydrate derivatives where chemical modification of the pyranose ring has occurred. What follows next is a summary of the limiting conformations for the pyranose ring, namely the chair (C), boat (B), half-chair (H) and skew (S) forms, together with their modern descriptors (it is obviously necessary to avoid such terms as ``normal'' and ``inverted''). Chair:
4 5 2
4C

O 1 4

5 O 3
1C 4

1

3

2

1

Only two forms are possible. The descriptors arise according to the following protocol:8 the lowest-numbered carbon of the ring (C1) is taken as an exoplanar atom; O, C2, C3, C5 define the reference plane of the chair; viewed clockwise (O P 2 P 3 P 5), C4 is above (below) this plane and C1 is below (above); atoms that are above (below) the plane are written as superscripts (subscripts) which precede (follow) the letter; 4 C1 and 1C4 result.

Boat: Six forms are possible, with only two of these shown (the reference plane in each form is unique and obvious).
4 1 5 3
1,4B

4 O 5 B2,5 1

3

O 2

2

The Shape of Things to Come 31

Half-chair: Twelve forms are possible and again only two of these are shown (the reference plane is defined by four contiguous atoms and is again unique).
4 3
o o

5 2 1 5 O 3 4
5H 4 o

2

1

o

O

4H

5

Skew: Six forms are possible, with only one of these shown (the reference plane is not obvious, being made up of three contiguous atoms and the remaining non-adjacent atom8).
4 5 3
1S 5

O

1 2

The chair form is more stable than the skew form, which is again more stable than both the boat and half-chair forms. In pyranose rings that contain a double bond, it is the half-chair that is the normal conformation. The conformations available to the furanose ring are just the envelope (E) and the twist (T); both have ten possibilities and the energy differences among all of the conformations are quite small.
1 4 3
1

3 2 1 EO

4 1 O

2 4 O
2

O 2 E

3

T3

Let us now take time to reflect on the familiar equilibrium that is established when D-()-glucose is dissolved in water:
OH O HO HO acyclic HO 36% OH HO HO OH O OH OH 64%

The two main components of the mixture are present in the indicated amounts and each in the preferred 4C1 conformation. The free energy difference for such an equilibrium amounts to about 1.5 kJ mol1 in favour of the b-anomer, somewhat short of the accepted value (3.8 kJ mol1) for an equatorial over an axial hydroxyl

32

Carbohydrates: The Sweet Molecules of Life

group, the only difference between the two molecules in question. This propensity for the formation of the a-anomer over that which would normally be expected was first noted by Edward9 and termed the anomeric effect by Lemieux.10,11 So wide ranging and important is the effect that it virtually ensures the axial configuration of an electronegative substituent at the anomeric carbon:
OAc O AcO AcO AcO known AcO AcO Br OAc O Br AcO unknown

As well, the anomeric effect is responsible for the stabilization of conformations which would otherwise seemingly capitulate to other, unfavourable interactions:
Cl O AcO AcO 2% Cl OAc OAc 98% OAc CHCl3 OAc O

The origin of the anomeric effect, which itself increases with the electronegativity of the substituent and decreases in solvents of high dielectric constant, has been explained in several ways, including unfavourable lone pair± lone pair or dipole ±dipole interactions in the equatorial anomer and favourable dipole±dipole interactions in the axial anomer:12

.. O .. X O X

O

X

However, the most favoured and accepted explanation involves the interaction between a lone pair of electrons located ``axially'' in a molecular orbital (n) on O5 and an unoccupied, anti-bonding molecular orbital ('B) of the Cl±X bond.13
.. 5 O n σ 1 X

The Shape of Things to Come 33

The ``anti-periplanar'' arrangement found in the axial anomer favours this ``back-bonding'', resulting in a slight shortening of the O5 ± Cl bond, a slight lengthening of the Cl ±X bond and a general increase in the electron density at X. The causes of the anomeric effect continue to be discussed.14 ±17 The reverse anomeric effect18,19 places an electropositive group at the anomeric carbon in a favoured equatorial disposition; for example, N-(tetra-Oacetyl-a-D-glucopyranosyl)-4-methylpyridinium bromide exists essentially in the normally unfavoured 1C4 conformation:
CH2OAc OAc O OAc OAc Br– + N CH3 O X+

The obvious explanation for the origin of this ``reverse'' effect is a simple and favourable interaction of opposing dipoles. There has been a great deal of discussion recently as to whether the reverse anomeric effect even exists.20 ± 23 Probably one of the greatest contributions by Lemieux to the field of carbohydrate chemistry has been his delineation of the importance of the exoanomeric effect.24 ±27 In a simple acetal derived from a carbohydrate, there operates the normal anomeric effect which stabilizes the axial anomer over the equatorial anomer.
.. C2 C5 OR C1-O5 .. H .. 5 2 OR O 5 2 .. O.. O R C2 .. R H C1-O1 .. O5

However, in the appropriate conformation of the exocyclic alkoxy group, there is again an anti-periplanar arrangement of a lone pair on oxygen (of OR) and the Cl ± O5 bond the so-called ``exo-anomeric effect''.d Because these two anomeric effects operate in opposite directions, the exo-anomeric effect is not considered important with such axial acetals. However, in an equatorial acetal, where there is no contribution from a normal anomeric effect, it is the

d

As a consequence of this new term, the ``anomeric effect'' is sometimes referred to as the ``endoanomeric effect''.

34

Carbohydrates: The Sweet Molecules of Life

exo-anomeric effect that is dominant and dictates the preferred conformation of the alkoxy group at the anomeric carbon atom:
5 2 O .. O .. R O5 R H .. C2 ..

Taken to its logical conclusion, the exo-anomeric effect appears to be responsible for the helical shape of many polysaccharide chains it is certainly important in determining the shape of many biologically important oligosaccharides.28,e We have seen in these chapters that the seminal studies of Fischer were carried along in the early part of the next century by people such as Haworth and Hudson. However, it was to be Lemieux29,f who would dominate carbohydrate chemistry for the major part of the twentieth century, with enormous contributions to nuclear magnetic resonance (n.m.r.) spectroscopy, conformational analysis, glycobiology and synthesis. His final words on the factors that govern carbohydrateaprotein binding are truly memorable.30

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
e f

Hassel, O. and Ottar, B. (1947). Acta Chem. Scand., 1, 929. Barton, D. H. R. (1950). Experientia, 6, 316. Barton, D. H. R. (1953). J. Chem. Soc., 1027. Lemieux, R. U., Kullnig, R. K., Bernstein, H. J. and Schneider, W. G. (1957). J. Am. Chem. Soc., 79, 1005. Karplus, M. (1963). J. Am. Chem. Soc., 85, 2870. Angyal, S. J. (1984, 1991). Adv. Carbohydr. Chem. Biochem., 42, 15; 49, 19. Collins, P. M. and Ferrier, R. J. (1995). Monosaccharides: Their Chemistry and Their Roles in Natural Product, John Wiley & Sons, Chichester, p. 33. Schwarz, J. C. P. (1973). J. Chem. Soc., Chem. Commun., 505. Edward, J. T. (1955). Chem. Ind., 1102. Lemieux, R. U. (1964). In Molecular Rearrangements, de Mayo, P. ed., Interscience Publishers: John Wiley and Sons, New York, p. 709. Lemieux, R. U. (1971). Pure Appl. Chem., 25, 527. Wolfe, S., Rauk, A., Tel, L. M. and Csizmadia, I. G. (1971). J. Chem. Soc. B, 136. Juaristi, E. and Cuevas, G. (1992). Tetrahedron, 48, 5019. Ma, B., Schaefer, H. F., III and Allinger, N. L. (1998). J. Am. Chem. Soc., 120, 3411. Thatcher, G. R. J. (1993). The Anomeric Effect and Associated Stereoelectronic Effects, ACS Symposium Series 539, American Chemical Society, Washington DC. Juaristi, E. and Cuevas, G. (1995). The Anomeric Effect, CRC Press, Boca Raton.

A general term for small chains of monosaccharides, with up to ten residues in the chain. Raymond U. Lemieux (1920 ±2000), PhD under C. B. Purves (McGill University).

The Shape of Things to Come 35

17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Box, V. G. S. (1998). Heterocycles, 48, 2389. Lemieux, R. U. and Morgan, A. R. (1965). Can. J. Chem., 43, 2205. West, A. C. and Schuerch, C. (1973). J. Am. Chem. Soc., 95, 1333. Perrin, C. L., Fabian, M. A., Brunckova, J. and Ohta, B. K. (1999). J. Am. Chem. Soc., 121, 6911. Perrin, C. L. (1995). Tetrahedron, 51, 11901. Vaino, A. R., Chan, S. S. C., Szarek, W. A. and Thatcher, G. R. J. (1996). J. Org. Chem., 61, 4514. Randell, K. D., Johnston, B. D., Green, D. F. and Pinto, B. M. (2000). J. Org. Chem., 65, 220. Lemieux, R. U., Pavia, A. A., Martin, J. C. and Watanabe, K. A. (1969). Can. J. Chem., 47, 4427. Praly, J.-P. and Lemieux, R. U. (1987). Can. J. Chem., 65, 213. Tvaros ka, I. and Bleha, T. (1989). Adv. Carbohydr. Chem. Biochem., 47, 45. Tvaroska, I. and Carver, J. P. (1998). Carbohydr. Res., 309, 1. Meyer, B. (1990). Topics Curr. Chem., 154, 141. Lemieux, R. U. (1990). Explorations with Sugars: How Sweet it Was, American Chemical Society, Washington DC. Lemieux, R. U. (1996). Acc. Chem. Res., 29, 373.


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