S. G. Sunderwirth
Conformational Analysis of
and Gary G. Olson Colorado State University Fort Collins
the Pyranoside Ring
The fact that most monosaccharidesdonot exist in the free aldehyde form can be demonstrated by a negative Schiff aldehyde test, by mutarotation, and by formation of isomeric pentaacetates and glycosides. Most aldohexoses exist in the hemiacetal structure which is formed by the reaction of the aldehyde group with the alcohol function on carbon number five. The two anomeric ring forms, shown in the Fischer formulas (Fig. l),are called pyranose forms because of their relationship to pyran. Cantor and Peniston (1) used the dropping mercury electrode to determine the amount of free aldehyde form present in the aqueous equilibrium mixture. At pH = 7, the equilibrium mixture contained only 0.024 % of the free aldehyde form.
I
H-+-OH HO-F-H H-?-OH
H-?-OH O A HO-J;-H 7 H-?-OH H-;-OH CHIOH
I
H-9-
C$OH
-
L
0-~glucopyrenose ddehydo-n-glucose Figure
1.
arrangements of the hydrogens and hydroxyls are not evident in the Haworth formula. The pyranoside ring actually may exist in eight different structures. These structures, formed by simple rotation about the carbon-carbon or carbonoxygen bonds, are referred to as conformers. The study of the different conformers and their reactions is called conformational analysis. The ring forms consist
HO-C-H I H-C-OH -H ;CHpOH
8-D-ghcopyranose
Fircher convention.
Because of the important role which the ring forms play in carbohydrate reactions, a better understanding of the structures of these rings is extremely important. The Fischer formulas shown give very little information as to the actual shapes of the rings. A much better representation of the pyranose structure is shown below in the Haworth (2) formulas. I n this convention (Pig. 2) the viewer is looking a t the molecule from the side with the heavy line toward the eye of the viewer. Those groups which were on the right side of the molecule in the Fischer convention are placed down in the Haworth convention, and those which were on the left are placed up in the Haworth representation. This latter convention is a much better representation of the true shape of the molecule than the Fischer convention. However, a molecular model of WDglucopyranose shows clearly that even the Haworth representation leaves much to be desired. The spatial
Choir and boat conformotionr of the pyronoride ring (3).
of six boat forms and two chair forms (Fig. 3). The existence of the boat forms is excluded except in special cases such as methyl 2, 6-anhydro-a-D-altropyranoside (4),which is capable of existing only in the boat form B% The general argument against the boat forms is
Perspective Figure 2.
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Journol o f Chemical Education
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03 Figure 3.
Figure 4.
Newman Convehtion
83 conformation of 0.1)-glucopyranore.
essentially the same as that against the boat forms of cyclohexane (5). In the boat forms many of the groups on adjacent carbon atoms are in an eclipsed arrangement. Consider, for example, p-D-glucopyranose in the BS conformation (Fig. 4). Here the groups attached to carbon atoms one and two and also four and five1 are in an eclipsed arrangement. This eclipsed arrangement is not as conformationally stable as either of the two chair forms which do not have this eclipsed arrangement. In the C1 chair form for 8-Dglucopyranose all the adjacent groups are staggered (Fig. 5). This is a much more stable arrangement than having the adjacent groups eclipsed. The instability of the eclipsed form is due to the non-bonded interaction of the adjacent groups. Therefore, the boat forms are not considered in studying the conformational arrangements of the pyrauosides.
Perspective Figure 5.
Newman Convention
C i Conformation o t 6-D-giumpyranore.
I n deciding which conformation is more stable, a number of factors need to be considered. Reeves (6) has assigned numerical values to each of these instability factors. Any erected group (i.e., axial) other than hydrogen is said to lend an element of instability to the molecule due to non-bonded interaction of the groups. Reeves assigns a value of one to this interaction. If the primary carbinol on carbon number five is erected on the same side of the ring as an axial hydroxyl group, an instability number of 0.5 is assigned to this interaction. This number is in addition to the instability numbers assigned to the axial carbinol (one unit) and to the axial hydroxyl (one unit). The non-bonded interaction between the bulky primary carbinol group (-CHzOH) and a hydroxyl group would certainly be greater than that between two hydroxyl groups. In fact, it is quite likely that the additional instability factor of 0.5 assigned by Reeves is too low. This interaction involving the primary carbinol and another axial group is called the Hassel-Ottar (H) effect (7). Another element of instability is that caused by a hydroxyl group on carbon number two which bisects the angle between the two oxygen atoms on carbon number one (Fig. 7). This effect (called A2) has been assigned an instability factor of 2.5. The instability number of the axial hydroxyl group (one unit) on carbon number two is included in the A2 effect.
Favorable Chair Conformations
The pyranosides are capable of existing in either of two conformations, the C1 or the 1C (Fig. 6). Since the two forms are in equilibrium, that conformer which is more stable will predominate. A close examination of the structures above, or preferably of molecular models, will reveal that there are two different types of substituents attached to each carbon atom. One type of substituent is perpendicular to the plane of the ring. These substituents, illustrated by the hydrogen atoms in the C1 conformation, are called axial (a) groups (indicated by solid lines in Fig. 6). The other groups are parallel to the plane of two sides of the ring.
CI Figure 6.
IC
6-D-glumpyranore.
These groups, illustrated by the hydrogen atoms in the 1C conformation, are called equatorial (e) groups (indicated by dotted lines in Fig. 6). It is apparent that the axial groups in one conformation are equatorial in the other.2 All figures (except Fig. 3 ) are numbered clockwise from the oxygen as s reference point except the Fisher convention, which ia numbered from top to bottom, and the Newman convention. The latter may be numbered by imagining the oxygen to he in the foreground, then counting from left to right around the ring. V n all perspective formulas throughout this paper, the axid substituents are indicated by solid lines and the equatorial substituents are indicated by dotted lines.
Figure 7.
A2 Effect in 7C conformation of a-D-glucopyranore,
Use of Instability Factors to Predict the More Stable Anomer
These instability factors can be used to predict which anomer of an u-8 anomeric pair would be more stable a t equilibrium. The equilibrium between the two anomeric forms of glucose is illustrated in Figure 2. Consider first 8-D-glucopyranose. I n the C1 conformation (Fig. 6) there are no instability factors. However, in the 1C conformation there is a Hassel-Ottar effect (0.5) and five axial hydroxyl groups. This gives an instability number of 5.5. Since the 1C and the C1 forms are in equilibrium, the more stable form (C1) would predominate. Now consider the or-anomer (Fig. 8). Here it can be seen that the C1 form contains one axial hydroxyl group for an instability number of one. The 1C conformation has a A2 (2.5 units) effect, a Hassel-Ottar effect (0.5 units) and three other axial hydroxyl groups (3 units) for a total instability number of 6.0 units.
IC
CI Figure 8.
m-D-glucopyronore.
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It is again apparent that the molecule would exist predominately in the C1 conformation. I n support of the conformational stability of the C1 form, Lemieux et al. have shown by proton magnetic resonance that the anomeric pentaacetates of glucose, galactose, and mannose exist in the C1 conformation (8). They have also shown that corresponding glycosyl chlorides of glucose exist in the favored C1 conformation (9). In choosing which anomer is more stable, we should consider the instability factors in the more stable conformation of each anomer. Since the stable conformation (Cl) of the 8-D-glucopyranose has no instability factors, and the stable conformation of the a-anomer has an instability number of one, we would expect the equilibrium between the anomeric forms to favor the 8-anomer. This has been found to be true. I t is known that an aqueous solution of glucose is composed of about 63% of the p-anomer and 37% of the u-anomer. This same correlation can be shown for a number of other sugars.
side forms. This has been used as an argument for Scheme B, in which the ring is opened during the reaction. Inspection of a scale model will reveal that the pyran ring need not he opened in order to form a furan ring. The hydroxyl group on carbon four in the 1C conformation (Figs. 6 and 8) could initiate a nucleophilic attack on carbon number one in the carbonium ion I11 (Fig. 10). This would account for the formation of the fnranose (or furanoside) without going through the intermediate carbonium ion V.
Conformational Analysis and Glycoside Hydrolysis
The anomeric methyl glycosides of the hexoses and pentoses have been prepared for most of the known sugars (Fig. 9). In the case of aldohexoses these glycosides exist in the pyranoside form. Pyranoside forms have also been prepared for the aldopentoses.
a-D-glucopyranose Figure 9.
Methyl a-D-glucopyranoside
Glyceride formotion
Figure 10.
Proposed hydro1y.i~ mechanimr
Scheme A, I -111;
scheme
B, I-VI.
The above reaction (Fig. 9) is an equilibrium since the glycosides may be readily hydrolyzed using aqueous HCI. Bunton et al. (10) proposed the following two mechanisms (Fig. 10) as the only ones which are in agreement with their experiments and also with accepted acetal hydrolysis (11, 19, IS). Although I1 111 (Scheme A) or IV V (Scheme B) are the slow steps, the equilibrium between I and I1 or I and IV would have an effect on the over-all rate of reaction. The larger the equilibrium constant in either case the greater the overall rate of hydrolysis of the glycoside. Shafizadeh and Thompson (14) have indicated that the availability of the ring oxygen (Scheme B) plays a significant role in controlling the rate of hydrolysis. These workers have assumed that hydrolysis occurs by breaking the ring as shown in Scheme B. Indeed, there is experimental evidence in the literature to support the assumption that the ring oxygen is attacked rather than the methoxyl oxygen (15, 16, 17). Much of this work was carried out using acetylated sugars in acetic anhydride solutions. Comparison of these reaction conditions with the aqueous acid-catalyzed glycoside hydrolysis does not seem valid. On the other hand, glycoside formation itself is a reversible reaction, and a correlation between hydrolysis and glycoside formation may he valid. Mowery et al. (18) showed that furanosides (5-membered rings) are formed in the first stages of glycoside formation and these are slowly converted to the more stable pyrano-
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-
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If the availability of the ring oxygen plays a significant role in glycoside hydrolysis, then a significant difference in the steric hindrance of this oxygen to proton attack should be obvious by a study of scale models in the C1 conformation. For example, it is known that methyl p-D-glucopyranoside hydrolyzes nearly twice as fast as the a-anomer (Table 1). Then if Scheme B is the correct pathway for hydrolysis, a difference in the availability of the ring oxygen should be readily seen in the scale models. Actually, it is difficult to determine, using models, in which anomeric form the ring oxygen is more exposed to attack. Certainly, the difference in availability of the ring oxygen could not account for such a large difference in hydrolysis rates. Possibly a better way to explain the effect of conformations on the rate of glycoside hydrolysis would he to assume that the availability of the methoxyl oxygen (Scheme A), rather than the ring oxygen, exerts an influence on the rate. To do this, consider the two conformations of the u-form (Fig. 8) and the two conformations of the p-form (Fig. 6). The hydroxyl group on carbon number one of the free sugar would be replaced by the methoxyl group to form the glycoside. This should have very little effect on the relative stabilities of the conformations. These glycosides, in both the u- and &forms, would he expected to exist predominately in the C1 conformations. I d t h e C1
conformation of the p-anomer the methoxyl group is in an equatorial position. I n the C1 conformation of the a-anomer the methoxyl group is in the axial position. A study of scale models will reveal a very significant fact about the difference in these anomers. In the equatorial positon (6-anomer) the methoxyl oxygen is open to attack by a proton (or hydronium ion) from many sides. In the axial position (a-anomer) the methoxyl oxygen is greatly shielded from proton attack. Thus, in the 6-form the equilibrium between I and I1 (Fig. 10) would be shifted in the forward direction more than for the a-form. This could account for the more rapid hydrolysis of the p-form. Foster and Overend (19) are in agreement with the concept that initial proton attack occurs at the methoxyl oxygen. A general rule which might apply to the glycoside hydrolysis of pyranosides may be stated as follows: That anomer, in any anomeric pair of methyl pyranosides, in which the more stable conformer contains the methoxyl group in a n equatorial position will hydrolyze faster than its corresponding anomer if the methoxyl group of the latter i s axial in the more favored conformation. This rule has been applied to several methyl pyranosides, and the results are shown in Table 1. I t can be seen that the rule stated above holds for all the anomeric pairs listed. Gulose was included to bring out the point that there are other factors involved besides the axial or equatorial arrangements of the methoxyl group in the more favored conformer. Both a- and 0-anomers of D-gulose have the methoxyl group in an equatorial position in the favored conformer. Therefore, other factors must be in operation to account for the large differences in rates of hydrolysis. An interesting piece of work was done by Haworth and his co-workers (21, 22) that tends to support the generalization that equatorial glycoside groups are more readily hydrolyzed than axial glycoside groups. Haworth prepared the a- and 8-anomers of methyl 2, 4 - di - 0 -methyl- 3,6 - anhydro - D - glucopyranoside. These compounds cannot exist in the C1 conformation. Excluding any boat forms, these glycosides must exist in the 1C conformation. Haworth found that the a-anomer hydrolyzed faster than the p-anomer. This is just the opposite of the results shown in Table 1. As shown in Fig. 11, the a-anomer must have the methoxyl on carbon number one in an equatorial position. Thus, the p-anomer must have this methoxyl in an axial position. These results are in agreement with th6 greater availability of the equatorial position
over that of the axial position. The interesting point is that Haworth's work was done almost ten years before carbohydrate chemists began to use conformational analysis. The examples presented here illustrate how conformational analvsis is ~resentlvbeing used in the field of carbohydrate chemistry.
OCH, Figure 11.
Methyl 2, 4-di-0-methyl-3, 6-anhydro-a-D-glucopyrono~ide.
Literature Cited (1) CANTOR, S. M., AND PENISTON, Q. P., J. Am. Chem. Soc., 62, 2113 (1940). (21 W. N.. J . Chem. Soc., . . DREW.H. D . K.. AND HAWORTH. 2303 (1926). ' (3) REEVES,R. E., J. Am. Chem. Soc., 72, 1500 (1950). (4) ROSENFELD, D. A., RICHTMEYER, N. K., A K D HUDSON, C. S., J . Am. C h a . Soe., 70,2201 (1948). (5) NEWMAN,M. S., "Steric Eflects in Organic Chemistry," John Wiley & Sons, Inc., New York, 1956, p. 13. (6) REEVES,R. E.,Advances in Carbohydrate Chem., 6, 124 (1951). (7) HASSEL,O., AND OTTAR,B., Ada. C h a . Scand., 1, 929 (1947). (8) LEMIEUX,R. U., ET A L . , J. Am. Chem. Soc., 79, 1005 I~-...,. lqR7i
(9) LEMIEUX, R. U., ET AL.,J . Am. Chem. Soe., 80,6098 (1958). (10) BUNTON, C. A,, ET AL., J . C h a . SOC.,4419 (1955). (11) O'GORMAN, J. M., AND LUCAS,H. J., J . Am. Chcm. Soe., 72, 5489 (1950). (12) KREEVOY, M. M., AND TAFT,R. W., JR.,J. Am. Chem. Soe. 77, 5590 (1953). (13) MCINTYRE, D., AND LONO,F. A,, J . Am. Chem. Soe., 76, 3240 (1954). (14) SHAFIZADEH, F., AND THOMPSON, A., J. O P ~Chem., . 21, 1059 1145Rj \ ",.
(15) LINDBERG, B., Ada. C h a . Scand., 3,1153 (1949). (16) MONTGOMERY, E. M., HANN,R. RI., AND HUDSON, C. S., J . Am. Chem. Soc., 59, 1124 (1937). (17) FREUDENBERG, K., AND SOPF,K., Ber., 70B, 264 (1937). (18) MOWERY, D. F., JR., AND FERRANTE, G . R., J. Am. Chem. Soc., 76,4103 (1954). (19) FOSTER,A. B., AND OVEREND,W. G., Chemistry &.Industry, 5fifi - - - 110ss> - - - - ,. (20) PIGMAN, W., "The Carbohydrates," Academic Press, Inc., New York, 1957, p. 209. (21) HAWORTH, W. N., OWEN,L. N., AXD SMITH,F., J . Chem. Soc., 88 (1941). W. N.. JACKSON. J.. AND SMITH.F.. J. Chem. (221 HAWORTH. \
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