Crystal-Structure Analysis in Carbohydrate Chemistry

CRYSTAL.-STRUCTURE ANALYSIS IN CARBOHYDRATE CHEMISTRY BY G. A. JEFFREYAND R. D. ROSENSTEIN The Crystallography Laboratory, The University of Pittsburgh, Pittsburgh, Pennsylvania

I. 11. 111. IV. V.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Determination af Configuration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Determination of Conformation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measurement of Bond Lengths and Valency Angles.. . . . . . . . . . . . . . . . . . . . . . Hydrogen Bonding and Molecular Packing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7 8 11 15

19

I. INTRODUCTION In two respects, x-ray crystal-structure analysis is remarkable amongst the physical methods available for studying organic molecuIes. One is the wide range of struotures which can be investigated by using fundamentally the same diffraction methods; for example, problems ranging from the structure of crystalline methane to that of hemoglobin. The second is the extraordinary wealth of detailed information which can be obtained concerning the stereochemistry of the molecule and its environs in the crystal, using only a very small amount of the substance. A single crystal of the compound, weighing about 0.1 mg., is required and, thereafter, all chemistry and chemical information can, if absolutely necessary, be dispenaed with. Of course, reliable information on chemical structure can be most valuable in determining a crystal structure and is used whenever available. Until about ten years ago, crystal-structure analysis was impeded by a very severe computational burden. However, the recent, rapid development of the general-purpose digital computer has eliminated this obstacle. This instrument has emancipated the techniques of crystar-structure analysis in a way which has decreased, by nearly an order of magnitude, the time required for a detailed determination of structure, and it has increased, to an even greater degree, the complexity of the problems that can be solved. For the crystallographer, the question “Can I solve this crystal structure?” has been replaced by the question “Is this structure worth solving?’’ To an increasing extent, the crystallographer’s approach to an area of research in which structure is relevant becomes one of a planned program envisaging the determination of several, perhaps a dozen, related structures. Then, ”

8

0. A. JEFFREY AND R. D. ROSENSTEIN

when these results are compared amongst themselves and with other physical and chemical information, the overall pattern is a much more meaningful contribution to chemistry than an isolated crystal-structure investigation. The modern computer has also placed many more technical demands on the crystallographer and greater financial demands on the organization which supports his research. This powerful slave is very expensive and has neither integrity nor sense. It can lead to a great waste of resources and can give misleadingly wrong answers if its power is inadvertently misuscd. Compared with the exciting contributions to organic chemistry which crystallography has been making recently in the field of rare, natural products of unknown configuration,’ the record in the carbohydrate area is not, to date, outstanding. However, over the past decade an appreciable numbcr of monosaccharides and disaccharides have been studied, either as the free sugars or as components of more complex molecules. Since there arc indications that the rate of production of these structural data in this field is beginning to increase rapidly with the crystallographer’s new power, it would appear that this is an appropriate time to review, critically, what has been accomplished so far. The present article is restricted to monoand di-saccharides, since the structure analysis of the polysaccharides presents problems which require discussion from a somewhat different point of view. This article is conceived in terms of the chemical information that crystal-structure analysis can provide, not as a chronological list of compounds which have been studied. The problems of interest to the carbohydrate chemist that can be solved by means of crystallography are: (1) determination of configuration, including absolute configuration; (2) determination of conformation and of other stereochemical features of particular significance; (3) measurement of bond lengths and valence angles; and (4) intermolecular stereochemistry, especially in relation to the system of hydrogen bonding, by means of which the molecules are associated in the crystal lattice.

11. DETERMINATION OF CONFIGURATION In the field of mono- and di-saccharides, chemically well-explored, the number of compounds of completely unknown configuration which are of sufficient importance to warrant a crystal-structure analysis is almost negligible. One of the earlier crystallographic studies, that of 2-amino-2deoxy-cu-D-glucose (“cu-D-chitosamine”), was, in fact, initiated to determine whether the compound was a derivative of D-glucose or D-mannose, but the (1)

J. M. Robertson, Proc. Chem. Soc., 229 (1963).

CRYSTAL-STRVCTURE

ANALYSIS IN CARBOHYDRATE CHEMISTRY

9

Fro. 1.-The Molecular Structure of L-Arabinose (p-Bromopheny1)hydrazone. Bond lengths in A. units. [Reproduced from Ada Chem. Scad., 16, 1539 (1962).]

problcm was solved chemically2before the crystal-structure determination3 had been completed! In the analysis of the crystal structure of the (p-bromophenyl)hydrazone of D-arabinose, by Furberg and Petersen,' the results of which are illustrated in Fig. 1, there were two surprises. The first was that the sugar residue is pyranoid (since it is believed to be preponderantly acyclic in solution) and the second waB that it is the CX-D anomer in a chair conformation ( l e 2e3e4a), since the free sugar customarily crystallizes as the P-D anomer. D-Glucose (p-bromophenyl) hydrazone also occurs as a chair conformation of the pyranoid form, and was shown to be the P-D anomer.S,6A study of D-ribose (pbromophenyl)hydrazone showed that the sugar residue exists in the acyclic form in the crystal, with an intru-molecular hydrogen bond and a non-planar C-C chain.6 Other acyclic carbohydrates which have been studied are potassium ~-gluconate'and the calcium and strontium salts of Larabinonic acid.8 In both ions, the zig-zag carbon chain is ap(2) (3) (4) (5)

W. N. Haworth, W. H. G. Lake, and 5.Peat, J . Chem. Soc., 271 (1939). E. G. Cox and G. A. Jeffrey, Nature, 143, 894 (1939).

S. Furberg and C. S.Petersen, Acta Chem. Scund., 16, 1539 (1962). K. Bjimer, S. Dahm, S. Furberg, and C. S. Petersen, A d a Chem. Scand., 17, 559 (1963). (6) S.Furberg, Private communication. (7) C. D. Littleton, Ada Crysl., 6, 775 (1953). (8) S. Furberg and 8.Helland, A& Chem. Scud., 16, 2373 (1962).

10

0. A. JEFFREY AND R. D. ROSENSTEIN

proximately planar, with the oxygen atoms of the hydroxyl groups lying above and below this plane. The rare sugars (for example, cordycepose CaHloO4, mycarose C7Hl4O4, cladinose C8HI604,digitalose C,H1406, and streptose CaHloOa)are current examples where complete x-ray configurational analyses might be worthwhile, because of the importance of their functions in biochemical processes. It is probable, however, that such structure-analyses will be directed toward the more complex molecules, containing a sugar residue in combination with other biologically active molecular moieties. Two examples of this type of work are the study of the structure of (i) the plant sulfolipid, 0(6-deoxy-6-sulfo-a-~-glucopyranosyl) -D-glycerol, by O k a ~ a and , ~ (ii) the

FIG.2.-The Dipositive Casimidine Ion, Showing the Stereochemistry of the 8-DGlucose Rwidue and its Point of Attachment to the Histamine Ring. [Reproduced from A& Cryst., 18, 364 (1963).]

alkaloid derivative, casimidine dihydrochloride, ClzHnaClzNaOa, which was known to contain D-glucose, with uncertainty as to (a) whether this is pyranoid or furanoid, (b) whether it is the a- or the p-D anomer, and (c) which nitrogen atom of the histamine ring the sugar is attached.l0 The conformation found for this molecule is shown in Fig. 2. If the crystal-structure analysis is made on a derivative contaiiiing a heavy atom, with x-rays of wavelength appropriate to the particular heavy atom (that is, Br or I with CuKa radiation), it is possible to determine the absolute configuration of an enantiomorphous molecule. This method was first demonstrated with the rubidium sodium salt of dextro-tartaric (Lthrearic) acid tetrahydrate by Bijvoet and coworkers11in 1951. The results confirmed the configuration of dextro-tartaric acid originally assigned by (9) Y. Okaya, Abstr. Papers Am. Cryst. Assoc. Meeting, June (1962). (10) S. Raman, J. Reddy, and W. N. Lipscomb, A d a Cryst., 18, 364 (1963). (11) A. F. Peerdemann, A. J. van Bommel, and J. M. Bijvoet, Koninkl. Ned. Akad. Wetensehap. Proc., 64, 3 (1951).

C R Y S T A G B T R U 6 I J R E ANbLYSIS IN CARBOHYDRATE CHEMISTRY

11

Fischer and, hence, those of the whole carbohydrate series. No determination of absolute configuration of a sugar derivative has been made since. However, this method is commonly applied to other natural products which are not part of a stereochemicallyrelated series, for example, to the structure of a1-bromopicrotoxinin.l2

111. DETERMINATION OF CONFORMATION The pyranoid forms of monosaccharides present an interesting problem in conformation because of the two different chair-conformations which, ignoring the non-bonded interactions in substituents, are energetically equivalent. The actual conformation of the free molecule is believed to be determined by the non-bonded interactions of substituent groups, as discussed principally by Hassel and Ottar,13 Reeves," and Barker and

0;

SUCROSE (Beevers

*

N a B r . 2H20

0-+A SUCROSE

a Cochran)

FIQ.3.-Comparison of Molecular Structures of Sucrose in Two Crystals. (View in each case is in plane of C'-2,0'-2, and C'-5, perpendicular to bond 0'-2-C'-2.) (Courtesy of Drs. G. M. Brown and H. A. Levy.) (12) B. M. Craven, Acta Cryet., 16, 387 (1962). (13) 0. Haasel and B. Ottar, Acta Chem. Smnd., 1, 929 (1947). (14) R. E. Reeves, J . A m . Chem. Soc., 72, 1499 (1950); Aduun. Carbohydrate Chem., 6, 107 (1951).

12

0. A. JEFFREY AND R. D. ROSENSTEIN

Shaw.I6 In the crystal structure and, to a lesser degree, in aqueous or polar solutions, intermolecular forces (particularly hydrogen bonding) may have a significant influence on the shape of the molecules. A recent comparison of the shape of the D-fructofurnnose moiety in sucrose and in sucrose sodium bromide dihydrate suggests that there are significant differences which can arise from the different molecular environment,16 as shown in Fig. 3. So far, however, all the pyranoid monosaccharides which have been studied by single-crystal analysis, either as the free sugars or as derivatives, conform to Reeves' prediction^,^^ with the exception of 2-deoxy-@-~-erythro-pentose.~~ In this molecule, however, the absence of 0-2

FIO.4.-The Conformation of 2-Deoxy-&~-erythro-pentose. [Reproduced from A d a Chem. Scand., 14, 1357 (1960).]

removes the principal destabilizing interaction of the 1 C conformation, which results from the proximity of the axial 0-2 and 0-4 atoms (see Fig. 4). There can be very little difference in energy between the la3e4a and the le3a4e conformation. Of the pyranoid conformations for which Reeves' rules do not permit clearcut decisions, none have been studied; examples include the a anomers of D-allose, D-altrose, D-idose, and D-gulose. It would be of interest to examine some of these, particularly those for which Lemieuxl" was able, definitely, to assign the conformation of the polyacetates in nonpolar solvents, and those for which Tipson and Isbelllo have studied the in(15) (16) (17) (18)

G. R. Barker and D. F. Shaw, J . Chem. Soc., 584 (1959). G. M. Brown and H. A. Levy, Science, 141, 921 (1963). S. Furberg, Acla Chem. Scand., 14, 1357 (1960).

R. U. Lemieux, R. K. Kullnig, H. J. Bernstein, and W. G . Schneider, J . A m . Chem. Soc., 80, 6098 (1958). (19) R. S. Tipson and H. S. Isbell, J . Res. Natl. Bur. Sld., 64A,239, 405 (1960); 66A, 249 (1961).

CRYSTAL-STRUCTURE ANALYSIS IN CARBOHYDRATE CHEMISTRY

13

frared absorption data in relation to the most stable conformation. BentleyzO has proposed an unstable, half-chair conformation for methyl

"

Icl

FIG.5.-Conformations of a Furanose Ring: (a) Unpuckered; (b) C-1 Displaced from Plane; (c) C-2 Displaced from Plane. [Reproduced from A c h Cryst., 12, 59 (1959).]

a-D-idopyranoside. It has also been suggestedz1 that the nonreducing moiety in maltose may exist as (or almost as) that skew conformation, Sl,sA, lying intermediatezzbetween the BIA and B3A conformations (B1 (20) R. Bentley, J. Am. Chem. Soc., 82, 2811 (1960). (21) R. Bentley, J. Am. Chem. Soc., 81, 1952 (1959). (22) H. S. Lbell and R,. 5.Tipson, J . Reu. Natl. Bur. Std., 64A, 171 (1960).

14

a.

A. JEFFREY AND R. D. ROSENSTEIN

and 9B in Reeves' systemzs);this should be investigated by a direct, physical method. In the only two disaccharides which have thus far been studied by x-ray analysis, namely, cellobiosez4and sucrose,16the pyranoid rings have the expected chair conformation. For the furanoid forms of monosaccharides, it is now well established that ~ ' ~ matter was discussed by Spencer2bin a paper the ring is n ~ n p l a n a r . This on the stereochemistry of the 2-deoxy-~-erythro-pentoseresidue in deoxyribonucleic acid. He considered it most likely that one of the carbon atoms is out of the plane consisting of the remaining three carbon atoms and the ring-oxygen atom, positioned as illustrated in Fig. 5 . This feature had been observed earlier, in the crystal-structure analysis of sucrose sodium bromide dihydrate by Beevers and Cochran,z6and of cytidine by F ~ r b e r g , ~ ' although neither of these analyses had been very accurate in detail. (The cytidine structure has now been refined three-dimensionally, with only small changes from the original parameters.28) The currently known data TABLE I Slereochemical Data

ME

D-Ribofuranose Rings Carbon atom out of plane

Furanose residue

D-Ribose D-Ribose D-Ribose 2-Deoxy-~-erythropentose ("2Deoxy-n-ribose") D-Ribose

Derivative studied

Number

cytidine cytidylic acid, b adenosine 5-phosphate calcium thymidylate

3 2 3 3

ribose 5-phosphate, barium salt

2

Distance out of plane

'

(A.)

References

0.5 0.5 0.5 0.5

27 29 30 31

0.5

32

(23) R. E. Reeves, J . Am. Chem. SOC.,71, 215 (1949). (24) R. A. Jacobson, J. A. Wunderlich, and W. N. Lipscomb, Acta Cryst., 14,598 (1961). (24a) See L. D. Hall, This Volume, p. 77. (25) M. Spencer, A d a Cryst., 12, 59 (1959). (26) C. A. Beevers and W. Cochran, Proc. Roy. SOC.(London), Ser. A , 190, 257 (1947). (27) S. Furberg, A d a Cryst., 3, 325 (1950). (28) S. Furberg, C. 8.Petersen, and C. R$mming, Private communication. (29) E. Alver and S. Furberg, A& Chem. Scand., 13, 910 (1959). (30) J. Kraut and L. H. Jensen, Acta Cryst., 16, 79 (1963). (31) K. N. Trueblood, P. Horn, and V. Luzzati, Acta Cryst., 14, 965 (1961). (32) S. Furberg and A. Mostad, Aeta Chem. Scad., 16, 1627 (1962).

CRYSTAL-STRU@TURE ANALYSIS IN CARBOHYDRATE CHEMISTRY

15

for the D-ribofurano* ring are shown in Table I. A redetermination of the structure of cytidylic acid by Jensen and S ~ n d a r a l i n g a mhas ~ ~ confirmed the earlier workzeand provided a more precise description of the stereochemistry. The major displacement of C-2 by 0.5 hL. was confirmed, and it was found that the remaining four atoms have very smali displacements (from their mean plane) of the order of 0.02 hi. These small displacements were considered significant by the authors. In no case, so far, has the ringoxygen atom of C-1 been found to be displaced, and the choice between C-2 and C-3 appears to be governed by the nature of the substituents on the D-ribofuranose ring. An independent refinement has also been completed by Donohue and F ~ r b e r g . ~ ' In the D-fructofuranose residue of sucrose sodium bromide dihydrate, C-1, C-2, C-5, and the ring-oxygen atom are nearly coplanar, and C-3 is about 0.5 A.out of this plane.26In sucrose, itself, however, such a simple description is not possible. The stereochemistry of the D-fructofuranose moiety is illustrated in Fig. 3. It seems likely that subsequent, accurate analyses of the other furanoid structures will reveal that the stereochemistry described in Fig. 5 is always an over-simplification, approximating to the true shape of the furanoid ring in certain molecules only. There have been two crystal-structure determinations of myo-inositol, the inositol stereoisomer having only one axial hydroxyl group. One of these studies, by Rabinowitz and Kraut,86was on the anhydrous form and the other, by Lomer, Miller, and Beevers,s6 was on the dihydrate. In both structures, the molecules have the expected chair conformation, and the proposal by P ~ s t e r n a kof~ an ~ axial hydroxyl group on C-4 was fully confirmed, The more accurate work on the anhydrous form provided evidence of small deviations, of the order of lo, from the ideal chair conformation.

IV. MEASUREMXNT OF BONDLENGTHS AND VALENCY ANGLES The accuracy of a crystal-structure analysis depends on (1) the magnitude and distribution of the experimental errors in the measurements of the x-ray diffraction spectra; (2) the ratio of the observational data/ variable parameters ; and (3) the completeness of the computational treatment of the data. Since the later 193Os, not much progress has been made toward increasing the accuracy of the measurements of the diffracted intensities, although it (33) L.Jensen and M. ~undaralingam,Private communication. (34) J. Donohue and S. Furberg, Private communication. (35) I. N. Rabinowita and J. Kraut, A c h Cryst., 17, 159 (1964). (36) T.R.Lomer, A. Miller, and C. A. Beevers, Acla Cryst., 16, 264 (1963). (37) T.Posternak, Helv. Chim. A&, 26, 746 (1942).

16

0.

A. JEFFREY AND R. D. ROSENSTEIN

is now common practice to make many more measurements and to measure all of the three-dimensional diffraction-data available. The slow improvement in the precision of x-ray intensity measurements, despite the technical improvements in apparatus and in x-ray detection by means of proportional and scintillation counters, is probably attributable to the fact that such measurement by counter technique is a painstaking and tedious process when it involves several thousand observations. Indeed, such measurement competes somewhat unfavorably with the photographic methods, where the recording of the spectra may take a long time but does not require continuous attention. Nevertheless, in some laboratories engaged in the analysis of complex molecules, the photographic methods have been entirely superseded by counter techniques. The technical accomplishment currently awaited in the field of crystal-structure analysis is the perfection of an automatic, single-crystal, diffraction instrument which can measure on the order of 100 to 1000 intensities in 24 hours with a precision of 1 to 3 percent. A t present, good photographic techniques give a precision in intensities of 5 to 10 percent, and fast, manual, counter techniques are of the same order, improving to 1 percent with a proportional increase in the time spent in the manual operation. The recent redeterminations of the structure of cytidylic acid by x-ray a n a l y ~ i sand ~ ~of~ ~sucrose ~ by neutron analysis16 are, so far, the only structure analyses of mono- or di-saccharides (or their derivatives) wherein the major objective was to obtain the most accurate data possible, using all the precautions and refinements of modern technique. Although, in both analyses, the positions of the hydrogen atoms were ascertained, the use of neutrons in the latter work permitted determination of the location of the hydrogen atoms with the same precision as for the carbon and oxygen atoms. In both structure analyses, the original analysis of cytidylic acid b by Alver and Furberg28and of sucrose by Beevers and coworkersS8constituted a solution to the phase problem and provided a satisfactory startingpoint for the high-precision, three-dimensional refinement. These studies were carried out with much more extensive experimental data and were made possible only by use of computers of the IBM 7090 class or larger. The absence of more work of this high quality and accuracy in the field of carbohydrate chemistry is probably due to two causes. First, although many of the existing data are comparatively inaccurate, they give no reason for expecting other than normal C-C bond lengths of 1.53 f 0.01 A., C-0 bond lengths of 1.42 f 0.01 A., and bond angles within a few degrees of tetrahedral. In the absence of more-detailed theory, there is little incentive encouraging exertion of the very considerable effort required for a (38) C. A. Beevers, T. R. It. McDonald, J. H. Robertson, and F. Stern, Ada Cryst., 6, (589 (1952).

TABLEI1 Bond Lengths and Angles in Pyramid Sugars and Derivatives Angles (degrees) Bond length Pyramid sugar or sugar residue

a-D-Glucose 6 anomer &D-Arabinose a-cRhamnose Methyl a-D-galactoside a-D-Glucose 2-Deoxy-&~-e~ythro-pen tose 2-Amino-2-deoxy-a-~-glucose B-D-Glucose &D-Glucuronk acid a

(A.)

Derivative studied

C-Ca

C-0)

O H n

C-O-lc

At carbon i n rings

sucrose free sugar free sugar free sugar, monohydrate Bbromo-Meox y derivative free sugar free sugar in HC1 and HBr cellobiose dihydrates of K and Rb salts

1.524 1.527 1.535 1.532

1.420 1.446 1.430 1.438

1.418 1.443 1.434 1.434

1.410 1.404 1.382 1.376

108-1 11 107-110 107-112 104-114

1.516 1.54 1.51 1.51 1.52 1.54

At

0,

References

116 113 113 120

16 46 39

1.434 1.41 1.43 1.41 1.40

1.42 1.42 1.41 1.41 1.42

40 41

1.32 1.40 1.37 1.39

102-1 15 107-111 107-1 12 105-115 109

112 112 113 116 109

Mean values. The symbol 0, indicates the ring oxygen-atom. Glycosidic link.

(39) A. Hordvik, Actu Chem. Scand., 16, 16 (1961). (40) H. M. McGeachin and C. A. Beevem, Actu Cryst., 10,227 (1957). (41) B. Sheldrick and J. H. Robertson, Private communication. (42) T. R. R. McDonald and C. A. Beevers, A d a Cryst., 5, 654 (1952). (43) G. A. Jeffrey and S. S. C. Chu, unpublished work. (44) G. E. Gurr, A d a Crysf.,16,690 (1963); S. Furberg, H. Hammer, and A. Mostad, A d a Chem. Scand., 17, 2444 (1963).

42 17 43 24 44

k? W 0 X

Bond Lengths and Angles in Furanoid Rings

G

$

Angles (d.wred

Bond length (A.) Furanoid sugar r d w &~-Fr~ctOee

Derivalive studied BUCrOBe

cytidylic acid cytidine a

Mean values.

C-Ca

Wr

WHa

At carbon in ring

1.524 1.526 1.522

1.425 1.440 1.430

1.418 1.426 1.411

102-106 100-106 102-107

M

'4 b Z

At

0,

References

111 110 110

33

16 28

u

td U

?! !

CRYSTAGSTRUCTURE ANALYSIS IN CARBOHYDRATE CHEMISTRY

19

modern precision-analysis, except for certain key structures, such as sucrose. Second, dmpite the existence and availability of modern computers, crystal-structure analysis of carbohydrates will, in most cases, still involve a very difficult stage of a phase-solving problem, because the crystal structures are non-centrosymmetrical, and the molecules are generally globular in shape and have no easily recognizable stereochemical features (such as a planar benzene-ring). The phase problem may be made more direct by using a derivative containing a heavy atom, but this has a detrimental effect on the accuracy of the final results. If the final objective is accurate bond-lengths and bond-angles, the carbohydrate crystal must contain only the aComs of the Carbohydrate. The more extensive use of low-temperature techniques, which sharpen up the electron-density distribution of the atoms by diminishing their thermal motion, will help to alleviate both the problem of solving the structure and of improving the accuracy of the final results. The bond-length and valence-angle data available at present are summarized in Tables I1 and 111. Different workers have different ways of estimating the accuracy of their own results, and the arrangement of the Tables is such that the more accurate results are presented first. There is a suggestion in some analyses that the glyeosidie C-0 bond is shorter than the other C - 0 bonds. However, in no analysis has this observation been made at the significant level, and it is not observed in sucrose. Nevertheless, the glycosidic hydroxyl group has a distinct, chemical difference from the other hydroxyl groups, and this is a feature worth clarifying by a precision analysis of a monosaccharide. Similarly, there have been reports of ring-oxygen valence angles larger than the usual 110 f 2". These observations are borne out by the sucrose analysis, in which the "ether" oxygen angle is 116". The same effect is observed in the D-fructofuranose residue of sucrose, where the carbon ring-angles are 104 f 2" and the oxygen ring-angle is significantly greater, 111". In the myo-inositol structures,36~36the C-C bond-lengths are normal. In the anhydrous crystd, the mean values are C-C, 1.521 f 0.007 A., and C-0,1.429 =t0.006 A. In the dihydrate, the mean values are C-C, 1.50 f 0.01 A., and C-0, 1.44 + 0.01 A.

V. HYDROGEN BONDING AND MOLECULAR PACKING The fourth type of chemical information provided by a crystal-structure analysis concerns the regular arrangement and packing of the molecules to form the crystal lattice. This information pertains specifically to the particular crystal-modification which has been investigated. Even for simple molecules, such as 02,Nz, or Clz, it is difficult to predict the way in

20

0 . A. JEFFREY AND R. D. ROSENSTEIN TABLE

Hydrogen Bonding in Crystal Structures

OH,

Pyranoid sugar or sugar residue

Derivative studied sucrose free sugar monohydrate

a-D-Glucose free sugar 2-Deoxy-j3-~-erythro-pentose free sugar j3-D-Glucose cellobiose &D-Glucuronic acid 2-Amino-2-deoxy-~glucose

0

dihydrates of K and Rb salts hydrochloride and hydrobromide

with no hydrogen bonding 0-4

OH, with donor and acceptor 0-2, 0-3 OL1, 0-2, 0-4

0-2, 0-3, 0-6, 0 - 4

0-3, 0-4 0-2, 0-3, 0-4, 0-6 0-2, 0-6 0-4, 0-6

0-3, 0-6

Carbonyl oxygen atom.

which the molecules will be arranged i n the crystal, because the diffcrcnces in lattice energies for several different structurcs are smaller than the accuracy with which these lattice energies can be determined from our present knowledge of intermolecular forces. For the carbohydrates, there is the added complication of hydrogen bonding, conccrning which there is very little quantitative understanding indeed. Nevertheless, it is worth while to examine the overall pattern of hydrogen bonding in carbohydrate crystals, to see if there are any apparent generalizations. Some data for pyranoid structures are collectcad in Table IV, and some rules are, indeed, apparent. For example, (1) the ring-oxygen atom is invariably a hydrogen-bond acceptor; (2) the most common situation is that each hydroxyl group is associated with two hydrogen bonds, one a donor and one an acceptor bond; (3) less common is an environment of one hydrogen bond, as donor only; (4) least common is an environment of three hydrogen bonds, with one donor bond and two acceptors; ( 5 ) in a disaccharide, there may be intramolecular hydrogen-bonding between the two residues, as is found in sucrose; and (6) hydroxyl groups not involved

21

CRYSTAL-STRUCTURE ANALYSIS IN CARBOHYDRATE CHEMISTRY

IV of Pyranoid Sugars and Derivatives ~~~

OH, with donor only 0-6 0-3 0-1, 0-4, 0-3

OH, mlh donor and 0, with 2 acceptors acceptor only 0-2

0-5 0-5 0-5, 0’-5

0-1 0-1 0’-1, 0’-3

0-1,0 - 3 0-1

0-5 0-5 0-5

0-2

0-5, 0-7O 0-5, 0 - 4 from NHa@only

~

Total no. of H bonds associated Range of H with each bond-lengths, molecule A. References

6 6

lO(H20 form 2 donors and 2 acceptors) 10 6 15(incl. one intramolecular bond) ll(inc1. four with HO)

2.78-2.86 2.68-3.04 2.69-2.91

16 39 40

2.70-2.86 2.82-2.89 2.70-2.85

42 17 24

2.67-2.88

44

2.75-2.95 to Cle, 3.14 from NH3@

43

in hydrogen bonding to other oxygen atoms can be present, as in sucrose and in the salts of %amino-2-deoxy-~-glucose. The hydrogen bond 0.* .O distance may have a value from 2.68 to 3.04 For a complete understanding of the significance of the data, more analyses need to be carried to the same degree of completion as for the sucrose structure, where the neutron-diff raction measurementsl8made possible the precise location of the hydrogen atoms. As so much of Carbohydrate chemistry involves reactions in solution, it must be emphasized that the degree to which this type of structural information is relevant to the dynamic stereorelationships existing between sugar and solvent molecules in sugar solutions depends upon inferences which must be critically examined by other experimental methods.4s There remain a number of crystal-structure studies on mono- and disaccharides (and their derivatives) which have not been mentioned thus far. The majority of these are still in progress or have not yet been pursued to a sufficient stage of structure refinement that they could confidently provide significantly new data for the carbohydrate chemist.

A.

(45) S. Furberg and B. Petemen, A d a Chem. Scund., 17, 1160 (1963).

22

0. A. JEFFREY AND R. D. ROSENSTEIN

These crystal-structure analyses are concerned with the following molecules: a-D-glucopyranose monohydrate," ~-xylopyranose,~* methyl &~-xylopyranoside,~~ di-&D-fructopyranoseatrontium chloride trihydrateJ60cellobiose (independent determination), D-glucaric acid, D-galactonic acid,61methyl a-D-lyxofuranoside,62P-D-lyxopyranose,68methyl 3 , 4 , 6-tri0 - acetyl - 2 - (chloromercuri)- 2 - deoxy - /3 - D - gluc~pyranoside,~~ D-glucopyranosyl (potassium sodium phosphate) tetrahydrate,66 and methyl 6-bromo-6-deoxy-a-wgalactopyranoside.6B

ACKNOWLEDGMENTS We are grateful to Dr. S. Furberg and Mr. S. H. Kim, who made suggestions for the improvement of this manuscript, and to the National Institutes of Health, U.S.Public Health Service, Department of Health, Education, and Welfare, for the support of research on problems in which our interest has been such aa to prompt this review. (46) W.G.Ferrier, Acta Cryst., 13, 678 (1960);16, 1023 (1963). (47) R. C.G.Killean, W. G . Ferrier, and D. W. Young, Acta Cryst., 16, 911 (1962). (48) M.M.Woolfson, Acta Crysl., 11, 393 (1958). (49) C.J. Brown, Acta Cryst., 13, 1049 (1960). (60) P. F. Eiland and R. Pepimky, A d a Cryst., 3, 160 (1950). (51) C.J. Brown, Private communication. (52) S.Furberg and H. Hammer, Ada Chem. Scand., 16, 1190 (1961). (53) A. Hordvik, Acla Chem. Sand., 16, 1780 (1961). (64) H. W.W.Ehrlich, J . Chem. Soc., 609 (1962). (56) R. Small, Private communication. (56) B. Sheldrick and J. H. Robertson, Acla Cylst., 16, A54 (1963).