CRYSTAL GROWTH & DESIGN
Multiple Molecules in the Asymmetric Unit (Z′ > 1) and the Formation of False Conglomerate Crystal Structures†
2009 VOL. 9, NO. 6 2890–2894
Roger Bishop* and Marcia L. Scudder School of Chemistry, The UniVersity of New South Wales, UNSW Sydney NSW 2052, Australia ReceiVed February 18, 2009; ReVised Manuscript ReceiVed April 1, 2009
ABSTRACT: Handed molecules that pack awkwardly with each other in the solid state are prone to forming crystals containing multiple independent molecules in the asymmetric unit (Z′ > 1). Three racemic examples with (Z′ ) 2, 2, and 5) each crystallize as a 1:1 mixture of enantiomorphous crystals by self-resolution of each independent molecule present. Their X-ray structures are analyzed to demonstrate how these enantiomorphs are generated in the solid state. These false conglomerate materials are rather similar to conglomerates and can be readily confused with them. They differ, however, in their solution properties. On dissolution, a conglomerate crystal yields an optically active solution, but a false conglomerate crystal will give an optically inactive solution (since independent molecules are not a solution-state property). The frequency of false conglomerate formation is estimated to be about 1% for organic compounds. Introduction Crystal structures containing multiple molecules in the asymmetric unit (Z′ > 1) are of considerable current interest,1,2 and several features of these fascinating structures are the subject of ongoing discussion. One of these aspects relates to the relative percentage of Z′ structures reported over time, with respect to concomitant advances in crystallographic methodology.3-6 Packing in multiple Z′ structures is also the receipt of considerable attention, for example, the pseudosymmetric relationships present between some independent molecules.1,7 Other workers are exploring links between the (Z′ > 1) phenomenon and that of polymorphism,8 or are seeking explanations of why multiple Z′ structures form in the first place.4,9 For example, are these simply kinetic “fossil relic” structures formed under nonequilibrium conditions, “a crystal on the way” as it were, rather than being thermodynamic minima?1,4 Healthy debate of these topics continues. In 2000, Steiner analyzed the frequency of Z′ values for reported organic and organometallic compounds and found that values of Z′ ) 0.5, 1, and 2 were found in 96.6% and 94.3% of their crystal structures, respectively.3 Structures with Z′ > 1 were observed with a frequency of 10.8% for all organic crystals, but there were notable variations between different classes of molecules. A more recent analysis by Steed gives a value of 11.5% for organic structures and 8.8% for the CSD as a whole.10 Wilson11 and Brock & Dunitz12 have analyzed Z′ values in the context of crystal symmetries, while Padmaja et al. have explored the frequency of Z′ > 1 occurring within specific space groups.13 Steiner also noted that Z′ > 1 structures occurred significantly more frequently for some homochiral molecular classes, such as steroids (18.8%) and nucleosides/nucleotides (20.8%), compared to organic compounds in general (10.8%).3 Similar anomalies have been highlighted in surveys of monoalcohols, phenols, and primary amines.14,15 The latter results can be rationalized in terms of the special requirements necessary for † This paper is Resolutions and Polymorphs, Part 5. Part 4 is Nguyen, V. T.; Chan, I. Y. H.; Bishop, R.; Craig. D. C.; Scudder, M. L. Crystallisation of C2symmetric endo,endo-bicyclo[3.3.1]nonane-2,6-diols: supramolecular synthons and concomitant degrees of enantiomer separation, New J. Chem., DOI:10.1039/ B900463G. * To whom correspondence should be addressed. E-mail: r.bishop@ unsw.edu.au.
formation of hydrogen bonding in the crystal.15 Since Z′ > 1 is such a significant parameter in crystal packing, it is unsurprising that this phenomenon also intrigues crystal engineers who would like to understand (and ultimately control) its occurrence.1,10,16 An effective means of obtaining new lattice inclusion compounds is to synthesize a compound that packs awkwardly with itself in the solid state. In many instances, such molecules can form a more energetically favored crystal by means of guest inclusion.17,18 This is also one of the strategies than can lead to multiple molecules being present in the asymmetric unit.1 The occurrence of Z′ > 1 structures is known also to be higher in chiral space groups (14.6%) than in the full CSD listing (8.8%).10 Hence, molecules that are both awkward and handed are likely to be good target compounds. In this paper we draw attention to a phenomenon involving racemic molecules of this dual nature, namely, the production of false conglomerate structures involving formation of Z′ > 1 crystals. Results and Discussion If a racemic solution (containing a 1:1 mixture of enantiomer A and its opposite enantiomer A*) is allowed to crystallize, then several of the possible outcomes are indicated in Figure 1. (i) The best-known, and most frequent, result is formation of racemic crystals containing an intimate mix of both enantiomers A and A*. (ii) In some cases, however, considerable enantiomer separation takes place. The resulting racemic crystal comprises domains of molecules of the same handedness A, alternating with domains of molecules of the opposite handedness A*.19 (iii) If complete enantiomer separation occurs then a conglomerate is produced.20-22 This is a mixture of (+)- and (-)crystals, each of which contains only enantiomerically pure A or A* molecules. In addition to such processes, crystallographically independent molecules may be present in the solid state. These are designated in this paper as A, B, C, etc. for one enantiomer, and as A*, B*, C* etc. for the second enantiomer of opposite handedness. (iv) The process (iv) illustrated in Figure 1 involves A, B and A*, B* molecules. This is an example of the false conglomerate structure that can be produced in some Z′ > 1 structures.23 A mixture of (+)- and (-)-crystals is formed, but
10.1021/cg9002143 CCC: $40.75 2009 American Chemical Society Published on Web 04/27/2009
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Figure 1. Four outcomes of allowing a 1:1 racemic solution of A and A* molecules to crystallize. The symbols A and B signify crystallographically independent molecules with the same chirality, and A* and B* are their enantiomers. (i) Formation of a racemic solid containing an intimate mix of A and A* molecules. (ii) Formation of a racemic solid containing domains of both enantiopure A and enantiopure A* molecules. (iii) Formation of a mixture of enantiopure A crystals and enantiopure A* crystals (a conglomerate). (iv) Formation of a false conglomerate: namely, a mixture of enantiopure A and B* crystals (and containing no A* and B molecules) and enantiopure A* and B crystals (and containing no A and B* molecules).
each of these contains both enantiomers as crystallographically independent molecules. Outcomes (iii) and (iv) produce handed crystals that must occupy one of the 65 enantiomorphic crystal space groups. Both produce a mixture of enantiomorphous (+)- and (-)-crystals, but it can be easy to confuse these two different processes.24,25 The fundamental test is that dissolution of one crystal from a conglomerate will give an optically active solution, whereas the same experiment for a false conglomerate will yield an optically inactive solution. For example, in outcome (iv), if Z′ ) 2 then the host combinations A and B* and A* and B have been fully resolved during crystal formation. The crystallographically independent molecules, however, only differ in the solid state. Hence, an individual crystal of a false conglomerate must simplify to just an A and A* racemic solution when dissolved. We will now examine three specific cases where molecules 1-3 (Figure 2) form false conglomerates and discuss how these structures are constructed. Crystal Structure of (1)2 · (trifluoromethylbenzene) (MUSDOT, Z′ ) 2). 26 The racemic dibromodiquinoline 1 forms a series of lattice inclusion compounds when crystallized from most common solvents. We have published crystallographic details for nine of these compounds and these structures were all closely related.26,27 Molecular pens are formed by two molecules of host 1 thereby enclosing the guest. These pens then associate into layers by means of aryl offset face-face (OFF) interactions,28,29 and adjacent layers are linked through double C-H · · · N weak hydrogen bonds.30 Seven examples in space group P21/c have isostructural host lattices in which the layers stack to create guest channels. These compounds have two independent host molecules in their asymmetric unit and the alternating layers of pens contain only centrosymmetric A/A* or B/B* pens. However, for (1)2 · (CF3C6H5), the adjacent layers are offset and therefore enclose the guests within cages. Furthermore, uniquely, these layers are constructed only from chiral A/B* pens in (+)-crystals or chiral A*/B pens in (-)-crystals (Figure 3). The respective interlayer C-H · · · N connectivity is -A-B*A-B*-A- (etc.) or -A*-B-A*-B-A*- (etc.) in the two types of crystals (Figure 4). Hence, it is the chiral specificity during the
Figure 2. Handed molecules 1-3 that are capable of forming false conglomerate crystal structures. Only one enantiomer of each chiral compound is represented here.
Figure 3. Part of a layer of molecular pens in the compound (1)2 · (CF3C6H5) shown as a projection onto the bc plane with the enantiomeric host molecules colored light or dark green. Only A/B* pens are present in one crystal enantiomorph, whereas the second contains only A*/B pens. Color code: Br brown, guest C purple, F yellow, H light blue, N dark blue.
pen construction that generates two enantiomorphous crystal structures, both in space group P212121, of this false conglomerate.26 Crystal Structure of (2)2 · (tetrahydrofuran) (XETBED, Z′ ) 2).31 The racemic dibromodiquinoxaline 2 yields crystals containing both enantiomers when crystallized from either chloroform or 1,1,2,2-tetrachloroethane, yielding compounds (2) · (CHCl3)2 in space group C2/c or (2)2 · (C2H2Cl4) in Pbcn, respectively.31 However, crystals of (2)2 · (C4H8O) in the noncentrosymmetric space group P212121 are produced from tetrahydrofuran solution and these contain two independent host molecules in the asymmetric unit. Molecules of 2 form infinite edge-edge chains in this solid-state structure, being linked by
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Figure 4. The interlayer arrangement in crystalline (1)2 · (CF3C6H5). Both bifurcated Ar-H · · · N · · · H-BrC- and centrosymmetric double Ar-H · · · N motifs (represented as dashed lines) link adjacent layers in this false conglomerate structure.
Bishop and Scudder
Figure 7. Part of the crystal structure of diol 3 projected onto the ab plane, with all hydrogen atoms omitted, and highlighting the two structural zones present in this solid. The (A-D)-type molecules have their three oxygen atoms colored red, orange, yellow, or blue, respectively. Opposite diol enantiomers are indicated by light or dark green carbon atoms. These diols form hydrogen bonded pillars, indicated here by the ellipses. The (E-F)-type molecules form hydrogen bonded columns located between the pillars and these are indicated using red oxygen atoms and purple carbon atoms.
Figure 5. Part of an infinite chain of host molecules in solid (2)2 · (tetrahydrofuran), showing their -A-B*-A-B*- linkage by means of four different C-H · · · N weak hydrogen bonds (dashed lines). The numerals indicate the interatomic D values in Å.
Figure 6. Cut-away view of part of one sinusoidal tube (along b) in solid (2)2 · (tetrahydrofuran), showing one arrangement only of the disordered tetrahydrofuran guest molecules in this chiral tubulate inclusion compound. Color code: O red, and guest H atoms omitted for clarity.
cyclic pairs of aryl-H · · · N and aliphatic BrC-H · · · N interactions. These pairs of weak hydrogen bonds have different lengths on either side of the participating aromatic wing (Figure 5). The chiral environment created through construction of these chains results in half of the crystals containing host molecules linked as -A-B*-A-B*- chains, while the other half are -A*-BA*-B- chains. These two types of crystals are enantiomorphous, with the A and A* enantiomers being separated totally (as are the B* and B enantiomers). However, molecules A and B (and similarly A* and B*) only differ from each other in the solid state. Therefore, this crystallization outcome has again yielded a false conglomerate. The host molecules form a series of parallel sinusoidal tubes in the crystal that are filled by the disordered tetrahydrofuran guest molecules as shown in Figure 6.31
Figure 8. One hydrogen bonded pillar (running along the c direction) in crystalline 3 with the hydroxy group hydrogen bonds indicated by dashed lines.
Crystal Structure of 3 (WASWAO, Z′ ) 5).32 The racemic dialcohol 3 has a relatively simple molecular structure, but it forms a very complex crystal structure in the enantiomorphous space group P21212 with six independent molecules, designated here as (A-F)-types, in the asymmetric unit and a total of 20 molecules in the unit cell. Guest molecules are not included in this crystal structure. The diol molecules, however, occupy two very different structural zones. The (A-D)-type molecules form
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column-pillar connectivity The F-type molecules do not contribute to this. Conclusions In this paper we have drawn attention to a further unusual property of some Z′ > 1 crystal structures, namely, the generation of enantiomorphous crystals containing crystallographically independent molecules. Generation of these false conglomerate crystals involves enantiomeric self-resolution of each racemic independent molecule in the solid. These materials differ from conglomerates, however, in their solution properties. On dissolution, a conglomerate crystal yields an optically active solution, whereas a false conglomerate crystal produces an optically inactive solution (since independent molecules are only a solid-state property). It is not possible to determine absolute numbers of conglomerate, or false conglomerate, structures in the Cambridge Structural Database35 without individually examining each reported chiral space group crystal structure, and this would be a daunting task.9a However, Jacques, Collet, and Wilen have estimated that around 5-10% of covalent compounds crystallize as conglomerates.21 On the basis of our own body of crystallographic work, it appears that the frequency of false conglomerate formation is around 1% for organic compounds, though this figure may be skewed by our choice of compounds. Acknowledgment. We gratefully acknowledge financial support from the Australian Research Council, and thank Bruce Foxman (Brandeis University) for helpful discussions during the preparation of this article. Figure 9. The construction of a column of E-F* molecules within a crystal of diol 3. This indicates the limited intracolumn and columnpillar hydrogen bonding present (dashed lines).
hydrogen bonded pillars with an octagonal cross-section in projection. These are indicated by the ellipses (and green carbon atoms) in Figure 7. Located between these pillars are hydrogen bonded columns of (E-F)-type diol molecules (purple carbon atoms) with a square cross-section in projection. Additional hydrogen bonds link the pillars and columns.33,34 The detailed arrangement of diol molecules in one pillar is illustrated in Figure 8 (hydrogen atoms omitted). Here, A and B molecules (O red or orange) are connected to C* and D* molecules (O yellow or blue). In a given crystal, all the pillars are of this identical construction, and this host-like zone of the structure comprises 16 of the 20 molecules per unit cell. The enantiomorphous crystals of diol 3 contain A*, B*, C, and D molecules. The pillars interlock in a herringbone fashion to leave cavities that are filled by the disordered columns of (E-F)-type molecules (Figure 7). This guest-like zone accounts for the remaining four molecules in the unit cell. A 2-fold axis runs through the column, and therefore Z′ ) 0.5 for both the E and F independent molecules. Hence, the crystal structure of 3 has overall Z′ ) 5 despite involving six independent molecules. E-F* diol molecules form pairs, utilizing one hydrogen bond only, that are repeated along the column as shown in Figure 9. Other columns in the same crystal can utilize E*-F pairs, but this arrangement had a slightly lower occupancy in the particular crystal we studied. Each E-type molecule forms donor hydrogen bonds with both the B- and D-type diols to generate all the
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Steed, J. W. CrystEngComm 2003, 5, 169–179. Steed, J. W. Z′ website: http://www.dur.ac.uk/zprime. Steiner, T. Acta Crystallogr. 2000, B56, 673–676. Desiraju, G. R. CrystEngComm 2007, 9, 91–92. Anderson, K. M.; Steed, J. W. CrystEngComm 2007, 9, 328–330. Bond, A. D. CrystEngComm 2008, 10, 411–415. (a) Britton, D. Acta Crystallogr. 2000, B56, 828–832. (b) Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. Acta Crystallogr. 2003, B59, 634–640. (c) Pidcock, E. Acta Crystallogr. 2006, B62, 268–279. (d) Collins, A. Acta Crystallogr. 2006, B62, 897–911. (e) Gavezzotti, A. CrystEngComm 2008, 10, 389–398. (a) Nichol, G. S.; Clegg, W. CrystEngComm 2007, 9, 959–960. (b) Anderson, K. M.; Goeta, A. E.; Steed, J. W. Crystal Growth Des 2008, 8, 2517–2524. (a) Brock, C. P.; Schweizer, W. B.; Dunitz, J. D. J. Am. Chem. Soc. 1991, 113, 9811–9820. (b) Roy, S.; Banerjee, R.; Nangia, A.; Kruger, G. J. Chem.sEur. J. 2006, 12, 3777–3788. (c) Bernstein, J.; Dunitz, J. D.; Gavezzotti, A. Cryst. Growth Des. 2008, 8, 2011–2018. Anderson, K. M.; Afarinkia, K.; Yu, H.; Goeta, A. E.; Steed, J. W. Cryst. Growth Des. 2006, 6, 2109–2113. Wilson, A. J. C. Acta Crystallogr. 1993, A49, 795–806. Brock, C. P.; Dunitz, J. D. Chem. Mater. 1994, 6, 1118–1128. Padmaja, N.; Ramakumar, S.; Viswamitra, M. A. Acta Crystallogr. 1990, A46, 725–730. Gavezzotti, A.; Fillippini, G. J. Phys. Chem. 1994, 98, 4831–4837. Brock, C. P.; Duncan, L. L. Chem. Mater. 1994, 6, 1307–1312. (a) Hao, X.; Parkin, S.; Brock, C. P. Acta Crystallogr. 2005, B61, 689–699. (b) Hao, X.; Siegler, M. A.; Parkin, S.; Brock, C. P. Cryst. Growth Des. 2005, 5, 2225–2232. (c) Nangia, A. J. Ind. Inst. Sci. 2007, 87, 133–147. (d) Babu, N. J.; Nangia, A. CrystEngComm 2007, 9, 980–983. (e) Todd, A. M.; Anderson, K. M.; Byrne, P.; Goeta, A. E.; Steed, J. W. Cryst. Growth Des. 2006, 6, 1750–1752. (f) Anderson, K. M.; Goeta, A. E.; Steed, J. W. Inorg. Chem. 2007, 46, 6444–6451. (g) Nichol, G. S.; Clegg, W. Cryst. Growth Des. 2006, 6, 451–460. (h) Aitipamula, S.; Desiraju, G. R.; Jaskolski, M.; Nangia, A.; Thaimattan, R. CrystEngComm 2003, 5, 447–450. (i) Das, D.; Banerjee, R.; Mondal, R.; Howard, J. A. K.; Boese, R.; Desiraju, G. R. Chem. Commun. 2006, 555–557.
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(17) Kitaigorodskii, A. I. Molecular Crystals and Molecules; Academic Press: New York, 1973. (18) MacNicol, D. D.; Downing, G. A. in ComprehensiVe Supramolecular Chemistry, Vol. 6: Solid-state Supramolecular Chemistry; MacNicol, D. D.; Toda, F.; Bishop, R., Eds.; Pergamon Press, Oxford, 1996; Ch. 17, pp 535-592. (19) Bishop, R. Enantiomer Ordering and Separation during Molecular Inclusion. In Separations and Reactions in Organic Supramolecular Chemistry; Toda, F.; Bishop, R., Eds.; Wiley: Chichester, 2004; Chapter 2, 33-60. (20) Collet, A.; Brienne, M.-J.; Jacques, J. Chem. ReV. 1980, 80, 215– 230. (21) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981. (22) Collet, A. The homochiral versus heterochiral packing dilemma. In Problems and Wonders of Chiral Molecules; Simonyi, M., Ed.; Akade´miai Kiado´: Budapest, 1990; pp 91-109. (23) Steiner’s analysis (ref 3) found values of Z′ between 1/96 and 32. Some biological macromolecules, however, have even larger values. The low values of Z′ arise from molecules with high internal symmetry, and/or molecules positioned on symmetry sites. Thus, as described by Desiraju (ref 4, see note 13) (as an example) some Z′ ) 1 structures are really Z′ ) 0.5 + 0.5. However, these are phenomenologically equivalent to Z′ ) 2 structures in the present context. Such situations, and possible alternative designators, are discussed more fully by Bond (ref 6). Hence it would be technically possible for a false conglomerate to be formed with Z′ e 1. We consider that the frequency of this happening will be low, however, given the inherent complexity of the false conglomerate arrangement compared to more conventional crystal structures. (24) Our original reports regarding the behavior of 1 and 2 (in refs 26 and 31) correctly described the arrangements of enantiomers in their
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crystals, but incorrectly ascribed these structures as being genuine conglomerates. Von Zelewsky, A. Stereochemistry of Coordination Compounds; Wiley, Chichester, 1995; p 56. Rahman, A. N. M. M.; Bishop, R.; Craig, D. C.; Scudder, M. L. Eur. J. Org. Chem. 2003, 72–81. Rahman, A. N. M. M.; Bishop, R.; Craig, D. C.; Scudder, M. L. Chem. Commun. 1999, 2389–2390. Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc., Perkin Trans. 2 2001, 651–669. Desiraju, G. R.; Gavezzotti, A. Acta Crystallogr. 1989, B45, 473– 482. Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in Structural Chemistry and Biology; Oxford Science Publications: Oxford, 1999. Marjo, C. E.; Bishop, R.; Craig, D. C.; Scudder, M. L. Eur. J. Org. Chem. 2001, 863–873. Pich, K. C.; Bishop, R.; Craig, D. C.; Dance, I. G.; Rae, A. D.; Scudder, M. L. Struct. Chem. 1993, 4, 41–51. The structural arrangement of molecules in solid 3 was described by us in ref 32 as being a pseudo-host-guest system. The term selfinclusion was deliberately avoided but has been employed elsewhere by others. The use and abuse of such descriptions has been eloquently analysed by Barbour and his colleagues in ref 34. Lloyd, G. O.; Alen, J.; Bredenkamp, M. W.; De Vries, E. J. C.; Esterhuysen, C.; Barbour, L. J. Angew. Chem., Int. Ed. 2006, 45, 5354– 5358. Allen, F. H.; Davies, J. E.; Galloy, J. J.; Johnson, O.; Kennard, O.; Macrae, C. F.; Mitchell, E. M.; Mitchell, G. F.; Smith, J. M.; Watson, D. G. J. Chem. Inf. Comput. Sci. 1991, 31, 187–204.
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