The Design of “Awkward” Molecules Expected to ... - ACS Publications

DOI: 10.1021/cg100883s

The Design of “Awkward” Molecules Expected to Yield Multiple Crystal Forms†

2010, Vol. 10 4582–4589

Isa Y. H. Chan, Vi T. Nguyen, Roger Bishop,* Donald C. Craig,‡ and Marcia L. Scudder School of Chemistry, The University of New South Wales, UNSW, Sydney, New South Wales 2052, Australia. ‡Deceased May 12, 2009. Received July 4, 2010; Revised Manuscript Received July 28, 2010

ABSTRACT: The very simple alicyclic compounds 3,7-dimethylbicyclo[3.3.0]octane-endo-3,endo-7-diol 3 and 2,6-dimethylbicyclo[3.3.0]octane-endo-2,endo-6-diol 5 were selected for study in the knowledge that these are awkwardly shaped molecules that are likely to pack in the solid state with some difficulty. The design philosophy behind the choice of these particular test molecules is explained. We expected that these isomeric diols would probably yield more than one crystal form if crystallized from a range of different solvents. Dialcohol 3 was found to give three (benzene clathrate, hemihydrate, and hydrate), and dialcohol 5 to give two (racemic and kryptoracemate/false conglomerate), crystal forms. The X-ray structures of these five very different crystalline solids (formed by two very similar model compounds) are described and contrasted. Our findings demonstrate that awkward molecules can be identified and indicate that the formation of alternative crystal forms is likely to be a comparatively frequent occurrence under ambient conditions.

Introduction When molecules assemble together into a crystal, it is generally expected that they will pack as a regular onecomponent array and as close to each other as possible in order to achieve the state of lowest potential energy.1 This close packing is not always the case, however, if the intermolecular attractive forces have strong directional requirements. Ice, for example, has a comparatively open crystal structure due to its tetrahedrally oriented hydrogen bonding, and therefore its density at 0 °C (0.9168 g cm-3) is considerably less than liquid water (0.9998 g cm-3) at the same temperature. Early studies of clathrate compounds2 suggested a second reason for the occurrence of lower density packing. If the compound under study had an awkward shape, then its molecules simply could not pack together efficiently.3 Void spaces were rarely observed in the crystals of such substances because guest molecules were normally included in the structure to increase the overall density and packing coefficient values. The concept of awkward shape has since become a powerful tool in the still-challenging design of new clathrate host molecules.4 An excellent illustration of this concept is Weber’s pioneering work on host compounds containing multiple aromatic rings. These may be combined in a molecule using both edge-edge and edge-face arrangements to produce crosswise, V-shape, T-shape, and other molecular geometries. Furthermore, functional groups such as triarylmethane provide wheel or propeller geometries. Combinations of these basic arrangements can also be incorporated within a molecule, thereby providing a huge range of new moderately complex clathrand hosts.5 It is often thought, consciously or otherwise, that there is a unique solution for the crystallization of a given compound: results are commonly presented describing “the crystal structure”. † This paper is Resolutions and Polymorphs, Part 6. Part 5 is Bishop, R.; Scudder, M. L. Multiple molecules in the asymmetric unit (Z0 > 1) and the formation of false conglomerate crystal structures. Cryst. Growth Des. 2009, 9, 2890-2894, DOI 10.1021/cg9002143. *Corresponding author. E-mail: [email protected].

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Published on Web 08/30/2010

There is an increasing realization, however, that a molecule crystallizing in more than one crystal form is not as rare an event as once believed. Indeed, this possibility has become a topic of considerable contemporary interest.6 These alternative crystal forms may, for example, be polymorphs,7 solvates,8 hydrates,9 or organic hydrogen-bonded cocrystals.10 Alternative crystal forms are different materials and may be individually patentable.11 Pharmaceutically active compounds are believed to show polymorphism with 30-50% probability.12 Therefore, it is important to discover how and why these different structures form, and perhaps learn how to predict and control such phenomena. We considered that molecules with an awkward shape might not just have an increased tendency of forming clathrate structures, but should also be more likely to crystallize in alternative ways. This paper describes the concepts behind our design of two test compounds and provides X-ray crystallographic evidence in support of our premise. Results Design of the Awkward Compounds. We wished to design two extremely simple, but awkward, test molecules that were isomers carrying the same functional groups. By doing so, we then could compare their crystallization outcomes with some validity. A major design difficulty is determining which molecular structures are likely to be “awkward” since the term is imprecise and this property is not always obvious. We chose derivatives of bicyclo[3.3.0]octane for the following reasons. This is an extremely simple structure, the ring system has a shape like a shallow dish, and its carbocyclic skeleton permits a small amount of bending and twisting conformational flexibility. In previous work, we have found the latter characteristic to be advantageous for clathrate formation since the molecular framework can adjust to guests of differing sizes and shapes.13 Although dishes usually stack in the convex face to concave face manner, this is not the case for some simple bicyclo[3.3.0]octane derivatives such as the racemic tetraester 1. The two bridgehead r 2010 American Chemical Society

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Scheme 1. Preparation of the Isomeric Diols 3 and 5a

Figure 1. Left: The molecular structure of one enantiomer of the racemic tetraester 1. This shows the ring numbering system and the black circles indicate the points used for measurement of the ring fold angle. Right: Opposite enantiomers of 1, with a shallow dishlike shape, pack as pairs in a concave face to concave face manner to form the repeat unit.14 Atom code: C green (opposite enantiomers light or dark), O red, and H light blue.

a Only one enantiomer of the racemic compounds 4 and 5 is illustrated.

H-C1 and H-C5 hydrogen atoms protrude above the convex exo-face and make this packing mode unattractive. This effect is exacerbated in 1 by the presence of the C4 and C8 exo-carbomethoxy substituents. The published X-ray crystal structure reveals that molecules of 1 form centrosymmetric concave face to concave face pairs as illustrated in Figure 1.14 Repetition of these cumbersome molecular pairs generates the full crystal lattice, but there is a dearth of effective interpair supramolecular synthons15 in this structure. This knowledge led us to choose 3,7-dimethylbicyclo[3.3.0]octane-endo-3,endo-7-diol 3 and 2,6-dimethylbicyclo[3.3.0]octane-endo-2,endo-6-diol 5 as our two test compounds. The H-C1 and H-C5 hydrogens, assisted by the two exo-methyl groups, will rule out convex face to concave face packing in each isomer. Presence of the two endo-hydroxy groups in each provides good opportunities for molecular assembly employing various hydroxy group supramolecular synthons.15,16 Further, the placement of two symmetrically equivalent hydroxy groups on each test molecule encourages propagation of a regular hydrogen bonded arrangement as each crystal grows. Finally, the difference in substitution positions affords different molecular symmetry in the two cases. Diol 3 contains two planes of symmetry and is achiral, whereas diol 5 has C2-symmetry and is chiral. Preparation and Crystallization of Compounds 3 and 5. Bicyclo[3.3.0]octane-3,7-dione 217 and racemic bicyclo[3.3.0]octane-2,6-dione 418 were methylated as shown in Scheme 1 to yield the corresponding test compounds 3 and racemic 5, respectively. Alkylation took place predominantly on the more exposed convex surface of the alicyclic skeleton to afford the pure diol products in good yield after purification. Crystallization of diol 3 from benzene gave crystals of (3)2 3 (benzene), crystals of (3)2.(water) were produced from toluene, cyclohexane, chloroform, 3-pentanone, mesitylene or trifluoromethylbenzene, and crystals of (3) 3 (water) were obtained from isooctane or p-xylene. No crystals of X-ray quality were obtained from acetonitrile, 2-butanol, d-chloroform, cyclooctane, diethyl ether, methanol, 1,1,1-trichloroethane, or m-xylene. Crystallization of racemic diol 5 from cyclohexane or ethanol gave crystals of solvent-free 5 in space group P21/ c. In contrast, crystals of solvent-free 5 in space group P41 (and its enantiomorph P43) were produced on its crystallization from acetone, benzene, 1,4-dioxane, or tetrahydrofuran. Crystals too small to allow their single crystal unit cell determination were produced from acetonitrile, 2-butanol, d-chloroform, dichloromethane, mesitylene, 1,1,1-trichloroethane and m-xylene. No crystals were obtained from diethyl ether, ethyl

acetate, pyridine, trifluoromethylbenzene, o-xylene, or water solutions. The numerical details relating to the data collection, data processing, and refinement of the X-ray structures of the five crystalline solids obtained are listed in Table 1. Crystal Structure of (3)2 3 (benzene). This clathrate compound forms in the monoclinic space group P21/c. The molecules of 3 associate as pairs in a concave face to concave face manner by means of Etter graph set notation19 R22(16) hydrogen bonding. These centrosymmetric dimers are then further hydrogen bonded together to create host layers in the bc plane as shown in Figure 2, in which each hydroxy group takes part in two hydrogen bonds, one as donor and one as acceptor. Benzene guest molecules occupy channels along the b direction and are located around centers of symmetry lying between the host layers. Inclusion of the benzene guests is facilitated by means of centrosymmetric host-guest C-H 3 3 3 π interactions (d = 2.88-3.08 A˚) on each face of the benzene molecule (Figure 3). Crystal Structure of (3)2 3 (water). This hemihydrate compound (composition 2:1) forms in the monoclinic space group P2/c and its crystal structure comprises hydrogen bonded layers in the bc plane. The molecules of 3 once again associate in a concave face to concave face orientation, but they are now no longer directly connected. Instead, water molecules are inserted between the diols to generate centrosymmetric R44(20) hydrogen bonded cycles. The water molecule, which is located on a 2-fold axis, participates in two donor and two acceptor hydrogen bonds, thereby acting as a tetrahedral bridging link between two adjacent 2-fold related cycles. Chains are thereby created along c. These are connected further by means of diol-diol O-H 3 3 3 O hydrogen bonds to the layers above and below in the b direction (Figure 4). Crystal Structure of (3) 3 (water). This hydrate compound (composition 1:1) forms in the monoclinic space group P21/c. The orientation of the diol molecules is completely different in this structure, but, once again, water molecules are inserted and these reduce direct O-H 3 3 3 O hydrogen bonding between the molecules of 3. The diol molecules are oriented as crosslinked chains instead of the previous concave face to concave face arrangement (Figure 5). This cross-linking produces layers in the bc plane. The hydrogen bonded link within and between the chains is a complex infinite structure along a. Two different centrosymmetric motifs alternate: a 12-membered (O-H)6 ring constructed from four diol hydroxy groups and two water molecules, in Etter notation R66(12), and fused onto

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Table 1. Numerical Details of the Solution and Refinement of the Crystal Structures compound formula formula mass space group a / A˚ b / A˚ c / A˚ β/° V / A˚3 T/K Z Dcalc / g cm-3 radiation, λ / A˚ μ / mm-1 scan mode 2θmax / ° no. of intensity meas criterion for observed ref no. of indep obsd ref no. of reflections (m) and variables in final ref Pm (n)P |ΔF|/ m|F R= P Po| m w|ΔF|2/ mw|Fo|2]1/2 Rw =P[ m 2 w|ΔF| /(m - n)]1/2 s=[ crystal decay R for (no. of) mult meas largest peak in final diff map/ e A˚-3 CCDC no.

(3)2 3 (benzene) C10H18O2 3 (C6H6)0.5 209.3 P21/c 8.997(4) 15.416(5) 9.007(3) 102.86(2) 1217.9(8) 294(1) 4 1.14 MoKR, 0.7107 0.073 θ/2θ 50 2288 I/σ(I) > 2 1169 1169 125 0.055 0.055 1.18 none 0.029 0.34 778288

(3)2 3 (water) C10H18O2 3 (H2O)0.5 179.3 P2/c 10.219(4) 6.155(1) 16.422(5) 102.10(1) 1010.0(5) 294(1) 4 1.18 MoKR, 0.7107 0.080 θ/2θ 50 1837 I/σ(I) > 2 1267 1267 114 0.048 0.054 1.42 none 0.024 0.29 778287

Figure 2. Part of the (3)2 3 (benzene) structure showing the concave face to concave face host dimers linked to form a layer. Hydroxy group hydrogen bonds are indicated by dashed lines.

two sides of this substructure are identical eight-membered rings R44(8) built from two diol hydroxy groups and two water molecules. The entire structure can be seen in cross section in Figure 5 (upper), whereas the tilted Figure 5 (lower) highlights the two different ring types but does not attempt to show the entire hydrogen bonded structure. This linker unit is illustrated more clearly in the Discussion section. The water molecule acts as a donor for two hydrogen bonds and acceptor for one. One hydroxy group, O2, also takes part in three hydrogen bonds, one as donor and two as acceptor, whereas the other hydroxy group, O1, is involved in only two hydrogen bonds, one as donor, and one as acceptor. Crystal Structure of 5 in P21/c. Crystals of this solvent-free material in the monoclinic space group P21/c contain two

(3) 3 (water) C10H18O2 3 H2O 188.3 P21/c 6.1656(1) 11.3559(2) 15.7414(3) 90.297(1) 1102.13(3) 150(1) 4 1.13 MoKR, 0.7107 0.079 θ/2θ 62.8 16425 I/σ(I) > 2 2582 2582 118 0.046 0.057 1.06 None 0.071 0.38 778289

5

5

C10H18O2 170.3 P21/c 8.794(3) 8.917(3) 25.524(9) 94.23(2) 1996(1) 294(1) 8 1.13 MoKR, 0.7107 0.075 θ/2θ 50 3752 I/σ(I) > 2 1289 1289 217 0.082 0.077 1.25 11% 0.028 0.70 778285

C10H18O2 170.3 P41 9.161(2) 9.161(2) 23.388(7) 90 1962.8(8) 294(1) 8 1.15 MoKR, 0.7107 0.076 θ/2θ 50 1992 I/σ(I) > 2 1062 1062 216 0.062 0.071 1.26 6% 0.016 0.38 778286

crystallographically independent molecules (A,B) and their enantiomers (A*,B*). Molecules of 5 form hydrogen bonded (O-H)n chains that run along the a direction. The enantiomers of 5 alternate along the chains in two ways: -A-B*-AB*-A- and -A*-B-A*-B-A*-. Both arrangements are present in the same crystal as illustrated in Figure 6. The hydrogen bonds are alternately inter- and intramolecular. Crystal Structure of 5 in P41 (and P43). This solvent-free material crystallizes in the tetragonal crystal system as a 1:1 mixture of enantiomorphous P41 and P43 crystals. Two crystallographically independent molecules (A,B) and their enantiomers (A*,B*) are present in the bulk sample. Molecules of 5 are assembled once again as hydrogen bonded (O-H)n chains that run along the a (and b) direction, and again alternate in being inter- and intramolecular. Individual crystals, however, contain only A and B* (or only A* and B) molecules. Thus, in a given crystal, the enantiomers of 5 alternate along the chains in only one manner, -A-B*-A-B*-A as shown in Figure 7. The alternative arrangement, -A*-B-A*-B-A*-, and the opposite helix direction occur in the second crystal type. This outcome is not a conglomerate,20 despite the presence of a 1:1 mixture of enantiomorphous crystals, since the individual crystal contents are racemic rather than homochiral.21 Instead, this is a kryptoracemate22 (or false conglomerate)23 structural outcome. Discussion General Comparison of the Crystal Structures. One parameter we have found useful in comparing a related series of crystal structures of bicyclic compounds is the fold angle (defined here on the molecular structure of compound 1). These values are (3)2 3 (benzene) 153.0, (3)2 3 (water) 156.6, (3) 3 (water) 153.9, 5 in P21/c A 154.6 and B 154.1, and 5 in P41 A 154.9 and B 155.6 deg, respectively. These values are remarkably consistent and indicate that conformational changes of the bicyclo[3.3.0]octane skeleton do not play an important role here. Numerical details of the hydroxy group hydrogen bonding for the five crystal structures are given in Table 2.

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Table 2. Numerical Details of Hydrogen Bonding in the Crystal Structures O-H (A˚)

compound, atoms,coordinates

H 3 3 3 O (A˚)

O 3 3 3 O (A˚)

bond angle (°)

(3)2 3 (benzene) O1-H1O1 3 3 3 O2i O2-H1O2 3 3 3 O1ii i 1-x, 1/2 þ y, 1/2 - z

1.00 1.00 ii 1 - x, 1 - y, -z

1.84 1.84

2.838(2) 2.843(3)

180 180

(3)2 3 (water) O1-H1O1 3 3 3 OWi O2-H1O2 3 3 3 O1ii OW-H1OW 3 3 3 O2 i 1 - x, -y, 1 - z

1.00 1.00 1.00 ii x, 1 - y, -1/2 þ z

1.85 1.84 1.81

2.854(2) 2.844(2) 2.799(2)

180 180 168

(3) 3 (water) O1-H1O1 3 3 3 OW1i O2-H1O2 3 3 3 O1ii OW1-H1OW1 3 3 3 O2 OW1-H2OW1 3 3 3 O2iii i 1 - x, 1/2 þ y, 1/2 - z

1.00 1.00 1.00 1.00 ii x, 1/2 - y, 1/2 þ z

1.68 1.67 1.84 1.81 iii -x, -y, 1 - z

2.6782(12) 2.6652(11) 2.8324(12) 2.7999(12)

180 180 173 172

5 in P21/c O1A-H10 O1A 3 3 3 O2A O2A-H1O2A 3 3 3 O2Bi O1B-H1O1B 3 3 3 O1Aii O2B-H10 O2B 3 3 3 O1B i 1 - x, -y, 1 - z

1.00 1.00 1.00 1.00 ii -x, -y, 1 - z

1.69 1.71 1.72 1.67

2.691(4) 2.707(4) 2.725(4) 2.668(4)

180 180 180 180

1.00 1.00 1.00 1.00

1.77 1.73 1.74 1.75

2.769(5) 2.726(5) 2.735(6) 2.750(5)

180 180 180 180

5 in P41 O1A-H1O1A 3 3 3 O1Bi O2A-H1O2A 3 3 3 O1A O1B-H1O1B 3 3 3 O2B O2B-H1O2B 3 3 3 O2A i x, -1 þ y, z

Comparison of the Crystal Forms Involving Diol 3. All three crystal forms adopted by 3 are two-component solids, one clathrate and two hydrates, and all three contain hydrogen bonded layer structures. As planned, in no case do the dishshaped bicyclo[3.3.0]octane molecules stack in the conventional convex face to concave face sense. Pairs of diol molecules are oriented in the concave face to concave face manner in both (3)2 3 (benzene) and the hemihydrate structure (3)2 3 (water), although with different hydrogen bonding connectivity. The hydrate structure (3) 3 (water) abandons this diol orientation in favor of cross-linked chains of molecules of 3. The hydrogen bonding in the three crystal forms is shown diagrammatically in Figure 8, where each diol 3 molecule has been reduced to a solid red rod and two hydroxy groups. Comparison of these arrangements reveals the remarkable increase in complexity of these hydrogen bonded arrays across the series. The arrangement in (3)2 3 (benzene) is extremely simple, with pairs of diols assembling by means of hydrogen bonding in a concave face to concave face manner. Since commercial benzene contains traces of water, it is remarkable that this clathrate structure is favored over one of the alternative hydrate outcomes. The likely explanation is the presence of the stabilizing host-guest C-H 3 3 3 π interactions shown in Figure 3. In contrast, the commercial solvents that led to hydrated crystals are not renowned for their water content. In these cases, it is likely that a small amount of water was sequestered from the atmosphere during the slow concentration of their solutions. The (3)2 3 (water) structure is of intermediate complexity. The water molecules are inserted between the diol 3 dimers and link these along the c direction. They also participate in four hydrogen bonds: two donor and two acceptor. This crystal form has a slightly higher density than the other two.

The greater proportion of water present in the compound (3) 3 (water) results in the most complex crystal structure being produced. In particular, the complicated hydrogen bonding motif discussed earlier can be seen most clearly in Figure 8 (bottom). Formation of this arrangement appears to be a compromise. The presence of more water provides strong hydrogen bonding interactions, but each water molecule participates in fewer hydrogen bonds (two donor and one acceptor) than in the hemihydrate structure. Statistically, this mode of water hydrogen bonding is very strongly favored in hydrate crystal structures over the two donor plus two acceptor alternative.24 Comparison of the Crystal Forms Involving Diol 5. Diol 3 is achiral, highly symmetrical, and forms different two-component crystal forms. In contrast, the isomeric diol 5 is chiral and has C2-symmetry. Racemic 5 accommodates its two enantiomers by assembly into linear hydrogen bonded assemblies without inclusion of a second molecular component. Both crystal forms identified involve two crystallographically independent molecules and these two structures are very closely related. The crystal form in P21/c contains both -A-B*-A-B*-A- and -A*-B-A*-B-A*- chains within the same crystal, whereas the crystals in P41 (Z0 = 2) contain -AB*-A-B*-A- chains only (and only -A*-B-A*-B-A*- chains in the P43 crystals). There is no obvious correlation between the properties of the solvents used and the selection of the particular crystal form of 5. The generation of a 1:1 mixture of enantiomorphous (but racemic) crystals (in P41 and P43 here) is a fascinating phenomenon that is only possible when more than one crystallographically independent chiral molecule and their enantiomers are present. Bernal22 and other workers25 have termed such crystals kryptoracemates, but in a recent publication emphasizing their requirement for Z0 > 1 we employed the description false conglomerate.23 These names

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Figure 4. Part of the crystal structure of the compound (3)2 3 (water). Upper: One R44(20) cycle constructed from two molecules of diol 3 and two water molecules. Lower: The unit cell diagram showing one complete hydrogen bonded layer, flanked by two half layers, in the bc plane. Atom code: water O (black).

Figure 3. Upper: The host-guest packing in (3)2 3 (benzene) showing the benzene guests aligned along the b direction. Lower: The host-guest C-H 3 3 3 π interactions indicated by arrows. Atom code: guest C (purple).

refer to the same crystal outcome but highlight different aspects of these materials. Formation of such crystals in which the enantiomers are crystallographically independent is a rare phenomenon. Brock has very recently described elegant techniques for identifying kryptoracemates in the Cambridge Structural Database and has listed 181 authentic organic examples.26 Our results suggest that the frequency of occurrence is higher than average for racemates of slightly twisted C2-symmetric organic molecules, such as diol 5 and the three other examples analyzed in our earlier paper.23 Conclusions In order to test our design concept that awkward molecules should be likely to crystallize in more than one crystal

form, we chose and prepared the isomeric test compounds 3,7-dimethylbicyclo[3.3.0]octane-endo-3,endo-7-diol 3 and 2,6-dimethylbicyclo[3.3.0]octane-endo-2,endo-6-diol 5. Both of these extremely simple models behaved as expected and yielded alternative crystal forms on merely changing the crystallization solvent. No attempt to vary the crystallization temperature and/or pressure was necessary. The single crystal X-ray structures of these materials were determined and analyzed. Compound 3 yielded three crystal forms (one clathrate compound and two hydrates of differing composition), whereas compound 5 gave two (a racemate, and a kryptoracemate or false conglomerate). These results indicate that the formation of multiple crystal forms is likely to be encountered frequently when crystallization is examined in a systematic manner. This is supported by the computed crystal energy landscapes determined by Price in which there are frequently several alternative arrangements within ca. 10 kJ mol-1 or so of the calculated energy minimum.27 On the other hand, the prediction of precisely which structural types will be readily isolable by experiment remains problematic at our current level of understanding. The arguments presented for expecting compounds 3 and 5 to yield more than one crystal form apply equally well to the racemic tetraester 1. Just one crystal form

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Figure 5. Part of the crystal structure of (3) 3 (water) showing the O-H 3 3 3 O hydrogen bonding between the diol 3 and water molecules. Upper: The layer arrangement projected on the bc plane. This illustrates the cross-linked chains and the complex hydrogen bonded cross-linking motif. Lower: A view of (3) 3 (water) showing the two different ring types comprising the substructures of the linking motif. No attempt to show the entire hydrogen bonding structure has been made here.

Figure 7. Upper: The crystal structure of 5 in space group P41 projected on the ab plane and showing the chains of -A-B*-A-B*-Amolecules along the a direction. Lower: The unit cell arrangement showing neighboring chains surrounding a 4-fold screw axis along c.

Experimental Section

Figure 6. The crystal structure of 5 in space group P21/c. Left: Projection in the ac plane and showing the (O-H)n chains running along the a direction. Right: Projection in the bc plane showing the hydrogen bonded chains from the top. The crystallographically independent molecules (A,B) are colored light green or light blue, respectively. Their enantiomers (A*,B*) are shown in dark green or dark blue, respectively. Hydrogen atoms other than hydroxy are omitted for clarity from the figure on the left and the hydrogen bonds are indicated by dashed lines.

of 1 has been published so far,14 but this is does not represent the complete behavior of this compound.28

NMR data were recorded using a Bruker DPX300 instrument at 25 °C (1H 300 MHz, 13C 75.4 MHz) and carbon substitution information was determined using the DEPT procedure. IR spectra were obtained on a Nicolet Avatar 370 FT-IR spectrophotometer. MS data (EI) were recorded by Dr. J. J. Brophy using a VG Quattro triple quadrupole instrument. The microanalytical data were determined at the Australian National University, Canberra. 3,7-Dimethylbicyclo[3.3.0]octane-endo-3,endo-7-diol (3). A solution of bicyclo[3.3.0]octane-3,7-dione 217 (0.60 g, 4.34 mmol) was stirred at -10 °C. Methylmagnesium chloride solution (34.8 mmol) in THF was added dropwise via cannulation. The cooling bath was removed after 30 min and then the mixture refluxed overnight. After cooling to rt, satd. aq. NH4Cl solution was added, and the organic material was extracted several times using diethyl ether. The combined extracts were dried (Na2SO4), and solvent evaporated from the filtrate to give a yellow oil. This was purified by column chromatography on SiO2, eluting with hexane and increasing amounts of Et2O. The diol 3 was obtained as a white solid (0.45 g, 61%), mp 105-107 °C (from diethyl ether). IR (paraffin mull) 3341s, 1322w, 1300w, 1284 m, 1218w, 1154 m, 1136 m, 1083w, 1057w, 1034w, 1014w, 957w, 943w, 931w cm-1. 1H NMR (CDCl3) δ

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Figure 8. Comparative diagrams of the hydrogen bonding present in the three crystal forms adopted by diol 3. The molecule 3 is represented here as a solid red rod bearing a hydroxy group at each end. Top: (3)2 3 (benzene), center: (3)2 3 (water), and bottom: (3) 3 (water). 1.24 (s, 6H), 1.73-1.79 (dd, 4H), 1.84-1.91 (dd, 4H), 2.56-2.61 (m, 2H), 3.99 (s, 2H). 13C NMR (CDCl3) δ 28.5 (CH3), 42.6 (CH), 48.7 (CH2), 82.0 (C). Calc. for C10H18O2 requires C, 70.55; H, 10.66. Found: C, 70.72; H, 10.57%. 2,6-Dimethylbicyclo[3.3.0]octane-endo-2,endo-6-diol (5). A solution of bicyclo[3.3.0]octane-2,6-dione 418 (0.69 g, 5.0 mmol) in dry diethyl ether (50 mL) was stirred at -10 °C. Methyl lithium (20.0 mmol) in diethyl ether was added by syringe through a septum. The cooling bath was removed after 30 min and then the mixture was stirred overnight at rt. Excess MeLi was destroyed by cautious addition of wet Et2O, satd. aq. NH4Cl solution was added, and the organic material was extracted several times using diethyl ether. The combined extracts were dried (Na2SO4), and solvent was evaporated from the filtrate to give a colorless oil that slowly crystallized. This solid was triturated with a small amount of Et2O, filtered, and then recrystallized from benzene to give diol 5 (0.64 g, 75%), mp 133-135 °C. IR (paraffin mull) 3225s, 3175s, 1320 m, 1295 m, 1250s, 1220w, 1180s, 1130w, 1085 m, 1050s, 1010w, 965 m, 945w, 910s, 875s, 840w cm-1. 1H NMR (CDCl3) δ 1.21 (s, 6H), 1.92-1.53 (m, 8H), 2.36-2.34 (m, 2H), 4.21 (s, 2H, exch. with D2O). 13C NMR (CDCl3) δ 20.1 (CH3), 25.2 (CH2), 44.7 (CH), 54.2 (CH2), 78.3 (C). MS m/z (significant peaks and >20%) 170 (Mþ, not observed), 152 (Mþ - H2O, 7%), 134 (Mþ - 2H2O, 11), 109 (29), 95 (35), 94 (84), 93 (21), 83 (24), 82 (24), 81 (87), 79 (74), 77 (22), 71 (22), 71 (32), 69

(28), 67 (58), 58 (34), 57 (23), 55 (54), 53 (32), 43 (100). Calc. for C10H18O2 requires C, 70.55; H, 10.66. Found: C, 70.32; H, 11.00%. Crystallization and Identification of the Crystal Forms. In all experiments, the pure diol 3 or 5 was dissolved with warming in a small volume of the chosen solvent. Crystals were allowed to form by slow concentration through evaporation from each sample at laboratory temperature and pressure. The full crystal structure solutions of the five different compounds were determined as described below. The cell parameters of all other single crystals obtained were determined using diffractometry to ensure that they were identical to one of these structures. Solution and Refinement of the Crystal Structures. Reflection data were measured with an Enraf-Nonius CAD-4 diffractometer, or a Bruker Kappa ApexII diffractometer for (3) 3 (water). Data were not corrected for absorption. The positions of all atoms in the asymmetric unit were determined by direct phasing (SIR92)29 with hydrogen atom included in calculated positions. In both structures of 5, the hydroxy hydrogen atoms were disordered over two equally occupied positions. All non-hydrogen atoms in all five structures were refined anisotropically, with the exception of those of the benzene guest molecule in (3)2 3 (benzene) which was refined as a rigid group with a TLX thermal group defining the thermal motion of the group. Full details of refinement30 can be found in the Supporting Information.

Article

Crystal Growth & Design, Vol. 10, No. 10, 2010

Acknowledgment. We thank the Australian Research Council for financial support of this work. Supporting Information Available: X-ray crystallographic information files (CIF) for the structures CCDC 778285-778289 (see Table 1). This material is available free of charge via the Internet at http://pubs.acs.org/.

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