Polymorphic Crystals Formed by an Achiral Diol under Ambient

Article pubs.acs.org/crystal

Polymorphic Crystals Formed by an Achiral Diol under Ambient Conditions† Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju Jiabin Gao,‡ Mohan M. Bhadbhade,§ and Roger Bishop*,‡ ‡

School of Chemistry, The University of New South Wales, UNSW Sydney, New South Wales 2052, Australia Mark Wainwright Analytical Centre, The University of New South Wales, UNSW Sydney, New South Wales 2052, Australia

§

S Supporting Information *

ABSTRACT: The crystallization behavior of 3,7-bis(2pyridyl)bicyclo[3.3.0]octane-endo-3,endo-7-diol (4) is very different from that of its known 3,7-bis(phenyl) analogue 3. It yields two solvent-free (apohost) polymorphs, a clathrate structure containing benzene, and two monohydrate polymorphs, which are produced simply by employing different recrystallization solvents at room temperature and pressure. The structures of the apohost compounds share little commonality and use quite different methods of crystal assembly. One of these polymorphs has, however, a very close relationship with the benzene clathrate crystal form. The monohydrate polymorph structures share gross structural features, but nonetheless differ considerably in their detailed construction. The X-ray structures of these five disparate crystal forms are analyzed in crystal engineering terms and illustrate how even a simple achiral molecule can yield polymorphs by using alternative interaction arrangements.

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INTRODUCTION We have shown recently that the simple bicyclo[3.3.0]octane diols 1−3 yield multiple crystal forms on crystallization from different solvents at room temperature and pressure. The bicyclic core of these molecules has a shallow dish-like shape. While domestic dishes stack simply in a concave face to convex face manner, this is not the case here. Instead, the compounds 1−3 show a strong tendency to form dimeric units by means of concave face to concave face assembly. This is the case for racemic 1 in its polymorph I structure,1,2 the clathrate (2)2·(benzene), and the hemihydrate (2)2·(water).3 The diol 3 behaves this way in its apohost structure, its clathrates (3)2·(benzene) and (3)·(o-xylene), in the hydrogen bonded cocrystal (3)·(methanol), and in several other closely related cocrystalline compounds.4 Molecules that fit together awkwardly for reasons of size and shape have difficulty in associating efficiently in the Kitaigorodsky close-packed manner.5 Consequently, they often combine with complementary guest species in order to attain higher density and lower energy crystal packing arrangements.6 This idea has long been applied in the deliberate design of new host molecules7 and their associated clathrate inclusion compounds.8 Our earlier work on other types of alicyclic diols illustrates the versatility of this synthetic concept.9 Whereas compound 1 has C2-rotational symmetry and is chiral, it should be noted that diols 2 and 3 are considerably simpler structures in being achiral and containing two formal

mirror planes. Concave face to convex face assembly is discouraged in all three cases by the protruding cis-hydrogen atoms at the C1 and C5 positions of the bicyclo[3.3.0]octane framework. In parallel with this, concave face to concave face assembly is strongly facilitated for 2 and 3 by the endoconfiguration of their C3 and C7 hydroxy groups. In several instances this occurs by means of the well-known (O−H)4 supramolecular synthon.10 Awkward molecules can also achieve low energy packing through means other than clathrate formation,8 and they often Received: August 29, 2012 Revised: October 16, 2012 Published: October 17, 2012

†

This paper is Resolutions and Polymorphs, Part 9. For Part 8 see ref 1. © 2012 American Chemical Society

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dx.doi.org/10.1021/cg301259f | Cryst. Growth Des. 2012, 12, 5746−5756

Crystal Growth & Design

Article

Table 1. Numerical Details of the Solution and Refinement of the Crystal Structures apohost polymorph I

apohost polymorph II

4 C18H20N2O2 296.36 monoclinic, C2/c temperature (K) 155 a 22.8627(10) b 7.3486(3) c (Å) 19.1526(10) β (°) 111.435(4) V (Å3) 2995.2(2) Z 8 μ (mm−1) 0.09 crystal size (mm) 0.39 × 0.27 × 0.22 Tmin, Tmax 0.967, 0.981 no. of measured, independent, and observed [I > 20326 2σ(I)] reflections 2639 2508 Rint 0.036 R [F2 > 2σ(F2)] 0.068 wR(F2) 0.145 S 1.25 no. of reflections 2639 no. of parameters 207 no. of restraints 2 Δ>max, Δ>min (e Å−3) 0.36, −0.45 CCDC number 897446

4 C18H20N2O2 296.36 orthorhombic Pna21 160 19.7275(18) 7.6198(5) 9.9770(9) 90 1499.7(2) 4 0.09 0.19 × 0.15 × 0.12 0.984, 0.990 6083 2825 2278 0.034 0.039 0.087 1.01 2825 207 1 0.14, −0.17 897445

crystal form compound formula formula mass crystal system, space group

benzene clathrate

hydrate polymorph I

hydrate polymorph II

(4)·(benzene) (C18H20N2O2)·(C6H6) 374.47 monoclinic P21/c

(4)·(water) (C18H20N2O2)·(H2O) 314.38 monoclinic P21/c

(4)·(water) (C18H20N2O2)·(H2O) 314.38 monoclinic P21/n

155 19.0145(9) 9.8544(4) 10.6615(4) 98.419(2) 1976.19(14) 4 0.08 0.41 × 0.27 × 0.17

155 12.5839(6) 6.0146(3) 21.2073(11) 101.632(2) 1572.15(14) 4 0.09 0.39 × 0.35 × 0.17

155 14.208(6) 7.401(3) 15.291(6) 98.77(2) 1589.1(11) 4 0.09 0.17 × 0.10 × 0.06

0.968, 0.986 15365 4293 3308 0.037 0.054 0.149 1.04 4293 255 0 0.54, −0.58 897447

0.966, 0.985 12788 3399 3038 0.027 0.036 0.099 1.02 3399 218 0 0.35, −0.19 897449

0.985, 0.994 7829 2690 1160 0.170 0.062 0.129 0.92 2690 224 0 0.29, −0.24 897448

Apohost Polymorph I Structure in C2/c. This crystal structure is relatively simple and uses intermolecular O−H···O hydrogen bonding to link the molecules of 4 into double stranded chains running along the b direction. The diols in the two strands are oriented concave face to concave face and are joined as centrosymmetric pairs, with neighboring dimers being connected by additional hydroxy group hydrogen bonding, as shown in Figure 1 (upper). This arrangement is further stabilized by several weak intramolecular attractions that will be discussed later. Adjacent double chains pack next to each other in the herringbone arrangement illustrated in Figure 1 (lower). One of the pyridyl wings of 4 participates in a double alkylH···π interaction (blue) with its neighbor in the same chain, and also in an Ar−H···π interaction (black) with a molecule of 4 in the adjacent chain. Numerical values of the intermolecular interactions observed in all five of the crystal structures are listed in Table 2. Apohost Polymorph II Structure in Pna21. The only strong hydrogen bonding present in this crystal is intramolecular in nature. Each molecule of 4 forms an internal hydrogen bond O2−H2O···O1, while the second hydroxy group forms an intramolecular hydrogen bond O1−H1O···N2 with one of the pyridyl substituents. These significant interactions are augmented by four weaker intramolecular attractions: aryl C10−H10···O2, alkyl C7−H7B···O1, and the two nitrogen interactions N1···H7A−C7 and N1···H4B−C4 involving the second pyridyl group (Figure 2). This group of six attractions produces a rigid diol building block with the two pyridyl groups being close to coplanarity. Molecules of 4 associate orthogonally into zigzag chains along the a direction by means of aryl C17−H17···π

tend to utilize more than one crystal form in doing so. Hence, structural alternatives such as polymorph,11 hydrate12 and/or hydrogen bonded cocrystal arrangements are also probable.13 All of these outcomes were observed during our crystallization screening of the diols 1−3. The formation of polymorphs and other alternative crystal packing arrangements has become a topic of considerable importance from both academic and economic perspectives.14−16

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RESULTS Preparation and Crystal Screening of the Diol 4. The bicyclo[3.3.0]octane compounds 2 and 3 are entirely hydrocarbon in nature apart from their hydroxy groups. We therefore wished to study a related diol containing heteroatoms that could utilize additional intermolecular attractions. The bis(pyridyl) compound 4 was selected and prepared from bicyclo[3.3.0]octane-3,7-dione17 using standard methodology. Samples of 4 were dissolved in a range of test solvents, and crystals were allowed to grow at room temperature by slow evaporation. Only five examples of X-ray quality crystals were obtained from these screening experiments, and their structures were determined using single crystal X-ray methods. Diol 4 yielded two monoclinic solvent-free (apohost) polymorphs, one in space group C2/c from diethyl ether solution, and the other in Pna21 from acetone and water. A benzene clathrate was also produced in space group P21/c, but the use of other aromatic solvents did not yield crystalline material. In addition, the diol 4 formed two hydrate polymorphs, one in P21/c from damp tetrahydrofuran and the other in space group P21/n from damp acetonitrile. Numerical details of the solution and refinement of these five structures are shown in Table 1. 5747



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Figure 1. Upper: Part of a double chain of diol 4 molecules running along b (horizontal direction) in the apohost polymorph I structure. The molecules associate as O−H···O hydrogen bonded concave face to concave face dimers that are connected by further hydroxy hydrogen bonding. Atom code: C gray, N blue, O red. All hydrogen atoms are omitted for clarity and the O−H···O hydrogen bonds are indicated by dashed lines. Lower: Adjacent chains pack in a herringbone arrangement. One of the pyridyl rings of 4 participates in two different C−H···π interactions: an intrachain double alkyl-H···π interaction (blue) and an interchain single Ar−H···π interaction (black).

but this time utilizing an aryl-H donor atom. The chains are joined additionally by two identical O−H···N interactions. This combination of these 12 attractive forces creates a novel centrosymmetric pairing of the two parallel chains. Hydrate Polymorph I Structure in P21/c. Pairs of diol 4 molecules are oriented concave face to concave face around an inversion center, but the simple dimer is made more complex by the presence of a water molecule near each outer face. This results in the two types of molecules forming twin O−H···O− H···O−H hydrogen bonded chains along the b direction, as shown in Figure 6 (upper). These helical chains are identical apart from their opposite handedness. In addition, the second hydroxy group of each water molecule forms an O−H···N hydrogen bond with one of the pyridyl rings of 4. The resulting twin helical units pack parallel to each other: translated along the a direction and repeated with alternating handedness along c. Figure 6 (lower) shows the weaker hydrogen bonding associations within these twin helical units along a. The second pyridyl ring of 4 forms C11−H11···O1A (water) and C12− H12···O2 (alcohol) interactions (black), and also a pyridyl C13−H13···π (pyridyl) interaction (blue), with the adjacent unit along a. Hence the molecules of 4 are positioned as inphase pairs when viewed as a projection on the ac plane. Adjacent twin helical units along the c direction associate by means of C−H···O, C−H···π, and π···π weak interactions. Hydrate Polymorph II Structure in P21/n. Pairs of diol 4 molecules are once again oriented concave face to concave face, but now are displaced out-of-phase with respect to each other.

interactions as illustrated in Figure 3 (upper). This donor hydrogen belongs to the N2 pyridyl ring involving the O− H···N interaction, and the H-atom acceptor is the π system of the N1 pyridyl ring. Adjacent chains are joined by one C− H···O and the two C−H···N interactions shown in Figure 3 (lower). Clathrate (4)·(benzene) Crystal Structure in P21/c. Single molecules of 4 form an intramolecular multi-interaction arrangement that is remarkably similar to that of the apohost polymorph II structure. Here, however, the O−H···O interaction has become somewhat stronger at the expense of the O−H···N (see the values listed in Table 2), and the central bicyclo[3.3.0]octane ring has become more eclipsed. This results in loss of the intramolecular alkyl C−H···O interaction and forces two pyridyl rings even nearer to coplanarity (Figure 4). The benzene guest molecule is sandwiched between two host molecules by means of two pairs of Ar−H···π interactions and results in a chain structure. One pair of Ar−H atoms is provided by the N1 pyridyl ring and the second pair by the N2 pyridyl ring, as shown in Figure 5 (upper). Parallel chains associate on one face by means of a bifurcated O···H···O motif that utilizes both O1 and O2 of the intramolecular hydrogen bond discussed above. The hydrogen donor is C1−H1 of the bicyclo[3.3.0]octane unit. The other face of the parallel chains involves association using the complex motif illustrated in Figure 5 (lower). Once again, the intramolecular O−H···O hydrogen bond participates in a bifurcated O···H···O assembly, 5748



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Table 2. Numerical Details of the Intermolecular Attractions (Å, °) Apohost Polymorph Ia type

donor (D)−H···acceptor (A)

interdimer intrachain intrachain intrachain intrachain intrachain intrachain interchain interchain interchain

O(1)−H(1A)···O(1)a O(2)−H(2)···O(1)b C6−H6b···N2 C8−H8a···N2 C15−H15···O2 C2−H2b···O2 C10−H10···O1 C6−H6a···Cgc C4−H4b···Cgc C11−H11···Cgd

type


intramol. intramol. intramol. intramol. intramol. intramol. interchain interchain interchain interchain interchain

O(2)−H(2O)···O(1) O(1)−H(1O)···N(2) C(4)−H(4B)···N(1) C(7)−H(7A)···N(1) C(10)−H(10)···O(2) C7−H7B···O1 C(13)−H(13)···O(2)a C11−H11···N1b C5−H5B···O1c C7−H7A···N2 c C17−H17···Cgd

D−H 0.84(4) 0.84(6) 0.99 0.99 0.95 0.99 0.95 0.99 0.99 1.05 Apohost Polymorph IIb D−H 0.84(2) 0.89(3) 0.99 0.99 0.95 0.99 0.95 0.95 0.99 0.99 0.95 Benzene Clathratec

H···A

D···A

D−H···A

2.03(4) 1.99(5) 2.72 2.70 2.40 2.61 2.40 3.48 2.90 2.75

2.858(3) 2.779(3) 3.002(4) 3.063(4) 2.640(4) 3.168(4) 2.745(4) 4.146(3) 3.536(3) 3.569(3)

167(7) 157(5) 102 102 104 116 101 126 123 144

H···A

D···A

D−H···A

1.91(3) 1.94(3) 2.61 2.48 2.35 2.71 2.58 2.64 2.87 2.71 2.51

2.744(2) 2.538(2) 3.007(2) 2.926(3) 2.695(3) 3.104(3) 3.492(3) 3.575 (3) 3.292(3) 3.521(3) 3.420(3)

171(3) 123(3) 104 107 101 104 160 170 107 140 160

type


D−H

H···A

D···A

D−H···A

intramol. intramol. intramol. intramol. intramol. host−guest host−guest host−guest host−guest interchain interchain interchain interchain interchain interchain

O1−H1A···N2 O2−H2A···O1 C6−H6A···N1 C10−H10···O2 C8−H8B...N1 C17−H17···Cg C16−H16···Cg C11−H11···Cg C12−H12···Cg C1−H1···O1a C1−H1···O2a C18−H18···O1b C18−H18···O2b O1−H1A···N2 b O1−H1A···N2 b

0.84 0.84 0.99 0.95 0.99 0.95 0.95 0.95 0.95 0.99 0.99 0.95 0.95 0.84 0.84 Hydrate Polymorph Id

2.01 1.80 2.45 2.34 2.71 2.90 3.60 3.33 3.04 2.68 2.66 2.76 2.65 2.78 2.57

2.5656(19) 2.634(2) 2.900(2) 2.669(2) 3.081(2) 3.711(2) 4.062(2) 3.913(2) 3.767(2) 3.568(2) 3.548(2) 3.311(2) 3.462(2) 3.294(2) 2.566(2)

123 175 107 100 103 144 112 121 134 148 148 117 144 120 123

type


intraunit intraunit intraunit intraunit intramol. intramol. intraunit interunit intraunit intraunit

O(1)−H(1A)···O(2)a O(1A)−H(1W)···N(2) O(2)−H(2)···O(1A)b O(1A)−H(2W)···O(1)a C(2)−H(2B)···O(1) C(4)−H(4B)...N(2) C(12)−H(12)···O(2)c C(16)−H(16)···N(1)d C11−H11···O1Ae C13−H13···Cgf

D−H

type


D−H

intraunit intraunit intramol. intraunit

O1−H1O1···O1W O1W−H1W···O2a O2−H1O2···N2 O1W−H2W···O1b

0.86(4) 0.89(6) 0.85(4) 0.96(6)

0.84 0.92(2) 0.84 0.88(2) 0.99 0.99 0.95 0.95 0.95 0.95 Hydrate Polymorph IIe

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H···A

D···A

D−H···A

1.90 1.86(2) 1.83 1.97(2) 2.50 2.49 2.51 2.51 2.78 3.57

2.728(1) 2.779(1) 2.657(1) 2.835(1) 3.110(1) 2.903(1) 3.459(1) 3.423(2) 3.444(2) 4.022(2)

168 173(2) 166 166(2) 119 105 178 160 128 112

H···A

D···A

D−H···A

1.88(4) 1.96(6) 2.06(5) 1.81(6)

2.718(4) 2.834(4) 2.560(4) 2.766(4)

165(4) 168(5) 117(4) 171(5)



Article

Table 2. continued Hydrate Polymorph IIe type intramol. intramol. intraunit interunit interunit

donor (D)−H···acceptor (A) C6−H6B···N1 C10−H10···O1 C18−H18···O2c C18−H18···Cgd C13−H13···N1e

D−H

H···A

0.99 0.95 0.95 0.95 0.95

2.55 2.45 2.60 3.27 2.80

D···A 2.937(5) 2.792(5) 3.232(5) 3.883(5) 3.494(5)

D−H···A 103 101 125 124 130

Cg is the centroid of ring C14/C15/C16/C17/C18/N2. a = 1/2 − x, 1/2 − y, 1 − z; b = 1/2 − x, 3/2 − y, 1 − z; c = x, 1 + y, z; d = x, 1 − y, 1/2 + z. bCg is the centroid of the ring C9/C10/C11/C12/C13/N1. a = 1/2 − x, 1/2 + y, −1/2 + z; b = 1/2 − x, 1/2 + y, 1/2 + z; c = −x, 1 − y, −1/2 + z. d = −1/2 + x, 1/2 − y, z. cCg is the centroid of the ring C1B/C2B/C3B/C4B/C5B/C6B. a = x, 1.5 − y, 1/2 + z; b = 1 − x, 1 − y, −z. dCg is the centroid of the ring C14/C15/C16/C17/C18/N2. a = 1 − x, 1 − y, −z; b = x, −1 + y, z; c = −1 + x, y, z. d = 1 − x, −1/2 + y, 1/2 − z. e = −1 + x, −1 + y, z; f = −1 + x, y, z. eCg is the centroid of the ring C9/C10/C11/C12/C13/N1. a = x, 1 + y, z; b = 3/2 − x, 1/2 + y, 3/2 − z. c = 1 − x, −y, 1 − z; d = −1/2 + x, 1/2 − y, −1/2 + z. e = 2 − x, 2 − y, 1 − z. a

Figure 4. The strong and weak hydrogen bonding interactions present within a single unit of (4)·(benzene) in the benzene clathrate crystal. This should be compared to the closely related arrangement in the apohost polymorph II crystal (shown in Figure 2).

Figure 2. The strong and weak intramolecular hydrogen bonding interactions operating within a single molecule of 4 in the apohost polymorph II crystal. This group of six attractions imparts significant rigidity to the nearly planar diol framework.

Diol pairs are no longer directly hydrogen bonded due to the insertion of two water molecules. The outcome is a single, but more complex, diol-water combination than that in the hydrate polymorph I. This comprises O−H···O−H···O−H hydrogen bonding surrounding a 21 screw axis, as shown in Figure 7 (upper). These helical units are further linked along a by means of N2···H1O2−O2 (solid blue lines) and pyridyl C18− H18···O2 (black dashes) interactions, Figure 7 (lower). These associations create two five-membered cyclic interactions surrounding an inversion center. There is very little interaction between the helical units in the c direction of this structure but there is a linking centrosymmetric six-membered ring motif involving two C13−H13···N1 attractions (blue dashes).

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DISCUSSION As predicted, the bis(pyridyl) diol 4 was indeed found to yield alternative crystal forms when crystallized from different solvents at room temperature and pressure. However, its manner of doing so is very different from its close bis(phenyl) relative 3:4 diol 4 is particularly prone to yielding polymorphs and prefers to form hydrate rather than organic cocrystal structures. These differences are a direct consequence of the nitrogen heteroatoms present in the molecular structure of diol 4, even though their influence is often more subtle than dominating. Figure 8 compares the conformations of diol 4 in the five crystal structures obtained. This overlap diagram clearly reveals the two cases where its two hydroxy groups are proximal due to their intramolecular hydrogen bonding, and the three distal examples in which this interaction is absent. The latter structures are those in which concave face to concave face orientation of the diol molecules is favored (as it was earlier for the diol 3). The different orientations possible for one pyridyl substituent of 4 are also apparent among this latter group of three conformations.

Figure 3. Upper: Part of a zigzag chain of diol 4 molecules with adjacent molecules linked through Ar−H···π interactions involving both pyridyl substituents. The axis a is horizontal and b vertical. Lower: The weak C−H···O and C−H···N attractions present between neighboring chains. 5750



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Figure 5. Upper: Part of two parallel chains of the (4)·(benzene) clathrate showing a sandwiched guest molecule and how one face of the parallel chains is linked by means of bifurcated O···H···O motifs. The axis a is horizontal and c vertical. Lower: The complex cluster of 12 intermolecular attractions that creates a centrosymmetric connection between the second faces of the parallel chains.

At first sight, the apohost polymorphs I and II share almost no supramolecular similarities in their crystal packing. Polymorph I has a rather conventional structure, in being constructed from O−H···O hydrogen bonded double strands that pack in parallel. It should be noted, however, that this hydrogen bonding only extends over three consecutive bonds and does not comprise a cooperative chain as is often the case for alcohol compounds.18 Further, the hydrogen bonded links between the diol dimers are disordered (see Experimental Section). Attractions between adjacent helices involve only weak forces, and the nitrogen atoms play a minor role. These various characteristics make it easier for alternative structural behavior to occur. The apohost polymorph I is the preferred form and was obtained from solutions of 4 in dry acetone, diethyl ether, pyridine, dry tetrahydrofuran, toluene or m-xylene. On heating, its crystals undergo no phase change before melting at 125− 126 °C. The apohost polymorph II structure was only formed from aqueous acetone solution. Surprisingly, it is produced in preference to the two hydrate polymorphs obtained when only traces of water were present in the solvent. Here, the diol 4 has a crystal structure totally unlike any previously observed for its close analogue 3.4 Its configuration initially appears to be an unusual choice, since the strong intermolecular O−H···O hydrogen bonding of polymorph I has been abandoned in favor of intramolecular attractions. Both the nitrogen atoms and C− H···π interactions now participate more prominently in its crystal structure.

The diol configuration in the (4)·(benzene) clathrate is nearly identical to that present in the apohost polymorph II. Minor changes result from the central bicyclo[3.3.0]octane ring being more eclipsed, which causes loss of the weak intramolecular C−H···O interaction and the two pyridyl substituents to become almost coplanar. The benzene guest molecules are efficiently sandwiched between these aromatic groups using four aryl-H···π interactions and thereby linking the hosts and guests into chains. Adjacent chains pack in parallel utilizing clusters of weak molecular attractions. Figure 9 compares the crystal structure of the apohost polymorph II with that of the benzene clathrate, both projected onto the ab plane, and reveals packing similarities. The former structure comprises zones of molecules of 4: diol orientation A, diol orientation B, diol orientation A, etc. along a. The latter compound comprises zones of diol orientation A, benzene, diol orientation A, etc. along the same direction. In both cases, the adjacent zones are linked by aryl-H···π interactions. The solid remaining after loss of the benzene guest melted at the same temperature as the apohost polymorph I. Crystals of hydrate19 polymorph I were produced from ethanol, damp methanol or damp tetrahydrofuran, while the hydrate polymorph II was only obtained from damp acetonitrile solution. The two solids are closely related in structure, and also share packing similarity with the apohost polymorph I since the diol 4 molecules are oriented concave face to concave face in all three cases. The conformations adopted by 4 in these crystals are shown in Figure 10. This comparison reveals that all employ intramolecular C−H···N and C−H···O attractions, with 5751



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Figure 6. Upper: Part of the crystal structure of hydrate polymorph I shown as a projection on the ac plane. The twin helical units appear end-on with the helical hydrogen bonding seen as a triangular projection. The internal (water) O−H···N (pyridyl) hydrogen bond is also indicated. Lower: Two adjacent twin helical units along a, emphasizing the in-phase relationship of the diol 4 pairs. The interunit pyridyl Ar−H···O (black dashes) and pyridyl Ar−H···π (blue dashes) attractions are illustrated.

Figure 7. Upper: Part of the crystal structure of hydrate polymorph II shown as a projection on the ac plane. The helical units are viewed end-on, with the central helical hydroxy group hydrogen bonding appearing as a rectangular projection. Lower: One and a half adjacent helical units emphasizing the out-of-phase relationship of the diol 4 pairs. Two linking five-membered cycles, with their O−H···N (solid blue lines) and C−H···O (black dashes) interactions, are indicated. Interaction between the helical units along c is limited to centrosymmetric six-membered ring motifs formed from two identical C−H···N interactions (blue dashes).

the latter motifs replacing the intramolecular O−H···O hydrogen bond in the apohost polymorph II and benzene clathrate structures. The geometrical consequence results in the similarity of the left-hand portion of diol 4 in all five conformations of overlap Figure 8, despite different supramolecular synthons being employed in the two groups of structures. In hydrate polymorph I (P21/c) the diol pairs are positioned in-phase with respect to each other. This results in two enantiomeric diol-water helices giving a twin helical unit of parallelogram cross-section (Figure 6). In the hydrate polymorph II (P21/n) the diol 4 molecules are positioned out-of-phase, resulting in just one diol-water helix of a more complex nature. This results in an elongated parallelogram cross-section (Figure 7). A further significant difference is the organization of the water molecules within their helical units. The P21/c structure contains water molecules oriented along the +b direction in one helix and along −b in the other helix, as illustrated in Figure 11. In contrast, each helical unit in the P21/n structure contains only one hydrogen bonded helix with unidirectional water orientations (Figure 12). However, the opposite helical sense

(and hence water orientation) is present in adjacent units, thereby providing the overall achiral crystal.

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CONCLUSIONS Despite its extremely simple achiral molecular structure, the bis(pyridyl) diol 4 yields different crystal forms when crystallized from different solvents at room temperature and pressure. In common with its close bis(phenyl) analogue 3, the dish-shaped molecules of 4 orientate themselves in the counterintuitive concave face to concave face manner in three of these structures. However, diol 4 shows marked behavioral differences in forming hydrates instead of organic cocrystalline compounds, and in yielding both guest-free and watercontaining polymorphic crystals. The apohost polymorph II and (4)·(benzene) clathrate crystals abandon the intermolecular O−H···O hydrogen bonding normally employed by alcohols and adopt instead a diol configuration that employs a suite of multiple intramolecular attractive forces. Prediction of 5752



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area. However, the prediction of how exactly this will be achieved in practice still remains elusive.

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EXPERIMENTAL SECTION

1

H (300 MHz) and 13C (74.5 MHz) NMR spectra were recorded in CDCl3 using a Bruker DPX300 instrument and are reported as chemical shifts (δ) relative to SiMe4. The HRMS measurement was recorded using an Orbitrap FTMS instrument (nanospray ionization mode) at the Bioanalytical Mass Spectrometry Facility, UNSW. 3,7-Bis(2-pyridyl)bicyclo[3.3.0]octane-endo-3,endo-7-diol (4). 2-Chloropyridine (14.5 mmol) and 1-butyllithium (14.5 mmol) were allowed to react in dry tetrahydrofuran (10 mL) at −78 °C. A solution of bicyclo[3.3.0]octane-3,7-dione17 (0.50 g, 3.62 mmol) in dry THF (20 mL) was then added with stirring at rt. After 30 min, the mixture was refluxed overnight. Satd. aq. NH4Cl solution (20 mL) was added at rt, THF was removed under reduced pressure, and the organic material extracted using dichloromethane. The combined extracts were dried (Na2SO4), filtered, and solvent removed under reduced pressure. The resulting black oil was eluted through a column of silica gel using CH2Cl2/MeOH to give 4 as a white powder (0.35 g, 33%), mp 125−126 °C (from ethyl acetate/hexane). HRMS ESI m/z (M + Na)+: Found 319.1411, Calc. for (C18H20O2N2Na)+ 319.1417. 1 H NMR δ 2.12−2.17 (m, 4H), 2.57−2.69 (m, 4H), 3.13−3.26 (m,

Figure 8. Overlap of the diol 4 conformations present in the five crystal structures. Color code: apohost polymorphs I (red) and II (purple), benzene clathrate (light green) and hydrate polymorphs I (yellow) and II (blue). The upper right-hand region shows that the two structures with intramolecular hydrogen bonding (apohost polymorph II and the benzene clathrate) are extremely similar. The remaining three conformations in the lower right-hand zone are quite different to these, but are generally similar to each other apart from the orientation of one pyridyl ring.

the likely appearance of multiple crystal forms, even for simple achiral molecules such as 4, can be made with confidence in this

Figure 9. Comparison of the apohost polymorph II (upper) and the benzene clathrate (lower) structures projected onto the ab plane. The diol molecules 4 share nearly identical conformations in the two compounds and structural similarities extend to the overall crystal packing. Color code: aryl-H···π interactions (blue dashes). 5753



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Figure 10. Comparison of the conformations and intramolecular attractions adopted by diol 4 in the three concave face to concave face crystals: apohost polymorph I (upper), hydrate polymorph I (center), and hydrate polymorph II (lower).

2H), 6.61 (s, 2H), 7.15−7.19 (m, 2H), 7.59−7.63 (m, 2H), 7.67−7.73 (m, 2H), 8.53−8.55 (m, 2H). 13C NMR δ 45.2, 50.5, 85.8, 119.5, 121.7, 136.9, 147.8, 165.1. Crystallization and Identification of the Crystal Forms. The pure diol 4 was dissolved with warming in a small volume of the chosen solvent. Crystals were allowed to form by slow concentration through evaporation at laboratory temperature and pressure and then characterized using X-ray diffractometry. The crystal structure solutions of the five different compounds were determined as described below. Solution and Refinement of the Crystal Structures. Suitable single crystals, selected under the polarizing microscope (Leica M165Z), were picked up on a MicroMount (MiTeGen, USA) consisting of a thin polymer tip with a wicking aperture. The X-ray diffraction measurements were carried out on a Bruker kappa-II CCD diffractometer at 155−160 K by using graphite-monochromated Mo− Kα radiation (λ = 0.710723 Å). The single crystals, mounted on the goniometer using cryo loops for intensity measurements, were coated with paraffin oil and then quickly transferred to the cold stream using an Oxford Cryo stream attachment. Symmetry related absorption corrections using the program SADABS20 were applied, and the data were corrected for Lorentz and polarization effects using Bruker APEX2 software.21 All structures were solved by direct methods and the full-matrix least-squares refinements were carried out using SHELXL.22 The non-hydrogen atoms were refined anisotropically. The molecular graphics were generated using Mercury.23 In the structure of apohost polymorph I, the hydroxy oxygen on O1 was not located in the difference Fourier. The stereochemically fixed H-atom in the direction of its centrosymmetrically related counterpart makes short H···H contact (1.23 Å). This suggests a dynamic situation of the two protons, in which only one O−H···O contact is made at any given time while the other H-atom is left without any acceptor.

Figure 11. One twin helical unit of the hydrate polymorph I structure emphasizing the organization of its water molecules. Upper: Projection of the unit onto the ac plane. Lower: The unit running along the b direction (vertical) showing the opposing water orientations present in its two hydrogen bonded helices. Color code: water molecules (dark blue), hydrogen bonds (black dashes).

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ASSOCIATED CONTENT

* Supporting Information S

X-ray crystallographic information files (CIF) for the structures CCDC 897445−897449 (see Table 1). This material is available free of charge via the Internet at http://pubs.acs. org/.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 5754



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(6) (a) Powell, H. M. J. Chem. Soc. 1948, 61−73. (b) Powell, H. M.; Wetters, B. D. P. Chem. Ind. (London) 1955, 256−257. (c) Desiraju, G. R. in Comprehensive Supramolecular Chemistry; MacNicol, D. D.; Toda, F.; Bishop, R., Eds.; Pergamon Press: Oxford, 1996; Vol. 6, Chapter 1, pp 1−22. (d) Rahman, A. N. M. M.; Bishop, R.; Craig, D. C.; Scudder, M. L. Chem. Commun. 1999, 2389−2390. (e) Dunitz, J. D.; Filippini, G.; Gavezzotti, A. Tetrahedron 2000, 56, 6595−6601. (f) Bishop., R. New Aspects of aromatic π···π and C−H···π interactions in crystal engineering. In The Importance of Pi-Interactions in Crystal Engineering: Frontiers in Crystal Engineering; Tiekink, E. R. T., Zukerman-Schpector, J., Eds.; Wiley: Chichester, 2012; Chapter 2, pp 41−77. (7) (a) MacNicol, D. D.; Downing, G. R. Symmetry in the evolution of host design. In Comprehensive Supramolecular Chemistry, Vol. 6 Solidstate Supramolecular Chemistry: Crystal Engineering; MacNicol, D. D.; Toda, F.; Bishop, R., Eds.; Pergamon Press: Oxford, 1996; Chapter 14, pp 421−464. (b) Goldberg, I. in Inclusion Compounds; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Eds.; Oxford University Press: Oxford, 1991; Vol. 4, Chapter 10, pp 406−447. (c) Weber, E. Shape and symmetry in the design of new hosts. In Comprehensive Supramolecular Chemistry, Vol. 6 Solid-state Supramolecular Chemistry: Crystal Engineering; MacNicol, D. D., Toda, F., Bishop, R., Eds.; Pergamon Press: Oxford, 1996; Chapter 17, pp 535−592. (d) Bishop, R. Synlett 1999, 1351−1358. (e) Pigge, F. C. CrystEngComm 2011, 13, 1733−1748. (f) Bishop, R. Aust. J. Chem. 2012, 65, 1361−1370. (8) (a) Inclusion Compounds; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Eds.; Academic Press: London, 1984; Vols. 1−3. (b) Comprehensive Supramolecular Chemistry, MacNicol, D. D.; Toda, F.; Bishop, R., Eds.; Pergamon Press: Oxford, 1996, Vol. 6. (c) Herbstein, F. H. Crystalline Molecular Complexes and Compounds: Structures and Principles, Oxford University Press: Oxford, 2005. (d) Bishop, R. Synthetic clathrate systems. In Supramolecular Chemistry: From Molecules to Nanomaterials; Gale, P. A., Steed, J. W., Eds.; Wiley, Chichester, 2012; pp 3033−3056. (9) (a) Bishop, R.; Dance, I. J. Chem. Soc., Chem. Commun. 1979, 992−993. (b) Bishop, R.; Choudhury, S.; Dance, I. J. Chem. Soc., Perkin Trans 2 1982, 1159−1168. (c) Bishop, R.; Dance, I. G.; Hawkins, S. C. J. Chem. Soc., Chem. Commun. 1983, 889−891. (d) Bishop, R.; Dance, I. G.; In Inclusion Compounds, Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D., Eds.; Oxford University Press: Oxford, 1991; Vol. 4, Chapter 1, pp 1−26. (e) Hawkins, S. C.; Bishop, R.; Dance, I. G.; Lipari, T.; Craig, D. C.; Scudder, M. L. J. Chem. Soc., Perkin Trans. 2 1993, 1729−1735. (f) Kim, S.; Bishop, R.; Craig, D. C.; Dance, I. G.; Scudder, M. L. J. Org. Chem. 2002, 67, 3221−3230. (10) (a) Hawkins, S. C.; Scudder, M. L.; Craig, D. C.; Rae, A. D.; Abdul Raof, R. B.; Bishop, R.; Dance, I. G. J. Chem. Soc., Perkin Trans. 2 1990, 855−870. (b) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311−2327. (11) (a) Desiraju, G. R. Polymorphism − the nemesis of crystal design? In Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam, 1989; Chapter 10, pp 285−301. (b) Bernstein, J.; Henck, J.-O. Cryst. Eng. 1998, 1, 119−128. (c) Bernstein, J.; Davey, R. J.; Hencke, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440. (d) Bernstein, J. Polymorphism in Molecular Crystals; Oxford Science Publications: Oxford, 2002. (e) Braga, D; Brammer, L.; Champness, N. R. CrystEngComm 2005, 7, 1−5. (f) Nangia, A. Acc. Chem. Res. 2008, 41, 595−604. (g) Caira, M. R. Polymorphism. In Handbook of Thermal Analysis and Calorimetry, Vol. 5: Recent Advances, Techniques and Applications; Brown, M. E.; Gallagher, P. K., Eds.; Elsevier: Amsterdam, 2008; Chapter 16, pp 597−629. (h) Fucke, K.; Qureshi, N.; Yufit, D. S.; Howard, J. A. K.; Steed, J. W. Cryst. Growth Des. 2010, 10, 880−886. (12) (a) Hatt, H. H. Rev. Pure Appl. Chem. 1956, 6, 153−190. (b) Jeffrey, G. A. Acc. Chem. Res. 1969, 2, 344−352. (c) Desiraju, G. R. J. Chem. Soc., Chem. Commun. 1991, 426−428. (d) Custelcean, R.; Afloroaei, C.; Vlassa, M.; Polverejan, M. Angew. Chem., Int. Ed. 2000, 39, 3094−3096. (e) Mascal, M.; Infantes, L.; Chisholm, J. Angew. Chem., Int. Ed. 2006, 45, 32−36. (f) Van de Streek, J. CrystEngComm 2007, 9, 350−352. (g) Sansam, B. C. R.; Anderson, K. M.; Steed, J. W.

Figure 12. One helical unit of the hydrate polymorph II structure emphasizing the organization of its water molecules. Upper: Projection of the unit onto the ac plane. Lower: The unit running along the b direction (vertical direction) shows the unidirectional water molecules present in its single hydrogen bonded helix.

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DEDICATION This paper celebrates the 60th birthday of Gautam R. Desiraju and his truly pioneering contributions to crystal engineering and solid-state organic chemistry.

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Polymorphic Crystals Formed by an Achiral Diol under Ambient

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