The Same but Different: Isostructural Polymorphs and the Case of 3

Feb 20, 2014 - Isostructural polymorphs: qualitative insights from energy frameworks. Kunal Kumar Jha , Sanjay Dutta , Vijay Kumar , Parthapratim Muns...
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The Same but Different: Isostructural Polymorphs and the Case of 3‑Chloromandelic Acid Simon J. Coles,* Terence L. Threlfall, and Graham J. Tizzard Chemistry, Faculty of Natural and Environmental Science, University of Southampton, Highfield, Southampton SO17 1BJ, U.K. S Supporting Information *

ABSTRACT: The expression “isostructural polymorphs” would appear to be an impossible combination of two mutually incompatible words. “Isostructural” implies a high degree of structural similarity; however, conversely, “polymorph” implies structural distinguishability. The structures of two newly determined polymorphs of 3-chloromandelic acid nevertheless justify the use of this expression, for they differ only in crystal symmetry and hardly at all in molecular position or conformation within the crystalline lattice. We demonstrate that parameters derived by the XPac program can be useful in establishing the limits of isostructurality.

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polymorph has been considered by Desiraju6 within the ambit of similarity and difference. What differences can a molecule show and still fall under the umbrella of being a polymorph? For example, are tautomers polymorphs?7 When does a conformational change become a configurational one?8 How little difference can a structure show and yet still be considered to be a polymorph rather than an identity? Bernstein has commented9 that McCrone’s definition of polymorphism has stood the test of time. Nevertheless, there are situations which are difficult to fit into any definition of polymorphism, as discussed by Bernstein and by Desiraju. The quest for definitions of isostructurality has largely been driven by considerations of how different two structures can be and yet still be considered isostructural. Fabian and Kalman10 have offered the following definition: isostructurality refers to the similarity of the spatial arrangements of the molecules of different compounds in their crystals. It is traditionally interpreted in three dimensions (i.e., isostructurality involves whole structures), which are infinite in three dimensions by means of three crystallographic translations. However, it is possible to extend the interpretation of the phenomenon to one- and two-dimensional (1D and 2D, respectively) isostructurality. If two crystal structures contain similar infinite 2D molecular arrangements (layers) then they are termed twodimensionally isostructural. Accordingly, structures with similar rows of molecules are one-dimensionally isostructural. So, on the face of it, the terms polymorph and isostructural would appear contrary and it would therefore be highly unlikely that an isostructural polymorph would exist. Fabian and Kalman11 have continued their work to provide the only systematic study, that the authors are aware of, into the unlikely phenomenon of isostructural polymorphism. From a survey of

INTRODUCTION McCrone’s 1965 definition of a polymorph as “a solid crystalline phase of a given compound resulting from the possibility of at least two crystalline arrangements of the molecules of that compound in the solid state” leads one to conclude that polymorphism is a phenomenon where a chemical compound can occur in at least two crystalline forms.1 The key word, nevertheless, is “phase”, for one can have structural variation without phase change, but one cannot have a phase change without some structural change.2 Modern progress since McCrone’s definition was published has shown just how much structural change without polymorphic change can result from high pressure3 and very low temperature crystal structure determination. Such changes affect supramolecular more than molecular structure because the intermolecular forces are the weaker ones. However, one cannot get lattice changes without changing the molecular geometry also, although this may be very subtle and within the error of detection of the experiment and especially for rigid molecules. Within the molecule, torsions tend to be more affected than rotations, rotations than bendings, and bending than stretchings reflecting the relative strengths. On the other hand, alterations to the stronger forces may yield more relief than to the weaker, which may modify this order. So structural variation may exceed the crystal to crystal variation noted by Bernstein.4 Therefore, a polymorph is best considered essentially as a different phase, although most often nowadays it is so identified via a different structure. Note that this view of polymorphism avoids the ambiguity associated with phrases such as “significantly different structures.”5 Subsequently, there have been attempts at alternative definitions, mostly reflecting the increasingly crystallographic view of polymorphism. In so far as the phase aspect of polymorphism has been weakened in later definitions, these definitions have become less satisfactory as has been noted by Bernstein.4 The concept of structural landscape within a © 2014 American Chemical Society

Received: November 5, 2013 Revised: February 10, 2014 Published: February 20, 2014 1623

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Figure 1. Molecular (depicting numbering scheme employed and with ellipsoids at 50% probability) and crystal structures of 3-chloromandelic acid at room temperature.

and describes a simple quantitative approach to classifying their similarity. Isostructurality cannot be stretched as far as identity because it has mainly been applied to relating structures of different molecular composition. In the present case, the molecularity is identical, so the issue is one of closeness and not difference, and so all definitions of polymorphism, including that of McCrone, cover the case.

22 polymorphic systems, a degree of isostructurality [1D, 2D, or three-dimensional (3D)] was found in approximately half of them. There has been a considerable amount of work in the past decade12 that has uncovered 1D and 2D isostructurality in both polymorphic and homologous (or related) systems; however, the subject of this paper is particularly concerned with the situation of 3D isostructurality (i.e., a near 100% match in packing behavior, in polymorphic systems). Fabian and Kalman report six cases of 3D isostructural polymorphs in their paper and note that they are mainly concerned with an increased ordering of the system. In fact five out of the six cases presented are concerned with disordered systems becoming more ordered and the remaining example is that of a phase transition. This latter example is a temperature-dependent reversible single-crystal-to-single-crystal phase transition of 4,6dimethoxy-3-methyldihydrotriazine-2-one (ZEXXOP).13 To our knowledge, this is the only case of a phase transition being associated with the phenomenon of isostructural polymorphism and herein we present another case: that of 3chloromandelic acid. However, we also postulate that this phenomenon may be more widespread than the literature would lead us to believe, but virtually all cases remain undiscovered as the phase behavior of single crystals (thermal, pressure, etc.) is so rarely systematically probed. There are however a number of reported cases of single crystal−single crystal “soft mode” transitions; these are predominantly exhibited by inorganic materials but are increasingly being observed in molecular systems.14 In these cases, a lattice deformation occurs when two high-temperature phase independent but closely related molecules become equivalent at lower temperatures due to a reduction in lattice vibration. The two structures that result from this phenomenon could be considered to be isostructural in that the transition is not only essentially a zero-enthalpy lattice deformation but also polymorphic due to structural differences observable in the diffraction pattern. In this situation, systematic absences arise and thus a higher symmetry space group can be assigned to the lower temperature form and these displacive transitions can be characterized by symmetry mode analysis.15 This paper is, however, not concerned with the characterization of phase transitions but merely considers the resultant structures, in much the way Mnyukh does (particularly in the addendum to his classic book:16 we do not necessarily agree with his mechanistic proposals but are merely using his methodology)

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CHARACTERIZATION OF THE CASE OF 3-CHLOROMANDELIC ACID 3-Chloromandelic acid readily forms single crystals with block morphology at room temperature from several polar aprotic solvents, including DCM and butyl ether. Single crystal experiments have been routinely performed according to previously published procedures;17 CIFs are available as Supporting Information and have also been deposited with the cambridge crystallographic data centre (CCDC970350 and CCDC970351) The room temperature single crystal structure is monoclinic18 and crystallizes in the space group P21/c, with no unusual molecular geometry or conformation (Figure 1a). The crystal structure is comprised of hydrogen-bonded sheets oriented in the bc plane of the unit cell, as shown in Figure 1b, and has two distinct ring motifs. The first has a graph set notation19 of R2,2(10) for the dimers between hydroxyl group and carbonyl moiety of carboxylate group and the second is a larger 22-membered ring with 6 donors and acceptors [R6,6(22)] that incorporates the hydroxyl moiety of the carboxylate group as well as bifurcating the hydroxyl group. With all possible donor and acceptor groups now occupied, the sheets stack along the a axis with interlocking aromatic rings, as shown in Figure 1c. On taking the single crystal down to a temperature of 100 K, a triclinic unit cell20 is observed and the crystal structure of this form solves in the space group P1̅. The system therefore undergoes a single crystal to single crystal phase transition, indicating a difference in phase, and therefore, one would logically conclude that this is a system containing at least two different polymorphs. The fact that these polymorphs exist in two separate crystal systems is conclusively backed up by inspection of simulated precession photographs generated from the raw data (Figure 2). For the room temperature form, systematic absences in the h0l layer and 0k0 row arising from a c glide and a 21 screw axes 1624

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Unit cell data from these collections are shown in Table 1 and shows a transition between 260 K and 293 K when raising the temperature and the reversal of this between 260 K and 210 K when lowering the temperature. The difference in temperature range between heating and cooling for this transition can be ascribed to a hysteresis effect. The DSC trace (Figure 3)

Figure 3. Two cycles of DSC plots on cooling from 25 °C to −150 °C then reheating to 25 °C at a rate of 10 °C/min with phase transitions highlighted.

Figure 2. Synthetic precession images of the h0l layers of the (a) triclinic polymorph and (b) monoclinic polymorph.

shows an exotherm on cooling (from 25 °C to −150 °C), which must lie below the thermodynamic transition point and an endotherm on heating (back to 25 °C at a rate of 10 °C/ min) above the transition point, as indeed a reversible process must do.21 Since the structures are so similar, a very small enthalpy of transition is to be expected and indeed the peak is barely visible above the noise. There is no possibility of increasing this by faster cooling because that would rapidly run the transition to lower temperatures and reduce the transformation rate and so make it unobservable.22 The triclinic form contains 2 independent molecules in the asymmetric unit (Figure 4a). However, a close inspection of the molecular conformation and crystal packing of the triclinic form indicates that it is almost identical to the monoclinic form. Figure 4 (panels b and c) depict the overlay between the molecular structure of the monoclinic form with that of the triclinic form molecules 1 and 2, respectively. A comparison of bond lengths and angles between corresponding molecules and the fit of the overlay plots shows that the molecular conformation of the monoclinic form as compared to both molecules of the triclinic form is almost identical.

respectively are clearly observed. These absences are not present in the triclinic form, low temperature data. Details of systematic absence data are provided as Supporting Information. It is also important to note that during polymorph screening experiments, 25 different crystals were examined at low temperature (100 K) and the triclinic form was observed on every occasion. The phase transition has been characterized by performing data collections at different temperatures. A single crystal was flash-cooled to 100 K, and a strategy was calculated to collect all reflections to a 0.77 Å resolution based on the triclinic unit cell derived from 15 initial images. This strategy was used for all data collections. Data were collected on the same crystal at 100 K, 210 K, 260 K, and 293 K with the crystal being heated at 120 K/hour and equilibrating at the set temperature for 20 min before data collections were undertaken. The crystal was then cooled to 100 K with data collections undertaken with the same regime.

Table 1. Unit Cell Parameters Derived from Data Collected from a Single Crystal Heated and Cooled to Temperatures Indicateda

a

exptl

T (K)

a

b

c

α

β

γ

1 2 3 4 5 6 7

100 210 260 293 260 210 100

8.5710(5) 8.6231(5) 8.6239(5) 8.6101(5) 8.6173(5) 8.5968(10) 8.5910(5)

10.3612(7) 10.4514(7) 10.4584(7) 10.4552(7) 10.4452(7) 10.3943(14) 10.3855(7)

9.2373(5) 9.3486(7) 9.3780(7) 9.3914(7) 9.3773(7) 9.3356(12) 9.2577(5)

91.818(9) 91.472(8) 91.317(9) 90 90 91.174(6) 91.855(6)

93.118(9) 93.353(8) 93.421(9) 93.690(6) 93.549(11) 93.351(7) 93.168(6)

90.226(9) 90.234(8) 90.188(9) 90 90 90.139(6) 90.299(6)

The b and c lattice parameters have been interchanged in the triclinic form in order to provide a direct comparison with the monoclinic form. 1625

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Figure 4. (a) Molecular structure and numbering scheme for the triclinic form and (b and c) molecular overlays of monoclinic and triclinic forms. An indication of conformational similarity is given by comparison of the primary torsion angles of O1−C7−C8−O2 (O101−C107−C108−O102), monoclinic form = −13.5(5)°, triclinic form = −10.1(2)° [−16.4(2)°] and O1−C7−C8−O3 (O101−C107−C108−O103) monoclinic form = 166.0(3)°, triclinic form =170.06(13)°, [163.54(13)°].

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QUANTIFICATION OF ISOSTRUCTURAL POLYMORPHISM The XPac program24 allows comparison of different crystal structures through creation of sets of vectors between the component atoms of an arbitrary “seed” molecule within each crystal structure to be compared and the equivalent atoms of the neighboring molecules of this “seed” within the crystal structures. The (a) angles and (p) torsion angles generated by equivalent vectors in a pair of structures can then be compared with a match being generated when Δa and Δp are close to 0°. In practice, the user sets a cutoff limit for these parameters to generate a match with values of Δa = 5° and Δp = 7° considered tight tolerances. The number of matches of angles and torsion angles generated from these vector sets determines the level of similarity between the structures, so that if all match, they are considered 3D isostructural and if none match there is no similarity. Values between these two extremes indicate matching planes (2D similarity), tapes (1D similarity), or discrete assemblies [e.g., dimers (0D similarity)] between structures. The advantage of this approach is its flexibility, allowing comparison of multicomponent systems, Z′ > 1 structures and families of related compounds as well as polymorphs. The XPac program can compute a quantitative assessment of each of these types of similarities25 by means of the Δa and Δp values, and so it is ideal for the comparison now being made. In order to provide comparisons for structural systems where 3D similarity arises for different reasons, an XPac study was performed on paracetamol structures taken from the Cambridge Structural Database (CSD).26 By drawing from such an extensively studied system, it was possible to quantitatively assess similarity using XPac in the same way as we do for the system being presented herein, where the structures have been derived from (a) different temperatures, (b) different pressures, and (c) different polymorphs (see Table 2). Comparison of the Δa and Δp parameters for these systems reveals the following. (1) There is no similarity between different polymorphs. (2) Structures performed at different temperatures are really very similar. (3) Structures performed at different pressures (same phase) show a greater deviation from similarity than different temperatures but are well within the XPac cut off and would be considered to be 3D isostructural.

A comparison between the two forms of the whole crystal lattice is particularly revealing. Figure 5 depicts the overlay

Figure 5. Whole-lattice overlay for structures of the monoclinic (red) and triclinic (green) forms.

between the two lattices of the respective forms and it is clear that the packing arrangement and nature of the intermolecular interactions are identical. This figure is generated by the structure comparison tool in CCDC Mercury23 and fits 15 out of 15 molecules with an RMS deviation of 0.19 Å, which indicates strong similarity. 1626

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Table 2. Δa and Δp Parameters for Structure Determinations of Paracetamol at Different Temperatures, Pressures, and Different Polymorphs conditions different temperature different pressure different polymorphs isostructural polymorphs presented herein

reference HXACAN0127 (283−303K) HXACAN0628 (100K) HXACAN0929 (1 GPa) HXACAN1219 (4 GPa) HXACAN06 HXACAN0830 triclinic monoclinic

temperatures and those determined at different pressures. This observation makes absolute sense and thereby enables a quantitative definition for isostructural polymorphism. The values of Δa and Δp from different structures depend on the corresponding ordered set of points (see ref 24 for a definition) chosen, so they are not strictly comparable. However, the figures present an indication of the magnitude of the effects observed in comparison with other compounds. This shows the closeness of the geometry and topology of the two structures, which lie within the ranges expected for adjustment of structure of polymorph due to different conditions during the data collection. In order to provide a wider context for the application of Δa and Δp to the quantification of isostructurality in polymorphic systems, we have performed a study on a subset of the structures that were categorized by Fabian and Kalman (vide supra)11 as being similar in 1D, 2D, or 3D. Table 3 outlines the results of calculating Δa and Δp for these sets of polymorphs

Δa (deg), Δp (deg) 0.4, 0.8 2.6, 6.3 no similarity 1.6, 3.1

In the case of the isostructural polymorphs of 3chloromandelic acid being presented here, the Δa and Δp parameters derived are 1.6° and 3.1°, respectively, and these lie midway between those for structures determined at different

Table 3. Comparison of the Categorisation of the Degree of Isostructurality in an Established Set of Polymorphic Families XPac structure polymorph 1 polymorph 2 polymorph 3 polymorph 1 polymorph 2 polymorph I polymorph II polymorph I polymorph II low-temperature form high-temperature form high-temperature polymorph low-temperature polymorph polymorph polymorph polymorph polymorph

I II III IV

α form β form γ form α form β form monoclinic polymorph orthorhombic polymorph MH1 triclinic polymorph MH2 monoclinic polymorph MH3 monoclinic polymorph a

CSD refcode

isostructurality

Δa (deg), Δp (deg)

6-Hydroxy-4,4,5,7,8-pentamethyl-3,4-dihydrocoumarin MEZKEH02 1, 2: 3D 0.7, 2.3 MEZKEH04 1, 3: 3D 3.7, 7.5 MEZKEH12 2, 3: 3D 4.4, 11.8 7b-(2,4-Dinitrophenyl) fluoradene RAKWIJ 3D 3.6, 6.8 RAKWIJ03 3D 3.6, 6.8 m-Tetrachlorodicyanobenzene hexamethylbenzene MOCCOW01 2D 0.9, 2.6 MOCCOW 2D 0.9, 2.6 2,3,7,8-Tetrahydrobenzo[1,2-b:4,5-b′] bis[1,4]dithiin-5,10-dione GUKPEH01 3D 2.4, 9.5 GUKPEH 3D 2.4, 9.5 4,6-Dimethoxy-3-methyl-2,3-dihydrotriazine-2-one ZEXXOP01 3D 2.5, 7.8 ZEXXOP03 3D 2.5, 7.8 5-Bromobenzfurazan-1-oxide a a BBZFRO01 a a BBZFRO02 p-Tetrachlorodicyanobenzene hexamethylbenzene ADULEQ01 I, II: 1D 0.9, 7.0 ADULEQ02 II, III: 1D 2.1, 5.4 ADULEQ03 II, IV: 1D 0.5, 2.7 ADULEQ04 III, IV: 1D 1.1, 3.0 glycine GLYCIN19 α, β: 2D 1.5, 8.3 GLYCIN α, γ: 1D 0.8, 5.4 GLYCIN16 β, γ: 1D 1.4, 10.4 acetonitrile QQQCIV05 2D 4.3, 9.0 QQQCIV04 2D 4.3, 9.0 4,6-Dimethoxy-3-methyl-1,3,5-triazine-2(3H)thione QOYNOH 1D 1.3, 6.6 QOYNOH01 1D 1.3, 6.6 maleic hydrazide MALEHY11 MH1, MH2: 1D 1.0, 8.0 MALEHY01 MH1, MH3: 2D 0.7, 4.5 MALEHY12 MH2, MH3: 1D 0.9, 7.4

Fabian and Kalman isostructurality 1, 2, 3: 3D 1, 2, 3: 3D 1, 2, 3: 3D 3D 3D 3D 3D 3D 3D 3D 3D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D 1D

Disordered structure not suitable for XPac analysis. 1627

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L. S.; Threlfall, T. L. Org. Process Res. Dev. 2009, 1231−1240 and references therein. (13) Kaftory, M.; Botoshansky, M.; Kapon, M.; Shteiman, V. Acta Crystallogr., Sect. B: Struct. Sci. 2001, 57, 791−799. (14) Dunitz, J. D. Pure Appl. Chem. 1991, 63, 177−185 and citations thereof. (15) Aroyo, M. I.; Perez-Mato, J. M. Acta Crystallogr. 1998, A54, 19− 30. (16) Mnyukh, Y. Fundamentals of Solid-State Phase Transitions, Ferromagnetism and Ferroelectricity; 1st Books Library: Bloomington, IN, 2001. Addendum C published at http://www.mnyukh.com/ contentpages/addendum_c.html (accessed 07/02/2014). (17) Coles, S. J.; Gale, P. A. Chem. Sci. 2012, 3, 683−689. (18) Crystal data for monoclinic form: C8H7ClO3, M = 186.59, monoclinic, a = 8.6101(5) Å, b = 10.4552(7) Å, c = 9.3914(7) Å, α = 90°, β = 93.690(6)°, γ = 90°, V = 843.66(10)Å3, T = 293(2) K, ρ = 1.469 M gm−3, space group P21/c, Z = 4, μ(Mo Kα) = 0.413 mm−1, 7537 reflections measured, 1483 independent reflections (Rint = 0.1178). The final R1 values were 0.0676 [I > 2σ(I)]. The final wR(F2) values were 0.1678 [I > 2σ(I)]. The final R1 values were 0.1224 (all data). The final wR(F2) values were 0.1978 (all data). The goodness of fit on F2 was 1.038. CCDC number CCDC 970351. (19) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (20) Crystal data for monoclinic form: C8H7ClO3, M = 186.59, triclinic, a = 8.5710(5) Å, b = 9.2373(5) Å, c = 10.3612(7) Å, α = 91.818(9)°, β = 90.226(9)°, γ = 93.118(9)°, V = 818.69(9)Å3, T = 100(2) K, ρ = 1.514 M gm−3, space group P1̅, Z = 4, μ(Mo Kα) = 0.426 mm−1, 10803 reflections measured, 3723 independent reflections (Rint = 0.0329). The final R1 values were 0.0381 [I > 2σ(I)]. The final wR(F2) values were 0.0870 [I > 2σ(I)]. The final R1 values were 0.0554 (all data). The final wR(F2) values were 0.0938 (all data). The goodness of fit on F2 was 1.010. CCDC number CCDC 970350. (21) Threlfall, T. L. Org. Process Res. Dev. 2009, 13, 1224−1230. (22) Coles, S. J.; Gelbrich, T.; Greisser, U. J.; Hursthouse, M. B.; Pitak, M. B.; Threlfall, T. L. Cryst. Growth Des. 2009, 9, 4610−4612. (23) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466−470. (24) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2005, 7, 324− 336; ibid 2006, 8, 448−460. (25) Gelbrich, T.; Threlfall, T. L.; Hursthouse, M. B. CrystEngComm 2012, 14, 5454−5464. (26) Allen, F. H. Acta Crystallogr. 2002, B58, 380−388. (27) Haisa, M.; Kashino, S.; Kawai, R.; Maeda, H. Acta Crystallogr., Sect. B 1976, 32, 1283. (28) Wilson, C. C. J. Mol. Struct. 1997, 405, 207. (29) Boldyreva, E. V.; Shakhtshneider, T. P.; Vasilchenko, M. A.; Ahsbahs, H.; Uchtmann, H. Acta Crystallogr., Sect. B: Struct. Sci. 2000, 56, 299. (30) Nichols, C.; Frampton, C. S. J. Pharm. Sci. 1998, 87, 684.

and provides our classification of degree of isostructurality while comparing it to the corresponding classification by Fabian and Kalman (and references to the original structures therein). The results presented demonstrate a remarkable fit between the two approaches, and the “automated” approach presented here confirms the results arising from the meticulous “manual” approach of Fabian and Kalman. It should be noted that a mismatch between approaches arises from an inability of XPac to handle complicated systems that the human eye can, such as crystallographic disorder and multiple component systems.

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CONCLUSIONS The nature of the term isostructural polymorphism is wellillustrated by the circumstances to hand, the case of two of the polymorphs of 3-chloromandelic acid. The two polymorphs are exceedingly close in crystal structure and are only distinguishable crystallographically by their differing symmetry elements, as observed via systematic absences. Their single-crystal to single-crystal transition distinguishes them with certainty as different phases. We have been able to place a quantitative measure on the closeness of the structures via the XPac program.

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ASSOCIATED CONTENT

S Supporting Information *

CIFs for the monoclinic and triclinic forms and a table of systematic absences for the monoclinic form. 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]. Tel: +44-2380596721. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the U.K. Engineering and Physical Sciences Research Council for funding the National Crystallography Service.

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REFERENCES

(1) McCrone, W.C. Polymorphism, in Physics and Chemistry of the Organic Solid State; Wiley Interscience: New York1965; Vol. 2, pp 725−767. (2) Threlfall, T. L.; Gelbrich, T. Cryst. Growth Des. 2007, 7, 2297. (3) Moggach, S. A.; Parsons, S.; Wood, P. A. Crystallogr. Rev. 2008, 14, 143−184. (4) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon: Oxford, 2002; p 3. (5) Bernstein, J.; Dunitz, J. D.; Gavezotti, A. Cryst. Growth Des. 2008, 8, 2011−2018. (6) Desiraju, G. R. Cryst. Growth Des. 2008, 8, 3−5. (7) Elguero, J. Cryst. Growth Des. 2011, 11, 4731−4738. (8) Cruz-Cabeza, A. J.; Bernstein, J. Chem. Rev. 114, 2170−2191. (9) Bernstein, J. Cryst. Growth Des. 2011, 11, 632−650. (10) Fabian, L.; Kalman, A. Acta Crystallogr., Sect. B: Struct. Sci. 2004, 60, 547−558. (11) Fabian, L.; Kalman, A. Acta Crystallogr. 1999, B55, 1099−1108. (12) (a) Zencirci, N.; Gelbrich, T.; Kahlenberg, V.; Griesser, U. J. Cryst. Growth Des. 2009, 9, 3444−3456. (b) Hursthouse, M. B.; Huth, 1628

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