Exploring the Crystal Structure Landscape with a Heterosynthon

Nov 19, 2014 - Exploring the Crystal Structure Landscape with a Heterosynthon Module: Fluorobenzoic Acid:1,2-Bis(4-pyridyl)ethylene 2:1 Cocrystals ...
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Exploring the Crystal Structure Landscape with a Heterosynthon Module: Fluorobenzoic Acid:1,2-Bis(4-pyridyl)ethylene 2:1 Cocrystals Ritesh Dubey and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India S Supporting Information *

ABSTRACT: The crystal structure landscape of the 2:1 benzoic acid:dipyridylethylene cocrystal (BA:DPE-I) is explored experimentally with fluorosubstituted benzoic acids and extended with studies employing the Cambridge Structural Database (CSD). The interpretation of the cocrystal landscape is facilitated by considering the kinetically favored and robust acid−pyridine heterosynthon as a modular unit. Information based on high-throughput crystallography shows that polymorphs and pseudopolymorphs may belong to the same landscape but arise from different crystallization pathways because of complex and different kinetic features, and secondary synthon preferences. Using the CSD as a guide, the coformer was changed from 1,2-bis(4pyridyl)ethylene (DPE-I) to 1,2-bis(4-pyridyl)ethane (DPE-II) and this provides an extended interpretation of the BA:DPE-I cocrystal landscape, also highlighting the complexity of the kinetic−thermodynamic dichotomy during the molecule-to-crystal progression.

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INTRODUCTION The crystal structure landscape of a compound is the mapping of various dynamic events during the process of crystalliza-

manifestation of dynamic events that are energetically interrelated and which correspond to a variety of crystallization routes across the crystal landscape.5−7 The quantitative approach called crystal structure prediction (CSP), which also tries to map these various crystallization routes, gives rise to the crystal energy landscape,8,9 but this technique monitors only the stability associated with polymorphs using an energy− density profile.10 The drawback of CSP, which is based on enthalpies rather than free energies, is that it oversimplifies the kinetic features even as crystallization itself is a kinetic phenomenon.11,12 The interrelationships among multiple crystalline phases may be understood based on the nature of intermolecular interactions using diffraction-based techniques.13 Spectroscopic methods may additionally provide some useful information about the molecular recognition and aggregation in the earlier stages of crystallization.14−16 In this context, the efforts of Davey et al. to correlate the structures of supramolecular synthons in solution and in crystal structures, using FT-IR spectroscopy, are notable.17 Alternatively, we have utilized fluoro substitution as a chemical probe for the crystal landscape exploration of the native compound.3 This subtle chemical perturbation is, effectively, the experimental mimic of changes in the force field used in computational exploration of energy minima in crystal structure prediction (CSP). Extending to cocrystals, fluoro substitution was used in the study of the 1:1 benzoic acid:isonicotinamide (BA:INA) cocrystal landscape; the fluoro derivatives are the experimental “equivalent”

Figure 1. Comparison of modules in the 1:1 BA:INA (top), 2:1 BA:DPE-I (middle), and 2:1 BA:DPE-II (bottom). Note the supramolecular−molecular mimicry in the blue-shaded regions. The acid−pyridine heterosynthon is present in all cases.

tion.1,2 These events correspond to continuous energetic and structural modifications that occur during the later stages of crystallization.3 The realization of polymorphs, multiple crystalline forms of a compound, is the experimental © XXXX American Chemical Society

Received: October 20, 2014 Revised: November 19, 2014

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Figure 2. Comparison of modules in different structure types left, (9-4-24); center, (7-7-12); and right, (3-11-26). The module planes are inclined differently in the three cases. atoms were refined isotropically. Aromatic hydrogen atoms were fixed on carbon atoms based on the riding model. Acidic hydrogens were located in Fourier maps.

of high energy structures in the BA:INA landscape.18 Operationally, the structures of a large number of cocrystals of fluorobenzoic acids with INA were determined. Synthon modularity,19 predictability of hierarchy, and consistent reliability at increasing levels of fluorination are important features that allows one to successfully move in the entire high energy surface and achieve the (22-5-20) and (7-7-12) structure types regularly.20 We note that of these two families, which have different hydrogen bonding arrangements, only the (22-5-20) is found for the native BA:INA crystal structure under ambient conditions. The next step is therefore to look at some molecular alteration in the module which may allow for the exploration of more extended domains of the hyperenergy surface. In this context, we selected 1,2-bis(4-pyridyl)ethylene (DPE-I) as a coformer instead of isonicotinamide (INA). This system too contains the robust acid−pyridine heterosynthon.21,22 This cocrystal system highlights another idea in crystal engineering, namely the interchangeability of molecular and supramolecular synthons in crystal structures (Figure 1).23 Accordingly, we set out to crystallize 2:1 cocrystals of fluorobenzoic acids and DPE-I.

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RESULTS All FBAs:DPE-I cocrystals that we studied contain the acid− pyridine heterosynthon except one of the forms of

EXPERIMENTAL DETAILS Figure 3. Similarity of synthon patterns in BA:DPE-I (top) and 34DFBA:DPE-I (bottom) cocrystals. Both take the (9-4-24) structure.

Materials. All compounds [fluorobenzoic acids, 1,2-bis(4-pyridyl)ethylene, and 1,2-bis(4-pyridyl)ethane] were purchased from Alfa Aesar and Sigma-Aldrich and utilized without further purification. Crystals were obtained with liquid-assisted grinding (MeOH) of 1:1 and/or 2:1 mixtures of fluorobenzoic acid with DPE-I and DPE-II followed by crystallization. The exact experimental conditions are the decisive factors in the exploration of the crystal structure landscape of an organic compound. Keeping this in mind, we employed manual high-throughput crystallization to obtain suitable diffraction quality crystals with various crystallization techniques like solvent evaporation, sublimation, antisolvents, use of desiccators, and so on. The specific crystallization details are given in the Supporting Information. Data Collection and Refinement Details. A large segment of data sets were collected on a Rigaku Mercury 375R/MCCD (XtaLABmini) diffractometer with a graphite monochromator using Mo Kα radiation, attached with a Rigaku low-temperature gas spray cooler. The data were processed with Rigaku CrystalClear.24 Some crystal structures, 3FBA:DPE-I and 235TFBA:DPE-I, were collected on an Oxford Xcalibur diffractometer with a microfocus X-ray source (Mo Kα) equipped with a Cryojet-HT nitrogen gas stream cooling device, and data were processed with CrysAlisPro. 25 The 25DFBA:DPE-I, 234TFBA:DPE-I, and 245TFBA:DPE-I crystal structure data sets were collected on a Bruker Kappa Apex II CCD diffractometer using Mo Kα radiation and an Oxford cryosystems N2 open-flow cryostat.26 Cell refinement, data integration, and reduction were carried out using SAINTPLUS. The crystal structures were solved by direct methods and refined in the spherical-atom approximation using SHELXL201227 from the WinGX suite.28 All nonhydrogen atoms were refined anisotropically, whereas all hydrogen

26DFBA:DPE-I, which is dimorphic and shows synthon polymorphism. The exploration of the BA:DPE-I crystal landscape, using FBAs:DPE-I cocrystals, is based on secondary molecular recognition that is usually facilitated by fluorinecontaining weak supramolecular synthons like C−H···F, C− F···π, and F···F.29 This cocrystal landscape consists of three different (9-4-24), (7-7-12), and (3-11-26) structure types which are distinguished by the arrangement of hydrogenbonded modules in their corresponding crystal structures (Figure 2). Structural Analysis of the 2:1 BA:DPE-I Cocrystal Landscape. The 2:1 benzoic acid−1,2-bis(4-pyridyl)ethylene cocrystal, BA:DPE-I, is the native cocrystal and has been previously reported.30 This structure contains the robust acid− pyridine supramolecular synthon and forms a termolecular module that is fully “saturated” with respect to hydrogen bonding (Figure 1) and which further assembles into the threedimensional crystal structure using weaker intermolecular interactions. On the basis of our earlier publications,3,18 we use a similar convention and designate this crystal structure as being in the (9-4-24) structure type. The other members of this structure type are 3FBA:DPE-I and 34DFBA:DPE-I, which successfully interchange the secondary synthon, C−H···π, from B

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Figure 4. Similarity in the topology of synthon patterns in 4FBA:DPE-I (top), 24DFBA:DPE-I (center), and 2FBA:DPE-I benzene solvate (bottom) of (7-7-12) structure type.

Figure 5. Similarity of molecular module and supramolecular synthon patterns in 235TFBA:DPE-I (top) and 236TFBA:DPE-I (bottom) cocrystals of (3-11-26) structure type.

tains a similar hydrogen-bonding pattern which further leads to comparable three-dimensional crystal structures (Figure 3). Similar to the 1:1 BA:INA landscape, the BA:DPE-I also contains the (7-7-12) structure type (see Figure 4). This family encompasses the mono-to-multifluoro-substituted derivatives of native BA:DPE-I cocrystal like 4FBA:DPE-I, 24DFBA:DPE-I, and 246TFBA:DPE-I. Even among those that are polymorphic in nature, 2FBA:DPE-I (benzene solvate), 245TFBA:DPE-I, and 345TFBA:DPE-I, one of the forms is (7-7-12). This is because the basic module is able to find alternative ways of achieving this structure using other distinctive combinations of secondary interactions. These examples also suggest that by using fluoro substitution at certain positions of the aromatic

Table 1. Crystal Structure Landscape of 2:1 BA:DPE-I Cocrystal experimentally equivalent compounds BA:DPE-I, 3FBA:DPE-I, 34DFBA:DPE-I 2FBA:DPE-I (benzene solvate), 4FBA:DPE-I, 24DFBA:DPE-I, 245TFBA:DPE-I, 246TFBA:DPE-I, 345TFBA:DPE-I 25DFBA:DPE-I, 35DFBA:DPE-I, 235TFBA:DPE-I, 236TFBA:DPE-I

structure type (9-4-24) (7-7-12) (3-11-26)

the pool of synthons having comparable energy and directionality.31 With insulation of the primary supramolecular synthon, smooth secondary synthon interchangeability mainC

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Figure 6. Polymorphism in BA:DPE-I cocrystal landscape: (a) 26DFBA:DPE-I, (b) 245TFBA:DPE-I, and (c) 345TFBA:DPE-I cocrystals.

ular, while C−H···F involves parallel arrangement of modules. This set of examples is different from previously discussed structure types in that it facilitates the alternative parallel arrangement of incoming modules via C−H···F intermolecular interactions (Figure 5). All members of 2:1 BA:DPE-I crystal structure landscape are summarized in Table 1. CSD Statistical Studies. Similarities between DPE-Iand DPE-II-Based Cocrystals. Cambridge Structural Data-

nuclei, secondary recognition preferences may be amplified from the pool of synthons that finally lead to similar crystal structures.31 Moving further, the 25DFBA:DPE-I, 35DFBA:DPE-I, 235TFBA:DPE-I, and 236TFBA:DPE-I crystal structures constitute the (3-11-26) type. Previously discussed structure types are different based on the directionality associated with weaker supramolecular synthons; C−F···π involves perpendicD

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in 3FBA:DPE-I and 34DFBA:DPE-I cocrystals. These weak but directional hydrogen bonds provide a two-dimensional arrangement of modules which are further connected to another set of modules via C−H···π and C−F···π contacts. This topological similarity in the interaction arrangement further leads to a similarity of their three-dimensional crystal structures. What is the origin of this topological similarity? While H and F are chemically dissimilar, they are geometrically similar although there may be a hint of electrophilic character in F that permits a small extent of chemical similarity in these contacts. In this structure type, BA:DPE-I shows smooth C−H → C−F replacement for 3FBA:DPE-I, which does not perturb the general arrangement and binds neighboring modules via C− H···F hydrogen bonds more tightly compared to the hydrophobic C−H functionality. Even further, 34DFBA:DPE-I contains the interaction signature of the BA:DPE-I and 3FBA:DPE-I crystal structures, but surprisingly this crystal structure is sustained by C−F···π contacts rather than C−H···π hydrogen bonds. The representative crystal structures of the (7-7-12) structure type are 4FBA:DPE-I, 24DFBA:DPE-I, and 246TFBA:DPE-I. In these structures, modules form two-dimensional patterns similar to the previously discussed structure type but they are distinguished based on secondary molecular recognition of another set of modules. This is the definitive factor for all the members of the (7-7-12) structure type. In these three members of this family, the secondary molecular recognition consists of type I F···F or C−H···F dimer which leads to a parallel arrangement of other modules. The 246TFBA:DPE-I crystal structure is slightly different from the other members. The presence of fluorine substituents at the 2- and 6-positions forces the acid functionality out of the plane. This distortion in the molecular geometry provides differently oriented molecular modules, but the crystal structure still maintains similar kinds of secondary molecular recognition features so that one obtains a similar structure type. In the (3-11-26) structure type, the members use alternative locations of general and special positions. While 25DFBA:DPEI, 35DFBA:DPE-I, and 235TFBA:DPE-I are of the 2:(0.5 + 0.5) stoichiometry, 236TFBA:DPE-I is 1:0.5. In this family, the neighboring differently oriented modules are arranged to the primary module via C−H···F hydrogen bonds. The orientations of these neighboring modules are completely different from either of the previously discussed structure types and are responsible for their unique crystal structures (see Figure 5). Some of the fluoro-substituted acid cocrystals are polymorphic and offer suggestions about the molecular behavior during crystallization based on synthon hierarchy (Figure 6). The 2FBA:DPE-I benzene solvate belongs to the (7-7-12) structure type. On the basis of the rationalization of other members of this structure type crystal structures, this molecule does not fulfill the primary requirement for this structure type because of the absence of 4-F substitution. This crystal structure still belongs to the (7-7-12) structure type because of the insertion of benzene as a solvent molecule in the lattice that not only provides multiple weak C−H···π contacts but also provides the required topology of hydrogen bonds, which is responsible for the adoption of the (7-7-12) structure type. On the other hand, the anhydrous form shows a different molecular arrangement. In the context of the landscape this example supports the notion that all final outcomes, be they polymorphs and/or pseudopolymorphs, arise from a similar crystallization process and what emerges is based on experimental conditions.

base (CSD) studies were performed to rationalize the isostructurality features between DPE-I- and DPE-II-based cocrystals. In this study, we used the CSD 2014 with three database updates: November 2013, February 2014, and May 2014, along with several filters: 3D-coordinate, not polymeric, no ions, no powder structure, no errors, and only organics. After using the above-mentioned protocols, we got 188 and 100 crystal structures that contain DPE-I and DPE-II, respectively. These crystal structures include the single component DPE-I and DPE-II crystals and 187 and 99 multicomponent systems: cocrystals, their polymorphs, and pseudopolymorphs. Of these, there are 44 multicomponent pairs wherein DPE-I and DPE-II form cocrystals with the same coformer (that is, say A:DPE-I and A:DPE-II where A is the coformer common to both structures). For providing a better comparison, this group of 44 pairs was further refined to 35 pairs (see the Supporting Information) in which the asymmetric units are stoichiometrically the same and which are otherwise chemically equivalent (for example, both are hydrates). Inspection of these 35 pairs of DPE-I- and DPE-II-based cocrystals showed that 18 of them (51%) are isomorphous, while the other 17 (49%) are not. So, we may say that in roughly half the cases, replacement of DPE-I by DPE-II in a cocrystal will not affect the crystal structure.

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DISCUSSION Fluorosubstitution as a Chemical Probe. For the exploration of BA:DPE-I cocrystal landscape, the selected

Figure 7. Fourier map for the partial occupancy of the acidic hydrogen atom in form II of the 26DFBA:DPE-I cocrystal. Before (left) and after (right) assignment of Q-peaks.

module (Figure 1) is representative of a specific class of organic molecules having acid functionality, and as such, it highlights specific geometrical and associated chemical features of certain interactions that are particular to this coformer. The landscape consists of three different structure types based on the directionalities associated with weak C−H···F hydrogen bonds. All members of the (9-4-24) structural class are topologically similar with respect to their hydrogen-bonding patterns via multicentered C−H···O hydrogen bonds in BA:DPE-I or via surrogate C−H···O and C−H···F contacts E

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Figure 8. Comparison of multicomponent pairs: FERQEA:FERQIE (top, isostructurality), DATQIZ:DATQOF (center, nonisostructurality) conformational change is highlighted, and EJUZEO:ROBGEV (bottom, isostructural replacement of DPE-II with DPE-I).

and 345TFBA:DPE-I cocrystals also exist as dimorphs. In both cases, polymorphs have the basic two-dimensional arrangements of modules that show two alternative ways of further module aggregation. These examples provide an empirical understanding about the crystal structures, for example that the lateral weak interactions are the decisive factors for tuning the three-dimensional arrangement and that they provide an interrelation between different energetic events during the emergence of the final crystal structure. In summary, the chemical substitution in the heterosynthon-based module shows primary synthon insulation during the crystallization process and based on the recurring robust secondary synthons, one can explore the high-energy regions of the BA:DPE-I cocrystal landscape. The chemical probe of fluoro substitution again shows its usefulness in the exploration of the crystal structure landscape.3,18 CSD Studies. On the basis of our statistical studies, molecular cocrystals of DPE-I and DPE-II show a nearly

Scheme 1. Conformational Flexibility is More Important in DPE-II (Right) than in DPE-I (Left)a

a

This subtle geometrical feature allows the molecules to adopt conformations that are compatible with higher-energy forms, effectively accessing alternative crystal structures in DPE-II leading to nonisomorphous behavior.

The 2:1 26DFBA:DPE-I cocrystal is dimorphic and synthon polymorphism is present.32,33 The unusual form II of this cocrystal shows partial occupancy of hydrogen atoms between the acceptor sites (Figure 7). This example hints at the complexity of the crystallization mechanism and further suggests an alternative route which could be accessed by changing the experimental conditions. The 245TFBA:DPE-I F

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Figure 9. Coformer replacement: (a) BA:DPE-I (9-4-24) into BA:DPE-II (7-7-12) and (b) 235TFBA:DPE-I (3-11-26) into 235TFBA:DPE-II (7-712). Color coding highlights the geometry of the incoming module in different structure types.

molecular conformation and synthon preferences manifesting as different crystal structures. This slight perturbation in the molecule during crystallization provides sufficient energy for overcoming the energy barrier to access alternative domains of molecular arrangement in the landscape (Scheme 1). When this perturbation is subtle, one may control the delicate balance between overall loss and gain of energy in crystallization process (by varying the experimental conditions) thereby permitting coformer replacement. For example, in the EJUZEO:ROBGEV37,38 pair (Figure 8), there is a replacement of just one of the DPE-II molecules by DPE-I facilitating the formation of a well-ordered ternary molecular solid. 2:1 BA:DPE-I Cocrystal Landscape. High-Throughput Crystallization and CSD Studies. A combined use of highthroughput crystallization and CSD studies provides detailed information on the 2:1 BA:DPE-I crystal structure landscape. After replacing the DPE-I with the DPE-II coformer in the FBA cocrystals, we noted that these crystal structures show both isostructural and nonisostructural behavior, which is consistent with the CSD results. We also note the close energy relationships among the various structure types in the landscape. For example, the cocrystals of DPE-I with 23DFBA and 234TFBA are not within the landscape but the corresponding cocrystals with DPE-II lie within it. Also, a particular acid may form a cocrystal with DPE-I in a certain structure type in the landscape but the corresponding cocrystal with DPE-II is in another structure type (but still within the landscape, Figure 9, Table 2). To summarize, these structure types exemplify three consistent, recurring themes of molecular arrangements during crystallization, which are accessible by chemically perturbing the crystallization of the native compound.39,40 The crystallographic details of an isostructural set of examples, 24DFBA:DPE-II, 34DFBA:DPE-II, 245TFBA:DPEII, and 345TFBA:DPE-II, are given in the Supporting Information. In the nonisostructural set of examples (Figure 9), the coformer replacement becomes another chemical probe which highlights additional features about landscapes in general and establishes correlations among the different structure types: (9-4-24), (7-7-12), and (3-11-26). Thus, the BA:DPE-I cocrystal belongs to the (9-4-24) structure type, but BA:DPEII30 belongs to the (7-7-12) structure type. Energetic considerations are decisive in the context of the crystal structure landscape because its entire description is based on

Table 2. Extended Crystal Structure Landscape of 2:1 BA:DPE-I Cocrystal experimentally equivalent compounds BA:DPE-I, 3FBA:DPE-I, 34DFBA:DPE-I − 234TFBA:DPE-II 2FBA:DPE-I (benzene solvate), 4FBA:DPE-I, 24DFBA:DPE-I, 245TFBA:DPE-I, 246TFBA:DPE-I, 345TFBA:DPE-I − BA:DPE-II, 23DFBA:DPE-II, 235TFBA:DPE-II 25DFBA:DPE-I, 35DFBA:DPE-I, 235TFBA:DPE-I, 236TFBA:DPE-I

structure type (9-4-24) (7-7-12) (3-11-26)

equal propensity of isomorphous and nonisomorphous behavior in their respective crystal structures (Supporting Information). Nonisomorphous behavior owes generally to the flexibility associated with the C−C single bond in coformer DPE-II in comparison with the more rigid DPE-I. These structural possibilities give insights into the energy ordering of crystalline phases in the landscape. In the landscape context, any crystal structure is merely a data point on the complex horizon of intersecting and/or nonintersecting crystallization routes in the landscape and is quantitatively expressed by the energy-density profile.5,34 These data points are energetically interrelated. For hopping from one data point to another, one has to overcome a certain energy barrier. In this study, we have utilized coformer replacement during the crystallization process as a device that may facilitate this hopping process so that one may access different regions of the landscape. Isostructurality in cocrystals provides indirect information that the coformer replacement perturbs the hyperenergy surface in a subtle way, even as crystal formation is similar in the two cases. The energy penalty for the replacement of the coformer is smaller than what is required to overcome the energy barrier of the different potential wells and so the same crystal structure is adopted. For example, the FERQEA:FERQIE35 pair (Figure 8) shows an isomorphous behavior in the hydrogen-bonding pattern as well as in the crystal structures giving rise to smooth replacement of DPE-I by DPE-II. Thus, the isostructural examples hint that both coformers show similar type of molecular movement on the hyperenergy surface of the cocrystals and that is why this pair finally emerges with a similar three-dimensional arrangement of molecules. Another example is the DATQIZ:DATQOF36 pair (Figure 8), which is a representative example of nonisomorphous crystal structures upon the replacement of coformers. This example shows that after replacing the coformer, the compound changes its G

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(4) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, 2002; Vol. 14. (5) Thakur, T. S.; Dubey, R.; Desiraju, G. R. Annu. Rev. Phys. Chem. 2015, 66, 21. (6) Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 9952. (7) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342. (8) Gavezzotti, A. CrystEngComm 2003, 5, 439. (9) Price, S. L. Acc. Chem. Res. 2008, 42, 117. (10) Price, S. L. Chem. Soc. Rev. 2014, 43, 2098. (11) Desiraju, G. R. Science 1997, 278, 404−405. (12) Desiraju, G. R. Nat. Mater. 2002, 1, 77. (13) Das, D.; Banerjee, R.; Mondal, R.; Howard, J. A. K.; Boese, R.; Desiraju, G. R. Chem. Commun. 2006, 555. (14) Parveen, S.; Davey, R. J.; Dent, G.; Pritchard, R. G. Chem. Commun. 2005, 1531. (15) Davey, R. J.; Dent, G.; Mughal, R. K.; Parveen, S. Cryst. Growth Des. 2006, 6, 1788. (16) Kulkarni, S. A.; McGarrity, E. S.; Meekes, H.; ter Horst, J. H. Chem. Commun. 2012, 48, 4983. (17) Davey, R. J.; Schroeder, S. L. M.; ter Horst, J. H. Angew. Chem., Int. Ed. 2013, 52, 2166. (18) Dubey, R.; Desiraju, G. R. Chem. Commun. 2014, 50, 1181. (19) Tothadi, S.; Desiraju, G. R. Cryst. Growth Des. 2012, 12, 6188. (20) The structure types discussed here are represented as integers such as (22-5-20) and (7-7-12). These integers are approximations of the unit cell lengths of the corresponding crystal structures. (21) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311. (22) Almarssön, O.; Zaworotko, M. J. Chem. Commun. 2004, 1889. (23) Reddy, D. S.; Craig, D. C.; Desiraju, G. R. J. Am. Chem. Soc. 1996, 118, 4090. (24) Rigaku Mercury375R/M CCD. Crystal Clear-SM Expert 2.0 rc14; Rigaku Cooperation: Tokyo, Japan, 2009. (25) Oxford Diffraction. CrysAlis PRO CCD and CrysAlis PRO RED; Oxford Diffraction Ltd.: Yarnton, England, 2009. (26) Bruker APEX2 (version 1.0.22), BIS (Version 1.2.08), COSMO (version 1.48) and SAINT (version 7.06A), Bruker AXS Inc.: Madison, Wisconsin, 2006. (27) Sheldrick, G. Acta Crystallogr. A 2008, 64, 112. (28) Farrugia, L. J. Appl. Crystallogr. 1999, 32, 837. (29) Hathwar, V. R.; Thakur, T. S.; Dubey, R.; Pavan, M. S.; Guru Row, T. N.; Desiraju, G. R. J. Phys. Chem. A 2011, 115, 12852. (30) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 1106. (31) Dubey, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2014, DOI: 10.1002/anie.201402668. (32) Sreekanth, B. R.; Vishweshwar, P.; Vyas, K. Chem. Commun. 2007, 2375. (33) Mukherjee, A.; Desiraju, G. R. Chem. Commun. 2011, 47, 4090. (34) Dubey, R.; Pavan, M. S.; Guru Row, T.; Desiraju, G. R. IUCrJ 2014, 1, 8. (35) Masu, H.; Tominaga, M.; Azumaya, I. Cryst. Growth Des. 2013, 13, 752. (36) Zeng, Q.; Wu, D.; Wang, C.; Ma, H.; Lu, J.; Liu, C.; Xu, S.; Li, Y.; Bai, C. Cryst. Growth Des. 2005, 5, 1889. (37) Bhogala, B. R.; Nangia, A. Cryst. Growth Des. 2003, 3, 547. (38) Bhogala, B. R.; Nangia, A. New J. Chem. 2008, 32, 800. (39) Kirchner, M. T.; Reddy, L. S.; Desiraju, G. R.; Jetti, R. K. R.; Boese, R. Cryst. Growth Des. 2004, 4, 701. (40) Mukherjee, A.; Desiraju, G. R. Cryst. Growth Des. 2014, 14, 1375.

the putative nature of weak synthons and their associated energies. The 235TFBA:DPE-I belongs to the (3-11-26) structure type while on coformer replacement 235TFBA:DPE-II changes its secondary synthon preferences slightly and moves into the (7-7-12) structure type. Similarly, the 23DFBA:DPE-I and 234TFBA:DPE-I do not belong to either of the structure types but after replacing the coformer with DPE-II, their respective crystal structures move into (7-712) and (9-4-24) structure types, respectively. The extended 2:1 BA:DPE-I cocrystal landscape is summarized in Table 2. High-throughput crystallography and CSD studies symbiotically help to understand the kinetic features of the cocrystal landscape, but this discussion becomes even more fruitful by cocrystallizing with DPE-II. This establishes the interrelationship among the structure types.

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CONCLUSIONS In conclusion, high-throughput crystallography and a CSD study with coformer replacement from DPE-I to DPE-II provides an extended interpretation of the BA:DPE-I cocrystal landscape. This study confirms our earlier finding in that a cocrystal has a landscape just like a single component system. Fluoro substitution using high-throughput crystallization explores the BA:DPE-I cocrystal landscape and sheds some light on kinetic features. Polymorphs and pseudopolymorphs belong to the same crystal landscape but may follow different (crystallization) routes on the landscape. Secondary synthon preferences are the decisive factors that control the final crystal structures and determine the existence of various structure types. On the other hand, the CSD study provides information about the isomorphous behavior of cocrystals by coformer replacement. This article highlights that complex kinetic features involved during crystallization cannot be properly or solely modeled by the crystal energy landscape which is based only on enthalpies of polymorphs.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental details, CSD analysis, Table of isostructural and nonisostructural multicomponent pair details, normalized hydrogen bond distances, and crystallographic tables. 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.

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ACKNOWLEDGMENTS R.D. thanks the Indian Institute of Science for a senior research fellowship and G.R.D. thanks the DST for the award of a J. C. Bose fellowship.

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REFERENCES

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dx.doi.org/10.1021/cg501553m | Cryst. Growth Des. XXXX, XXX, XXX−XXX