Effect of Preorganization on the Polymorphism and ... - ACS Publications

Article pubs.acs.org/crystal

Effect of Preorganization on the Polymorphism and Cocrystallization of a Squaramide Compound Rafel Prohens,*,† Anna Portell,† and Xavier Alcobé‡ †

Unitat de Polimorfisme i Calorimetria and ‡Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain S Supporting Information *

ABSTRACT: A squaramido-based model compound with the ability to establish an intramolecular hydrogen bond has been designed to study the effect of preorganization on its polymorphism and the cocrystallization with resorcinol. Three out of the four expected supramolecular synthons have been observed in two polymorphs and two cocrystals with resorcinol, whose crystal structures have been solved from X-ray diffraction laboratory data using direct-space strategies.

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INTRODUCTION The attention that crystal engineering has received in the last years is due mainly to the impact that novel crystalline materials are having in fields such as supramolecular chemistry or pharmaceutical sciences in terms of improved drug properties and intellectual property.1 The rational design of new crystalline supramolecular structures has been traditionally based on supramolecular synthons, which is a probabilistic model that takes into account only the degree of occurrence of a particular pattern of interaction.2 Supramolecular synthons can be defined as arrangements of intermolecular noncovalent interactions with a highly occurring frequency in crystal structures. This concept is applied in supramolecular synthesis in such a manner as synthons are in covalent synthesis.3 Therefore, a deep knowledge of the preference for a particular synthon exhibited by a family of compounds can be used to design new supramolecular crystalline materials. This strategy has been applied successfully in numerous examples.4 Recently we have experimentally and computationally described the cooperative induction in self-assembled squaramides to explain the preference of this family of compounds for chains versus ribbons in the solid state.5 Moreover, this phenomenon explains why this strong homosynthon has resulted to be resistant against double donor H-bonding compounds such as resorcinol. However, it is well-known that the presence of competing H-bond donor/acceptors in the same molecule can affect the resulting synthons in the crystal. In this paper, we decided to study the effect that bringing an intramolecular interaction by introducing an extra H-bond acceptor can have over the resulting intermolecular synthons in a bis squaramide-esther model compound, and in particular to check the feasibility of breaking the omnipresent head-to-tail © 2012 American Chemical Society

synthons in squaramides through cocrystallization with Hbonding donors.

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EXPERIMENTAL SECTION

Materials. Diethylsquarate (98%) was purchased from SigmaAldrich. Synthesis of 1. Compound 1 was readily prepared from addition of 1,4-bis(3-aminopropyl)piperazine (0.68 g, 3.4 mmol) dissolved in diethyl ether (60 mL) to a solution of diethylsquarate (1.72 g, 10.1 mmol) (Sigma Aldrich) in diethyl ether (10 mL). The amine was added dropwise during 3 h, under argon atmosphere, and it was stirred overnight. A white solid precipitated immediately. The solid was filtered and washed with diethyl ether (3 × 10 mL), and it yielded 87%.6 1H-NMR (CDCl3, 400 MHz) δ: 8.21 (br, 1H), 8.01 (br, 1H), 7.94 (br, 1H), 7.75 (br, 1H), 4.76 (q, 4H, J = 8 Hz), 3.82 (m, 2H), 3.60 (m, 2H), 2.61 (m, 12H), 1.79 (m, 4H), 1.46 (t, 6H, J = 8 Hz) ppm. 13C-NMR (CDCl3, 400 MHz) δ: 189.8, 182.2, 173.0, 69.6, 57.7, 53.1, 45.7, 25.1, 16.1 ppm. MS (TOF) m/z (%): (M − I+) 449. X-ray Powder Diffraction. Laboratory X-ray powder diffraction data for the solids obtained were collected at ambient temperature in a Panalytical X’Pert PRO MPD capillary configuration (0.7 mm diameter capillary); focusing elliptic mirror; Cu Kα1,2, λ = 1.5418 Å; 0.01 radians Soller slits; PIXcel detector, active length 3.347°; 2θ range, 2°−70°, step size, 0.013°, data collection time, 60 h. After indexing using DICVOL047 and space group assignment, the structure was solved using the program FOX,8 followed by Rietveld refinement using FullProf.9 Differential Scanning Calorimetry (DSC). Experiments to define the multiphase system were performed in a Mettler-Toledo DSC-822e calorimeter. The samples were placed in aluminum crucibles of 40 μL Received: May 29, 2012 Revised: July 20, 2012 Published: July 23, 2012 4548

dx.doi.org/10.1021/cg300727r | Cryst. Growth Des. 2012, 12, 4548−4553

Crystal Growth & Design

Article

Figure 1. Expected supramolecular synthons for 1 together with their corresponding graph sets.15 volume, under an atmosphere of dry nitrogen with a 50 mL/min flow rate. The calorimeter was calibrated with indium of 99.99% purity. Modulate Differential Scanning Calorimetry (MDSC). Experiments to separate thermal phenomena of the polymorphic system were performed in a TA Instruments MDSC-Q2000 calorimeter. The samples were placed in aluminum crucibles of 40 μL volume, under an atmosphere of dry nitrogen with a 50 mL/min flow rate. The heat-flow curve was obtained at a heating rate of 0.5 °C/min, a period of 60 s, and an amplitude of 0.08 °C.10

order to study this hypothesis, a polymorphism screening was conducted. After testing the solubility of 1 in 23 solvents of different nature (MeOH, EtOH, IPA, tBuOH, ACN, THF, dioxane, Et2O, MTBE, MEK, acetone, MIBK, AcOEt, DMF, toluene, CH2Cl2, DMSO, xylene, ethyleneglycol, water, pentane, cyclohexane, and heptane), an intensive polymorphic screening was carried out comprising different experimental conditions. Kinetic conditions included fast cooling rate crystallizations from room temperature or from high temperature to 0 °C, obtaining form A in pure form with most of the solvents (only with tetrahydrofuran and chloroform did a mixture of A and B forms crystallize). On the other hand, thermodynamic conditions included slow cooling rate crystallizations from high temperature, solvent evaporations at room temperature, and slow antisolvent diffusions at room temperature, giving form B in pure form in most of the cases (only under some specific conditions does a mixture of forms crystallize). During the synthesis in ethanol, form A was always obtained in pure form. No other polymorphs were obtained. Table 1 shows the percentage in total number of experiments resulting in pure forms A and B or mixtures. The thermogram of polymorph A, registered at 10 °C/min, shows an exothermic peak at around 135 °C which was initially assigned to a solid−solid transition (Figure 2), but a more accurate analysis with modulated DSC revealed an overlapped melting and crystallization process. Solvent mediated transformation experiments at different temperatures, in which a mixture of forms A and B evolved to pure form B at all temperatures below the melting point of form A, confirmed that both forms are monotropically related. Polymorph B can also be obtained by heating polymorph A until 120 °C and then cooling down to room temperature, since both polymorphs are monotropically related (Figure 3).

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RESULTS AND DISCUSSION N,N′-Bis(3-aminopropyl)piperazine has been previously used as a spacer in ditopic thioureas. Piperazine nitrogen establishes intramolecular interactions with thiourea NH protons in the solid state, inducing the formation of “spiral galaxy” motifs with cis/cis polymerization synthons.11 Squaramides are stronger Hbonding donor/acceptors than ureas or thioureas, and the trans/trans intermolecular supramolecular synthon has been demonstrated to be very strong, due to cooperativity effects.12 However, monoalkyl esther-squaramides are not so previsible and other synthons have been observed, such as dimers formed through syn/syn H-bonding interactions5 and through amineamide H-bonding,13 and chains formed by monomers aligned in a pseudo head-to-tail manner (ref code: NEMMEX, SIXFIP).14 Bis-squaramide 1, which can be readily synthesized from diethylsquarate and N,N′-bis(3-aminopropyl)piperazine in diethyl ether, was designed because it has the possibility to establish an intramolecular H-bond, giving the possibility for both carbonyl oxygens to interact with H-bond donors. In principle, four different supramolecular synthons for 1 in the solid state were expected: the trans configuration can produce two synthons, the head-to-tail polymer and the intramolecular monomer, while the cis configuration can produce the ribbon synthons and another intramolecular monomer (Figure 1). In 4549



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with a Le Bail fit of the data using FullProf. The used background (estimated from a set of experimentally read points and interpolated) and the resulting cell, zero error, and shape parameters of the Le Bail fit were used in the structure solution procedure with FOX. The structures were solved using the parallel tempering algorithm implemented in FOX. The Z matrices were created with an optimized model by using SPARTAN,17 and FOX was instructed to treat cyclobutene rings as rigid bodies. Ten runs of two million trials each were performed. This process produced very similar structures with chemically sensible molecular arrangements, and the structure with the lowest overall cost function was the basis for Rietveld refinement with FullProf. Form A was obtained in pure form during the synthesis. It is monoclinic with space group P21/c and with half a molecule in the asymmetric unit. Unit cell dimensions a = 16.35960(1) Å, b = 9.99893(6) Å, c = 7.27435(3) Å, β = 98.818(5)°, V = 1175.86(12) Å3, Z = 2, dcalc = 1265 mg/m3 at room temperature. Rietveld refinement; 2θ range: 4.01−69.98°; 5076 profile points; 78 refined variables; Rwp = 2.63%, Rp = 1.81%, χ2 = 8.88 (compared to the Le Bail fit: Rwp = 2.48%, Rp = 1.63%, χ2 = 7.92) (Figure 4). CCDC 883948 contains the crystallographic data.

Table 1. Distribution of Forms Obtained during the Polymorph Screening polymorph distribution type of experiment synthesis

form A form B 100

Kinetic Crystallizations evaporations from high temp to 0 °C 17 evaporations from r.t. to 0 °C 0 Thermodynamic Crystallizations slow rate crystallizations from high temp to r.t. 0 evaporations at r.t. 0 antisolvent diffusion crystallizations at r.t 0

mixture

0

0

0 0

83 100

100 67 100

0 33 0

Figure 2. DSC of form A at 10 °C/min together with the corresponding MDSC.

Figure 3. PXRD of forms A (red) and B (blue) obtained from variable temperature experiments.

Unfortunately, no crystals of any of the forms suitable for structure determination by single-crystal XRD could be obtained. Therefore, we decide to solve their crystal structures from powder diffraction data by means of methods of direct space. In the last years, considerable advances have been made in the issue of solving organic structures from powder diffraction patterns, and some crystal structures have been solved when the requirement for a single crystal of appropriate size and quality has limited the use of single crystal X-ray diffraction.16 In this work we decided to use the user-friendly interface FOX developed by Czerny and Favre-Nicolin.8

Figure 4. Results of final Rietveld refinements of (a) form A and (b) form B. Each plot shows the experimental powder XRD profile (red + marks), the calculated powder XRD profile (black solid line), and the difference profile (blue, lower line).

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Form B was obtained by crystallization from the melt of form A at 160 °C in an aluminum DSC crucible under nitrogen atmosphere. The X-ray powder diffractogram data were collected at room temperature. An impurity was detected in the pattern (peaks at 2θ = 6.2, 8.5, 10.6, 15.8°) which was not considered in the indexation. The crystal is also monoclinic

INDEXING AND STRUCTURE SOLUTION OF FORMS A AND B The experimental powder diffraction diagrams were indexed with DICVOL04. The space groups were deduced from the systematic absences. The cell and space groups were validated 4550



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Figure 5. Crystal structures of forms A and B showing intermolecular and intramolecular H-bonding.

with pace group P21/c and with half a molecule in the asymmetric unit. Unit cell dimensions a = 12.89858(5) Å, b = 13.41816(2) Å, c = 6.81936(13) Å, β = 96.940(17)°, V = 1171.61(5) Å3, Z = 2, dcalc = 1270 mg/m3 at room temperature. Rietveld refinement; 2θ range: 2.00−69.99°; 5290 profile points; 134 refined variables; Rwp = 5.79%, Rp = 4.05%, χ2 = 44.4 (compared to the Le Bail fit: Rwp = 4.82%, Rp = 2.89%, χ2 = 30.6) (Figure 4). CCDC 883949 contains the crystallographic data. Form A presents a six-membered ring formed through intramolecular hydrogen bonds, roughly perpendicular to the plane defined by the piperazine ring (Figure 5). Strong hydrogen bonds between the amidic NH and the piperazine nitrogen [N−H···N 2.843(8) Å] make the molecule shrink in a symmetric way. The parallel layers of molecules are stabilized through π-stacking interactions (dcentroids 3.851 Å) of the cyclobutene rings and weak hydrogen bonds between the carbonyl oxygens and the piperazine hydrogens. A similar hydrogen bonding pattern had been reported in the “spiral galaxy” bis-thiourea derivatives from N,N′-bis(3-aminopropyl)piperazine which proved to be very strong.11 However, in the present case, this synthon corresponds to the metastable form. Form B instead appears relatively strain-free, showing a headto-tail hydrogen bonding motif similar to those already described in some other ester amides of squaric acid.18 The cyclobutene rings interact via π-stacking, where the interplanar and centroid−centroid distances are 3.844 and 3.554 Å, respectively. In both cases, the piperazine rings adopt a chair conformation. Interaction energy calculations of the different aggregates for the head-to-tail synthon were performed at the DFT level of theory and compared with the syn/syn synthon. A model corresponding to the H-bonding unit for each oligomer was extracted from the crystal structure, and the interaction energy was calculated (without further geometry optimization) using the counterpoise corrections for basis set superposition error (BSSE).19 The extrapolation to a high number of monomers gives roughly an interaction energy of 33 kJ/mol per H-bond, very similar to the 35 kJ/mol for the syn/syn dimer (69 kJ/mol for two H-bonds) (see Figure 6). However, although an intensive polymorph screening was conducted, no polymorphs showing the syn/syn synthon were obtained despite the fact that it seemed expected from both geometrically and energetically points of view. Once we confirmed that the intramolecular H-bond is established in one of the polymorphs, we decided to use this preorganization effect to drive the formation of cocrystals with double H-bond donor coformers. In order to study this possibility, a cocrystal screening was performed between 1 and resorcinol. The H-bonding donor abilities of resorcinol and 1

Figure 6. DFT interaction energies for the trans and cis oligomers.

are quite similar (Hunter’s α parameters20 of 3.7 and 3.5, respectively); thus, a qualitative prediction of the likeliness of cocrystallization by using the Hunter’s approach is particularly difficult in this case. However, resorcinol was chosen due to its geometrical and H-bonding complementarity (see Figure 7), and a cocrystal screening was conducted.21

Figure 7. Donor−acceptor complementarity between 1 and resorcinol.

Two new pure crystalline phases were obtained, whose crystal structures could be determined by means of methods of direct space.

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INDEXING AND STRUCTURE SOLUTION OF ANHYDROUS AND HYDRATE COCRYSTALS The indexation and the crystal structure procedures using FOX were the same as those in the case of polymorphs A and B. However, two and three independent objects were introduced instead of one in each case. The structures were solved as anhydrous and hydrate forms. Anhydrous cocrystals, with a 2:1 stoichiometry, were obtained pure from the dehydration of the hydrate cocrystal at 120 °C in an aluminum DSC crucible under nitrogen atmosphere. They are triclinic with space group P1̅, requiring half a molecule of 1 and one molecule of resorcinol in the asymmetric unit. Unit cell dimensions: a = 11.41571(9) Å, b = 4551



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9.99893(10) Å, c = 8.19298(5) Å, α = 86.5493(4)°, β = 99.3077(4)°, γ = 122.3577(4)°, V = 856.303(12) Å3, Z = 2, dcalc = 1295 mg/m3 at room temperature. Rietveld refinement; 2θ range: 2.02−69.98°; 5229 profile points; 88 refined variables; Rwp = 3.60%, Rp = 2.83%, χ2 = 15.3 (compared to the Le Bail fit: Rwp = 2.37%, Rp = 1.74%, χ2 = 6.62) (Figure 8). CCDC 883950 contains the crystallographic data.

The hydrate cocrystal, with a 1:2:2 stoichiometry, was obtained by crystallization with different solvents during the cocrystal screening. It is also triclinic with space group P1̅, containing half a molecule of 1, one molecule of resorcinol, and one molecule of water in the asymmetric unit. Unit cell dimensions: a = 7.04800(6) Å, b = 9.32696(15) Å, c = 14.50037(19) Å, α = 76.7937(7)°, β = 81.7078(9)°, γ = 77.4380(6)°, V = 901.286(20) Å3, Z = 2, dcalc = 1297 mg/m3 at room temperature. Rietveld refinement; 2θ range: 2.02−69.98°; 5229 profile points; 126 refined variables; Rwp = 4.97%, Rp = 3.70%, χ2 = 29.8 (compared to the Le Bail fit: Rwp = 4.27%, Rp = 2.53%, χ2 = 21.8) (Figure 8). CCDC 883951 contains the crystallographic data. Good quality crystalline structures could be achieved after Rietveld refinement demonstrating the formation of two cocrystals, though not with the expected synthon. In the anhydrous cocrystal, the most remarkable feature of the structure is that, besides the fact that the expected carbonyl− phenol interaction does not take place, each molecule of 1 interacts with another one via the dimeric syn/syn supramolecular synthon which, although expected, had not been observed previously in any of its two polymorphs. Moreover, two molecules of resorcinol interact through strong hydrogen bonds with both piperazine nitrogens and the free carbonyl groups of the squaramidic ring (Figure 9). On the other side, in the hydrate cocrystal, the presence of water produces a dramatic change in the supramolecular synthons present in the structure. In this cocrystal, squaramide molecules do not interact with each other; instead, all its acceptor and donor groups establish H-bonds with water and resorcinol molecules: carbonylic oxygens bond to water and phenol hydrogens while the amidic hydrogen bonds to the water oxygen. The other phenolic resorcinol’s hydrogen also bonds the water oxygen. The structure is completed with piperazine nitrogen−water interactions. Evidences of polymorphism in these multicomponent solids have been observed; therefore, other supramolecular synthons, including the R22(11), cannot be discarded. Research in this direction is still being conducted.

Figure 8. Results of the final Rietveld refinements of (a) anhydrous cocrystal and (b) hydrated cocrystal. Each plot shows the experimental powder XRD profile (red + marks), the calculated powder XRD profile (black solid line), and the difference profile (blue, lower line).

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CONCLUSIONS In summary, we have studied how the formation of an intramolecular H-bond affects the polymorphism of a bis-

Figure 9. Crystal structures of the resorcinol cocrystals. 4552



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(13) 3-Ethoxy-4-(2-ethylamino-2-pyridin)-3-cyclobutene-1,2-dione was readily prepared from 2-Aminoetilpiridina 99% and diethylsquarate in diethyl ether at room temperature. Crystal-structure determination data were collected at room temperature on an Apex II Brucker AXS diffractometer, Mo Kα radiation (λ = 0.71073 Å), C13H14N2O3, Mr = 246.26, colorless crystals. Crystal dimensions: 0.09 × 0.08 × 0.07 mm3; monoclinic P21/n, a = 7.435(5) Å, b = 14.028(7) Å, c = 12.008(6) Å, β = 92.07(3)°, V = 1495.2(5) Å3, Z = 4, Dcalc =1.307 g/cm3, Rint = 0.0380, R1 = 0.0475, wR2 = 0.1278 for all 3058 observed independent reflections; F(000) = 520: 2θ range = 2.90− 30.33°. CCDC 883964. All non-hydrogen atoms were refined anisotropically. SHELXL97 was used for structure solution and refinement on F2. (14) (a) Kolev, T.; Yancheva, D.; Schürmann, M.; Kleb, D. C.; Preut, H.; Bleckmann, P. Z. Kristallogr.New Cryst. Struct. 2001, 216, 241− 242. (b) Kolev, T.; Petrova, R.; Spiteller, M. Acta Crystallogr., E 2004, 60, 634−636. (15) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (16) Č erný, R.; Favre-Nicolin. Z. Kristallogr. 2007, 222, 105−113. (17) Spartan’10; Wavefunction Inc.: 18401 Von Karman, Irvin, CA 92715. (18) Kolev, T.; Koleva, B. B.; Spassov, T.; Cherneva, E.; Spiteller, M.; Mayer-Figge, H.; Sheldrick, W. S. J. Mol. Struct. 2008, 875, 372−381. (19) Simon, S.; Duran, M.; Dannenberg., J. J. J. Phys. Chem. A 1999, 103, 1640. (20) Hunter, C. Angew. Chem., Int. Ed. 2004, 43, 5310−5324. (21) A survey of the November 2011 Cambridge Structural Database has identified over 55 instances of the synthon R22(11).

squaramide compound. This preorganization produces, to the best of our knowledge, the first solid form without intermolecular NH···O bonding between secondary squaramides. However, this effect has been revealed not to be sufficient to drive the formation of a cocrystal with the double donor-double acceptor supramolecular synthon. On the other hand, three out of the four a priori possible supramolecular synthons predicted for 1 have been observed in its two polymorphs and its two cocrystals with resorcinol structures. All crystal structures have been solved from laboratory powder diffraction data by means of methods of direct space, including a ternary multicomponent crystal, which implies an increased difficulty. This work is also an example of how the rapidly expanding use of powder X-ray diffraction for ab initio structure determination of organic molecular crystals and its application to the examination of intermolecular forces may help to better address crucial questions about crystal engineering.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

S Supporting Information *

CIF files. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*Tel: + 34 93 4034656. Fax: + 34 93 4037206. E.mail: rafel@ ccit.ub.edu. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Cristina Puigjaner, Rafael Barbas, and Dr. Mercè Font-Bardia (Universitat de Barcelona) for valuable discussions. We also thank Dr. Carlos A. Gracia (TA Instruments) for MDSC measurements.

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REFERENCES

(1) (a) Bernstein, J.; Novoa, J.; et al. Eng. Cryst. Mater. Prop. 2008, 87−109. (b) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon Press: Oxford, 2002. (c) Desiraju, G. U. Crystal Engineering: The design of Organic Solids; Elsevier: Amsterdam, 1989. (2) Desiraju, G. U. Angew. Chem., Int. Ed. 1995, 34 (21), 2311−2327. (3) Sahoo, P.; Kumar, D. K.; Raghavan, S. R.; Dastidar, P. Chem. Asian J. 2011, 6, 1038−1047. (4) (a) Reddy, S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369−1371. (b) Aakeröy, C. B.; Scott, B. M. T.; Smith, M. M.; Urbina, J. F.; Desper, J. Inorg. Chem. 2009, 48, 4052. (c) Thaimattam, R.; Krishnamohan Sharma, C. V.; Clearfield, A.; Desiraju, G. R. Cryst. Growth Des. 2001, 1, 103. (5) Prohens, R.; Portell, A.; Puigjaner, C.; Barbas, R.; Alcobé, X.; Font-Bardia, M.; Tomàs, S. CrystEngComm 2012, DOI: 10.1039/ C2CE25576F. (6) Tomas, S.; Prohens, R.; Vega, M.; Rotger, M. C.; Deya, P.; Ballester, P.; Costa, A. J. Org. Chem. 1996, 61, 9394−9401. (7) Boultif, A.; Louër, D. J. Appl. Crystallogr. 2004, 37, 724. (8) Favre-Nicolin, V.; Czerny, R. J. Appl. Crystallogr. 2002, 35, 734− 743. (9) Rodriguez-Carvajal, J. Physica B 1993, 192, 55−69. (10) Gómez-Barreiro, S.; Gracia-Fernández, C. J. Mater. Res. 2012, 27 (0), 1379−1382. (11) Paisner, K.; Zakharov, L. M.; Doxsee, K. M. Cryst. Growth Des. 2010, 10 (8), 3757−3762. (12) Prohens, R.; Portell, A.; Puigjaner, C.; Tomàs, S.; Fujii, K.; D. M. Harris, K.; Alcobé, X.; Font-Bardia, M.; Barbas, R. Cryst. Growth Des. 2011, 11, 3725−3730. 4553


Effect of Preorganization on the Polymorphism and ... - ACS Publications

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