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Cooperativity in Solid-State Squaramides Rafel Prohens,*,† Anna Portell,† Cristina Puigjaner,*,† Salvador Tomas,*,‡ Kotaro Fujii,§ Kenneth D. M. Harris,*,§ Xavier Alcobe,† Merce Font-Bardia,† and Rafael Barbas† †
Plataforma de Polimorfisme i Calorimetria i Unitat de Difraccio de Raigs X, Centres Científics i Tecnologics, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain ‡ Department of Biological Sciences, School of Science, Birkbeck University of London, Malet Street, London WC1E 7HX, United Kingdom § School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, Wales
bS Supporting Information ABSTRACT: Using a dipyridyl squaramide derivative as a model, we have shown that cooperativity in hydrogen-bonded catemers plays a crucial role in defining the solid-state synthon of disecondary squaramides, overriding the preferred association mode in solution.
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ooperativity of weak interactions plays a crucial role in molecular recognition and self-assembly events. A good understanding of cooperativity is therefore essential for obtaining insights into the behavior of both biomolecular systems and synthetic materials. However, while it is often easy to identify cooperativity at work, it is more difficult to predict how it may influence the behavior of a particular system.1 For example, in cases for which H-bonding is the primary intermolecular interaction in the solid state, cooperativity in the form of mutual H-bond reinforcement within an H-bonded chain can play a major role in the supramolecular synthon observed in the crystal. Price has demonstrated2 that the induction energy contribution to the lattice energy of organic compounds is significant, particularly for molecules containing H-bonding groups such as carbamazepine; moreover, there is evidence that such induction effects are important even in crystals of nonpolar compounds.2 It has also been shown in silico that H-bonded amide chains exhibit a high degree of cooperativity,3 which arises from the reinforcement of individual H-bonds through the mutual polarization of acceptors and donors along the assembly. Such cooperative interactions are significant in the solid state but are secondary in the liquid or gas phases because the molecules are separated too far to interact in a cooperative way and the dynamics of the molecules also limit the effect.4 However, the preferred structure of molecular clusters in supersaturated solutions can sometimes resemble the mode of aggregation in the crystal structure, r 2011 American Chemical Society
suggesting a possible link between self-aggregation in solution and crystallization processes.5 In the solid state, disecondary squaramides typically show a head-to-tail arrangement comprising H-bonded chains. In this paper, we analyze the structural preferences of a disecondary squaramide model compound in order to understand the relationship between the structures of aggregates in solution and in the solid state, and the role played by cooperativity. In a previous paper,6 we investigated the polymorphism of dibenzylsquaramide, and the crystal structures of two of the three polymorphs were determined. Both of these structures have an identical catemer motif in which assemblies of squaramide units interact through H-bonding. The crystal structure of the other polymorph is still unknown. Dibenzylsquaramide and, in general, disecondary squaramides are insoluble in apolar organic solvents due to this strong H-bonding. In order to study the interactions of squaramides in solution prior to crystallization, a model compound soluble in organic solvents of low polarity was chosen: 3,4-bis(2-methylaminopyridyl)-1,2-dioxo-3-cyclobutene (1). Compound 1 is readily prepared from diethylsquarate and 2-methylaminopyridine in ethanol with very high yield. Received: June 18, 2011 Revised: August 2, 2011 Published: August 04, 2011 3725
dx.doi.org/10.1021/cg200772e | Cryst. Growth Des. 2011, 11, 3725–3730
Crystal Growth & Design The fact that 1 is soluble in chloroform and other organic solvents allows a broad range of crystallization conditions to be studied. The 1H NMR spectrum of 1 in CDCl3 at low temperature has three sets of signals, showing that 1 is present as a
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mixture of two different conformers, one symmetric and one asymmetric (Figure 1).7 The three sets of signals (NH, *, #), corresponding to three different environments of the methylpyridyl group, are assigned to the anti/anti (1a, Figure 3) and anti/syn (1b or 1c, Figure 3) dimers on the basis of 2D 1H NMR COSY dilution experiments (Figure 2).8 Of the two possible dimers (1b and 1c) for the anti/syn conformer, the 1b structure seems more likely on the basis of the observed chemical shifts of Ha and Hb upon dilution (i.e., small variability of Ha and
Figure 1. 1H NMR spectrum of 1 in CDCl3 at 240 K.
Figure 2. 2D 1H NMR COSY at 240 K of 1 upon dilution.
Figure 4. DSC of 1 showing the melting/crystallization phenomena (red) and the occasionally observed solid solid transition (blue).
Figure 3. Dimerization modes for 1. 3726
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Figure 5. Hot stage photomicrographs of 1, showing the solid-state phase transition from form I to form II together with melting and crystallization phenomena upon heating at 10 °C/min. Figure 7. Rietveld refinement of form I (figures of merit are given in footnote ). The plot shows the experimental powder XRD profile (red), the calculated powder XRD profile (black), and the difference profile (blue). Tick marks indicate peak positions.
Figure 6. X-ray powder diffraction diagrams of forms I and II.
large upfield shift of H b). All possible forms of 1 in solution are related through a thermodynamic cycle (Figure 3). The observed 1H NMR shifts for Ha, Hb, and Hc together with the concentration and integration values allow the equilibrium constants to be estimated (KCM = 2.5, KCD = 0.56, KDab = 8600 M 1, KDc = 790 M 1).9 The results indicate that, on increasing concentration at 240 K, the preferred selfassociated form of 1 is 1b. Thus, under circumstances in which the mode of solution-state aggregation is translated into the crystal structure, we would anticipate that crystals obtained from a supersaturated solution of 1 would contain the 1b motif. In order to explore this possibility further, crystallization screening was carried out, using different combinations of solvents at several concentrations and temperatures, with variable cooling rates, under both thermodynamic and kinetic conditions. These experiments always yielded the same polymorph (form I, mp = 166 °C). However, DSC10 revealed that a second polymorph (form II, mp =188 °C) crystallizes from the melt of form I. Occasionally, an endothermic solid solid transition was observed by DSC (Figure 4), starting from form I at low heating rate (1 °C/min), revealing an enantiotropic relationship between the two polymorphs, with form I being more stable below the transition temperature (ca. 160 °C). This thermal behavior was corroborated qualitatively by thermomicroscopy.11 When form I is heated, a partial solid solid transition to form II is observed around 168 169 °C.
Simultaneously, the remaining form I melts and form II crystallizes from the melt also around 169 °C. Finally, form II melts with decomposition around 190 °C (Figure 5). Form II could only be obtained by heating form I at 175 °C, and it was characterized by powder X-ray diffraction (Figure 6).12 The crystal structure of form I was determined by singlecrystal XRD using a crystal grown by slow diffusion of toluene into a solution of 1 in DMF at ambient temperature. The crystal had a low diffracting power (attempts of crystallization to obtain better quality single crystals were not successful). This fact together with the kind of detector used (image plate with spindle axis only) enabled crystal structure refinement using only the reflections below θ = 25°. To evaluate the goodness of the single crystal structure determination, a Rietveld refinement of powder diffraction data of form I considering the single crystal structural model was carried out. Figure 7 shows the corresponding Rietveld plot. The good coincidence between the observed and calculated patterns corroborates the crystal structure obtained from single crystal data.13 The crystal structure has a well-defined head-to-tail H-bonding motif between squaramide units [N H 3 3 3 O 2.843(8) Å and 2.848(6) Å] together with secondary π 3 3 3 π stacking (dcentroids 3.851 Å) and aryl C H 3 3 3 N pyridine [2.578(5) Å] interactions (Figure 8b). As single crystals of form II suitable for single-crystal XRD could not be grown, crystal structure determination was instead carried out directly from PXRD data (Figure 9),15 exploiting modern data analysis techniques that have been developed for this purpose19 (in particular, the direct-space strategy for structure solution).20 In the crystal structure 21 of form II, a H-bonded head-to-tail arrangement is again established, with rows of self-associated squaramide molecules running in opposite directions. The most relevant differences compared to form I are that π 3 3 3 π stacking interactions in form I are replaced by edge-to-face C H 3 3 3 π interactions in form II. Furthermore, while the aromatic groups are located on the same side of the squaric ring in form II, they are arranged in a zigzag manner in form I 3727
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Figure 8. Crystal structures and Hirshfeld surfaces of forms I and II.
(Figure 8a). Calculation of Hirshfeld surfaces 22 is a useful way to analyze the intermolecular interactions in molecular crystals. CrystalExplorer 23 was used to generate the Hirshfeld surfaces of forms I and II, highlighting the significant intermolecular contacts. The dominant C O 3 3 3 H N H-bonding interactions that give rise to catemeric assemblies are seen in the Hirshfeld surface plots for both polymorphs (brightest red areas in Figure 8b). However, different secondary interactions are established in each case, corresponding to the structural differences between the two polymorphs. In summary, intensive polymorph screening has resulted in two polymorphs of 1 containing the same catemeric headto-tail motif (based on 1a), with no evidence for any other polymorph with the dimeric motif (1b or 1c). This observation suggests that, although both modes of interaction are significant in low polarity solvents such as chloroform, cooperative H-bonding favors only the formation of clusters with the catemeric motif. Under a broad set of experimental conditions, these catemeric clusters crystallize into different
polymorphs with the same head-to-tail motif. These results may be extrapolated to all disecondary squaramides (on the assumption that other factors do not significantly influence the crystal structure, such as the presence of more strongly competitive H-bonding groups). 6,24 Our results suggest that the cooperative effect in H-bonded catemers 25 is sufficient to offset the interaction energy of discrete H-bonded dimers (1b and 1c) that cannot assemble into catemeric structures. On the basis of the dimerization constants determined for 1a (i.e., containing a head-to-tail motif) and 1b, the difference in binding energy for the two types of dimer is estimated to be ca. 3 kJ mol 1 (i.e., 1.5 kJ mol 1 per H-bond), which may be interpreted (in the absence of other influences on crystal packing) in terms of the solid-state cooperative effect being at least 1.5 kJ mol 1 per H-bond. This preferred cooperative self-associating interaction in the solid state may be used in synthetic design strategies for obtaining new cocrystals, as the catemer can act as an effective template with suitable cocrystal formers. Further cocrystallization experiments to explore this issue are in progress. 3728
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Figure 9. Results from powder XRD analysis of form II: (a) Le Bail refinement and (b) final Rietveld refinement (figures of merit are given in footnote ). Each plot shows the experimental powder XRD profile (red + marks), the calculated powder XRD profile (green solid line), and the difference profile (purple, lower line). Tick marks indicate peak positions. More detailed analysis of the Rietveld refinement suggests that the discrepancies in the difference profile in part b originate primarily from a small degree of conformational disorder concerning the orientations of the pyridyl rings.
’ ASSOCIATED CONTENT
bS
Supporting Information. Experimental conditions for the polymorph screening and CIF files. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Authors
*E-mail:
[email protected];
[email protected];
[email protected]; HarrisKDM@cardiff.ac.uk.
’ ACKNOWLEDGMENT We thank Dr. M. A. Molins for the NMR experiments. ’ REFERENCES (1) (a) Hunter, C. A.; Anderson, H. L. Angew. Chem., Int. Ed. 2009, 48, 7488. (b) Vishweshwar, P.; Nangia, A.; Lynch, V. M. Chem. Commun. 2001, 179. (2) Welch, G. W. A.; Karamertzanis, P. G.; Misquitta, A. J.; Stone, A. J.; Price, S. L. J. Chem. Theory Comput. 2008, 4, 522. (3) Kobko, N.; Paraskevas, L.; del Rio, E.; Dannenberg, J. J. J. Am. Chem. Soc. 2001, 123, 4348. (4) Dannenberg, J. J. Adv. Protein Chem. 2005, 72, 227. (5) (a) Musumeci, D.; Hunter, C. A.; McCabe, J. F. Cryst. Growth Des. 2010, 10, 1661. (b) Davey, R. J.; Allen, K.; Blagden, N.; Cross, W. I.; Lieberman, H. F.; Quayle, M. J.; Righini, S.; Seton, L.; Tiddy, G. J. T. CrystEngComm 2002, 4, 257.
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(6) Portell, A.; Barbas, R.; Braga, D.; Polito, M.; Puigjaner, C.; Prohens, R. CrystEngComm 2009, 11, 52. (7) Prohens, R. Ph.D. Thesis. (8) NMR experiments were run on a Bruker DMX500 instrument equipped with an indirect 1H 13C detection probe with gradients along the z axis. A standard sequence from Bruker software was used for COSY experiments (cosygpqf); a total of 128 increments, 4 scans each, were collected. (9) The conformational equilibrium constant of the monomer KCM was calculated as the ratio of the relevant integrals at the lowest concentration, for which >95% of 1 is monomeric. Dimerization constants were calculated from the variation in chemical shift with concentration using the program NMRDil_Dimer (Bisson, A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger, R. C.; Hunter, C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger, C.; Rowan, A. E. J. Am. Chem. Soc. 2000, 122, 8856). The conformational equilibrium constant of the dimer KCD was calculated from the other three constants: KCD = (KCM)2KDc/KDab. (10) Differential scanning calorimetry was carried out by means of a Mettler-Toledo DSC-822e calorimeter with aluminium crucibles of 40 μL volume, an atmosphere of dry nitrogen with a 50 mL/min flow rate, and heating rates of 1 °C/min and 10 °C/min. The calorimeter was calibrated with indium of 99.99% purity. (11) A Nikon polarization microscope (Nikon Eclipse 50i) equipped with a Linkam LTS350 hot stage and digital video recorder facilities was used. (12) Powder X-ray diffraction patterns (PXRD) were obtained on a PANalytical X’Pert PRO MPD diffractometer with Cu KR radiation (λ = 1.5418 Å), in transmission geometry with the samples introduced in glass capillaries of 0.5 mm diameter, using an incident beam elliptic focalizing mirror and a PIXcel detector with an active detection length of 3.347°. The analyzed samples were scanned from 2 to 70° in 2θ with a step size of 0.013° and a total measuring time of 18 h. (13) Crystal structure of form I. A prismatic crystal (0.19 0.18 0.09 mm3) was selected and mounted on a MAR345 diffractometer with an image plate detector with a spindle axis only. Intensities were collected with graphite monochromatized Mo KR radiation. Monoclinic Pc; a = 4.358(5) Å, b = 29.45(3) Å, c = 6.076(5) Å, β = 110.62(8)°; V = 729.8(12) Å3; Z = 2; F(calc) = 1.339 g cm 3; 2θmax = 31.86°; 5 e h e 5, 39 e k e 39, 7 e l e 7; λ = 0.71073 Å; T = 293 K; no. reflections = 3800 [2185 independent; R(int) = 0.053]; restraints/parameters = 2/199; full-matrix least-squares refinement on F2; R-factor (on F) = 0.070, wR (on |F|2) = 0.209; goodness of fit = 1.170 for all observed reflections. Max. and min peaks in final difference map, 0.269 and 0.142 e Å 3. Rietveld refinement was done using the Fullprof program.14 Figures of merit: Rwp = 4.30%, Rp = 6.48%. CCDC 805689 contains the crystallographic data. (14) Rodriguez-Carvajal, J. Physica B 1993, 192, 55. (15) Powder XRD data for form II were recorded at ambient temperature on a Bruker D8 diffractometer (transmission; Ge-monochromated Cu KR1; λ = 1.5406 Å; Vantec detector covering 12° in 2θ; 2θ range, 4° 70°; step size, 0.017°; data collection time, 16 h). After indexing using DICVOL0416 and space group assignment, the structure was solved using the direct-space genetic algorithm program EAGER,17 followed by Rietveld refinement using GSAS.18 (16) Boultif, A.; Lou€er, D. J. Appl. Crystallogr. 2004, 37, 724. (17) (a) Harris, K. D. M.; Habershon, S.; Cheung, E. Y.; Johnston, R. L. Z. Kristallogr. 2004, 219, 838. (b) Fujii, K.; Young, M. T.; Harris, K. D. M. J. Struct. Biol. 2011, 174, 461. (18) Larson, A. C.; Von Dreele, R. B. GSAS, Los Alamos Laboratory Report No. LA-UR-86-748; 1987. (19) (a) Harris, K. D. M. Cryst. Growth Des. 2003, 3, 887. (b) Guo, F.; Harris, K. D. M. J. Am. Chem. Soc. 2005, 127, 7314. (c) Harris, K. D. M.; Cheung, E. Y. Chem. Soc. Rev. 2004, 33, 526. (d) David, W. I. F.; Shankland, K. Acta Crystallogr. 2008, A64, 52. (20) Harris, K. D. M.; Tremayne, M.; Lightfoot, P.; Bruce, P. G. J. Am. Chem. Soc. 1994, 116, 3543. (21) Crystal structure of form II: triclinic; a = 6.0343(3) Å, b = 10.9211(5) Å, c = 11.9179(6) Å, R = 93.020(3)°, β = 103.176(3)°, 3729
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γ = 92.478(3)°; V = 762.42(8) Å3; Z = 2; 2θ range, 4.17 70.00°; 3868 profile points; 167 refined variables; Rwp = 7.57%, Rp = 5.27% (compared to Le Bail fit: Rwp = 4.82%, Rp = 3.55%). (22) (a) Spackman, M. A.; McKinnon, J. J. CrystEngComm 2002, 4, 378. (b) Jha, S.; Silversides, J. D.; Boyle, R. W.; Archibald, S. J. CrystEngComm 2010, 12, 1730. (c) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Chem. Commun. 2007, 3814. (d) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Acta Crystallogr. 2004, B60, 627. (23) Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer v2.1; University of Western Australia: Perth, Australia, 2007. (24) Rotger, C.; Soberats, B.; Qui~nonero, D.; Frontera, A.; Ballester, P.; Benet-Buchholz, J.; Deya, P. M.; Costa, A. Eur. J. Org. Chem. 2008, 1864. (25) Masunov, A.; Dannenberg, J. J. J. Phys. Chem. B 2000, 104, 806.
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