Obtaining Synthon Modularity in Ternary Cocrystals with Hydrogen

Article pubs.acs.org/crystal

Obtaining Synthon Modularity in Ternary Cocrystals with Hydrogen Bonds and Halogen Bonds Srinu Tothadi, Palash Sanphui, and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India S Supporting Information *

ABSTRACT: Design of ternary cocrystals based on synthon modularity is described. The strategy is based on the idea of extending synthon modularity in binary cocrystals of 4hydroxybenzamide:dicarboxylic acids and 4-bromobenzamide:dicarboxylic acids. If a system contains an amide group along with other functional groups, one of which is a carboxylic acid group, the amide associates preferentially with the carboxylic acid group to form an acid−amide heterosynthon. If the amide and the acid groups are in different molecules, a higher multicomponent molecular crystal is obtained. This is a stable pattern that can be used to increase the number of components from two to three in a multicomponent system. Accordingly, noncovalent interactions are controlled in the design of ternary cocrystals in a more predictable manner. If a single component crystal with the amide−amide dimer is considered, modularity is retained even after formation of a binary cocrystal with acid−amide dimers. Similarly, when third component halogen atom containing molecules are introduced into these binary cocrystals, modularity is still retained. Here, we use acid−amide and Br/I··· O2N supramolecular synthons to obtain modularity in nine ternary cocrystals. The acid−amide heterosynthon is robust to all the nine cocrystals. Heterosynthons may assist ternary cocrystal formation when there is a high solubility difference between the coformers. For a successful crystal engineering strategy for ternary cocrystals, one must consider the synthon itself and factors like shape and size of the component molecules, as well as the solubilities of the compounds.

■

INTRODUCTION When molecular functionalities, supramolecular synthons, and crystal packing features present in some structures occur repetitively in other structures, synthon modularity is obtained.1 There are many design strategies for binary cocrystals as seen from the literature.2 A ternary cocrystal contains three different neutral solid compounds in a definite stoichiometric ratio.3 However, both design and isolation of ternary cocrystals are challenging. This is because most crystallization experiments involving three components generally lead to single-component crystals or to polymorphs and hydrates/solvates of a single component or binary cocrystals.3 Ternary cocrystals are seldom if ever obtained. If specific interactions can be controlled, a binary cocrystal may be possible. Aakeröy et al. made ternary cocrystals based on hydrogen bond hierarchy;4 the strongest acid prefers the strongest base, followed by the next strongest acid to the next strongest base. 3,5-Dinitrobenzoic acid, isonicotinamide, and other acids were used for this purpose.5 Here the strongest acid−base pair was acid−pyridine, the acid being 3,5-dinitrobenzoic acid and the pyridine fragment being obtained from isonicotinamide. The strength of another acid was tuned accordingly via the acid−amide heterosynthon, leading to the successful isolation of ternary cocrystals. A similar strategy was also implemented with pyridyl and benzimidazolyl containing molecules.6 Ternary cocrystals were prepared with 1,3,5-cyclohexanetricarboxylic acid and a mixture of bipyridines by Nangia and co-workers.7 These are chemical approaches. Recently, chemical (intermolecular © XXXX American Chemical Society

interactions) and geometrical (size and shape) arguments were used, in our group, to obtain ternary cocrystals.8 A 2:3 binary cocrystal of 2-methylresorcinol and 4,4′-bipyridine was used as a model for the design of the target ternary cocrystal. Two bipyridine molecules are hydrogen bonded to 2methylresorcinol, and the third molecule is free to be substituted with molecules of similar shape and size, such as biphenyl, bithiophene, and pyrene, resulting in threecomponent solids. We have also designed ternary cocrystals based on interaction mimicry.9 Recently, Aitipamula et al. made isostructural ternary cocrystals of isoniazid:4-hydroxybenzoic acid:fumaric acid and isoniazid:4-hydroxybenzoic acid:succinic acid.10 Seaton et al. reported ternary cocrystals by exploiting charge-transfer interactions between 3,5-dinitrobenzoic acid and 4,4′-bipyridine pairing with a series of amino-substituted aromatic compounds.11 All these structures consist of only hydrogen bonds. Very recently our group has reported ternary cocrystals of 4,4′-bis-hydroxyazobenzene using weak C−H···N hydrogen bonds.12 Halogen bonding13 has gained considerable importance in the context of crystal engineering.14 Except for the size of atoms involved in halogen bonding, halogen bonds are similar to hydrogen bonds in terms of strength and directionality.15 Synthon modularity is one of the fine tools that is available to Received: July 24, 2014 Revised: August 22, 2014

A

dx.doi.org/10.1021/cg501115k | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Scheme 1. Design of Ternary Cocrystals with Hydrogen Bonds and Halogen Bonds

the crystal engineer.1,16 Synthons, which bear both chemical and geometrical information, are formed at the earliest stages of crystallization and are carried over until crystal nucleation.17 Formation of synthons leads to optimization of other weak intermolecular interactions, which direct the ultimate crystal packing.18 There are recent reports related to the design of binary cocrystals based on a combined use of halogen bonding and hydrogen bonding.16,19 Recently, three ternary cocrystals, which contain hydrogen bonds and halogen bonds, have been reported from our group.3 In this article, we show the generality of this strategy that uses the concept of synthon modularity. Nine new ternary cocrystals are reported. Among them, five have only hydrogen bonded synthons and the remaining four structures consist of both hydrogen and halogen bonds.

■

a minimum amount of THF. Good quality crystals, suitable for diffraction, were obtained after 1 week. 4-Hydroxybenzamide:Succinic Acid:Phenazine:H2O (2:1:2:2) Cocrystal Hydrate, 4. 4-Hydroxybenzamide, succinic acid, and phenazine were taken in a 2:1:1 mmol ratio and ground in a mortar with a pestle after adding 2−3 drops of EtOH. The ground sample was dissolved in a minimum amount of THF. Good quality crystals, suitable for diffraction, were obtained after 4 days. 4-Hydroxybenzamide:Adipic Acid:Phenazine (2:2:2) Cocrystal, 5. 4-Hydroxybenzamide, adipic acid, and phenazine were taken in a 2:1:1 mmol ratio and ground in a mortar with a pestle after adding 2−3 drops of EtOH. The ground sample was dissolved in a minimum amount of THF. Good quality crystals, suitable for diffraction, were obtained after 5 days. 4-Iodobenzamide:Oxalic Acid:1,4-Dinitrobenzene (2:1:1) Cocrystal, 6. 4-Iodobenzamide, oxalic acid, and 1,4-dinitrobenzene were taken in a 2:1:1 molar ratio and ground after adding 2−3 drops of EtOH. The ground sample was dissolved in MeOH. Good quality crystals, suitable for diffraction, were obtained after 4 days. 4-Bromobenzamide:1,4-Dinitrobenzene (1:1) Cocrystal, 7. 4Bromobenzamide and 1,4-dinitrobenzene were taken in a 2:1 molar ratio and ground after adding 2−3 drops of EtOH. The ground sample was dissolved in THF. Good quality crystals, suitable for diffraction, were obtained after 4 days. 1,4-Dibromobenzene:1,4-Dinitrobenzene (1:1) Cocrystal, 8. 1,4Bibromobenzene and 1,4-dinitrobenzene were taken in a 2:1 molar ratio and ground after adding 2−3 drops of EtOH. The ground sample was dissolved in THF. Good quality crystals, suitable for diffraction, were obtained after 5 days. 4-Bromobenzamide:Fumaric Acid:1,4-Dinitrobenzene (2:1:1) Cocrystal, 9. 4-Bromobenzamide, fumaric acid, and 1,4-dinitrobenzene were taken in a 2:1:1 molar ratio and ground after adding 2−3 drops of EtOH. The ground sample was dissolved in THF. Good quality crystals, suitable for diffraction, were obtained after 4 days. 4-Bromobenzamide:Succinic Acid:1,4-Dinitrobenzene (2:1:1) Cocrystal, 10. 4-Bromobenzamide, succinic acid, and 1,4-dinitrobenzene were taken in a 2:1:1 molar ratio and ground after adding 2−3 drops of EtOH. The ground sample was dissolved in a 1:1 mixture of MeOH/EtOAc. Good quality crystals, suitable for diffraction, were obtained after 4 days. 4-Bromobenzamide:Glutaric Acid:1,4-Dinitrobenzene (2:2:1) Cocrystal, 11. 4-Bromobenzamide, glutaric acid and 1,4-dinitrobenzene were taken in a 2:1:1 molar ratio and ground after adding 2−3 drops of EtOH. The ground sample was dissolved in a 1:1 mixture of MeOH/EtOAc. Good quality crystals, suitable for diffraction, were obtained after 4 days.

EXPERIMENTAL SECTION

Single Crystal X-ray Crystallography. Single crystal X-ray data for two binary and nine ternary cocrystals were collected on a Rigaku Mercury375/M CCD (XtaLAB mini) diffractometer using graphite monochromated Mo−Kα radiation at 150 K. The data were processed with the Rigaku Crystal clear software.20 Refinement of coordinates and anisotropic thermal parameters of nonhydrogen atoms were performed with the full-matrix least-squares method.21 The different treatment of H atoms in any structure depends on the data quality. Most of the hydrogen atoms are located from difference Fourier maps. In some cases H atom positions were calculated using the riding model. PLATON22 was used to prepare material for publication, and Mercury version 3.3 was utilized for molecular representations and packing diagrams. Cambridge Structural Database (CSD) Analysis Criteria. CSD structural data analysis was carried out with version 5.35 (November 2013, February 2014 update). The analysis was confined to purely organic compounds. The geometrical parameters and constraints were given using ConQuest 1.16. Unique intermolecular interactions were considered with longer and shorter Br···O2N nonbonded interactions, D1 and D2. As a reference 3.2 < D1 < 6.0 Å and 2.8 < D2 < 4.0 Å. For I···O2N, 3.2 < D1 < 7.5 Å and 2.8 < D2 < 4.5 Å Crystallization. 4-Hydroxybenzamide:Fumaric Acid:Pyrazine (2:1:1) Cocrystal, 1. 4-Hydroxybenzamide, fumaric acid, and pyrazine were taken in a 2:1:1 mmol ratio and ground in a mortar with a pestle after adding 2−3 drops of EtOH (solvent drop grinding23). The ground sample was dissolved in a minimum amount of EtOAc. Good quality crystals, suitable for diffraction, were obtained after 1 week. 4-Hydroxybenzamide:Succinic Acid:Pyrazine (2:1:1) Cocrystal, 2. 4-Hydroxybenzamide, succinic acid and pyrazine were taken in a 2:1:1 mmol ratio and ground in a mortar with a pestle after adding 2−3 drops of EtOH. The ground sample was dissolved in a minimum amount of MeOH. Good quality crystals were obtained after 1 week. 4-Hydroxybenzamide:Fumaric Acid:Phenazine:H2O (2:1:2:2) Cocrystal Hydrate, 3. 4-Hydroxybenzamide, fumaric acid, and phenazine were taken in a 2:1:1 mmol ratio and ground in a mortar with a pestle after adding 2−3 drops of EtOH. The ground sample was dissolved in

■

RESULTS AND DISCUSSION Design of Ternary Cocrystals Using Only Hydrogen Bonds. The basic strategy is that if the molecule contains an amide functional group along with other groups, it will preferably form the acid−amide heterosynthon when a dicarboxylic acid is added to the system. Other synthons are retained as such so that higher multicomponent molecular B



Article

Table 1. Crystallographic Parameters of Two Binary (2) and Ternary Cocrystals (9) in This Studya formula

HBZ:FA:PYZ, 1

HBZ:SA:PYZ, 2

(C7H7NO2) 0.5(C4H4O4) 0.5(C4H4N2) 235.22 triclinic P1̅ 5.896(4) 7.051(3) 13.503(8) 103.585(17) 93.612(15) 100.05(2) 534.1(5) 2 1.463 246.0 0.113 150 5629 2431 2148

(C7H7NO2) 0.5(C4H6O4) 0.5(C4H4N2) 236.23 triclinic P1̅ 6.078(16) 7.006(17) 13.49(4) 102.75(6) 92.91(11) 101.45(8) 546(3) 2 1.437 248.0 0.111 150 5430 2468 1239

formula weight crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z ρcalc (g cm−3) F(000) μ(mm−1) temp (K) total ref. unique ref. observed ref (I > 2σ(I)) R 0.0583 wR2 0.1650 S 1.065 CCDC Nos. 1015437 IBZ:OA:DNBZ, 6 (C6H4N2O4) (C2H2O) 2(C7H6INO) 752.20 monoclinic P21/c 13.891(2) 9.9912(15) 9.4857(14) 90 107.775(8) 90 1253.7(3) 2 1.993 728 2.573 150 12430 2864 2438 0.0608 0.1458 1.158 1015442

0.0846 0.3051 0.955 1015438 BRBZ:DNBZ, 7 DBRBZ:DNBZ, 8 2(C7H4Br N2O0.65) (C6H4N2O4) 571.11 monoclinic C2/m 9.0424(18) 9.787(2) 11.590(2) 90 90.054(6) 90 1025.7(3) 2 1.859 566.0 4.000 150 5153 1243 1100 0.0380 0.0975 1. 089 1015443

(C6H4Br2) (C6H4N2O4) 404.00 monoclinic C2/m 9.273(3) 9.716(3) 7.447(2) 90 92.109(7) 90 670.5(3) 2 2.001 392.0 6.059 150 3003 810 796 0.0877 0.0369 1.104 1015444

HBZ:FA:PHZE:H2O, 3

HBZ:SA:PHZE:H2O, 4

(C7H7NO2) 0.5(C4H4O4) (C12H8N2) H2O 393.39 monoclinic P21/c 24.541(8) 4.9496(12) 16.011(5) 90 107.800(13) 90 1851.7(10) 4 1.411 824.0 0.103 150 17984 4250 3349

(C12H8N2) 0.5(C4H6O4) (C7H6NO2) H2O 394.40 monoclinic P21/c 24.275(6) 5.0420(9) 16.045(4) 90 107.634(11) 90 1871.5(7) 4 1.400 828.0 0.102 150 18139 4311 3135

0.0632 0.1734 1.135 1015439 BRBZ:FA:DNBZ, 9

0.0719 0.2239 1.167 1015440 BRBZ:SA:DNBZ, 10

2(C7H6BrNO) (C4H4O4) C6H4N2O4 684.24 monoclinic P21/c 14.2552(16) 9.8264(11) 9.2969(11) 90 101.639(7) 90 1275.5(3) 2 1.782 684.0 3.244 150 9978 2926 1961 0.0466 0.0946 1.039 1015445

2(C7H6BrNO) (C4H6O4) (C6H4N2O4) 686.26 triclinic P1̅ 6.5176(8) 7.0831(9) 14.544(2) 96.138(8) 102.735(5) 92.629(6) 649.48(15) 1 1.755 344.0 3.186 150 6225 2973 2480 0.0499 0.1316 0.993 1015446

HBZ:AA:PHZE, 5 (C12H8N2) (C6H10O4) (C7H7NO2) 463.48 triclinic P1̅ 9.269(4) 14.626(5) 18.187(7) 105.186(10) 103.667(18) 90.30(2) 2306.2(16) 4 1.316 962.0 0.097 150 23006 10567 7592 0.1169 0.3682 1.077 1015441 BRBZ:GA:DNBZ, 11 2(C7H6BrNO) 2(C5H8O4) (C6H4N2O4) 832.40 monoclinic P21/c 17.7724(15) 9.9963(9) 9.3801(8) 90 95.898(7) 90 1657.6(2) 2 1.667 844.0 2.521 150 17237 3798 3332 0.0347 0.0994 1.135 1015447

a

Note: HBZ, 4-hydroxybenzamide; FA, fumaric acid; PYR, pyrazine; SA, succinic acid; PHZE, phenazine; AA, adipic acid; IBZ, 4-iodobenzamide; OA, oxalic acid; DNBZ, 1,4-ditrobenzamide; BRBZ, 4-bromobenzamide; DBRBZ, 1,4-dibromobenzene; GA, glutaric acid.

crystals are obtained with the same modularity as that of the native crystal structure. Once the binary cocrystal is formed, the next higher chemical component crystal (ternary) is obtained by adding a suitable compound, which can break the weak intermolecular interaction in the binary system (Scheme 1). Even in ternary cocrystals, some kind of modularity with respect to the single component and the binary can be seen.

The crystallographic parameters for the newly designed cocrystals are summarized in Table 1. 4-Hydroxybenzamide:Fumaric Acid:Pyrazine (2:1:1) Cocrystal, 1. The crystal structure takes the space group P1̅ with one molecule of 4-hydroxybenzamide and a half molecule each of fumaric acid and pyrazine present in the asymmetric unit. The acid and amide molecules are connected by robust acid− amide heterosynthons. 4-Hydroxybenzamide is hydrogen C



Article

Figure 1. Ternary cocrystal of 4-hydroxybenzamide:fumaric acid:pyrazine, (2:1:1), 1. Notice that the crystal structure is stabilized by acid−amide and hydroxyl−pyrazine heterosynthons.

Figure 2. Ternary cocrystal of 4-hydroxybenzamide:succinic acid:pyrazine (2:1:1), 2. Notice that the crystal structure is stabilized by acid−amide and hydroxyl−pyrazine heterosynthons.

4-Hydroxybenzamide:Fumaric Acid:Phenazine:H2O Cocrystal Hydrate (2:1:2:2), 3. The structure takes the space group P21/c with one molecule each of 4-hydroxybenzamide, phenazine, and H2O and a half molecule of the fumaric acid in the asymmetric unit. The acid−amide heterosynthon is observed as predicted. The structure is similar to the other two ternary cocrystals but differs at the hydroxyl part of the amide. The water molecule intercedes between phenazine and 4-hydroxybenzamide (Figure 3). Two consecutive heptameric aggregates, containing phenazine, water, amide, and acid, are arranged in AA′AA′ fashion along the a-axis. If the water molecule is excluded, the arrangements of molecules in the pentameric aggregates are similar to those seen in the other ternary cocrystals. 4-Hydroxybenzamide:Succinic Acid:Phenazine:H2O Cocrystal Hydrate (2:1:2:2), 4. The structure takes the space group P21/c, with one molecule each of 4-hydroxybenzamide, phenazine , and H2O and a half molecule of succinic acid in the

bonded to pyrazine via O−H···N (D = 2.762 Å) synthon (Figure 1). The hydroxyamide−acid−pyrazine aggregate is further connected by (anti) N−H···O hydrogen bonds (D1 = 3.103 Å; D2= 3.173 Å) at the N atom of the amide. The 2D packing gives the impression that the acid and pyrazine have been inserted on either side of 4-hydroxybenzamide in its second polymorph.1 It is interesting to note here that although the formation of the acid−pyridine synthon is favorable, O− H···N and the acid−amide synthons are obtained instead. 4-Hydroxybenzamide:Succinic Acid:Pyrazine (2:1:1) Cocrystal, 2. The structure is isostructural with ternary cocrystal 1. The structure takes the space group P1̅ with one molecule of 4hydroxybenzamide and a half molecule each of succinic acid and pyrazine in the asymmetric unit. The hydroxyamide, acid, and pyrazine molecules are assembled via acid−amide and the O−H···N (D = 2.805 Å) heterosynthons (Figure 2). The hydroxyamide−acid−pyrazine aggregate is further extended by (anti) N−H···O hydrogen bonds (D = 3.309 Å.). D



Article

Figure 3. Hydrogen bonding in ternary cocrystal of 4-hydroxybenzamide:fumaric acid:phenazine:H2O (2:1:2:2), 3. Notice water molecules act as spacers to interrupt the phenol···phenazine synthon.

Figure 4. Ternary cocrystal of 4-hydroxybenzamide:succinic acid:phenazine:H2O (2:1:2:2), 4. Note the connection role of the water molecules.

asymmetric unit. In all aspects such as packing, hydrogen bonding, and water insertion, cocrystals 4 (Figure 4) and 5 (Figure 5) are isostructural. Replacement of fumaric acid with succinic acid was reported in many cocrystals.1,16,24 So, the design protocol for ternary cocrystals based on binary cocrystals is once again validated. 4-Hydroxybenzamide:Adipic Acid:Phenazine (2:2:2) Cocrystal, 5. The structure takes the space group P1̅, with two molecules each of 4-hydroxybenzamide, adipic acid, and phenazine in the asymmetric unit. For diacids, one side of the molecule is connected by the robust acid−amide heterosynthon, and the other side is involved in O−H···O, O···H−N, and O···H−C hydrogen bonds. The structure still follows the design strategy but only on one side: diacid molecules are inserted in the amide−amide homodimers of 4hydroxybenzamide. In all these five ternary cocrystals, diacids are inserted between the amide−amide homodimer to form the acid−amide heterosynthon. Pyrazine and phenazine molecules are inserted in the O−H···O−H···O−H··· infinite synthon to give the O− H···N synthon. Water molecules appear in between the O−H··· N synthon in cocrystals of phenazine with 4-hydroxybenzamide

Figure 5. Hydrogen bonds in ternary cocrystal of 4-hydroxybenzamide:adipic acid:phenazine (2:2:2), 5. Notice the anti-OH carboxylic acid group.

and diacids to form the O−H···O and O−H···N synthon. In 4hydroxybenzamide:adipic acid:phenazine cocrystal, the design strategy is followed only on one side of the diacid because, on E



Article

Figure 6. The 2:1:1 ternary cocrystal of 4-iodobenzamide:oxalic acid:1,4-dinitrobenzene, 6. Molecules are stabilized by acid−amide heterosynthons and I···O2N halogen bonds.

Figure 7. Binary cocrystal of 4-bromobenzamide:1,4-dinitrobenzene, 7. Notice the amide−amide homodimer and the Br···O2N synthons. The amide group is disordered with s.o.f. of O being 0.65:0.35 and N being 0.52:0.48.

the other side of the acid, the OH group is anti to the carbonyl group (not so common) and hence is unlikely to form an acid− amide heterosynthon. Design of Binary and Ternary Cocrystals Using Combination of Hydrogen and Halogen Bonds. Desiraju and co-workers have previously illustrated the importance of the I···O2N synthon in the crystal design of 1,4-diiodobenzene and 1,4-dinitrobenzene cocrystal.25 The I···O2N interactions in this synthon are classical halogen bonds. Pedireddi and coworkers reported a predictable I···O2N synthon in 3,5dinitrobenzoic acid:1,4-diiodobenzene complex.26 Nangia and co-workers showed that the I···O2N synthon is stable enough to prevent synthon crossover in carboxylic acid, pyridine, iodo, and nitro groups.19a Recently, the importance of the I···O2N synthon in ternary cocrystals has been shown.3 With this background, a few more ternary cocrystals have been designed. Synthon modularity in the binary crystal structures was assessed at the beginning. Later, the strategy was used in the design of ternary cocrystals. Ternary Cocrystals with Acid−Amide and I···O2N Synthons. Ternary Cocrystal with 4-Iodobenzamide, Diacid, and Dinitrobenzene (2:1:1), 6. A (2:1:1) 4-iodobenzamide:oxalic acid:1,4-dinitrobenzene (6) ternary cocrystal was obtained in the space group P2 1 /c, with one molecule of 4iodobenzamide and a half molecule each of oxalic acid and 1,4-dinitrobenzene in the asymmetric unit. Oxalic acid is inserted between the homodimer of 4-iodobenzamide (Figure 6). Molecules are stabilized by the acid−amide heterosynthon

and by the I···O2N halogen bond. This ternary cocrystal is isostructural with the reported 4-nitrobenzamide:oxalic acid:1,4-diiodobenzene ternary cocrystal. Binary Cocrystals with Amide−Amide and Br···O2N Synthons. Earlier, the Br···O2N synthon was studied in 4bromo-4-nitrostyrene by Desiraju and co-workers.27 Recently, Ng and co-workers reported the Br···O2N synthon in 4-bromo1-nitrobenzene.28 Aakeröy and co-workers obtained the Br··· O2N synthon in 2-amino-5-bromopyridinium:4-nitrobenzoate salt.29 In the CSD (version 5.35, November 2013, Feb 2014 update), Br···O2N interactions are present in 226 crystal structures of which 21 are binary cocrystals. Like the earlier study, which involves I···O2N synthons, the present study began with the synthesis of binary cocrystals of 4bromobenzamide:1,4-dinitrobenzene and 1,4-dibromobenzene:1,4-dinitrobenzene. Later, by using the proposed design strategy, ternary cocrystals were prepared. 4-Bromobenzamide:1,4-Dinitrobenzene, 7. This structure takes the space group C2/m, with one molecule each of 4bromobenzamide and 1,4-dinitrobenzene in the asymmetric unit. Packing is stabilized by the amide−amide homosynthon and Br···O2N halogen bonds (D = 3.269 Å). Two consecutive layers AA′AA′ are further supported by auxiliary C−H···O hydrogen bonds along the b-axis (Figure 7). 1,4-Dibromobenzene:1,4-Dinitrobenzene, 8. This structure takes the space group C2/m, with one molecule each of 1,4dibromobenzene and 1,4-dinitrobenzene in the asymmetric unit. The packing is stabilized by Br···O2N synthons (D = 3.380 F



Article

Figure 8. The 1:1 binary cocrystal of 1,4-dinitrobenzene:1,4-dibromobenzene, 8. Notice the Br···O2N synthons.

Figure 9. Hydrogen bonding in (2:1:1) ternary cocrystal of 4-bromobenzamide:fumaric acid:1,4-dinitrobenzene, 9. Notice the acid−amide heterosynthon and the P-type Br···O2N synthon.30

Figure 10. The 2:1:1 ternary cocrystal of 4-bromobenzamide:succinic acid:1,4-dinitrobenzene, 10. Notice the acid−amide heterosynthon and the Qtype Br···O2N synthon.30

group P21/c, with one molecule of 4-bromobenzamide and a half molecule each of fumaric acid and 1,4-dinitrobenzene in the asymmetric unit. Similarly, when succinic acid was taken, a (2:1:1) ternary cocrystal of 4-bromobenzamide:succinic acid:1,4-dinitrobenzene, 10 (Figure 10), was obtained. Cocrystal 10 was refined in the space group P1̅ with one molecule of 4-bromobenzamide and a half molecule each of fumaric acid and 1,4-dinitrobenzene in the asymmetric unit. A 2:2:1 ternary cocrystal of 4-bromobenzamide:glutaric acid:1,4dinitrobenzene, 11(Figure 11), was obtained in the P21/c space group with a half molecule of 1,4-dinitrobenzene and one molecule each of 4-bromobenzamide and glutaric acid.

Å). Two consecutive layers AA′AA′ are further supported by C−H···O hydrogen bonds along the b-axis (Figure 8). Cocrystals 7 and 8 are isostructural. Ternary Cocrystals with Acid−Amide and Br···O2N Synthons. On the basis of synthon modularity, similar crystal packing can be observed in the binary cocrystals of 4nitrobenzamide:1,4-diiodobenzene, 4-iodobenzamide:1,4-dinitrobenzene, and 4-bromobenzamide:1,4-dinitrobenzene, 7. Ternary cocrystals can be designed by inserting dicarboxylic acids in 7. A (2:1:1) ternary cocrystal of 4-bromobenzamide:fumaric acid:1,4-dinitrobenzene, 9 (Figure 9), was obtained by the insertion of fumaric acid between the amide−amide homosynthon of 7. Cocrystal 9 was obtained in the space G



Article

Figure 11. The 2:2:1 ternary cocrystal of 4-bromobenzamide:glutaric acid:1,4-dinitrobenzene, 11. Notice the acid−amide heterosynthon and the acid−acid homodimer in the same crystal structure. The Q-type Br···O2N synthon is seen.

Figure 12. Probability of P, Q, and R bromo/iodo···nitro synthons. The analysis was carried out with CSD version 5.35, November 2013, Feb 2014 update.

unsymmetrical (Q), and sidewise (R) (Figure 12).30 This could be due to a balance achieved between the δ+ polarization of iodine/bromine and its size in the three cases different. Formation of the two-point synthon (P) is facilitated by space filling factors and polarizability. P and Q synthons were

Interestingly, along with the predicted acid−amide heterosynthon, the acid−acid homodimer is also seen. Different Approach of Atoms in the Br/I···O2N Synthons. The iodine/bromine atoms can approach the nitro group in three different ways, namely, symmetrical (P), H



■

Article

CONCLUSIONS Many issues follow from this study. A systematic approach to interaction selection allows for the designed synthesis of nine ternary cocrystals. Cocrystal architecture is based on a purely supramolecular synthon approach. Halogen bonds of suitable strength and directionality are used with hydrogen bonds in the design of ternary cocrystals. In general, the success rate in the design of binary cocrystals can be quite high because there are only two different chemical units involved, and there is less variability in terms of possible interactions. However, in the design of ternary cocrystals, three different chemical units (and also chemical and geometrical factors) need to be controlled, and sometimes binary cocrystals would be obtained. Hence, getting ternary cocrystals with modularity and robustness may be considered to be a success. On the basis of the idea of synthon modularity, ternary cocrystals that consist only of hydrogen bonds or combinations of hydrogen and halogen bonds have been obtained. The acid−amide heterosynthon is common to all the crystal structures. In order to obtain ternary cocrystals with only hydrogen bonds, diacids are first inserted between the zigzag amide−amide catemer of 4-hydroxybenzamide. Later, pyrazine and phenazine are introduced in the O− H···O−H···O−H infinite synthons. Ternary cocrystals with hydrogen and halogen bonds are obtained when 4-halogen/ nitro-substituted amide interact with diacids to form amide− amide dimers. 1,4-Disubstituted halogen/NO2 benzene are used to introduce I···O2N and Br···O2N supramolecular synthons. P or Q synthon types were observed in these halogen bond-containing cocrystals. Eleven cocrystals including nine ternary systems have been successfully obtained, and hence, the proposed design strategy appears to be valid for binary and ternary cocrystals in a general sense.

observed in the present study. In the binary cocrystals (7 and 8) and ternary cocrystals (6 and 9), the symmetrical approach (P) is observed. The two ternary cocrystals (10 and 11) have the unsymmetrical approach (Q). However, we did not observe the R type halo···nitro synthon in these cocrystals. Recently, we have studied P, Q, and R synthons using IR spectroscopy where it was noted that there is a chemical and geometrical distinction between these three synthons types.31 Solubility Issue. Criteria for cocrystal formation include comparable solubility, stable synthons, and shape/size mimicry among the coformers.32 The path toward cocrystallization may depend on the difference in solubility of the coformers in a certain solvent. Let us suppose that the lower the solubility difference between the coformers, the greater the probability of cocrystal formation. We attempted to correlate the appearance of multicomponent crystals with the solubility data of each coformer in MeOH. However, we faced difficulties in predicting the successful outcome of binary/ternary cocrystallization. Sometimes compounds with similar solubility do not form cocrystals. At other times, compounds with high solubility differences do form cocrystals. Yet, in other instances, compounds with similar solubilities form cocrystals. The possibility of forming a robust synthon may override the solubility difference factor between the coformers. Breaking homosynthons and forming heterosynthons may lower the Gibbs free energy and could favor cocrystal formation. However, if there are no complementary functional groups, there is almost no chance of cocrystal formation in spite of comparable solubility of coformers. Shape/size mimicry of the coformers in a cocrystal also dictates cocrystal (isostructural) possibility,1,16 for example, fumaric acid/succinic acid, bipyridine/biphenyl, and nicotinamide/isonicotinamide. Smaller and less flexible molecules are more likely to form cocrystals than long chain and flexible counterparts. Polymorphic compounds prefer to form cocrystals because of their conformational flexibility at the supramolecular level.33 Some General Considerations. The ternary cocrystals here have been obtained from molecules containing one or two functional groups each. The observed cocrystals are the result of a precise balance of size, shape, different intermolecular interactions, and synthon hierarchies. If the molecules become bigger or if the number of functional groups in the molecules becomes greater (as, for example, in systems of biological interest), the synthetic challenge is bound to increase. In such a scenario, the synthon cascading for a successful ternary cocrystal strategy should be sharply defined because of complications resulting from synthon interference from the “additional” functional groups. Large molecular size is not necessarily a problem unless crystallization itself is compromised because of excessive conformational freedom (entropic factors). A large size molecule may even tolerate a larger number of additional functional groups because the likelihood of synthon interference may decrease. The most challenging cases for cocrystallization are, in the opinion of the present authors, furnished by small but heavily functionalized molecules. The importance of shape factors in the molecules has also not been considered adequately in this study. All the molecules selected have their functional groups in roughly two opposite ends of the molecules. If the positioning of the functional groups is different, it is difficult to predict the crystallization outcome, as, for example, is seen in the contradistinctive crystal structures of 3- and 4-aminophenols.34

■

ASSOCIATED CONTENT

S Supporting Information *

ORTEP diagrams of all the crystal structures. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*(G.R.D.) E-mail: [email protected]. Fax: +91 80 23602306. Tel: +91 80 22933311. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS S.T. thanks IISc for Research Associate, P.S. thanks UGC for a Kothari fellowship, and G.R.D. thanks DST for a J. C. Bose fellowship.

■

REFERENCES

(1) Tothadi, S.; Desiraju, G. R. Cryst. Growth Des. 2012, 12, 6188− 6198. (2) Frišcǐ ć, T.; Jones, W. Faraday Discuss. 2007, 136, 167−178. (b) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013−1021. (c) Basavoju, S.; Boström, D.; Velaga, S. P. Pharm. Res. 2008, 25, 530. (d) Delori, A.; Frišcǐ ć, T.; Jones, W. CrystEngComm 2012, 14, 2350−2360. (e) Tothadi, S. CrystEngComm 2014, 16, 7587−7597. (3) Tothadi, S.; Desiraju, G. R. Chem. Commun. 2013, 49, 7791− 7793. (4) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (b) Etter, M. C. J. Phys. Chem. 1991, 95, 4601−4610. (c) Etter, M. C.; UrbanczykI



Article

Lipkowska, Z.; Ziaebrahimi, M.; Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415−8426. (d) Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc. 1991, 113, 2586−2598. (5) (a) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240−3242. (b) Aakeröy, C. B.; Desper, J.; Helfrich, B. A.; Metrangolo, P.; Pilati, T.; Resnati, G.; Stevenazzi, A. Chem. Commun. 2007, 4236−4238. (c) Aakeröy, C. B.; Schultheiss, N.; Rajbanshi, A.; Desper, J.; Moore, C. Cryst. Growth Des. 2009, 9, 432− 441. (6) Aakeröy, C. B.; Desper, J.; Urbina, J. F. Chem. Commun. 2005, 2820−2822. (7) Bhogala, B. R.; Basavoju, S.; Nangia, A. Cryst. Growth Des. 2005, 5, 1683−1686. (8) Tothadi, S.; Mukherjee, A.; Desiraju, G. R. Chem. Commun. 2011, 47, 12080−12082. (9) Thakur, T. S.; Azim, Y.; Srinu, T.; Desiraju, G. R. Curr. Sci. 2010, 98, 794−802. (10) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2013, 15, 5877−5887. (11) Seaton, C. C.; Blagden, N.; Munshi, T.; Scowen, I. J. Chem. Eur. J. 2013, 19, 10663−10671. (12) Chakraborty, S.; Rajput, L.; Desiraju, G. R. Cryst. Growth Des. 2014, 14, 2571−2577. (13) (a) Desiraju, G. R.; Ho, P. S.; Kloo, L.; Legon, A. C.; Marquardt, R.; Metrangolo, P.; Politzer, P.; Resnati, G.; Rissanen, K. Pure Appl. Chem. 2013, 85, 1711−1713. (b) Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386−395. (c) Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo, G. Angew. Chem., Int. Ed. 2008, 47, 6114−6127. (d) Legon, A. C. Phys. Chem. Chem. Phys. 2010, 12, 7736−7747. (14) (a) Mukherjee, A.; Tothadi, S.; Desiraju, G. R. Acc. Chem. Res. 2014, 47, 2514−2524. (b) Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam, The Netherlands, 1989. (c) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering: A Textbook; World Scientific: Singapore, 2011. (15) (a) Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 9952−9967. (b) Mukherjee, A.; Desiraju, G. R. IUCrJ 2014, 1, 49−60. (16) Tothadi, S.; Joseph, S.; Desiraju, G. R. Cryst. Growth Des. 2013, 13, 3242−3254. (17) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311−2327. (18) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342−8356. (19) (a) Saha, B. K.; Nangia, A.; Jaskólski, M. CrystEngComm 2005, 7, 355−358. (b) Aakeröy, C. B.; Chopade, P. D.; Desper, J. Cryst. Growth Des. 2011, 11, 5333−5336. (c) Cinčić, D.; Frišcǐ ć, T.; Jones, W. Chem.Eur. J. 2008, 14, 747−753. (d) Martí-Rujas, J.; Colombo, L.; Lü, J.; Dey, A.; Terraneo, G.; Metrangolo, P.; Pilati, T.; Resnati, G. Chem. Commun. 2012, 48, 8207−8209. (e) Valkonen, A.; Chukhlieb, M.; Moilanen, J.; Tuononen, H. M.; Rissanen, K. Cryst. Growth Des. 2013, 13, 4769−4775. (f) Raatikainen, K.; Rissanen, K. Chem. Sci. 2012, 3, 1235−1239. (g) Aakeröy, C. B.; Desper, J.; Fasulo, M.; Hussain, I.; Levin, B.; Schultheiss, N. CrystEngComm 2008, 10, 1816− 1821. (h) Yan, D.; Delori, A.; Lloyd, G. O.; Frišcǐ ć, T.; Day, G. M.; Jones, W.; Lu, J.; Wei, M.; Evans, D. G.; Duan, X. Angew. Chem., Int. Ed. 2011, 50, 12483−12486. (20) RigakuMercury375R/M CCD. CrystalClear-SM Expert 2.0 rc14; Rigaku Corporation: Tokyo, Japan, 2009. (21) (a) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122. (b) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838. (22) Spek, A. L. Acta Crystallogr. 2009, D65, 148−155. (23) (a) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2004, 890−891. (b) Trask, A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41−70. (24) (a) Clarke, H. D.; Hickey, M. B.; Moulton, B.; Perman, J. A.; Peterson, M. L.; Wojtas, Ł.; Almarsson, Ö .; Zaworotko, M. J. Cryst. Growth Des. 2012, 12, 4194−4201. (b) Cherukuvada, S.; Nangia, A. CrystEngComm 2012, 14, 2579−2588. (25) (a) Allen, F. H.; Goud, B. S.; Hoy, V. J.; Howard, J. A. K.; Desiraju, G. R. J. Chem. Soc. Chem. Commun. 1994, 2729−2730.

(b) Thalladi, V. R.; Goud, B. S.; Hoy, V. J.; Allen, F. H.; Howard, J. A. K.; Desiraju, G. R. Chem. Commun. 1996, 401−402. (26) Ranganathan, A.; Pedireddi, V. R. Tetrahedron Lett. 1998, 39, 1803−1806. (27) Pedireddi, V. R.; Sarma, J. A. R. P.; Desiraju, G. R. J. Chem. Soc., Perkin Trans. 2 1992, 311−320. (28) Ali, Q.; Shah, M. R.; Ng, S. W. Acta Crystallogr. 2011, E67, o548. (29) Aakeröy, C. B.; Hurley, E. P.; Desper, J. Cryst. Growth Des. 2012, 12, 5806−5814. (30) Desiraju, G. R.; Pedireddi, V. R.; Sarma, J. A. R. P.; Zacharias, D. E. Acta Chim. Hung. 1993, 130, 451−465. (31) Saha, S.; Ganguly, S.; Desiraju, G. R. Aust. J. Chem. 2014, accepted. (32) (a) Karki, S.; Frišcǐ ć, T.; Fábián, L.; Jones, W. CrystEngComm 2010, 12, 4038−4041. (b) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.; Nangia, A. Cryst. Growth Des. 2011, 11, 4135−4145. (c) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2011, 8, 1867−1876. (33) Lemmerer, A.; Adsmond, D. A.; Esterhuysen, C.; Bernstein, J. Cryst. Growth Des. 2013, 13, 3935−3952. (34) Allen, F. H.; Hoy, V. J.; Howard, J. A. K.; Thalladi, V. R.; Desiraju, G. R.; Wilson, C. C.; McIntyre, G. J. J. Am. Chem. Soc. 1997, 119, 3477−3480.

J


Obtaining Synthon Modularity in Ternary Cocrystals with Hydrogen

Recommend Documents