Three-Component Carboxylic Acid-Bipyridine Lattice Inclusion Host. Supramolecular Synthesis of Ternary Cocrystals Balakrishna R. Bhogala, Srinivas Basavoju, and Ashwini Nangia* School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 5 1683-1686
Received April 27, 2005
ABSTRACT: Cocrystallization of 1,3,5-cyclohexanetricarboxylic acid with 4,4′-bipyridine bases of different CH2 chain lengths (n ) 0, 2, 4) has afforded the ternary host framework [H3CTA‚bipy-eta(gauche)‚(bipy-bu)0.5] (2), sustained by O-H‚‚‚N hydrogen bonds. Inclusion of p-dichlorobenzene in the square voids of host 2 provides the first example of a quaternary cocrystal. Crystal structures of ternary cocrystals 1-3 show that methylene chains of bipy bases are not mere inert spacer units but have a conformational and structural role in controlling the supramolecular architecture of molecular complexes with carboxylic acids. 1,3,5-Benzenetricarboxylic acid1 (trimesic acid, H3TMA) and 1,3-cis,5-cis-cyclohexanetricarboxylic acid2 (H3CTA) are trigonal tectons for the construction of hexagonal networks and layered structures in hydrogen-bonded complexes with bipyridine bases. The 2:3 cocrystal of H3CTA with 1,2-bis(4-pyridyl)ethane (bipy-eta) has a porous hexagonal network2b that is topologically identical with the chicken-wire grid of H3TMA‚(4,4′-bipyridine)1.5.1a We report in this paper ternary cocrystals of H3CTA with 4,4′-bipy bases of varying CH2 chain lengths based on the carboxylic acid‚‚‚pyridine heterosynthon (Chart 1). Almarsson and Zaworotko3 have defined a pharmaceutical cocrystal as constituted of molecular components that are both solids at room temperature. Thus, binary, ternary, and quaternary cocrystals are made up of two, three, and four different molecular solids. Whereas binary acid‚‚‚pyr cocrystals abound, there are very few papers on designed three-component solid-state assemblies.4,5 Moreover, the reported examples of ternary hydrogen-bonded solids are finite supermolecules which do not have cavities/pores for interpenetration or guest inclusion. We reasoned that slight changes in N basicity and differences in conformations and close-packing modes of homologous bipy bases could be exploited to prepare novel ternary cocrystals with a tricarboxylic acid. Plater et al.6 analyzed several metal-bipy structures with CH2 chain length varying from 1 to 6, but the role of homologous bipy bases in carboxylic acid cocrystals has not been systematically examined. From the viewpoint of this study, we were surprised to find that there are no examples of any two 4-pyr-(CH2)n-4′-pyr bases (n ) 0-6) in the same crystal structure.7 Since several combinations of homologous bipy bases may be cocrystallized with a tricarboxylic acid, we expected to obtain a large number of ternary adducts with our library of starting reagents. Crystallization of H3CTA, bipy, and bipy-eta from EtOH/ benzene in a 2:2:1 ratio afforded the three-component crystal 1, as supported by NMR. The crystal structure of H3CTA‚bipy‚(bipy-eta)0.5 (C2/c)8 shows infinite helices of acid‚‚‚bipy O-H‚‚‚N bonds (O‚‚‚N ) 2.68, 2.65 Å) along the b axis, and such helices are connected via a bipy-eta base (O‚‚‚N ) 2.59 Å) with the ethylene chain lying on the 2-fold axis in the uncommon gauche conformation. See Table 1 for hydrogen bond metrics and Figure S1 (Supporting Information) for the 1H NMR spectrum of 1. The interaction of H3CTA with bipy and bipy-eta gives a hexagonal network of 25 × 32 Å voids, which are filled in the triply parallelinterpenetrated 6,3 network. Figure 1 shows the * To whom correspondence should be addressed.
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Chart 1. Molecular Components for the Assembly of Ternary Cocrystals 1-3 via the Carboxylic Acid‚‚‚Pyridine Heterosynthon
acid‚‚‚bipy-eta synthon connecting triple helices of acid‚‚‚bipy to form a 2D polar layer structure: i.e., helices within a layer have the same handedness.9 The crystal structure is centrosymmetric through the inversion center between adjacent layers of opposite helices. The gauche conformation of the CH2CH2 chain of bipy-eta is perhaps a consequence of achieving efficient close packing in the region between the helices. Cocrystal 1 is the first example of gauche-ethylene among acid‚‚‚bipy cocrystals, this less stable conformation of bipy-eta being present in 28 metalpyridine structures.7 The crystal structure of the threecomponent assembly H3CTA‚bipy-ete‚(bipy-eta)0.5 (P21/c; see Figure S2 in the Supporting Information) is identical with that of 1 and also with that of the binary complex2b H3CTA‚(bipy-eta)1.5 in that helices of carboxylic acid and bipy-ete along the screw axis are connected by bipy-eta through the COOH‚‚‚pyridine heterosynthon. These structures show that different bipyridine bases occupy the helix and connector domains in ternary adducts of H3CTA. We therefore explored acid-pyridine adduct formation with other bipy homologues. Cocrystallization with a longer bipy component, as in H3CTA, bipy-eta, and bipy-bu (2:2:1), did not afford crystals from n-PrOH after several attempts. Upon addition of an aromatic compound to the solution, e.g. toluene, p-xylene,
10.1021/cg058012p CCC: $30.25 © 2005 American Chemical Society Published on Web 07/14/2005
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Table 1. Geometrical Parameters of Hydrogen Bonds in Cocrystals 1-3a D-H‚‚‚A O-H‚‚‚N C-H‚‚‚O O-H‚‚‚N C-H‚‚‚O O-H‚‚‚N C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O
D‚‚‚A (Å)
H‚‚‚A (Å)
D-H‚‚‚A (deg)
C9H12O6‚C10H8N2‚(C12H12N2)0.5 (1) 2.681(3) 1.69 3.237(4) 2.44 2.655(3) 1.68 3.335(4) 2.68 2.591(3) 1.62 3.389(4) 2.71 3.341(4) 3.443(4) 3.420(3) 3.541(3)
2.26 2.37 2.41 2.54
177.6 128.8 168.5 117.9 167.7 119.6 175.6 166.8 152.9 153.1
[C9H12O6‚C12H12N2‚(C14H16N2)0.5]‚(C8H10)0.5 (2‚(p-xylene)0.5) O-H‚‚‚N 2.629(3) 1.65 169.1 C-H‚‚‚O 3.516(3) 2.86 118.6 O-H‚‚‚N 2.665(3) 1.68 172.9 C-H‚‚‚O 3.360(3) 2.65 121.9 O-H‚‚‚N 2.652(2) 1.67 176.3 C-H‚‚‚O 3.353(3) 2.63 123.3 C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O
3.325(3) 3.344(3) 3.449(3) 3.447(3)
2.30 2.36 2.40 2.56
157.2 150.1 162.3 138.2
[C9H12O6‚C12H12N2‚(C14H16N2)0.5]‚(C6H4Cl2)0.5 (2‚(p-dichlorobenzene)0.5) O-H‚‚‚N 2.637(2) 1.65 173.4 C-H‚‚‚O 3.459(3) 2.79 119.4 O-H‚‚‚N 2.651(2) 1.66 177.0 C-H‚‚‚O 3.361(2) 2.66 121.2 O-H‚‚‚N 2.650(2) 1.66 176.2 C-H‚‚‚O 3.339(2) 2.62 122.6 C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚Cl O-H‚‚‚N C-H‚‚‚O O-H‚‚‚OC-H‚‚‚O O-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚O C-H‚‚‚N C-H‚‚‚O
3.383(3) 3.351(3) 3.448(2) 3.655(3)
2.35 2.39 2.40 2.83
158.7 146.5 162.2 132.0
H3CTA‚(bipy)0.5‚(bipy-ete-N-oxide)0.5 (3) 2.653(3) 1.683 168.2 3.107(6) 2.321 127.9 2.501(3) 1.520 174.3 3.440(4) 2.641 130.0 2.674(4) 1.731 159.3 3.440(4) 3.154(5) 3.624(4) 3.546(4) 3.305(4) 3.342(4) 3.665(4) 3.339(4)
2.527 2.073 2.584 2.501 2.547 2.529 2.633 2.279
141.3 175.3 160.6 161.7 126.1 131.1 158.9 165.6
Figure 1. Crystal structure of ternary cocrystal 1: (a) COOH‚‚‚bipy and COOH‚‚‚bipy-eta heterosynthons aggregating in the shape of a molecular necklace with voids of 25 × 32 Å; (b) triply interpenetrated network showing COOH‚‚‚bipy helices along [010] and gauche CH2CH2 connections along [100].
a Carboxylic acid‚‚‚pyridine O-H‚‚‚N/C-H‚‚‚O interactions are listed in pairs. C-H and O-H distances are neutron normalized to 1.083 and 0.983 Å.
or anisole, diffraction-quality single crystals appeared in the p-xylene batch. The X-ray crystal structure of [H3CTA‚ bipy-eta(gauche)‚(bipy-bu)0.5]‚(p-xylene)0.5 (P1 h )8 confirmed that the aromatic guest is included in the three-component host framework 2, wherein “component” means different molecules in the adduct and not multiple occurrences of the same molecule in the crystallographic unit cell. Two COOH groups of H3CTA are bonded to different bipy-eta molecules in a gauche conformation (O‚‚‚N ) 2.63, 2.66 Å), and such dimeric units form square cavities of 10 × 12 Å. These loops are connected via O-H‚‚‚N H bonds (O‚‚‚N ) 2.65 Å) between the third COOH of H3CTA and bipy-bu base (Figure 2). Auxiliary C-H‚‚‚O interactions stabilize the COOH‚‚‚pyr synthon (Table 1). The termolecularaggregate containers stack to produce channels for p-xylene guest inclusion. The construction of a ternary cocrystal host lattice has not been reported to our knowledge. Despite
Figure 2. (a) Closed loop COOH‚‚‚bipy-eta(gauche) units forming square boxes which are connected via COOH‚‚‚bipy-bu to form the three-component host 2. Molecular stacks produce square channels of 10 × 12 Å. (b) Inclusion of p-xylene and p-dichlorobenzene guests in the cavity.
being assembled by flexible molecular components, the ternary host 2 is quite robust toward a variety of aromatic guests (methyl-halogen exchange; Chart 1). Isostructural
Communications adducts were obtained with o-xylene, o-chlorotoluene, o-dichlorobenzene, and anisole, except that these unsymmetrical molecules are disordered (the disorder is modeled) because they reside on the inversion center. Incidentally, there is no example of four different organic solids present in the same cocrystal. Encouraged by the inclusion of p-xylene and o-dichlorobenzene, we used pdichlorobenzene (mp 53-56 °C) as the guest (van der Waals volume: CH3, 24 Å3; Cl, 20 Å3). [H3CTA‚bipy-eta‚(bipy-bu)0.5]‚(p-dichlorobenzene)0.5 is the first quaternary cocrystal to be synthesized by deliberate design. The bent conformation of the CH2CH2 chain and the wrapping of host channel 2 around aromatic guests are facilitated by weak hydrophobic host‚‚‚guest interactions. The flat framework of H3TMA poses a challenge to induce guest inclusion,1c because the voids are eliminated through interpenetration.1a In contrast, the cyclohexane-based host lattice of 2 forms a dozen isostructural channel inclusion adducts. Attempts to obtain a guest-free form afforded a structure with disordered bipy-bu guests. The folded conformation of bipyeta in 2 is reminiscent of coordination polymer structures,10 with metal-ligand bonds being replaced by O-H‚‚‚N H bonds. MacGillivray and Atwood11 have elegantly manipulated the calixarene host cavity in complexes with pyridine and 4,4′-bipyridine. The stoichiometry in which the molecular components are mixed during crystallization is crucial. When 4,4′-bipy is used in excess, ternary cocrystal 1 is obtained, but if bipy-eta is present in excess, the binary adduct2b H3CTA‚ (bipy-eta)0.5 is isolated. Lattice energies (Cerius2, Dreiding, normalized to 1000 Å3 volume of the unit cell) of the ternary crystals 1 and 2‚(p-xylene)0.5 are higher than that of the binary cocrystal by 6.5 and 26.5 kcal/mol. The formation of more stable H3CTA‚(bipy-eta)0.5 can be avoided under optimized crystallization conditions. We believe that crystallization of ternary adducts in our tricarboxylic acid plus two bipy system is a kinetic phenomenon which involves formation of acid‚‚‚pyr helices with one bipy base, and then these helices connect through the second bipy, perhaps in a sequential manner. The assembly of similar molecular components to form a hexagonal network in 1 and a square loop in 2 is better visualized as networks, by treating the H3CTA tecton as the node and the COOH‚‚‚pyr synthon as the node connector. Differences in CH2 chain lengths of bipy bases are ignored, and the connector molecules can be bent or linear. The helix, infinite chain, and square box motifs are supramolecular isomers.12 As shown in Figure 3, helices of the hexagonal framework 1 isomerize to the square box structure of 2 by closing the hydrogen bond to a molecule in the same row instead of extending the interaction to the next row. The third O-H‚‚‚N heterosynthon connects the helices or loops to complete the structure. Even though crystal structures 1 and 2 with hexagonal voids and square loops are very different, their self-assembly is easily understood from similar molecular components through the network representation. Our supramolecular synthesis method utilizes different bipy base connectors with a tricarboxylic acid tecton to generate diverse ternary architectures. The electrostatic surface potential (ESP, Spartan, 6-31G**) charge on the N atom is a useful guide in estimating hydrogen bond acceptor strengths.13 The ESP charge on the N acceptor of 4-pyridyl-(CH2)n-4′-pyridyl increases with chain length (-45.49, -47.74, and -48.89 kcal/mol for n ) 0, 2, 4), and this increase parallels the higher basicity of ethylpyridine compared to pyridine (pKa 6.02 vs 5.17).2b Despite the approximations involved in correlating ESP charges (a calculated property in the gas
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Figure 3. (a) 6,3 network of Figure 1, analyzed as built from helices (red and blue) and connectors (black). (b) Infinite motif of (a) closing to form the finite loops of Figure 2 (red and blue). Legend: red, H3CTA tecton; blue and black, bipy connectors.
Figure 4. Crystal structure of ternary complex 3 sustained by O-H‚‚‚N, O-H‚‚‚-O-N+, and O-H‚‚‚O H bonds.
phase) and pKa values (a solution measurement) with H-bonding preferences in the solid state, we expanded the scope of our preliminary results based on differential acceptor strength by using a combination of bipyridine and bis-N-oxide, the latter being a stronger acceptor (ESP -55.47 kcal/mol). The crystal structure of the ternary cocrystal H3CTA‚(bipy)0.5‚(bipy-ete-NO)0.5 (3),8 with zigzag tapes of COOH‚‚‚pyr and COOH‚‚‚-O-N+ H bonds (Figure 4; O‚‚‚N ) 2.65 Å, O‚‚‚O ) 2.50 Å), demonstrates the generality of cocrystallizing bipy subunits of differential basicities and close-packing arrangements with an acidic molecule to synthesize multicomponent cocrystals. Whereas there are several examples of COOH‚‚‚bipy and COOH‚‚‚ pyr-NO binary complexes, three-component cocrystals, as in 1-3, are novel. To summarize, one can assemble hexagonal,2a,b,d layered,2b diamondoid,2c and channel structures (this paper) from the same trigonal tecton, H3CTA, by selecting appropriate partner molecules and templates. We have shown that the CH2 chain in bipy bases is not an inert spacer but could have a conformational and structural role in controlling the supramolecular architecture. Over a dozen new examples of ternary cocrystals and the first example of a quaternary cocrystal have been reported using a combination of H3CTA and common bipy bases. Why does combinatorial cocrystallization of a triacid with homologous bipy bases produce ternary adducts? In our opinion, helices or loops of acid‚‚‚bipy molecules are constructed with the less rigid bipy partner, whereas connections between these helices/loops involve the longer/ flexible bipy base. Detailed analysis of these ternary structures to delineate the role of pKa values, ESP charges, methylene chain conformations, hydrogen bonding, and
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hydrophobic interactions in directing the observed structures from the molecular components will be reported in a full article. Whereas solvates and host-guest complexes (one of the components is a liquid) are commonplace, cocrystals have been relatively unexplored. Their synthesis is much more difficult and challenging, because any one or more of the solid components will usually precipitate separately during crystallization if hydrogen bonding between the multiple components is not strong and specific. The design of tunable crystals as functional solids is useful in materials science, and the engineering of cocrystals offers exciting avenues in pharmaceutical development.14 Acknowledgment. We thank CSIR for funding (01(1738)/02/EMR-II), and UGC and CSIR for fellowship to B.R.B. and S.B. The X-ray diffractometer is funded by DST (IRPHA) and UGC is thanked for the UPE program. Supporting Information Available: Text giving experimental details, Figures S1 and S2, and crystallographic data for cocrystals 1-3 (.cif format). This material is available free of charge via the Internet at http://pubs.acs.org.
References (1) (a) Sharma, C. V. K.; Zaworotko, M. J. Chem. Commun. 1996, 2655. (b) Paz, F. A. A.; Bond, A. D.; Khimyak, Y. Z.; Klinowski, J. New J. Chem. 2002, 26, 381. (c) Ma, B.-Q.; Coppens, P. Chem. Commun. 2003, 2290. (2) (a) Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2002, 2, 325. (b) Bhogala, B. R.; Nangia, A. Cryst. Growth Des. 2003, 3, 547. (c) Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2005, 5, 1271. (d) Shan, N.; Bond, A. D.; Jones, W. New J. Chem. 2003, 27, 365. (3) Almarsson, O ¨ .; Zaworotko, M. J. Chem. Commun. 2004, 1889. (4) (a) Aakero¨y, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240. (b) Aakero¨y, C. B.; Desper, J.; Urbina, J. F. Chem. Commun. 2005, 2820. (5) Smolka, T.; Boese, R.; Sustmann, R. Struct. Chem. 1999, 10, 429. (6) Plater, M. J.; Foreman, M. R. St. J.; Gelbrich, T.; Coles, S. J.; Hursthouse, M. B. Dalton 2000, 3065.
Communications (7) The Cambridge Structural Database (www.ccdc.cam.ac.uk) was searched (CSD, ConQuest1.7, Nov 2004 update). (8) Crystal data are as follows. 1: C25H26N3O6, Mr ) 464.49, 298(2) K, monoclinic, C2/c, a ) 33.167(7) Å, b ) 9.954(2) Å, c ) 14.988(3) Å, β ) 110.91(3)°, V ) 4622.3 (19) Å3, Z ) 8, µ(Mo KR) ) 0.097 mm-1, R1(I >2σ(I)) ) 0.0530. 2‚(pxylene)0.5: C32H37N3O6, Mr ) 559.65, 100(2) K, triclinic, P1 h, a ) 5.7110(4) Å, b ) 14.1003(10) Å, c ) 18.3960(13) Å, R ) 86.100(1)°, β ) 84.560(1)°, γ )82.123(1)°, V ) 1458.51(18) Å3, Z ) 2, µ(Mo KR) ) 0.088 mm-1, R1(I > 2σ(I)) ) 0.0641. 2‚(p-dichlorobenzene)0.5: C31H34ClN3O6, Mr ) 580.06, 100(2) K, triclinic, P1 h , a ) 5.6882(7) Å, b ) 14.0309(18) Å, c ) 18.390(2) Å, R ) 85.767(2)°, β ) 84.034(2)°, γ ) 81.877(2)°, V ) 1442.5 (3) Å3, Z ) 2, µ(Mo KR) ) 0.182 mm-1, R1(I > 2σ(I)) ) 0.0479. 3: C20H21N2O7, Mr ) 401.39, 298(2) K, monoclinic, P21/n, a ) 6.1002(12) Å, b ) 12.531(3) Å, c ) 25.138(5) Å, β ) 93.73(3)°, V ) 1917.6(7) Å3, Z ) 4, µ(Mo KR) ) 0.106 mm-1, R1(I > 2σ(I)) ) 0.0618. See the Supporting Information for experimental details. (9) We are aware of only one example of a noncentrosymmetric parallel-interpenetrated (6,3) network structure: Komatsu, T.; Sato, H.; Nakamura, T.; Matsukawa, N.; Yamochi, H.; Saito, G.; Kusonki, M.; Sakaguchi, K.; Kagoshima, S. Bull. Chem. Soc. Jpn. 1995, 68, 2233. (10) (a) Fujita, M.; Kwon, Y. J.; Miyazawa, M.; Ogura, K. Chem. Commun. 1994, 1977. (b) Hennigar, T. L.; MacQuarrie, D. C.; Losier, P.; Rogers, R. D.; Zaworotko, M. J. Angew. Chem., Int. Ed. 1997, 36, 972. (c) Tabellion, F. M.; Seidel, S. R.; Arif, A. M.; Stang, P. J. J. Am. Chem. Soc. 2001, 123, 11982. (11) (a) MacGillivray, L. R.; Atwood, J. L. J. Am. Chem. Soc. 1997, 119, 6931. (b) MacGillivray, L. R.; Atwood, J. L. Chem. Commun. 1999, 181. (c) MacGillivray, L. R.; Spinney, H. A.; Reid, J. L.; Ripmeester, J. A. Chem. Commun. 2000, 517. (12) (a) Moulton, B.; Zaworotko, M. J. Chem. Rev. 2001, 101, 1629. (b) Abourahama, H.; Moulton, B.; Kravtsov, V.; Zaworotko, M. J. J. Am. Chem. Soc. 2002, 124, 9990. (c) MacMahon, J. A.; Zaworotko, M. J.; Remenar, J. F. Chem. Commun. 2004, 278. (13) Vishweshwar, P.; Babu, N. J.; Nangia, A.; Mason, S. A.; Puschmann, H.; Mondal, R.; Howard, J. A. K. J. Phys. Chem. A 2004, 108, 9406. (14) (a) Gardner, C. R.; Walsh, C. T.; Almarsson, O ¨ . Nature Rev. 2004, 3, 926. (b) Datta, S.; Grant, D. J. W. Nature Rev. 2004, 3, 42.
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