Design of Cocrystals via New and Robust Supramolecular Synthon between Carboxylic Acid and Secondary Amide: Honeycomb Network with Jailed Aromatics Lalit Rajput and Kumar Biradha*
CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 1 40–42
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India ReceiVed October 11, 2008; ReVised Manuscript ReceiVed NoVember 9, 2008
ABSTRACT: A new synthon involving carboxylic acid and a secondary amide with anti geometry has been identified and used as a designing element to engineer the cocrystals of symmetrically substituted triamides, tricarboxylic acids, and aromatic guest molecules. The robustness of the synthon has been explored by considering the pyridine functional groups in the amide molecules. The rational design of cocrystals has attracted the attention of crystal engineers due to their implications in pharmaceutical industries.1 For the facile design of cocrystals, knowledge about supramolecular synthons of various functional groups is a very important aspect.2 For instance, amide and carboxylic acid functional groups are ubiquitous in several biological systems and drug molecules. Both functional groups are well-known to form selfcomplementary homosynthons.3 Also several cocrystals are known based on heterosynthons of primary or secondary amides with syn geometry and carboxylic acid.4 However, no cocrystal has been reported to date between these two functional groups when the amide is 2° with anti geometry. Here we present an exclusive and predictable formation of a heterosynthon-I between an antiamide and -COOH functional group. The synthon was found to form repeatedly even in the presence of a strong acceptor such as a pyridine N-atom. The results observed here are the first examples of cocrystals which are formed by the secondary amide having anti geometry and carboxylic acid functionalities. Compound 1 has been synthesized anticipating columnar architectures via amide-to-amide hydrogen bonds.5 To our dismay, the compound refused to crystallize despite several crystallization attempts with various solvents and their combinations. Therefore, it occurred to us that the trimesic acid (H3TMA) could be a good cocrystallizing agent for 1 given the formation of a supramolecular synthon-I. Database analysis reveals that a similar type of motif exists in a couple of the crystal structures.6 This observation encouraged us further to consider H3TMA as a cocrystallizing agent for 1.
The crystallization of 1 and H3TMA from an EtOH and toluene system resulted in the cocrystals of (4)2 · toluene (4 ) 1 · H3TMA). The structure analysis reveals that (4)2 · toluene crystallized in the hexagonal space group P31 and the asymmetric unit contains two units each of 1 and H3TMA and one toluene moiety. More importantly it exhibits synthon-I (N · · · O 2.838(5)-2.900(5) Å and O · · · O 2.611(4)-2.646(4) Å) as expected and forms a twodimensional layer in which all the benzyl groups point toward one side of the layer (Figure 1). In effect, the layer is constituted by
Figure 1. Illustration for (4)2 · toluene: (a) the geometry of 1; (b) the hydrogen bond layer formed by 1 and H3TMA (solid blue circles) and (pink triangles) represents synthon-I and II, respectively; (c) the enclosure of toluene molecules by two symmetry independent layers.
* To whom correspondence should be addressed. E-mail: kbiradha@ chem.iitkgp.ernet.in.
two types of synthons: hydrogen bonding synthon-I and the edgeto-face aromatic interactions synthon-II between the phenyl groups.
10.1021/cg801132r CCC: $40.75 2009 American Chemical Society Published on Web 12/10/2008
Communications
Figure 2. (a) The packing of the layers (four layers shown) in the crystal structure of (5)2 · m-xylene · H2O (side view); red dots represent H2O molecules; (b) representation of guest (green) inclusion by benzyl groups in 4 and (c) by picolyl groups in 5 (anisole is disordered).
The adjacent layers are symmetry independent and pack in -ABABfashion such that the benzyl groups from these layers point either toward or away from each other. Between the layers cavities exist which enclathrate toluene. Indeed the aromatic solvent was found to be an essential requirement for obtaining these crystals. Similar types of cocrystals of (4)2 · G were also obtained with G ) benzene, anisole, nitrobenzene, or benzonitrile. In order to verify the robustness of the supramolecular synthon-I we have prepared two more derivatives of 1 in which the phenyl groups are replaced by 2-pyridyl (2) or 3-pyridyl (3) groups. The pyridine group has been considered as it is a strong hydrogen bond acceptor than amide carbonyl and also it is well-known to form a robust heterosynthon with -COOH.7 The crystallization of H3TMA with 2 and 3 from methanolanisole and methanol resulted in cocrystals of (5)2 · anisole · 2H2O (5 ) 2 · H3TMA) and 6 · MeOH (6 ) (H3TMA · H2TMA · 3H), respectively. The cocrystal of 5 was crystallized in triclinic space group and the asymmetric unit is constituted by one unit each of 2, H3TMA, and H2O and a half unit of anisole molecule. Although 5 is not isostructural with 4, it also contains a 2D layer similar to 4. The 2-pyridyl group does not show any interference in the formation of synthon-I (N · · · O 2.875(3) Å, 2.910(3) Å, 2.875(3) Å and O · · · O 2.650(3) Å, 2.656(3) Å, 2.634(3) Å) and involves hydrogen bonds with water molecules which lie between the layers. Here it is noteworthy that, except for the presence of water between the layers (Figure 2), the molecular geometry, packing, and inclusion of aromatics are exactly the same as those of 4. Further, unlike in 4 (hexagonal), the supramolecular symmetry of the layer in 5 (triclinic) is not reflected in the overall crystallographic symmetry. A similar type of cocrystals (5)2 · G · 2H2O also formed with G ) toluene and m-xylene. The crystal structure of 6 · MeOH deviates from the above two structures but interestingly still exhibits synthon-I. The asymmetric unit is constituted by one each of 3H+, H3TMA, H2TMA-1, and MeOH. The molecular geometry of 3 differs from the above two structures (Figure 3a). The molecule 3 with H3TMA forms a one-dimensional chain via synthon-I (N · · · O 2.868(2)-2.916(2) Å and O · · · O 2.600(2)-2.640(2) Å) and H2TMA-1 forms a zigzag chain with itself via charge-assisted O-H · · · O hydrogen bonds (O · · · O 2.697(2) Å). These two chains are interconnected further via synthon-I to form a twodimensional layer which is terminated by MeOH molecules ((O · · · O 2.681(4) Å). The protonated pyridine of 3 from the adjacent layers interact with O-atom of H2TMA-1 via N-H · · · O (N · · · O: 2.531(2) Å) hydrogen bond. The popular synthon
Crystal Growth & Design, Vol. 9, No. 1, 2009 41
Figure 3. Illustration for the crystal structure of 6 · MeOH: (a) the geometry of 3, (b) the discrete layer through synthon-I and chargeassisted O-H · · · O hydrogen bonds; symmetry dependent molecules are colored differently.
between -COOH and pyridine moiety is not observed here. The presence of aromatic solvents during the crystallization had not shown any effect in the crystallization of 6 · MeOH. We note here that the hydrogen bonding distances and angles of synthon-I are similar to those of the popular amide-acid synthon. The results observed here demonstrate that the synthon-I is robust enough to be sustained even in the presence of competing functional groups such as pyridine and COO- groups. The powder X-ray diffraction studies indicate that the materials (4)2 · toluene and 6 · MeOH can also be synthesized by solvent drop grinding but (5)2 · m-xylene · H2O cannot. We are further investigating other carboxylic acids to extrapolate our findings about synthon-I.
Acknowledgment. We thank DST-FIST for CCD-facility at IIT-KGP and CSIR for financial support. L.R. thanks IIT-KGP for a research fellowship. Supporting Information Available: The synthetic procedures, crystallographic and hydrogen bonding details, XRPD patterns and additional figures. This material is available free of charge via the Internet at http://pubs.acs.org.
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