A 2:1 co-crystal of p-nitrobenzoic acid and N,N′-bis(pyridin-3-ylmethyl)ethanediamide: crystal structure and Hirshfeld surface analysis

The components of the 2:1 co-crystal are linked by hydroxy-O—H⋯N(pyridyl) hydrogen bonds into a three-molecule aggregate having the shape of the letter Z. These are connected into a supramolecular ladder by tight amide-N—H⋯O(nitro) hydrogen bonds.


Chemical context
Arguably, the most prominent motivation for the study of cocrystals relates to their potential applications in the pharmaceutical industry whereby co-crystals of active pharmaceutical ingredients (APIs) formed with generally regarded as safe (GRAS) co-crystal coformers might provide drugs with enhanced useful properties, e.g. stability, solubility, bioavailability, etc. (Aakerö y, 2015; Almarsson & Zaworotko, 2004). Further impetus for investigating co-crystals relates to ascertaining reliable supramolecular synthons that might be exploited to direct crystal growth, or at least aggregates within crystals (Mukherjee, 2015;Tiekink, 2014). Co-crystals of N,N 0bis(pyridin-3-ylmethyl)ethanediamide, see Scheme, figured prominently in early investigations of halogen bonding (e.g. Goroff et al., 2005) and also has been co-crystallized with carboxylic acids (e.g. Nguyen et al., 2001). As a continuation of recent work related to the study of co-crystal formation of pyridyl-containing molecules with carboxylic acids (Arman et al., 2013), the co-crystallization of N,N 0 -bis(pyridin-3-ylmethyl)ethanediamide with p-nitrobenzoic acid was investigated, yielding the title 2:1 co-crystal. The results of this investigation are reported herein. ISSN 2056-9890
Twists are noted in the acid molecule so that the dihedral angle between the benzene ring and the non-hydrogen atoms of the carboxylic acid group is 10.16 (9) . The comparable angle involving the nitro group is 4.24 (4) , consistent with a smaller twist. The substituents have a conrotatory disposition forming a dihedral angle of 13.50 (8) . The crystal structure of the free acid was first reported almost fifty years ago (Sakore & Pant, 1966) and has been the subject of several subsequent investigations. The overall conformation for the acid in the title co-crystal matches the literature structures to a first approximation but it exhibits greater and smaller twists for the carboxylic acid and nitro groups, respectively, compared to those found in the two polymorphic forms of the free acid (A2/a: Tonogaki et al., 1993;P2 1 /m: Bolte, 2009) , Table 1.
The diamide features an essentially flat central residue with the r.m.s. deviation for the eight non-hydrogen atoms (O1, N2, C6 and C7, and symmetry equivalents) being 0.025 Å . This planar arrangement allows for the formation of intramolecular amide-N-HÁ Á ÁO(amide) hydrogen bonds ( Table 2). The pyridyl rings lie to either side of this plane and occupy positions approximately perpendicular to the plane, forming dihedral angles of 77.22 (6) . Overall, the molecule has the shape of a distorted letter Z. A number of co-crystals of the diamide have been described and salient geometric parameters for these are collated in Table 3. All but one of these structures features a centrosymmetric diamide molecule. The range of dihedral angles between the central chromophore and the pendant pyridyl rings span the range 61.24 (5) to 84.6 (2) . This conformational flexibility is reflected in the sole example of an organic salt of the diamide where the two dihedral angles vary by approximately 18 , Table 3. The other feature of these structures worth highlighting are the relatively long central C-C bond lengths, their length often resulting in a PLATON (Spek, 2009) alert. In the structures included in Table 3, the central C-C bond lengths vary from 1.515 (3) to 1.550 (17) Å , cf. 1.530 (3) Å in the title co-crystal.

Analysis of the Hirshfeld surfaces
The packing of the title compound was also investigated by an analysis of the Hirshfeld surfaces (Spackman & Jayatilaka, 2009) with the aid of CrystalExplorer (Wolff et al., 2012). The two-dimensional fingerprint plots (Rohl et al., 2008) were calculated for the crystal as well as for the individual coformers, as were the electrostatic potentials using TONTO (Spackman et al., 2008;Jayatilaka et al., 2005), also with CrystalExplorer; the electrostatic potentials were mapped on the Hirshfeld surfaces using the STO-3G basis set at the level of Hartree-Fock theory over a range of AE0.075 au. The presence of strong hydroxyl-O-HÁ Á ÁN(pyridyl) and amide-N-HÁ Á ÁO(nitro) interactions between the pair of acid molecules and a diamide molecule can be observed through their corresponding Hirshfeld surfaces mapped over the electrostatic potential, Fig. 5. From symmetry, each diamide forms two pairs of interactions, visualized as bright-red spots on the Hirshfeld surface mapped over d norm and labelled as 1 and 3, respectively, in Fig. 6. The full fingerprint plot for the co-crystal is shown in Fig. 7. The prominent spikes at d e + d i = 1.6 Å are due to NÁ Á ÁH/HÁ Á ÁN contacts. Thus, the long spike in the upper left region is due to the hydroxyl-O-HÁ Á ÁN(pyridyl) interaction and the similar long spike at the same d e + d i distance in the lower right region indicates the contribution of the amide-N-HÁ Á ÁO(nitro) interaction. The donor-acceptor contributions of these co-crystal constituents are highlighted with the label 'd 0 in the fingerprint plot, Fig. 7. The intermolecular OÁ Á ÁH and HÁ Á ÁO contacts, which are prominent in the molecular packing, Table 2     with a 37.1% contribution to surface (featured as 'b' in Fig. 7). The donors and acceptors corresponding to intermolecular C-HÁ Á ÁO interactions are seen as pale-red spots and are labelled as 2, 4, 5 and 6 in Fig. 6. The contribution from CÁ Á ÁH/ HÁ Á ÁC contacts (10.4% of the Hirshfeld surface) results in a symmetrical pair of wings, see 'c' in Fig. 7. The CÁ Á ÁC contacts assigned tostacking interactions appear as a distinct triangle in the fingerprint plot, see 'e' in Fig. 7, at around d e = d i = 1.8 Å . The presence of thesestacking interactions is justified by the appearance of red and blue triangle pairs on the Hirshfeld surface mapped with shape index identified with arrows in the images of Fig. 8 and in the flat regions on the Hirshfeld surfaces mapped with curvedness in Fig. 9. The HÁ Á ÁH contacts appear as the scattered points along with a single broad peak in the middle region of the fingerprint plot for each of the co-crystal constituents; the peak positions are at d e = d i = 1.2 and 1.0 Å , and the % contributions are 24.3% and 29.7% for acid and diamide, respectively. Thus, the overall 28.6% contribution to the Hirshfeld surface of the co-crystal is just the superimposition of these individual fingerprint plots, and results in the peak marked with 'a' in Fig. 7

Figure 9
Hirshfeld surfaces mapped over curvedness for (a) the acid and (b) the diamide, highlighting the regions involved instacking interactions.
various contacts to the Hirshfeld surfaces of acid, diamide and the co-crystal are tabulated in Table 4. A further analysis of Hirshfeld surfaces was conducted using a new descriptor, i.e. the enrichment ratio, ER (Jelsch et al., 2014), Table 5. The ER relates to the propensity of chemical species to form specific interactions in the molecular packing. The ER value of approximately 1.5 for the OÁ Á ÁH/ HÁ Á ÁO contacts clearly provides evidence for the formation of O-HÁ Á ÁN, N-HÁ Á ÁO and C-HÁ Á ÁO interactions. The high propensity of N-heterocycles, e.g. pyridyl, to formstacking interactions with benzene is also evident from the high ER values corresponding to CÁ Á ÁC contacts in the structure. On the other hand, the values of ER, i.e. < 0.6, reflects the low propensity for CÁ Á ÁH/HÁ Á ÁC contacts in the structure as the result of significant interactions involving OÁ Á ÁH and NÁ Á ÁH contacts. The enrichment ratios are closer to unity for the NÁ Á ÁH/HÁ Á ÁN contacts, an observation that is consistent with their relatively low contribution to the overall surface area. Finally, ER values close to but slightly less than unity for the HÁ Á ÁH contacts are noted, in accord with expectation (Jelsch et al., 2014). The ER values for other contacts are of low significance as they are derived from less important interactions with small contributions to the overall Hirshfeld surface.

Synthesis and crystallization
The diamide (0.5 mmol), prepared in accord with the literature procedure (Schauer et al., 1997), in ethanol (5 ml) was added to a ethanol solution (5 ml) of 4-nitrobenzoic acid (Merck, 0.5 mmol). The mixture was stirred for 3 h at room temperature. After standing for a few minutes, a white precipitate formed which was filtered off by vacuum suction. The filtrate was then left at room temperature, yielding colourless blocks of the title compound after 2 weeks.