A 2:1 co-crystal of 2-methylbenzoic acid and N,N′-bis(pyridin-4-ylmethyl)ethanediamide: crystal structure and Hirshfeld surface analysis

The 2:1 acid/diamide co-crystal sees the components connected into three-molecule aggregates via hydroxy-O—H⋯N(pyridyl) hydrogen bonds. The aggregates are linked into a supramolecular layer via amide-N—H⋯O(carbonyl) and methylene-C—H⋯O(amide) interactions. The three-dimensional packing is consolidated by π–π interactions involving all the aromatic residues.


Chemical context
Multi-component crystals, incorporating co-crystals, salts and co-crystal salts, attract continuing interest for a wide variety of applications as this technology may be employed, for example, to provide additives to promote the growth of crystals, to stabilize unusual and unstable coformers, to generate new luminescent materials, to separate enantiomers, to facilitate absolute structure determination where the molecule of concern does not have a significant anomalous scatterer, etc. (Aakerö y, 2015;Tiekink, 2012). Arguably, the areas attracting most interest in this context are the applications of multicomponent crystals in the pharmaceutical industry (Duggirala et al., 2016). Controlled/designed crystallization of multicomponent crystals requires reliable synthon formation between the various components and that, of course, is the challenge of crystal engineering, let alone engineering small aggregates within crystals (Tiekink, 2014).
Systematic work on synthon propensities in multi-component crystals have revealed that carboxylic acids have a great likelihood of forming hydroxy-O-HÁ Á ÁN hydrogen bonds when co-crystallized with molecules with pyridyl residues (Shattock et al., 2008). A plausible explanation for this reliability is the formation of a supporting carbonyl-OÁ Á ÁH interaction involving the hydrogen atom adjacent to the pyridyl-nitrogen atom. Indeed, in the absence of competing hydrogenbonding functionality, the resulting seven-membered {Á Á ÁHOCOÁ Á ÁHCN} heterosynthon is formed in more than 98% of relevant crystal structures (Shattock et al., 2008). Recent systematic work in this phenomenon relates to molecules shown in Scheme 1, where isomeric molecules with two pyridyl rings separated by a diamide residue have been cocrystallized with various carboxylic acids Arman et al., 2013Jotani et al., 2016). As a continuation of these studies, the title 2:1 co-crystal was isolated and characterized crystallographically and by Hirshfeld surface analysis.

Structural commentary
The title co-crystal, Fig. 1, was formed from the 1:1 co-crystallization of 2-methylbenzoic acid (hereafter, the acid) and N,N 0 -bis(pyridin-4-ylmethyl)ethanediamide (hereafter, the diamide) conducted in ethanol solution. The asymmetric unit comprises a full acid molecule in a general position and half a diamide molecule, located about a centre of inversion, so the co-crystal is formulated as a 2:1 acid:diamide co-crystal.
In the acid, the carboxylic acid group is twisted out of the plane of the benzene ring to which it is attached with the O3-C8-C9-C10 torsion angle being 150.23 (14) , and, to a first approximation, with the carbonyl-O3 atom and methyl group lying to the same side of the molecule as indicated in the O2-C8-C9-C10 torsion angle of À27.92 (17) . The structure of the parent acid and several co-crystals featuring coformers shown in Scheme 2 are available for comparison; data are collected in Table 1. The common feature of all structures is the relative orientation of the carbonyl-O and methyl groups. Twists in the acid molecules vary from almost co-planar to the situation found in the title co-crystal, with an even split of conformations amongst the six known co-crystal structures.
In the centrosymmetric diamide, the central C 4 N 2 O 2 core is essentially planar with an r.m.s. deviation (O1, N2, C6, C7 and symmetry equivalents) = 0.031 Å . This arrangement facilitates The molecular structures of the molecules comprising the title co-crystal showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level: (a) 2-methylbenzoic acid and (b) N,N 0 -bis(pyridin-4-ylmethyl)ethanediamide; unlabelled atoms in the diamide are generated by the symmetry operation (À1 À x, 2 À y, 1 À z). Table 1 Dihedral and torsion angles ( ) for 2-methylbenzoic acid in the title co-crystal and in literature precedents.  Table 3. Finally, the central C-C bond length, considered long for a Csp 2 -Csp 2 bond (Spek, 2009), matches the structural data included in Table 3; see Scheme 3 for chemical diagrams of coformers.

Analysis of the Hirshfeld surfaces
Crystal Explorer 3.1 (Wolff et al., 2012) was used to generate Hirshfeld surfaces mapped over d norm , d e , electrostatic potential, shape-index and curvedness for the title 2:1 cocrystal. The electrostatic potentials were calculated using TONTO (Spackman et al., 2008;Jayatilaka et al., 2005) integrated with Crystal Explorer, using the experimentally determined geometry as the input. Further, the electrostatic potentials were mapped on Hirshfeld surfaces using the STO-3G basis set at Hartree-Fock theory over a range AE0.15 au. The contact distances d i and d e from the Hirshfeld surface to the nearest atom inside and outside, respectively, enabled the analysis of the intermolecular interactions through the mapping of d norm .  Table 3 Selected geometric details (Å , ) for N,N 0 -bis(pyridin-4-ylmethyl)ethanediamide molecules and protonated forms a .
The prominent long spike at d e + d i $1.8 Å in the upper left (donor) region for the FP plot of the acid corresponds to HÁ Á ÁN contacts and the spike at the same distance in the lower right (acceptor) region of the FP plot for the diamide are the result of hydroxy-O-HÁ Á ÁN(pyridyl) interactions, Fig. 5a and b, respectively. However, these spikes are not apparent in the overall FP for the 2:1 co-crystal as they no longer contribute to the surface of the resultant aggregate, Fig. 5c. Pairs of somewhat blunted spikes corresponding to NÁ Á ÁH/HÁ Á ÁN contacts at d e + d i $ 2.9 Å result from amide-N-HÁ Á ÁO(carbonyl) interactions between the acid and diamide molecules are evident in the overall FP, Fig. 5c.
The OÁ Á ÁH/HÁ Á ÁO contacts, which make a significant contribution to the molecular packing, show different characteristic features in the respective delineated FP plots of the acid and diamide. For the acid, Fig. 5a, a long prominent spike at d e + d i $ 2.5 Å in the acceptor region corresponds to a 6.6% contribution from HÁ Á ÁO contacts to the Hirshfeld surface, and a short spike at d e + d i $ 2.15 Å in the donor region with a 14.0% contribution. The reverse situation is observed for the diamide molecule wherein the FP plot, Fig. 5b

Figure 4
Hirshfeld surfaces mapped over d norm showing hydrogen bonds with neighbouring molecules with the reference molecule being the (a) acid and (b) diamide.
prominent spike in the donor region and the short spike in the acceptor at the same d e + d i distance, and with 10.7 and 14.9% contributions from OÁ Á ÁH and HÁ Á ÁO contacts, respectively. FP plots for the co-crystal delineated into HÁ Á ÁH, OÁ Á ÁH/ HÁ Á ÁO, CÁ Á ÁH/HÁ Á ÁC, NÁ Á ÁH/HÁ Á ÁN and CÁ Á ÁC are shown in Fig. 6a-e, respectively. The HÁ Á ÁH contacts appear as asymmetrically scattered points covering a large region of the FP plot with a single broad peak at d e = d i $ 1.2 Å for each of the co-crystal constituents, with percentage contributions of 48.7 and 45.7% for the acid and diamide molecules, respectively.
The overall 49.9% contribution to Hirshfeld surface of the cocrystal results in nearly symmetric through the superimposition of individual fingerprint plots, Fig. 6a.
The FP plot for OÁ Á ÁH/HÁ Á ÁO contacts, Fig. 6b, has two pairs of spikes superimposed in the (d e , d i ) region with minimum d e + d i distances $ 2.2 and 2.5 Å . These correspond to a 21.3% contribution to the Hirshfeld surface, and reflect the presence of intermolecular N-HÁ Á ÁO and C-HÁ Á ÁO interactions, identified with labels 1 and 2 in Fig. 6b. The 15.9% contribution from the CÁ Á ÁH/HÁ Á ÁC contacts to the Hirshfeld surface results in a symmetric pair of wings, Fig. 6c. The FP plot corresponding to CÁ Á ÁC contacts, Fig. 6e, in the (d e , d i ) region between 1.7 to 2.2 Å appears as the two distinct, overlapping triangles identified with red and yellow boundaries in Fig. 6e, and shows two types ofstacking interactions: one between dissimilar rings (pyridyl and benzene) and the other between symmetry-related rings (benzene and benzene, and pyridyl and pyridyl). The presence of thesestacking interactions is also indicated by the appearance of red and blue triangles on the shape-indexed surfaces identified with arrows in the images of Fig. 7, and in the flat regions on the Hirshfeld surfaces mapped with curvedness in Fig. 8.
The intermolecular interactions were further assessed by using the enrichment ratio, ER (Jelsch et al., 2014). This is a relatively new descriptor and is based on Hirshfeld surface analysis. The ER for the co-crystal together with those for the acid and diamide molecules are listed in  Table 6 Enrichment ratios (ER) for the acid, diamide and co-crystal.   Hirshfeld surfaces mapped over the shape index for (a) the acid and (b) the diamide, highlighting the regions involved instacking interactions.
contribution to the Hirshfeld surfaces are from HÁ Á ÁH contacts,

Database survey
As mentioned in the Chemical context, the diamide in the title 2:1 co-crystal and isomeric forms have attracted considerable interest in the crystal engineering community no doubt owing to the variable functional groups and conformational flexibility. Indeed, the diamide in the title co-crystal featured in early studies of halogen IÁ Á ÁN halogen bonding (Goroff et al., 2005). Over and above these investigations, the role of the diamide in coordination chemistry has also been studied. Bidentate bridging is the prominent coordination mode observed in both neutral, e.g. [HgI 2 (diamide)] n (Zeng et al., 2008) and charged, e.g. polymeric [Ag(diamide)NO 3 ] n (Schauer et al., 1998) and oligiomeric {[Ph 2 PCH 2 PPh 2 Au 2 (diamide)] 2 (ClO 4 ) 4 (EtOEt) 4 } (Tzeng et al., 2006), species.

Figure 8
Hirshfeld surfaces mapped over curvedness for (a) the acid and (b) the diamide, highlighting the regions involved instacking interactions.
stand under ambient conditions, yielding colourless prisms after 2 weeks.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 7. The carbon-bound H-atoms were placed in calculated positions (C-H = 0.95-0.99 Å ) and were included in the refinement in the riding-model approximation, with U iso (H) set to 1.2U eq (C). The oxygen-and nitrogenbound H-atoms were located in a difference Fourier map but were refined with distance restraints of O-H = 0.84AE0.01 Å and N-H = 0.88AE0.01 Å , and with U iso (H) set to 1.5U eq (O) and 1.2U eq (N).

Computing details
Data collection: CrysAlis PRO (Agilent, 2014); cell refinement: CrysAlis PRO (Agilent, 2014); data reduction: CrysAlis PRO (Agilent, 2014); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2010). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.