Crystal structure, Hirshfeld surface analysis and computational study of the 1:2 co-crystal formed between N,N′-bis(pyridin-4-ylmethyl)ethanediamide and 4-chlorobenzoic acid

In the title 1:2 co-crystal, 4 LH2:2CBA, two independent three-molecule aggregates, i.e. 4 LH2(CBA)2, are formed, each located about a centre of inversion and sustained by carboxylic acid-O—H⋯N(pyridyl) hydrogen bonding. The three-molecule aggregates are connected into a supramolecular tape by amide-N—H⋯O(amide) hydrogen bonding.

The asymmetric unit of the title 1:2 co-crystal, C 14 H 14 N 4 O 2 Á2C 7 H 5 ClO 2 , comprises two half molecules of oxalamide ( 4 LH 2 ), as each is disposed about a centre of inversion, and two molecules of 4-chlorobenzoic acid (CBA), each in general positions. Each 4 LH 2 molecule has a (+)antiperiplanar conformation with the pyridin-4-yl residues lying to either side of the central, planar C 2 N 2 O 2 chromophore with the dihedral angles between the respective central core and the pyridyl rings being 68.65 (3) and 86.25 (3) , respectively, representing the major difference between the independent 4 LH 2 molecules. The anti conformation of the carbonyl groups enables the formation of intramolecular amide-N-HÁ Á ÁO(amide) hydrogen bonds, each completing an S(5) loop. The two independent CBA molecules are similar and exhibit C 6 /CO 2 dihedral angles of 8.06 (10) and 17.24 (8) , indicating twisted conformations. In the crystal, two independent, three-molecule aggregates are formed via carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonding. These are connected into a supramolecular tape propagating parallel to [100] through amide-N-HÁ Á ÁO(amide) hydrogen bonding between the independent aggregates and ten-membered {Á Á ÁHNC 2 O} 2 synthons. The tapes assemble into a three-dimensional architecture through pyridyl-and methylene-C-HÁ Á ÁO(carbonyl) and CBA-C-HÁ Á ÁO(amide) interactions. As revealed by a more detailed analysis of the molecular packing by calculating the Hirshfeld surfaces and computational chemistry, are the presence of attractive and dispersive ClÁ Á ÁC O interactions which provide interaction energies approximately one-quarter of those provided by the amide-N-HÁ Á ÁO(amide) hydrogen bonding sustaining the supramolecular tape.

Chemical context
This paper describes the X-ray crystal structure determination of, and an analysis of the supramolecular association in the 1:2 co-crystal formed between bis(pyridin-4-ylmethyl)ethanediamide and 4-chlorobenzoic acid, (I). The isomeric bis(pyridinn-ylmethyl)ethanediamide molecules, i.e. molecules of the general formula n-NC 5 H 4 CH 2 N(H)C( O)C( O)CH 2 -C 5 H 4 N-n, for n = 2, 3 and 4, hereafter abbreviated as n LH 2 , are of interest as co-crystal co-formers owing to the presence of amide and pyridyl hydrogen bonding possibilities in their molecular structures (Tiekink, 2017). In a recent survey of cocrystals formed between 4 LH 2 and carboxylic acids (Tan & Tiekink, 2020), the formation of carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonds in their co-crystals was reported to be universal with only one exception. The odd cocrystal was the 1:1 co-crystal formed between 4 LH 2 and 2-[(4hydroxyphenyl)diazenyl]benzoic acid (Arman et al., 2009). ISSN 2056-9890 Within the acid, an intramolecular carboxylic acid-O-HÁ Á ÁN(azo) hydrogen bond is instituted instead, leading to the formation of a S(6) loop, an observation entirely in accord with expectation (Etter, 1990). The remaining co-crystal structures of 4 LH 2 with different carboxylic acids were stabilized by the expected carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonds, at both ends of the 4 LH 2 molecule. The formation of such O-HÁ Á ÁN hydrogen bonding is consistent with literature precedent, which indicates a very high propensity for these hydrogen-bonding patterns between carboxylic acids and pyridyl entities, at least in the absence of competing supramolecular synthons (Shattock et al., 2008). In only one case of co-crystallization experiments of 4 LH 2 with carboxylic acids was a salt formed owing to proton transfer, i.e. in the structure of [ 4 LH 4 ][2,6-dinitrobenzoate] 2 , where pyridinium-N-HÁ Á ÁO(carboxylate) hydrogen bonds are formed instead (Arman, Miller et al., 2012). The title co-crystal, (I), was studied in continuation of on-going investigations of 4 LH 2 co-crystals of carboxylic acid co-formers (Arman et al., 2012(Arman et al., , 2013(Arman et al., , 2014Syed et al., 2016;Tan, Halcovitch et al., 2019;.

Structural commentary
The crystallographic asymmetric unit of (I) comprises two half molecules of 4 LH 2 , each being disposed about a centre of inversion, and two molecules of 4-chlorobenzoic acid (CBA), each in a general position. Pairs of 4 LH 2 and CBA molecules are connected via carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonding, Table 1, and with the application of symmetry, two independent, three-molecule aggregates eventuate, i.e. 4 LH 2 (CBA) 2 , as shown in Fig. 1.
As each 4 LH 2 molecule is centrosymmetric, the central C 2 N 2 O 2 chromophore in each is strictly planar. As is usually found in these molecules (Tiekink, 2017;Tan & Tiekink, 2020), the central C7-C7 i [1.537 (2) Å ] and C14-C14 ii [1.539 (2) Å ] bond lengths are longer than usual owing to the electronegative substituents connected to both carbon atoms [symmetry operations (i) 1 À x, 2 À y, À z and (ii) 2 À x, 2 À y, À z]. The conformation of each 4 LH 2 molecule is (+)antiperiplanar whereby the pyridin-4-yl residues lie to either side of the planar region of the molecule. The dihedral angles between the respective central core and the N1-and N3pyridyl rings are 68.65 (3) and 86.25 (3) , respectively. This represents the greatest conformational difference between the 4 LH 2 molecules and is emphasized in the overlay diagram of Fig. 2 which shows the two independent, three-molecule aggregates. Finally, the carbonyl groups are anti, enabling the formation of intramolecular amide-N-HÁ Á ÁO(amide) hydrogen bonds that complete S(5) loops, Table 1.

Figure 2
An overlay diagram of the two independent, three-molecule aggregates in (I). The N1-pyridyl/O3-carboxylic acid (red image) and N3-pyridyl/O5carboxylic acid (blue image) aggregates have been overlapped so that the central C 2 N 2 O 2 chromophores are coincident.

Figure 1
The molecular structures of the two centrosymmetric three-molecule aggregates in the crystal of (I) showing the atom-labelling scheme and displacement ellipsoids at the 70% probability level. In (a), the unlabelled atoms are related by the symmetry operation (i) 1 À x, 2 À y, À z and in (b), by (ii) 2 À x, 2 À y, À z.
ably shorter than the C15-O4(hydroxy) bond of 1.3196 (16) Å ; the bonds of the O5-benzoic acid follow the same trend with C22-O5 of 1.2173 (17) Å compared with C22-O6 of 1.3181 (16) Å . As seen from Fig. 2, the attached benzoic acid molecules are each twisted out of the plane through the pyridyl ring they are connected to as seen in the N1-pyridyl/O3-carboxylic acid dihedral angle of 41.70 (4) ; the corresponding angle for the second three-molecule aggregate is 35.47 (3) .

Supramolecular features
The formation of two independent, three-molecule aggregates has already been noted above in the crystal of (I) as has the intramolecular amide-N-HÁ Á ÁO(amide) hydrogen bonds,  Fig. 3(a). The tapes are consolidated into a three-dimensional architecture by pyridyl-and methylene-C-HÁ Á ÁO(carbonyl) and CBA-C-HÁ Á ÁO(amide) interactions, Fig. 3(b).

Hirshfeld surface analysis
The calculation of the Hirshfeld surfaces and two-dimensional fingerprint plots were accomplished with the program Crystal Explorer 17 (Turner et al., 2017) using procedures described in the literature (Tan, Jotani et al., 2019;Jotani et al., 2019). The input for the calculations were the two independent threemolecule aggregates, hereafter 3M-I and 3M-II, shown in Fig. 2, whereby two chlorobenzoic acid (CBA) molecules are connected to each 4 LH 2 molecule via carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonds. Analogous calculations were also performed on the symmetry expanded N1-and N3oxalamide molecules, hereafter 4 LH 2 -I and 4 LH 2 -II, respectively, and on the independent O3-and O5-chlorobenzoic acid molecules, hereafter CBA-I and CBA-II, respectively. The d norm distances for short contacts identified through the Hirshfeld surface analysis are given in Table 2. Several d norm maps showing red spots ranging from moderate to strong intensity are illustrated in Fig

Table 2
A summary of short interatomic contacts (Å ) in (I) a .
Qualitatively, the d norm maps for 3M-I and 3M-II exhibit similarity for the corresponding 4 LH 2 and CBA molecules with the exception of CBA-II. Pairs of CBA-II are aligned around an inversion centre with Cl2 and H25 being directly opposite each other, ostensibly forming an eight-membered heterosynthon despite the distance being longer than the cutoff value of 2.84 Å (Spek, 2020); such an alignment is not observed for CBA-I. In addition, there are other close contacts: C1-H1Á Á ÁO3, C6-H6AÁ Á ÁO3, C7Á Á ÁCl1, Cl2Á Á ÁC14, O1Á Á ÁCl1 and Cl2Á Á ÁO2, which were not identified in the PLATON (Spek, 2020) analysis.
To establish the nature of the intermolecular interactions, particularly for the weaker contacts, a mapping of the electrostatic potential (ESP) was performed over the Hirshfeld surfaces through DFT-B3LYP/6-31G(d,p) for the independent 4 LH 2 and CBA molecules in (I), Fig. 5. The results indicate the C1-H1Á Á ÁO3, C6-H6AÁ Á ÁO3, C7Á Á ÁCl1, Cl2Á Á ÁC14, O1Á Á ÁCl1 and Cl2Á Á ÁO2 contacts are indeed electrostatic in nature, as shown from the red (electronegative) and blue (electropositive) regions on the ESP maps despite being relatively less intense when compared to those arising from the classical hydrogen bonds.
ESP calculations were also performed on the individual molecules through Gaussian 16 (Frisch et al., 2016) using the long-range corrected wB97XD density functional with Grimme's D2 dispersion density functional theoretical model (Chai & Head-Gordon, 2008) coupled with Pople's 6-311+G(d,p) basis set (Petersson et al., 1988) in order to validate the above results. The calculations show that the individual 4 LH 2 and CBA molecules possess similar electrostatic surface potentials with the red and blue regions representing the extremities of the electrostatic potential spectrum, Fig. 6.
Of particular interest is the observation that the chlorine atom interacts with the amide-C O residue through an electron-deficient -hole region. To complement the ESP findings on these OÁ Á ÁCl and CÁ Á ÁCl contacts, non-covalent interaction plots were generated for the relevant pairwise molecules using NCIPLOT (Johnson et al., 2010). The results, as shown from the green domain on the isosurface between the 4 LH 2 and CBA molecules in Fig. 7  (a) The NCI plot highlighting the OÁ Á ÁCl and CÁ Á ÁCl contacts between 4 LH 2 -I and CBA-I molecules, showing the weak, but attractive interactions through the green domain and (b) the two-dimensional reduced density gradient versus the electron density times the sign of the second Hessian eigenvalue which reveals the overall contact profile of the pairwise molecules. The gradient cut-off is set at 0.4 and the colour scale is À0.25 < < 0.25 a.u.

Figure 6
The electrostatic potential surface mapping for 4 LH 2 and CBA as obtained from Gaussian 16, showing the average ESP charge on the surface of the point of contact for the Cl1/Cl2, C7/C14 and O1/O2 interactions. The electrostatic potential was mapped onto the isodensity surface (0.0004 a.u.) within the scale of À0.0312 to 0.0312 a.u.
surface at the point of contacts calculated with Crystal Explorer 17 employing B3LYP/6-31G(d,p) are comparable to the data obtained from Gaussian 16, in which Cl1, O1, Cl2 and O2 possess charges of +0.0054, À0.0147, +0.0054 and À0.0125 atomic units (a.u.), respectively; while the C7 and C14 atoms each exhibit a weak electrostatic potential charge of +0.0251 and +0.0263 a.u., respectively. Therefore, the C7Á Á ÁCl1 and C14Á Á ÁCl2 interactions are dispersive in nature. On the other hand, the apparent charge complementarity between the Cl2 and H25 atoms, which align around a centre of inversion as described above, indicate the existence of an electrostatic interaction between two CBA-II molecules, Fig. 5   The two-dimensional fingerprint plots were generated in order to quantify the close contacts for 4 LH 2 -I, 4 LH 2 -II, CBA-I, CBA-II, 3M-I and 3M-II. The overall fingerprint plots for the specified molecules/aggregates are shown in Fig. 8(a) and those decomposed into HÁ Á ÁO/OÁ Á ÁH/ HÁ Á ÁC/CÁ Á ÁH, HÁ Á ÁN/ NÁ Á ÁH and HÁ Á ÁCl/ClÁ Á ÁH plots are shown in Fig. 8 The overall fingerprint plot of the individual components and the corresponding three-molecule aggregates exhibit a paw-like profile with asymmetric spikes indicating the interdependency of the intermolecular interactions between molecules to sustain the packing.  For HÁ Á ÁCl/ClÁ Á ÁH in 3M-II, the contacts are each tipped at $2.80 Å owing to the pair of (internal)-H25Á Á ÁCl2-(external) and (internal)-Cl2Á Á ÁH25-(external) interactions. As for the HÁ Á ÁH and HÁ Á ÁC/ CÁ Á ÁH contacts, their d i + d e distances are longer than the sum of their respective van der Waals radii of 2.18 and 2.79 Å , and hence contribute little to the overall packing of the crystal despite providing the predominant surface contacts.

Computational chemistry
The calculation of the interaction energies for all pairwise interacting molecules was performed through Crystal Explorer 17 (Turner et al., 2017) based on the method reported previously (Tan, Jotani et al., 2019) in order to study the strength of each interaction identified from the Hirshfeld surface analysis. The calculations showed that the tenmembered synthons formed between 4 LH 2 -I and 4 LH 2 -II  x, 1 + y, À1 + z C6-H6AÁ Á ÁO3/ C2-H2Á Á ÁO3 À11.9 À3.2 À12.5 16.5 À15.8 À6.4 À0.7 À13.5 16.7 À8.7 Àx, À y, À z C27-H27Á Á ÁO1 À10.4 À1.6 À23.4 19.7 À20.4 1 À x, 1 À y, 1 À z through amide-N2-H2NÁ Á ÁO2(amide) and amide-N4-H4NÁ Á ÁO1(amide) hydrogen bonds has the greatest energy among all close contacts present in the crystal with an interaction energy (E int ) of À61.9 kJ mol À1 . This is followed by the seven-membered heterosynthon formed between 4 LH 2 -II and CBA-II through the carboxylic acid-O4-H4OÁ Á ÁN1(pyridyl) hydrogen bond with the supporting pyridyl-C-H8Á Á Á O5(carbonyl) contact so that E int = À52.0 kJ mol À1 . For the analogous contact between 4 LH 2 -I and CBA-I but lacking the supporting pyridyl-C-HÁ Á ÁO5(carbonyl) contact, it is gratifying to note the interaction energy is correspondingly less, i.e. E int = À49.4 kJ mol À1 . The interactions between amide-C7Á Á ÁCl1 and amide-O1Á Á ÁCl1, summing to E int of À16.6 kJ mol À1 , are also significant, as are the interactions between methylene-C-H6AÁ Á ÁO3(amide) and pyridyl-C2-H2Á Á ÁO3(amide) with E int = À15.8 kJ mol À1 . The equivalent interactions surrounding the 4 LH 2 -II molecule follow the same trends and give similar energies, Table 3. The benzoic-C25-H25Á Á ÁCl2 dimer arising from the connection between two CBA-II molecules is weakly interacting with E int of À8.7 kJ mol À1 . Finally, the C27-H27Á Á ÁO1(amide) interaction exhibits an E int of À20.4 kJ mol À1 . The crystal of (I) is mainly governed by electrostatic forces (E ele ) as highlighted by the rod-shaped energy framework with a zigzag topology due to the combination of several strong interactions, Fig. 9(a). Specifically, the combination of interactions between 4 LH 2 -I and CBA-I through the terminal O4-H4OÁ Á ÁN1 hydrogen bonding as well as between 4 LH 2 -II and CBA-II via O6-H6OÁ Á ÁN3 and C8-H8Á Á ÁO5 interactions leads to the formation of the core framework parallel to (101). The overall E ele of these interactions is much greater than that associated with the ten-membered synthons formed by a combination of N2-H2NÁ Á ÁO2 and N4-H4NÁ Á ÁO1 hydrogen bonds as evidenced from the relatively small rod radius in the energy model of the latter interactions, which align in a parallel fashion along the b axis, Fig. 9(a).
Apart from the electrostatic forces, the crystal is also sustained by substantial dispersion forces, which are mainly associated with the ten-membered {Á Á ÁHNC 2 O} 2 synthon along with the peripheral C7Á Á ÁCl1/O1Á Á ÁCl1 and C14Á Á ÁCl2/ O2Á Á ÁCl2 interactions which lead to a ladder-like topology, Fig. 9(b). The combination of the electrostatic and dispersion forces results in an enhancement of the influence of the tenmembered synthons which supersedes the energy force for the terminal carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonds as seen in the total energy framework, Fig. 9(c).

Database survey
The formation of carboxylic acid-O-HÁ Á ÁN(pyridyl) hydrogen bonds, involving both pyridyl rings, leading to threemolecule aggregates, is an almost universal trait when cocrystals are formed between 4 LH 2 and mono-functional carboxylic acids; one exception was noted in the Chemical context. A different situation pertains when bi-functional carboxylic acids are employed in co-crystal formation. In these circumstances, e.g. when the carboxylic acid is bis(carboxymethyl)urea and diglycineoxamide (Nguyen et al., 2001), twodimensional sheets result, owing to strands of {Á Á ÁHO 2 C-R-CO 2 HÁ Á Á 4 LH 2 Á Á ÁHO 2 C-R-CO 2 HÁ Á Á} n being connected by almost orthogonal tapes comprising ten-membered {Á Á ÁHNC 2 O} 2 synthons provided by the 4 LH 2 molecules. These are reinforced by hydrogen bonding afforded by the R residues of the bi-functional carboxylic acids, e.g. linked by sixmembered synthons {Á Á ÁHNCNHÁ Á ÁO} provided by the urea bridges in the case of bis(carboxymethyl)urea (Nguyen et al., 2001). Clearly, scope remains for the development of novel Perspective views of the energy frameworks of (I), showing the (a) electrostatic force, (b) dispersion force and (c) total energy. The radius of the cylinders is proportional to the relative strength of the corresponding energies and they were adjusted to the same scale factor of 100 with a cut-off value of 8 kJ mol À1 within a 2 Â 2 Â 2 unit cells. supramolecular architectures in co-crystals comprising 4 LH 2 and multi-functional carboxylic acids.