Using cocrystals as a tool to study non-crystallizing molecules: crystal structure, Hirshfeld surface analysis and computational study of the 1:1 cocrystal of (E)-N-(3,4-difluorophenyl)-1-(pyridin-4-yl)methanimine and acetic acid

Using a cocrystal of a molecule that does not crystallize, we reveal that π–π interactions between aromatic rings are present with only two F atoms in the aromatic ring.


Introduction
Understanding intermolecular interactions is fundamental to designing and synthesizing functional solid-state materials.Although there are significant advances in our understanding, there is still much to comprehend (Brammer, 2017;Galek et al., 2014;Gunawardana & Aakero ¨y, 2018).Our research investigates small molecules derived from Schiff bases having an aromatic ring ( F Ar) and a pyridyl group (py).These molecules can form three different types of intermolecular interactions: hydrogen bonds (H-bonds), interactions between the aromatic rings (�-� and C-H� � ��) and halogen bonds (X-bonds) when F, Br or I atoms are present.We have introduced F atoms to the Ar ring ( F Ar) to increase the likelihood of �-interactions between the aromatic rings.We are looking to understand how the number and position of F atoms in F Ar affect the interactions and organization of the molecules in the crystal.Previous studies have indicated that the perfluorinated F Ar ring interacts with the py ring through �-� interactions in both Schiff base (Jaime-Ada ´n et al., 2024) and alkene analogue molecules [Cambridge Structural Database (CSD; Groom et al., 2016) refcodes ADUJOA (Orbach et al., 2012), EQOTOU (Mondal et al., 2011), EQOTOU (Lucassen et al., 2005) and RIDMOH (Aakero ¨y et al., 2007)], while non-fluorinated or mono-fluorinated rings of the Schiff base and the analogue alkene only present C-H� � �� interactions.We aim to investigate how many F atoms are necessary to promote �-� interactions.
Despite our best efforts, we were unable to crystallize disubstituted compounds successfully.However, we did manage to obtain a cocrystal of (E)-N-(3,4-difluorophenyl)-1-(pyridin-4-yl)methanimine (DFPPI) with acetic acid (AcOH), which is an acid that does not contain aromatic rings that may interfere with the possible aromatic interactions.In this article, we present the crystal structure of the 1:1 DFPPI-AcOH cocrystal, (1) (Scheme 1), and reveal the interactions that govern its stability through Hirshfeld surface analysis and computational methodologies.

Experimental
All solvents, starting materials and carboxylic acids were purchased from commercial sources and used without further purification.IR data were collected using a Nicolet 380 FT-IR instrument.The melting point (uncorrected) was determined using a Fischer-Johns Mel-Temp melting-point apparatus.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1.Carbon-bound H atoms were placed in calculated positions and included in the refinement in the riding-model approximation, with U iso (H) values set to 1.2U eq (C).In the final analysis, we explored the isotropic displacement parameter refinement of the O and N atoms, but the results were not significant, so thermal anisotropy was applied.The oxygen-bound H atom was located from a difference Fourier map and refined with U iso (H) = 1.5U eq (O).

Computational studies
The analysis of electron density and interaction energies aims to discern the nature and strength of interactions within the cocrystal.The study began with calculating the Hirshfeld surface (Spackman et al., 2021), where the d norm and shape index (S) were then mapped to identify intermolecular inter-actions and detect �-� interactions, respectively.Afterward, pairwise interaction energies were computed to quantify interaction strength, and an energy framework was derived to characterize the stabilizing interactions within the network.Both the calculation of the Hirshfeld surface and the energy analysis were conducted in CrystalExplorer, employing the CE-B3LYP/6-31G(d,p) level with TONTO (Jayatilaka & Grimwood, 2003;Turner et al., 2015;Mackenzie et al., 2017).Further insights into the interactions were achieved through theoretical electron-density analysis using the GPUAM code (Cruz et al., 2019;Herna ´ndez-Esparza et al., 2014, 2018), which combines two methodologies, namely, the Quantum Theory of Atoms in Molecules (QTAIM) and the Non-Covalent Interactions (NCI) Index.The theoretical electron density was generated using GAUSSIAN16 [B3LYP/6-31G(d,p)] (Frisch et al. 2016).

Results and discussion
Cocrystal (1) consists of one DFPPI molecule and one acetic acid molecule in its asymmetric unit (Fig. 1).The crystal system is triclinic and belongs to the space group P1.The imine group has an E conformation.The DFPPI molecule is not planar, as evidenced by the relevant torsion angles (Table 2) and the dihedral angle of 29.89 (5) � between the planes of the pyridine (py) and aromatic ( F Ar) rings.The AcOH molecule shows C-O distances according to single and double C-O bonds, in agreement with the presence of an acid group and not a carboxylate, as expected for a cocrystal.The C-O bonds in the AcOH molecule are nearly in the same plane as the py ring.This is confirmed by the angle formed between the py ring and the heavy atoms of AcOH, which measures 10.80 (6) � .The AcOH molecule forms an O1-H1� � �N1 i hydrogen bond with the N1 atom of the py from the imine (Table 3).Moreover, it shows py� � �py and F Ar� � � F Ar �-� interactions, with centroid-centroid distances of Cg(py)� � �Cg(py) = 3.8047 (6) A ˚and Cg( F Ar)� � �Cg( F Ar) = 3.8047 (7) A ˚; these interactions organize the molecules in columns [Fig.2(a)] and the columns close pack to build the crystal [Fig.2(b)].
We used the CrystalExplorer program to generate Hirshfield surfaces and mapped them with d norm and shape index, and two-dimensional (2D) fingerprints to determine the intermolecular interactions (McKinnon et al., 2007).Fig. 3 shows the 2D fingerprints of DFPPI and AcOH.The plots show the typical wing structures with a non-symmetric long pick, which corresponds to the N1� � �H1 interaction on the DFPPI molecule and H1� � �N1 in the AcOH molecule, corresponding to the O1-H1� � �N1 i hydrogen bond between both molecules.There is another hydrogen bond, namely, C2-H2� � �O2 ii , i.e.C2-H2� � �O2 in DFPPI and O2� � � H2-C2 in AcOH.Additionally, the fingerprint of DFPPI indicates bonds of the type C-H� � �F and interactions between the C atoms, suggesting �-� interactions.Table 4 presents selected results from the calculation of pairwise interaction energies relative to the DFPPI molecule, along with a colour-coded molecular cluster illustrating these interactions.As expected, the most robust interaction, highlighted in red, was observed between the DFPPI molecule and the AcOH molecule.This interaction involves a hydrogen bond between O-H(acid) and N(py), with a total interaction energy (E tot ) of À 49.4 kJ mol À 1 .The interactions between DFPPI molecules stacked on top of each other, coloured in green in Table 4,  Selected geometric parameters (A ˚, � ).

Table 4
Pairwise interaction energy analysis using B3LYP/6-311G(d,p) as the energy model.
The energies (E) are in kJ mol À 1 and the radial distance (R) in A ˚.The colour-coded molecular cluster is related to the specific interaction energy.electrostatic forces, with dispersive interactions having an important contribution, which is more significant between stacked molecules.
Theoretical electron-density analysis generates a spatial visualization and classifies pairwise interactions as attractive or repulsive (Fig. 6).Focusing on the four pairs with the most Hirshfeld surface mapped with (a) d norm , with the hydrogen bonds between molecules, and (b) shape index.The red and blue triangles inside the rings agree with the presence of �-� interactions.

Figure 5
Perspective and top views of the energy frameworks of the cocrystal, showing the (a) electrostatic energy, (b) dispersion energy and (c) total energy.The radius of the cylinders is proportional to the relative strength of the corresponding energies.They were adjusted to the same scale factor of 80 with a cutoff value of 0 kJ mol À 1 within a 2 � 2 � 2 unit cell.

Figure 6
Plots of the reduced gradient of the density s(r) versus the electron density multiplied by the second Hessian eigenvalue (top) and molecular diagrams with the isosurfaces (isovalue = 0.5) of the s(r), the bond trajectories (pink) and the critical points (yellow) that exhibit the contacts for the dimers where the interactions were the strongest, based on the magnitude of E tot .Parts (a)-(d) are for dimers corresponding to entries 1-4 of Table 4.
negative E tot values, we observe bond trajectories for O-H� � �N and C-H� � �O hydrogen-bond contacts.Based on the NCI index, these interactions are attractive.Electrostatic interactions play a significant role in the total interaction energy of molecular pairs.Regarding stacking interactions, bonding trajectories connecting C atoms of interacting DFPPI molecules are identifiable, accompanied by a prominent isosurface indicative of weakly attractive stacking.Such characteristics align with the heightened dispersive character suggested by the E tot components for these pairs.
Our assumption that a cocrystal would help study the intermolecular interactions of molecules that do not crystallize was successful.We found that having two F atoms in the aromatic ring is sufficient to promote �-� interactions between the aromatic rings, and further halogenation of the F Ar ring is unnecessary.

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.

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Sa ´nchez-Pacheco et al. � Cocrystals as a tool to study non-crystallizing molecules Acta Cryst.(2024).C80, 343-348 Fig. 4(a) displays the Hirshfeld surface, mapped with d norm , which shows the existence of O-H� � �N(py) and C-H� � �O hydrogen bonds.Fig. 4(b) shows the Hirshfeld surface mapped with shape index; the complementary blue and red triangles observed in the aromatic rings indicate the presence of �-� interactions between the F Ar and py rings (McKinnon et al., 2004).

Figure 2
Figure 2 The intermolecular interactions in (1).Hydrogen bonds are indicated as red dashed lines and �-� interactions as green dashed lines.(a) View of the molecules organized in columns through �-� interactions.(b) The packing of molecules along the a axis, showing the O-H� � �N(py) hydrogen bonding.

Figure 1 Figure 3
Figure 1The asymmetric unit of cocrystal (1), showing the atom-numbering scheme.Displacement ellipsoids are drawn at the 50% probability level and H atoms at an arbitrary size.

Table 1
Experimental details.