Crystal structure of diclazuril, C17H9Cl3N4O2

The crystal structure of diclazuril has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Diclazuril crystallizes in space group P21/a (#14) with a = 27.02080(18), b = 11.42308(8), c = 5.36978(5) Å, β = 91.7912(7)°, V = 1656.629(15) Å3, and Z = 4. The crystal structure consists of layers of molecules parallel to the ac-plane. A strong N–H⋯O hydrogen bond links the molecules into dimers along the a-axis with a graph set R2,2(8). The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

This work was carried out as part of a project (Kaduk et al., 2014) to determine the crystal structures of largevolume commercial pharmaceuticals, and include high-quality powder diffraction data for them in the Powder Diffraction File (Gates-Rector and Blanton, 2019).

II. EXPERIMENTAL
Diclazuril was a commercial reagent, purchased from TargetMol (Lot #112009), and was used as-received. The white powder was packed into a 1.5 mm diameter Kapton capillary, and rotated during the measurement at ∼50 Hz. The powder pattern was measured at 295 K at beamline 11-BM Lee et al., 2008;Wang et al., 2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.458208(2) Å from 0.5 to 50°2θ with a step size of 0.0009984375 and a counting time of 0.1 s per step. The high-resolution powder diffraction data were collected using twelve silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A silicon (NIST SRM 640c) and alumina (SRM 676a) standard (ratio Al 2 O 3 :Si = 2:1 by weight) was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.
The pattern was indexed using N-TREOR (Altomare et al., 2013) on a primitive monoclinic cell with a = 27.02114, b = 11.43736, c = 5.37083 Å, β = 91.810°, V = 1659.0 Å 3 , and Z = 4. A reduced cell search in the Cambridge Structural Database (Groom et al., 2016) with the chemistry H, C, Cl, N, and O only yielded one hit, but no structures of diclazuril. The suggested space group was P2 1 /a, which was confirmed by successful solution and refinement of the structure. A diclazuril molecule was downloaded from PubChem (Kim et al., 2019) as Conformer3D_CID_465389.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., 2020). The structure was solved by Monte Carlo simulated annealing as implemented in EXPO2014 (Altomare et al., 2013).
Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, 2013). Only the 1.8-30.0°portion of the Figure 1. The 2D molecular structure of diclazuril. a) Author to whom correspondence should be addressed. Electronic mail: kaduk@polycrystallography.com pattern was included in the refinement (d min = 0.885 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., 2004;Sykes et al., 2011). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 4.2% to the final χ 2 . The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2021). The U iso of the heavy atoms were grouped by chemical similarity. The U iso for the H atoms were fixed at 1.2× the U iso of the heavy atoms to which they are attached. No preferred orientation model was necessary for this rotated capillary specimen. The peak profiles were described using the generalized microstrain model. The background was modeled using a 6-term shifted Chebyshev polynomial, and a peak at 5.72°2θ to model the scattering from the Kapton capillary and any amorphous component.
The final refinement of 106 variables using 28 245 observations and 68 restraints yielded the residuals R wp = 0.0633 and GOF = 1.16. The largest peak (1.67 Å from C11) and hole (1.77 Å from C22) in the difference Fourier map were 0.31(7) and −0.33(7) eÅ −3 , respectively. The largest errors in the difference plot ( Figure 2) are very small.
The crystal structure was optimized using density functional techniques as implemented in VASP (Kresse and Furthmüller, 1996) (fixed experimental unit cell) through the MedeA graphical interface (Materials Design, 2016). The calculation was carried out on 16 2.4 GHz processors (each with 4 GB RAM) of a 64-processor HP Proliant DL580 Generation 7 Linux cluster at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å −1 leading to a 3 × 2 × 3 mesh, and took ∼127 h. A single-point density functional calculation (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., 2018). The basis sets for the H, C, and O atoms in the calculation were those of Gatti et al. (1994), and that for Cl was that of Peintinger et al. (2013). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ∼1.8 h.

III. RESULTS AND DISCUSSION
The root-mean-square (rms) Cartesian displacement between the Rietveld-refined and DFT-optimized structures of diclazuril is 0.051 Å (Figure 3). The excellent agreement provides strong evidence that the refined structure is correct (van de Streek and Neumann, 2014). This discussion concentrates on the DFT-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 4. The best view of the crystal structure is down the short c-axis ( Figure 5). The crystal structure consists of layers of molecules parallel to the ac-plane.
All of the bond distances and bond angles fall within the normal ranges indicated by a Mercury/Mogul Geometry Check (Macrae et al., 2020). The torsion angles involving rotation about the C13-N6 bond are flagged as unusual. For example, the C16-C13-N6-N7 angle of 74°lies on the tail  of one part of a bimodal distribution of similar torsion angles, with peaks at ∼40 and ∼140°. These torsion angles indicate the angle between the triazine ring and one of the phenyl rings seems to be slightly unusual.
Quantum chemical geometry optimization of the diclazuril molecule (DFT/B3LYP/6-31G*/water) using Spartan '18 (Wavefunction, 2020) indicated that the observed conformation is 55.9 kcal mol −1 higher in energy than the local minimum. The major differences are in the orientations of the outer rings of the molecule. A conformational analysis (MMFF force field) indicates that the minimum-energy conformation is 21.1 kcal mol −1 lower in energy, but the  molecule folds on itself to make the Cl-containing rings parallel. Intermolecular interactions are thus important in determining the solid-state conformation.
Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault, 2021) suggests that the intramolecular deformation energy terms are small, but that torsion deformation terms are the largest. The intermolecular energy is dominated by electrostatic attractions, which in this force field analysis include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation.
Hydrogen bonds are prominent in the structure ( Table I). The most noteworthy is the strong N8-H34⋯O5 hydrogen bond, which links the molecules into dimers along the a-axis with a graph set R2,2(8) (Etter, 1990;Bernstein et al., 1995;Shields et al., 2000). The energy of the N-H⋯O hydrogen bond was calculated using the correlation of Wheatley and Kaduk (2019). The methyne carbon C10 forms an intramolecular C-H⋯Cl hydrogen bond. Intermolecular C-H⋯Cl and C-H⋯O hydrogen bonds also contribute to the lattice energy.
The volume enclosed by the Hirshfeld surface of diclazuril ( Figure 6, Hirshfeld, 1977;Turner et al., 2017) is 406.45 Å 3 , 98.14% of 1/4 the unit cell volume. The packing density is thus fairly typical. The only significant-close contacts (red in Figure 6) involve the hydrogen bonds. The volume/non-hydrogen atom is smaller than usual at 15.9 Å 3 .

IV. DEPOSITED DATA
The Crystallographic Information Framework (CIF) files containing the results of the Rietveld refinement (including the raw data) and the DFT geometry optimization were deposited with the ICDD. The data can be requested at pdj@icdd. com.  Figure 6. The Hirshfeld surface of diclazuril. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white. Image generated using CrystalExplorer (Turner et al., 2017).