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Crystal structure of haloxon, C14H14Cl3O6P

Published online by Cambridge University Press:  03 October 2022

James A. Kaduk*
Affiliation:
Illinois Institute of Technology, 3101 S. Dearborn St., Chicago, IL 60616, USA North Central College, 131 S. Loomis St., Naperville, IL 60540, USA
Stacy Gates-Rector
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, PA 19073-3273, USA
Thomas N. Blanton
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, PA 19073-3273, USA
*
a)Author to whom correspondence should be addressed. Electronic mail: [email protected]
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Abstract

The crystal structure of haloxon has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Haloxon crystallizes in space group P21/n (#14) with a = 19.60382(6), b = 10.05473(3), c = 8.73591(2) Å, β = 92.6617(2)°, V = 1720.088(11) Å3, and Z = 4. The structure consists of discrete molecules. The mean planes of the fused ring systems are approximately 0–11 and 011. The rings form staggered stacks perpendicular to these planes. There are no traditional hydrogen bonds in the structure, but several C–H⋯O and C–H⋯Cl hydrogen bonds contribute to the crystal energy. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Type
New Diffraction Data
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited
Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press on behalf of International Centre for Diffraction Data

I. INTRODUCTION

Haloxon (sold under the brand names Galloxon, Loxon, and Luxon among others) is an anthelminthic agent used in veterinary medicine to treat cattle. Haloxon is an antiparasitic drug that kills parasitic worms (helminths) and other internal parasites without causing significant damage to the host. The systematic name (CAS Registry Number 321-55-1) is bis(2-chloroethyl) (3-chloro-4-methyl-2-oxochromen-7-yl) phosphate. A two-dimensional molecular diagram is shown in Figure 1.

Figure 1. The 2D molecular structure of haloxon.

Haloxon was first mentioned by Brown et al. (Reference Brown, Hollinshead, Kingsbury and Malone1962). Several secondary sources indicate a Belgian patent BE610896, to Cooper, McDougall and Robertson, but we have been unable to obtain a copy, and are not aware of any published X-ray powder diffraction data on haloxon.

This work was carried out as part of a project (Kaduk et al., Reference Kaduk, Crowder, Zhong, Fawcett and Suchomel2014) to determine the crystal structures of large-volume commercial pharmaceuticals, and include high-quality powder diffraction data for them in the Powder Diffraction File (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019).

II. EXPERIMENTAL

Haloxon was a commercial reagent, purchased from Sigma (Lot #BO2641881), 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 (Antao et al., Reference Antao, Hassan, Wang, Lee and Toby2008; Lee et al., Reference Lee, Shu, Ramanathan, Preissner, Wang, Beno, Von Dreele, Ribaud, Kurtz, Antao, Jiao and Toby2008; Wang et al., Reference Wang, Toby, Lee, Ribaud, Antao, Kurtz, Ramanathan, Von Dreele and Beno2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.458963(2) Å from 0.5 to 50° 2θ with a step size of 0.009984375 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 Al2O3: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., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013), on a primitive monoclinic cell with a = 19.62613, b = 10.05116, c = 8.73551 Å, β = 92.725°, V = 1721.3 Å3, and Z = 4. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) with the chemistry H, C, Cl, O, and P only yielded no hits. The suggested space group was P21/n, which was confirmed by successful solution and refinement of the structure. The structure was solved by direct methods using EXPO2104 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013). Some of the atom types had to be reassigned manually.

Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 2.5–25.0° portion of the pattern was included in the refinement (d min = 1.060 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Orpen2004; Sykes et al., Reference Sykes, McCabe, Allen, Battle, Bruno and Wood2011). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 6.4% 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 three Cl atoms were refined anisotropically. The U iso of the other heavy atoms were grouped by chemical similarity. The U iso for the H atoms were fixed at 1.3× the U iso of the heavy atoms to which they are attached. 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 6.28° 2θ to model the scattering from the Kapton capillary and any amorphous component.

The final refinement of 119 variables using 22 536 observations and 60 restraints yielded the residuals R wp = 0.0809 and GOF = 1.74. The largest peak (0.32 Å from C19) and hole (1.87 Å from Cl2) in the difference Fourier map were 0.56(13) and −0.48(13) eÅ−3, respectively. The largest errors in the difference plot (Figure 2) are in the shapes and intensities of some of the strong low-angle peaks, and may indicate subtle changes in the specimen during the measurement.

Figure 2. The Rietveld plot for the refinement of haloxon. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 20× for 2θ >120°. The row of blue tick marks indicates the calculated reflection positions.

The crystal structure was optimized using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996) (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 2 × 2 × 1 mesh, and took ~21 h. A single-point density functional calculation (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., Reference Dovesi, Erba, Orlando, Zicovich-Wilson, Civalleri, Maschio, Rerat, Casassa, Baima Salustro and Kirtman2018). The basis sets for the H, C, and O atoms in the calculation were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994), and those for P and Cl were that of Peintinger et al. (Reference Peintinger, Vilela Oliveira and Bredow2013). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ~2.1 h.

III. RESULTS AND DISCUSSION

The root-mean-square (rms) Cartesian displacement between the Rietveld-refined and DFT-optimized structures of the haloxon molecule is 0.135 Å (Figure 3); the maximum difference is 0.353 Å at C24. The excellent agreement provides evidence that the refined structure is correct (van de Streek and Neumann, Reference van de Streek and Neumann2014). 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 b-axis (Figure 5). The structure consists of discrete molecules. The mean planes of the fused ring systems are approximately (0–11) and (011). The rings form staggered stacks perpendicular to these planes.

Figure 3. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of haloxon. The rms Cartesian displacement is 0.135 Å. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).

Figure 4. The asymmetric unit of haloxon, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids. Image generated using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020).

Figure 5. The crystal structure of haloxon, viewed down the b-axis. Image generated using Diamond (Crystal Impact, 2022).

All of the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury/Mogul Geometry Check (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020). Quantum chemical geometry optimization of the haloxon cation (DFT/B3LYP/6-31G*/water) using Spartan ‘18 (Wavefunction, 2020) indicated that the observed conformation is 3.6 kcal mol−1 higher in energy than the local minimum. The major differences (rms Cartesian displacement = 0.564 Å) occur at the chloromethyl and methyl groups. A conformational analysis (MMFF force field) indicates that the minimum-energy conformation is 1.5 kcal mol−1 lower in energy. The major difference is that the phosphate ester group is rotated by ~180°; the molecule is thus fairly flexible. Although weak, the intermolecular interactions are 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 is dominated by angle deformation terms, as might be expected in a molecule containing a fused ring system. The intermolecular energy is dominated by electrostatic attractions, which in this force field analysis also include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation. There are no traditional hydrogen bonds in the structure (Table I), but several C–H⋯O and C–H⋯Cl hydrogen bonds contribute to the crystal energy.

TABLE I. Hydrogen bonds (CRYSTAL17) in haloxon

a Intramolecular.

The volume enclosed by the Hirshfeld surface of haloxon (Figure 6; Hirshfeld, Reference Hirshfeld1977; Turner et al., Reference Turner, McKinnon, Wolff, Grimwood, Spackman, Jayatilaka and Spackman2017) is 421.82 Å3, 98.09% 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 17.9 Å3.

Figure 6. The Hirshfeld surface of haloxon. 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.

The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect blocky morphology for haloxon, with perhaps {100} as major faces. A second-order spherical harmonic model was included in the refinement. The texture index was 1.003(0), indicating that preferred orientation was slight in this rotated capillary specimen. The powder pattern of haloxon from this synchrotron dataset has been submitted to ICDD for inclusion in the Powder Diffraction File.

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 .

ACKNOWLEDGEMENTS

The use of the Advanced Photon Source at Argonne National Laboratory was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. This work was partially supported by the International Centre for Diffraction Data. We thank Lynn Ribaud and Saul Lapidus for their assistance in the data collection.

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.

References

Altomare, A., Cuocci, C., Giacovazzo, C., Moliterni, A., Rizzi, R., Corriero, N., and Falcicchio, A. (2013). “EXPO2013: a kit of tools for phasing crystal structures from powder data,” J. Appl. Crystallogr. 46, 12311235.CrossRefGoogle Scholar
Antao, S. M., Hassan, I., Wang, J., Lee, P. L., and Toby, B. H. (2008). “State-of-the-art high-resolution powder X-ray diffraction (HRPXRD) illustrated with Rietveld refinement of quartz, sodalite, tremolite, and meionite,” Can. Mineral. 46, 15011509.CrossRefGoogle Scholar
Bravais, A. (1866). Etudes Cristallographiques (Gauthier Villars, Paris).Google Scholar
Brown, N. C., Hollinshead, D. T., Kingsbury, P. A., and Malone, J. C. (1962). “A new class of compounds showing antihelmintic properties,” Nature 194, 379379.CrossRefGoogle ScholarPubMed
Bruno, I. J., Cole, J. C., Kessler, M., Luo, J., Motherwell, W. D. S., Purkis, L. H., Smith, B. R., Taylor, R., Cooper, R. I., Harris, S. E., and Orpen, A. G. (2004). “Retrieval of crystallographically-derived molecular geometry information,” J. Chem. Inf. Sci. 44, 21332144.CrossRefGoogle ScholarPubMed
Crystal Impact - Dr. H. Putz & Dr. K. Brandenburg (2022). Diamond - Crystal and Molecular Structure Visualization. Kreuzherrenstr. 102, 53227 Bonn, Germany. Available at: https://www.crystalimpact.de/diamond.Google Scholar
Dassault Systèmes (2021). Materials Studio 2021 (BIOVIA, San Diego, CA).Google Scholar
Donnay, J. D. H. and Harker, D. (1937). “A new law of crystal morphology extending the law of Bravais,” Am. Mineral. 22, 446447.Google Scholar
Dovesi, R., Erba, A., Orlando, R., Zicovich-Wilson, C. M., Civalleri, B., Maschio, L., Rerat, M., Casassa, S., Baima Salustro, J., and Kirtman, B. (2018). “Quantum-mechanical condensed matter simulations with CRYSTAL,” WIREs Comput. Mol. Sci. 8, e1360.CrossRefGoogle Scholar
Friedel, G. (1907). “Etudes sur la loi de Bravais,” Bull. Soc. Fr. Mineral. 30, 326455.Google Scholar
Gates-Rector, S. and Blanton, T. (2019). “The Powder Diffraction File: a quality materials characterization database,” Powd. Diffr. 39(4), 352360.CrossRefGoogle Scholar
Gatti, C., Saunders, V. R., and Roetti, C. (1994). “Crystal-field effects on the topological properties of the electron-density in molecular crystals - the case of urea,” J. Chem. Phys. 101, 1068610696.CrossRefGoogle Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P., and Ward, S. C. (2016). “The Cambridge Structural Database,” Acta Crystallogr. Sect. B: Struct. Sci., Cryst. Eng. Mater. 72, 171179.CrossRefGoogle ScholarPubMed
Hirshfeld, F. L. (1977). “Bonded-atom fragments for describing molecular charge densities,” Theor. Chem. Acta 44, 129138.CrossRefGoogle Scholar
Kaduk, J. A., Crowder, C. E., Zhong, K., Fawcett, T. G., and Suchomel, M. R. (2014). “Crystal structure of atomoxetine hydrochloride (Strattera), C17H22NOCl,” Powd. Diffr. 29(3), 269273.CrossRefGoogle Scholar
Kresse, G. and Furthmüller, J. (1996). “Efficiency of ab-initio total energy calculations for metals and semiconductors using a plane-wave basis set,” Comput. Mater. Sci. 6, 1550.CrossRefGoogle Scholar
Lee, P. L., Shu, D., Ramanathan, M., Preissner, C., Wang, J., Beno, M. A., Von Dreele, R. B., Ribaud, L., Kurtz, C., Antao, S. M., Jiao, X., and Toby, B. H. (2008). “A twelve-analyzer detector system for high-resolution powder diffraction,” J. Synchrotron Radiat. 15(5), 427432.CrossRefGoogle ScholarPubMed
Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M., and Wood, P. A. (2020). “Mercury 4.0: from visualization to design and prediction,” J. Appl. Crystallogr. 53, 226235.CrossRefGoogle ScholarPubMed
Materials Design (2016). MedeA 2.20.4 (Materials Design Inc, Angel Fire, NM).Google Scholar
Peintinger, M. F., Vilela Oliveira, D., and Bredow, T. (2013). “Consistent Gaussian basis sets of triple-zeta valence with polarization quality for solid-state calculations,” J. Comput. Chem. 34, 451459.CrossRefGoogle ScholarPubMed
Sykes, R. A., McCabe, P., Allen, F. H., Battle, G. M., Bruno, I. J., and Wood, P. A. (2011). “New software for statistical analysis of Cambridge Structural Database data,” J. Appl. Crystallogr. 44, 882886.CrossRefGoogle Scholar
Toby, B. H. and Von Dreele, R. B. (2013). “GSAS II: the genesis of a modern open source all purpose crystallography software package,” J. Appl. Crystallogr. 46, 544549.CrossRefGoogle Scholar
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D., and Spackman, M. A. (2017). CrystalExplorer17 (University of Western Australia). Available at: http://hirshfeldsurface.net.Google Scholar
van de Streek, J. and Neumann, M. A. (2014). “Validation of molecular crystal structures from powder diffraction data with dispersion-corrected density functional theory (DFT-D),” Acta Crystallogr. Sect. B: Struct. Sci., Cryst. Eng. Mater. 70(6), 10201032.CrossRefGoogle ScholarPubMed
Wang, J., Toby, B. H., Lee, P. L., Ribaud, L., Antao, S. M., Kurtz, C., Ramanathan, M., Von Dreele, R. B., and Beno, M. A. (2008). “A dedicated powder diffraction beamline at the advanced photon source: commissioning and early operational results,” Rev. Sci. Instrum. 79, 085105.CrossRefGoogle ScholarPubMed
Wavefunction, Inc. (2020). Spartan ‘18 Version 1.4.5, Wavefunction Inc., 18401 Von Karman Ave., Suite 370, Irvine, CA 92612.Google Scholar
Figure 0

Figure 1. The 2D molecular structure of haloxon.

Figure 1

Figure 2. The Rietveld plot for the refinement of haloxon. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 20× for 2θ >120°. The row of blue tick marks indicates the calculated reflection positions.

Figure 2

Figure 3. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of haloxon. The rms Cartesian displacement is 0.135 Å. Image generated using Mercury (Macrae et al., 2020).

Figure 3

Figure 4. The asymmetric unit of haloxon, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids. Image generated using Mercury (Macrae et al., 2020).

Figure 4

Figure 5. The crystal structure of haloxon, viewed down the b-axis. Image generated using Diamond (Crystal Impact, 2022).

Figure 5

TABLE I. Hydrogen bonds (CRYSTAL17) in haloxon

Figure 6

Figure 6. The Hirshfeld surface of haloxon. 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.