research communications
Crystal structures of tolfenamic acid polymorphic forms I and II with precise hydrogen-atom positions for nuclear magnetic resonance studies
aOral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, SK10 2NA, United Kingdom, bC4X Discovery, 53 Portland Street, Manchester, M1 3LD, United Kingdom, and cSchool of Chemistry, The University of Manchester, Oxford Road, Manchester, United Kingdom
*Correspondence e-mail: charles.blundell@c4xdiscovery.com
The structures of tolfenamic acid [TFA; 2-(3-chloro-2-methylanilino)benzoic acid, C14H12ClNO2] polymorph forms I and II have been redetermined [compare Andersen et al. (1989). J. Chem. Soc., Perkin Trans. 2, pp. 1443–1447] with improved precision using high-resolution X-ray diffraction data and Hirshfield atom in order to better define both hydrogen-atom locations and their associated bond lengths. lengths to hydrogen were found to be significantly longer throughout both structures, especially for the anilino H atom, which is involved in an important intramolecular N—H⋯O hydrogen bond to the carboxylic acid group. This hydrogen bond is shown to clearly perturb the electron density around both oxygen atoms in the latter group. The extended structures of both polymorphs feature carboxylic acid inversion dimers. These structures provide an improved foundation for nuclear magnetic resonance studies in both solution and the solid state.
1. Chemical context
Tolfenamic acid (TFA; 2-[(3-chloro-2-methylphenyl)amino]benzoic acid; C14H12ClNO2) is a non-steroidal anti-inflammatory drug (NSAID). It is frequently used as a model for crystallography studies because it displays interesting with eight forms identified to date (Andersen et al., 1989; López-Mejías et al., 2009; Case et al., 2018). Moreover, its small size and simple crystal structures permit timely computational calculations, which is advantageous for studies investigating its behaviour by nuclear magnetic resonance (NMR).
The two most common polymorphs of TFA (forms I and II) differ principally in the dihedral angles between the phenyl rings, giving different overall conformations and attendant packing arrangements (Andersen et al., 1989). A number of experimental and theoretical studies have been performed on TFA to explore the origin of this (see e.g. Ang et al., 2016; Du et al., 2015; Mattei & Li, 2012, 2014; Mattei et al., 2013). Both form I and form II are easily prepared in sufficient amounts and purity under standard laboratory conditions to permit solid-state NMR studies and they are readily distinguishable by their colour (form I, white; form II, yellow) (Andersen et al., 1989). TFA is soluble in a variety of crystallization solvents and is suitable for having its conformational behaviour precisely characterized by solution-state NMR methods (Blundell et al., 2013).
Our motivation for the present study was the desire to generate high resolution structures of both forms I and II in which the locations of the hydrogen atoms and their attendant bond lengths were precisely resolved. Accurate hydrogen positions are important for both solid- and solution-state NMR studies because 1H is a chief nucleus for acquiring experimental data through and a variety of experimental observables depend sensitively on bond lengths to hydrogen (e.g. chemical shifts of hydrogen atoms involved in hydrogen bonding, see Siskos et al., 2017; residual dipolar couplings, see Lipsitz & Tjandra, 2004). Structures with precise hydrogen positions therefore provide more robust starting points for density functional theory (DFT) calculations of NMR observables in the solid-state and, in the solution state, a better mean-average geometry to found upon.
Accordingly, large single crystals (needles 0.5–1 mm in length) of forms I and II were grown that diffracted to d ≃ 0.48 Å (2θmax = 95.5°, T = 100 K) and 0.53 Å (83.6°, 150 K), respectively with Mo Kα radiation. The structures of each form were solved and refined using Hirshfeld atom which determines the structural parameters from single crystal X-ray diffraction data by using an aspherical atom partitioning of ab initio quantum mechanical molecular electron densities (Capelli et al., 2014). Significantly for our purpose, the precision of the determined bond lengths and anisotropic displacement parameters for the hydrogen atoms calculated with Hirshfeld atom with data of this resolution is comparable to that from neutron diffraction measurements (Fugel et al., 2018).
2. Structural commentary
The ). Both forms are monoclinic, with form I in P21/c and form II in P21/n; both structures comprise Z′ = 1 and Z = 4 and form an internal hydrogen bond between N7—H7 and O15 with very similar geometry (Tables 1 and 2); this internal hydrogen bond makes the aminobenzoic acid group adopt an essentially planar conformation. The chief difference between the two forms is the dihedral angle between the C1–C6 and C8–C13 phenyl rings, being 72.82 (4)° for form I and 44.34 (3)° for form II. This is also seen in the torsion angle C8—N7—C1—C6, with values of 74.34 (12) and −143.00 (6)° for forms I and II, respectively (in the crystal an equal number of molecules have the opposite sign for these torsion angles). Additionally, the C8—N7—C1 angle also differs somewhat [form I 123.97 (7); form II 129.34 (5)°]. The methyl group torsion angle differs between the two structures, with form I having one hydrogen atom almost coplanar with the 3-chloro-2-methylphenyl ring and form II having one hydrogen atom orthogonal to it. The displacement parameters of the ellipsoids show that the methyl groups in both structures display greater motion relative to the rest of their structures.
determination of forms I and II was achieved (Fig. 13. Supramolecular features
The packing arrangement for both forms are shown in Fig. 2. In both structures, O—H⋯O hydrogen-bonding interactions between the carboxylic acid groups on pairs of TFA molecules result in the formation of symmetrical hydrogen-bonded dimers that are related by an inversion centre (Tables 1 and 2; Figs. 3 and 4).
The and 4). Very clear differences between the carboxylate oxygen atoms in the dimer hydrogen-bonding motif are now apparent. Bond C14—O15 has more electron density than C14—O16, revealing its greater double-bond character. Oxygen atom O15 accordingly adopts an sp2 geometry, with its two lone-pairs clearly located in the expected co-planar positions (i.e., at ±120° from the C15—O16 bond); one lone pair accepts the intramolecular hydrogen bond from H7 while the other receives an intermolecular hydrogen bond from H16. Atom O16 in contrast has a to H16, for which electron density is clearly visible. Despite the apparently dominant double-bond character of C14—O15, O16 is interestingly not simply forming a purely single bond with C14 and adopting an sp3 hydridization state: the typical positions of the two sp3 molecular orbitals projecting away from and above and below the carboxylate plane have smeared into a single lobe of density with a significant amount of coplanar (i.e., sp2-like) electron density.
has precisely resolved not only hydrogen-atom positions but also the shape and positions of the electron density corresponding to the molecular orbitals throughout the structure (Figs. 3In short, the typical equivalence of the O atoms in the carboxylic acid has been significantly perturbed by the N7—H7⋯O15 intramolecular hydrogen bond. These electronic perturbations should be remembered when molecules containing carboxylic acid groups are being designed to interact with protein targets via hydrogen bonding.
4. Database survey
A search for crystal structures containing TFA explicitly in its protonated state was performed within the Cambridge Structural Database (CSD version 5.41, update November 2019; Groom et al., 2016). There are eight polymorphs of pure TFA (CSD reference codes KAXXAI, KAXXAI01–07, Andersen et al., 1989; López-Mejías et al., 2009; Case et al., 2018) and six forms (EXAQIE, Fábián et al., 2011; SIMDOK/01 & SIMFUS/SIMGAZ/SIMGED, Case et al., 2018; UZUZIA & UZUZOG, Bouanga Boudiombo & Jacobs, 2016; XOWKAX/01, Surov et al., 2015, Wittering et al., 2015). In all cases, the internal hydrogen-bond equvialent to N7—H7⋯O15 in the present structures is present and the hydroxyl hydrogen atom is attached to the corresponding O16 equivalent. The C8—N7—C1—C6 torsion angle ranges from 75.0 to 138.4° in the pure forms and from 76.1 to 156.9° in the co-crystals.
The database structures with refcodes KAXXAI01 and KAXXAI correspond to the crystal structures of form I and form II redetermined here at higher resolution. The locations of the heavy atoms in these new structures do not differ significantly from those reported previously even though, as expected, some hydrogen-atom locations differ substantially (Fig. 5). H7 is in a significantly different position in both structures, materially affecting both its associated hydrogen-bond geometries (compare Tables 1 and 2 with Table 3) and lengths. The N—H bond length is some 23% longer for form I and 17% for form II, which would correspond to a considerable calculated difference in residual dipolar couplings by factors of 1.9 and 1.6 times smaller, respectively. The O—H bond length is slightly longer by 5% for form I and 6% for form II. Carbon–hydrogen bond lengths are also notably longer at 13 ± 3% (min. 6%, max. 17%) for form I and 10 ± 3% (min. 5%, max. 14%) for form II; C—C—H bond angles differ absolutely by 2.6 ± 1.8% (min. 0.0, max 5.7°) for form I and 1.6 ± 1.3° (min. 0.2, max 5.2°) for form II. This improved precision in hydrogen-atom placement provides a significant structural enhancement for subsequent solid- and solution-state NMR studies.
5. Synthesis and crystallization
Tolfenamic acid was used as received from Sigma–Aldrich (Gillingham, UK).
Large single crystals of form I (needles 0.5–3 mm in length) were grown by slow evaporation at room temperature: 3 mg of compound was dissolved in an initial volume of 200 µl of ethyl acetate and the mixture was allowed to evaporate to dryness over 24–36 h.
Large single crystals of form II (needles 0.3–1 mm in length) were obtained serendipitously from an attempted salt crystallization experiment, during which form II crystals suitable for single-crystal X-ray diffraction were isolated. A 1:1 molar ratio of TFA (20 mg of compound) and N-(2-hydroxyethyl)pyrrolidine were dissolved into approximately 5 ml ethyl acetate. The mixture was then left to slowly evaporate, during which large yellow needles formed. Single-crystal diffraction performed on multiple crystals indicated that these were pure form II. There was no evidence of form I within the product, nor of any inclusion of N-(2-hydroxyethyl)-pyrrolidine within the form II crystals. Clearly the presence of N-(2-hydroxyethyl)-pyrrolidine either inhibited the growth of form I crystals and/or promoted the growth of form II crystals; the mechanism for this has not been investigated.
6. Refinement
Crystal data, data collection and structure .
details are summarized in Table 4
|
Intensity data for form I and form II were collected using Mo Kα radiation at 100 and 150 K respectively using a Rigaku FR-X rotating anode diffractometer, equipped with an HyPix-6000HE detector and an Oxford Cryosystems nitrogen flow gas system. Data were measured and reduced using the CrysAlis PRO suite of programs. Absorption correction was performed using empirical methods implemented in the SCALE3 ABSPACK scaling algorithm (Blessing, 1995; Sheldrick, 1996). The crystal structures were solved and refined against all F2 values using the SHELXL and OLEX2 suite of programs (Sheldrick, 2008, 2015b; Dolomanov et al., 2009). All atoms (including H atoms) were refined anisotropically.
Hirshfeld atom OLEX2 (Fugel et al., 2018). It precisely estimates the atomic positions and deformation electron densities in crystal structures by deconvolution of accurate static electron density calculated by TONTO from the thermally smeared electron density calculated from an independent atomic model (IAM) obtained from the X-ray diffraction data (Capelli et al., 2014).
was achieved using the recently implemented HARt option inThe wavefunctions of crystal structures of form I and form II were calculated using TONTO (Capelli et al., 2014), with the cc-pVTZ basis set (Dunning, 1989) and the Hartree–Fock method. Wavefunctions for each were calculated with the grown in order to account for the hydrogen bond formed between the carboxylate groups. Each model obtained was then refined against the single crystal X-ray diffraction data collected, using OLEX2 and the L-M method (Fugel et al., 2018).
Supporting information
https://doi.org/10.1107/S2056989020010841/hb7936sup1.cif
contains datablocks global, I, II. DOI:Supporting information file. DOI: https://doi.org/10.1107/S2056989020010841/hb7936Isup2.cml
For both structures, data collection: CrysAlis PRO (Rigaku OD, 2017); cell
CrysAlis PRO (Rigaku OD, 2017); data reduction: CrysAlis PRO (Rigaku OD, 2017); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: olex2.refine (Bourhis et al., 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).C14H12ClNO2 | F(000) = 544.838 |
Mr = 261.71 | Dx = 1.448 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
a = 4.8283 (2) Å | Cell parameters from 9015 reflections |
b = 32.0832 (10) Å | θ = 3.8–52.9° |
c = 8.0221 (3) Å | µ = 0.31 mm−1 |
β = 104.936 (4)° | T = 100 K |
V = 1200.70 (8) Å3 | Plank, clear light colourless |
Z = 4 | 1.0 × 0.4 × 0.2 mm |
XtaLAB AFC11 (RINC): Kappa single diffractometer | 11328 independent reflections |
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source | 8616 reflections with I ≥ 2σ(I) |
Graphite monochromator | Rint = 0.039 |
ω scans | θmax = 47.8°, θmin = 3.8° |
Absorption correction: multi-scan (CrysAlisPro; Rigaku, 2017) | h = −10→6 |
Tmin = 0.457, Tmax = 1.000 | k = −62→72 |
39154 measured reflections | l = −18→18 |
Refinement on F2 | 0 constraints |
Least-squares matrix: full | Primary atom site location: dual |
R[F2 > 2σ(F2)] = 0.064 | All H-atom parameters refined |
wR(F2) = 0.127 | w = 1/[σ2(Fo2) + (0.P)2 + 0.987P] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max = 0.0004 |
11328 reflections | Δρmax = 0.82 e Å−3 |
271 parameters | Δρmin = −0.69 e Å−3 |
0 restraints |
Refinement. Refinement using NoSpherA2, an implementation of NOn-SPHERical Atom-form-factors in Olex2. Please cite: F. Kleemiss, H. Puschmann, O. Dolomanov, S.Grabowsky - to be publsihed - 2020 NoSpherA2 makes use of tailor-made aspherical atomic form factors calculated on-the-fly from a Hirshfeld-partitioned electron density (ED) - not from spherical-atom form factors. The ED is calculated from a gaussian basis set single determinant SCF wavefunction - either Hartree-Fock or B3LYP - for a fragment of the crystal embedded in an electrostatic crystal field. The following options were used: SOFTWARE: Tonto METHOD: rhf BASIS SET: def2-SVP CHARGE: 0 MULTIPLICITY: 1 DATE: 2019-10-18_17-21-04 CLUSTER RADIUS: 0 |
x | y | z | Uiso*/Ueq | ||
Cl17 | 0.75639 (6) | 0.759893 (7) | 0.58628 (4) | 0.02423 (5) | |
O16 | 0.07003 (16) | 0.49986 (2) | 0.28719 (9) | 0.01785 (11) | |
O15 | 0.23425 (15) | 0.53749 (2) | 0.52534 (9) | 0.01694 (11) | |
N7 | 0.58438 (18) | 0.60116 (2) | 0.51594 (10) | 0.01698 (12) | |
C9 | 0.39509 (16) | 0.55388 (2) | 0.27629 (10) | 0.01206 (10) | |
C8 | 0.56974 (17) | 0.58797 (2) | 0.35212 (10) | 0.01279 (11) | |
C10 | 0.38168 (19) | 0.54232 (3) | 0.10596 (11) | 0.01506 (12) | |
C6 | 0.66873 (18) | 0.67645 (3) | 0.54885 (11) | 0.01456 (12) | |
C5 | 0.84386 (19) | 0.70814 (3) | 0.63887 (12) | 0.01590 (13) | |
C14 | 0.22811 (17) | 0.53019 (2) | 0.37277 (11) | 0.01293 (11) | |
C13 | 0.73019 (19) | 0.60848 (3) | 0.25247 (12) | 0.01624 (13) | |
C11 | 0.5414 (2) | 0.56279 (3) | 0.01027 (12) | 0.01743 (14) | |
C1 | 0.75379 (18) | 0.63527 (3) | 0.59655 (11) | 0.01417 (11) | |
C2 | 1.0000 (2) | 0.62691 (3) | 0.72745 (12) | 0.01740 (13) | |
C3 | 1.1660 (2) | 0.65937 (3) | 0.81486 (13) | 0.02070 (16) | |
C4 | 1.0886 (2) | 0.70036 (3) | 0.77028 (13) | 0.01962 (15) | |
C12 | 0.7174 (2) | 0.59587 (3) | 0.08645 (12) | 0.01759 (14) | |
C18 | 0.4031 (2) | 0.68604 (3) | 0.41021 (15) | 0.02055 (16) | |
H10 | 0.245 (4) | 0.5165 (5) | 0.050 (2) | 0.032 (4) | |
H12 | 0.851 (4) | 0.6117 (6) | 0.015 (3) | 0.039 (5) | |
H2 | 1.055 (4) | 0.5947 (6) | 0.760 (3) | 0.035 (5) | |
H4 | 1.216 (4) | 0.7266 (6) | 0.835 (3) | 0.040 (5) | |
H3 | 1.356 (4) | 0.6530 (7) | 0.919 (3) | 0.048 (6) | |
H13 | 0.868 (4) | 0.6342 (6) | 0.312 (2) | 0.039 (5) | |
H11 | 0.535 (4) | 0.5528 (6) | −0.120 (2) | 0.040 (5) | |
H16 | −0.038 (5) | 0.4851 (7) | 0.364 (3) | 0.028 (6) | |
H7 | 0.484 (5) | 0.5821 (7) | 0.584 (3) | 0.045 (6) | |
H18a | 0.455 (5) | 0.7026 (9) | 0.303 (3) | 0.071 (8) | |
H18b | 0.291 (5) | 0.6586 (7) | 0.363 (4) | 0.078 (9) | |
H18c | 0.264 (5) | 0.7068 (8) | 0.451 (3) | 0.067 (8) |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl17 | 0.03142 (12) | 0.01403 (8) | 0.02626 (12) | −0.00050 (8) | 0.00568 (9) | 0.00054 (8) |
O16 | 0.0216 (3) | 0.0181 (3) | 0.0145 (2) | −0.0072 (2) | 0.0059 (2) | −0.0029 (2) |
O15 | 0.0214 (3) | 0.0177 (3) | 0.0128 (2) | −0.0073 (2) | 0.0065 (2) | −0.00110 (19) |
N7 | 0.0226 (3) | 0.0172 (3) | 0.0131 (3) | −0.0077 (2) | 0.0082 (2) | −0.0018 (2) |
C9 | 0.0133 (3) | 0.0127 (2) | 0.0106 (2) | −0.0002 (2) | 0.0040 (2) | 0.0006 (2) |
C8 | 0.0140 (3) | 0.0142 (3) | 0.0115 (3) | −0.0020 (2) | 0.0057 (2) | 0.0005 (2) |
C10 | 0.0181 (3) | 0.0162 (3) | 0.0116 (3) | 0.0000 (2) | 0.0051 (2) | −0.0005 (2) |
C6 | 0.0137 (3) | 0.0153 (3) | 0.0150 (3) | −0.0024 (2) | 0.0042 (2) | 0.0002 (2) |
C5 | 0.0176 (3) | 0.0148 (3) | 0.0157 (3) | −0.0022 (2) | 0.0048 (2) | −0.0015 (2) |
C14 | 0.0144 (3) | 0.0127 (3) | 0.0122 (3) | −0.0019 (2) | 0.0043 (2) | 0.0000 (2) |
C13 | 0.0180 (3) | 0.0186 (3) | 0.0141 (3) | −0.0037 (2) | 0.0079 (2) | 0.0010 (2) |
C11 | 0.0226 (4) | 0.0193 (3) | 0.0120 (3) | 0.0012 (3) | 0.0074 (3) | 0.0014 (2) |
C1 | 0.0164 (3) | 0.0147 (3) | 0.0123 (3) | −0.0032 (2) | 0.0052 (2) | −0.0005 (2) |
C2 | 0.0203 (3) | 0.0163 (3) | 0.0148 (3) | 0.0002 (3) | 0.0031 (3) | 0.0004 (2) |
C3 | 0.0212 (4) | 0.0206 (4) | 0.0171 (3) | −0.0003 (3) | −0.0009 (3) | −0.0018 (3) |
C4 | 0.0206 (4) | 0.0184 (3) | 0.0180 (3) | −0.0037 (3) | 0.0014 (3) | −0.0028 (3) |
C12 | 0.0202 (3) | 0.0207 (3) | 0.0145 (3) | −0.0007 (3) | 0.0092 (3) | 0.0022 (3) |
C18 | 0.0150 (3) | 0.0231 (4) | 0.0221 (4) | −0.0005 (3) | 0.0022 (3) | 0.0012 (3) |
H10 | 0.045 (12) | 0.030 (10) | 0.020 (10) | −0.008 (9) | 0.006 (9) | 0.002 (8) |
H12 | 0.045 (12) | 0.041 (12) | 0.040 (13) | −0.013 (10) | 0.025 (11) | −0.003 (10) |
H2 | 0.039 (12) | 0.032 (11) | 0.035 (12) | −0.002 (9) | 0.009 (10) | 0.001 (9) |
H4 | 0.047 (13) | 0.039 (12) | 0.033 (13) | −0.009 (10) | 0.009 (10) | 0.003 (10) |
H3 | 0.033 (12) | 0.071 (16) | 0.031 (13) | 0.000 (11) | −0.007 (10) | 0.002 (11) |
H13 | 0.053 (13) | 0.043 (12) | 0.024 (11) | −0.015 (10) | 0.015 (10) | 0.001 (9) |
H11 | 0.048 (13) | 0.042 (12) | 0.030 (12) | −0.006 (10) | 0.010 (10) | −0.010 (10) |
H16 | 0.029 (13) | 0.029 (13) | 0.028 (14) | −0.018 (11) | 0.010 (11) | 0.001 (11) |
H7 | 0.059 (17) | 0.039 (14) | 0.044 (15) | −0.019 (12) | 0.026 (13) | −0.001 (12) |
H18a | 0.043 (15) | 0.11 (2) | 0.048 (16) | 0.000 (15) | 0.001 (12) | 0.031 (16) |
H18b | 0.038 (13) | 0.039 (13) | 0.12 (2) | −0.007 (11) | −0.035 (14) | 0.014 (15) |
H18c | 0.047 (15) | 0.09 (2) | 0.061 (18) | 0.032 (14) | 0.007 (13) | 0.006 (15) |
Cl17—C5 | 1.7383 (9) | C5—C4 | 1.3887 (13) |
O16—C14 | 1.3154 (10) | C13—C12 | 1.3780 (13) |
O16—H16 | 1.02 (2) | C13—H13 | 1.090 (19) |
O15—C14 | 1.2389 (11) | C11—C12 | 1.3979 (14) |
N7—C8 | 1.3650 (11) | C11—H11 | 1.087 (19) |
N7—C1 | 1.4184 (11) | C1—C2 | 1.3943 (13) |
N7—H7 | 1.02 (2) | C2—C3 | 1.3890 (14) |
C9—C8 | 1.4188 (11) | C2—H2 | 1.081 (18) |
C9—C10 | 1.4012 (11) | C3—C4 | 1.3885 (14) |
C9—C14 | 1.4659 (11) | C3—H3 | 1.089 (19) |
C8—C13 | 1.4110 (11) | C4—H4 | 1.093 (19) |
C10—C11 | 1.3858 (12) | C12—H12 | 1.092 (17) |
C10—H10 | 1.080 (17) | C18—H18a | 1.09 (2) |
C6—C5 | 1.3983 (12) | C18—H18b | 1.05 (2) |
C6—C1 | 1.4072 (12) | C18—H18c | 1.06 (2) |
C6—C18 | 1.4969 (13) | ||
H16—O16—C14 | 110.3 (12) | C12—C11—C10 | 118.69 (8) |
C1—N7—C8 | 123.97 (7) | H11—C11—C10 | 120.9 (10) |
H7—N7—C8 | 114.6 (13) | H11—C11—C12 | 120.4 (10) |
H7—N7—C1 | 120.9 (13) | C6—C1—N7 | 120.45 (8) |
C10—C9—C8 | 119.68 (7) | C2—C1—N7 | 118.33 (8) |
C14—C9—C8 | 121.36 (7) | C2—C1—C6 | 121.18 (8) |
C14—C9—C10 | 118.95 (7) | C3—C2—C1 | 120.34 (9) |
C9—C8—N7 | 121.96 (7) | H2—C2—C1 | 118.3 (10) |
C13—C8—N7 | 120.08 (8) | H2—C2—C3 | 121.3 (10) |
C13—C8—C9 | 117.96 (7) | C4—C3—C2 | 119.87 (9) |
C11—C10—C9 | 121.48 (8) | H3—C3—C2 | 120.6 (12) |
H10—C10—C9 | 118.4 (10) | H3—C3—C4 | 119.5 (12) |
H10—C10—C11 | 120.2 (10) | C3—C4—C5 | 119.05 (9) |
C1—C6—C5 | 116.55 (8) | H4—C4—C5 | 119.1 (11) |
C18—C6—C5 | 121.50 (8) | H4—C4—C3 | 121.8 (11) |
C18—C6—C1 | 121.95 (8) | C11—C12—C13 | 121.07 (8) |
C6—C5—Cl17 | 119.50 (7) | H12—C12—C13 | 119.0 (10) |
C4—C5—Cl17 | 117.51 (7) | H12—C12—C11 | 119.9 (10) |
C4—C5—C6 | 122.99 (8) | H18a—C18—C6 | 111.1 (12) |
O15—C14—O16 | 121.23 (7) | H18b—C18—C6 | 111.0 (12) |
C9—C14—O16 | 115.60 (7) | H18b—C18—H18a | 109 (2) |
C9—C14—O15 | 123.17 (7) | H18c—C18—C6 | 113.1 (13) |
C12—C13—C8 | 121.09 (8) | H18c—C18—H18a | 103 (2) |
H13—C13—C8 | 117.8 (10) | H18c—C18—H18b | 109 (2) |
H13—C13—C12 | 121.1 (10) | ||
Cl17—C5—C6—C1 | 179.26 (7) | N7—C1—C6—C18 | −1.38 (10) |
Cl17—C5—C6—C18 | −1.32 (9) | N7—C1—C2—C3 | −177.36 (9) |
Cl17—C5—C4—C3 | −179.56 (8) | C9—C8—C13—C12 | 0.13 (9) |
O16—C14—C9—C8 | 178.63 (7) | C9—C10—C11—C12 | −0.45 (10) |
O16—C14—C9—C10 | −1.64 (9) | C8—C13—C12—C11 | 1.09 (11) |
O15—C14—C9—C8 | −1.98 (10) | C10—C11—C12—C13 | −0.93 (11) |
O15—C14—C9—C10 | 177.76 (8) | C6—C5—C4—C3 | 0.35 (11) |
N7—C8—C9—C10 | 178.26 (8) | C6—C1—C2—C3 | 0.52 (10) |
N7—C8—C9—C14 | −2.01 (10) | C5—C4—C3—C2 | 0.40 (12) |
N7—C8—C13—C12 | −179.60 (9) | C1—C2—C3—C4 | −0.82 (11) |
N7—C1—C6—C5 | 178.03 (8) |
D—H···A | D—H | H···A | D···A | D—H···A |
N7—H7···O15 | 1.02 (2) | 1.85 (2) | 2.6650 (10) | 134.0 (19) |
O16—H16···O15i | 1.02 (2) | 1.63 (2) | 2.6448 (10) | 175 (2) |
C18—H18A···Cl17ii | 1.09 (3) | 2.81 (3) | 3.8674 (11) | 163 (2) |
Symmetry codes: (i) −x, −y+1, −z+1; (ii) x, −y+3/2, z−1/2. |
C14H12ClNO2 | F(000) = 544.838 |
Mr = 261.71 | Dx = 1.456 Mg m−3 |
Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
a = 3.84618 (14) Å | Cell parameters from 6709 reflections |
b = 21.9502 (7) Å | θ = 2.3–40.6° |
c = 14.1764 (5) Å | µ = 0.31 mm−1 |
β = 94.235 (4)° | T = 150 K |
V = 1193.57 (7) Å3 | Needle, clear light colourless |
Z = 4 | 0.55 × 0.05 × 0.05 mm |
XtaLAB AFC11 (RINC): Kappa single diffractometer | 7967 independent reflections |
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source | 5973 reflections with I ≥ 2σ(I) |
Graphite monochromator | Rint = 0.032 |
ω scans | θmax = 41.8°, θmin = 2.4° |
Absorption correction: multi-scan (CrysAlisPro; Rigaku, 2017) | h = −7→7 |
Tmin = 0.154, Tmax = 1.000 | k = −33→40 |
22189 measured reflections | l = −26→19 |
Refinement on F2 | 0 constraints |
Least-squares matrix: full | Primary atom site location: dual |
R[F2 > 2σ(F2)] = 0.046 | All H-atom parameters refined |
wR(F2) = 0.077 | w = 1/[σ2(Fo2) + (0.0284P)2] where P = (Fo2 + 2Fc2)/3 |
S = 1.10 | (Δ/σ)max = 0.001 |
7967 reflections | Δρmax = 0.81 e Å−3 |
271 parameters | Δρmin = −0.54 e Å−3 |
0 restraints |
Refinement. Refinement using NoSpherA2, an implementation of NOn-SPHERical A tom-form-factors in Olex2. Please cite: F. Kleemiss, H. Puschmann, O. Dolomanov, S.Grabowsky - to be publsihed - 2020 NoSpherA2 makes use of tailor-made aspherical atomic form factors calculated on-the-fly from a Hirshfeld-partitioned electron density (ED) - not from spherical-atom form factors. The ED is calculated from a gaussian basis set single determinant SCF wavefunction - either Hartree-Fock or B3LYP - for a fragment of the crystal embedded in an electrostatic crystal field. The following options were used: SOFTWARE: Tonto METHOD: rhf BASIS SET: def2-SVP CHARGE: 0 MULTIPLICITY: 1 DATE: 2019-10-22_21-03-05 CLUSTER RADIUS: 0 |
x | y | z | Uiso*/Ueq | ||
Cl17 | 0.16061 (4) | 0.163247 (7) | 0.476783 (12) | 0.02253 (4) | |
C5 | 0.30783 (14) | 0.20431 (2) | 0.38283 (4) | 0.01663 (10) | |
C6 | 0.34927 (14) | 0.26716 (2) | 0.39149 (4) | 0.01586 (10) | |
C8 | 0.48962 (13) | 0.40676 (2) | 0.26010 (4) | 0.01554 (10) | |
C2 | 0.55157 (16) | 0.26655 (3) | 0.23271 (5) | 0.01887 (11) | |
C1 | 0.47434 (14) | 0.29837 (2) | 0.31392 (4) | 0.01676 (10) | |
C4 | 0.37873 (15) | 0.17219 (3) | 0.30233 (5) | 0.01955 (11) | |
C9 | 0.60895 (14) | 0.46663 (2) | 0.28302 (4) | 0.01549 (10) | |
O16 | 0.89072 (14) | 0.53791 (2) | 0.38625 (4) | 0.02738 (11) | |
C11 | 0.39417 (16) | 0.50278 (3) | 0.12791 (5) | 0.02097 (12) | |
N7 | 0.54116 (16) | 0.36075 (2) | 0.32481 (4) | 0.02311 (11) | |
C13 | 0.31026 (14) | 0.39744 (2) | 0.17112 (4) | 0.01695 (10) | |
O15 | 0.81422 (14) | 0.44483 (2) | 0.44188 (4) | 0.02923 (12) | |
C10 | 0.56103 (15) | 0.51329 (2) | 0.21575 (5) | 0.01865 (11) | |
C3 | 0.50114 (16) | 0.20406 (3) | 0.22700 (5) | 0.02053 (11) | |
C12 | 0.26535 (15) | 0.44447 (3) | 0.10676 (5) | 0.01917 (11) | |
C14 | 0.77823 (15) | 0.48161 (2) | 0.37589 (5) | 0.01896 (11) | |
C18 | 0.26524 (18) | 0.29999 (3) | 0.47953 (5) | 0.02301 (12) | |
H13 | 0.202 (2) | 0.3529 (4) | 0.1536 (7) | 0.036 (2) | |
H10 | 0.657 (3) | 0.5586 (4) | 0.2342 (7) | 0.042 (3) | |
H2 | 0.662 (2) | 0.2909 (4) | 0.1761 (7) | 0.039 (2) | |
H4 | 0.340 (3) | 0.1233 (4) | 0.3007 (8) | 0.046 (3) | |
H11 | 0.358 (3) | 0.5389 (5) | 0.0775 (9) | 0.055 (3) | |
H12 | 0.121 (3) | 0.4359 (4) | 0.0404 (8) | 0.043 (3) | |
H3 | 0.560 (3) | 0.1790 (5) | 0.1640 (8) | 0.045 (3) | |
H7 | 0.635 (3) | 0.3758 (4) | 0.3898 (8) | 0.042 (3) | |
H16 | 1.001 (4) | 0.5449 (6) | 0.4513 (10) | 0.039 (3) | |
H18A | 0.043 (3) | 0.2800 (6) | 0.5101 (10) | 0.070 (4) | |
H18B | 0.199 (5) | 0.3458 (5) | 0.4672 (10) | 0.093 (6) | |
H18C | 0.466 (3) | 0.2985 (8) | 0.5334 (9) | 0.089 (5) |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl17 | 0.02704 (7) | 0.01987 (6) | 0.02118 (8) | −0.00156 (5) | 0.00511 (5) | 0.00733 (5) |
C5 | 0.0188 (2) | 0.0144 (2) | 0.0168 (3) | −0.00081 (16) | 0.00133 (19) | 0.00219 (18) |
C6 | 0.0194 (2) | 0.0147 (2) | 0.0134 (2) | −0.00062 (16) | 0.00050 (19) | 0.00098 (18) |
C8 | 0.0197 (2) | 0.0135 (2) | 0.0132 (2) | −0.00254 (16) | −0.00056 (18) | −0.00060 (17) |
C2 | 0.0249 (3) | 0.0176 (2) | 0.0144 (3) | −0.00347 (19) | 0.0033 (2) | 0.0002 (2) |
C1 | 0.0226 (2) | 0.0138 (2) | 0.0137 (3) | −0.00380 (17) | −0.00006 (19) | 0.00040 (18) |
C4 | 0.0251 (3) | 0.0138 (2) | 0.0199 (3) | −0.00124 (17) | 0.0027 (2) | 0.00004 (19) |
C9 | 0.0187 (2) | 0.0128 (2) | 0.0146 (2) | −0.00135 (16) | −0.00103 (19) | −0.00116 (17) |
O16 | 0.0437 (3) | 0.01627 (18) | 0.0208 (2) | −0.00765 (17) | −0.0076 (2) | −0.00184 (17) |
C11 | 0.0278 (3) | 0.0165 (2) | 0.0179 (3) | 0.00172 (19) | −0.0031 (2) | 0.0022 (2) |
N7 | 0.0388 (3) | 0.0147 (2) | 0.0149 (2) | −0.00749 (18) | −0.0045 (2) | 0.00098 (17) |
C13 | 0.0196 (2) | 0.0160 (2) | 0.0148 (3) | −0.00141 (17) | −0.00178 (19) | −0.00154 (18) |
O15 | 0.0505 (3) | 0.01728 (19) | 0.0180 (2) | −0.00828 (18) | −0.0106 (2) | −0.00045 (16) |
C10 | 0.0240 (2) | 0.0132 (2) | 0.0182 (3) | −0.00090 (18) | −0.0019 (2) | 0.00082 (19) |
C3 | 0.0279 (3) | 0.0167 (2) | 0.0172 (3) | −0.00086 (19) | 0.0038 (2) | −0.0019 (2) |
C12 | 0.0222 (2) | 0.0184 (2) | 0.0162 (3) | 0.00175 (18) | −0.0037 (2) | −0.0005 (2) |
C14 | 0.0264 (3) | 0.0137 (2) | 0.0161 (3) | −0.00261 (17) | −0.0035 (2) | −0.00178 (19) |
C18 | 0.0300 (3) | 0.0226 (3) | 0.0166 (3) | 0.0012 (2) | 0.0029 (2) | −0.0015 (2) |
H13 | 0.040 (6) | 0.040 (5) | 0.027 (7) | −0.011 (5) | −0.002 (5) | −0.012 (5) |
H10 | 0.051 (6) | 0.032 (6) | 0.041 (7) | −0.007 (5) | −0.005 (5) | 0.004 (5) |
H2 | 0.046 (6) | 0.038 (6) | 0.033 (7) | −0.004 (5) | 0.010 (5) | −0.002 (5) |
H4 | 0.070 (7) | 0.020 (5) | 0.052 (8) | −0.002 (5) | 0.025 (6) | −0.003 (5) |
H11 | 0.074 (8) | 0.033 (6) | 0.057 (9) | 0.008 (5) | −0.008 (6) | 0.006 (6) |
H12 | 0.052 (6) | 0.033 (6) | 0.041 (7) | −0.001 (4) | −0.013 (5) | 0.004 (5) |
H3 | 0.064 (7) | 0.031 (6) | 0.040 (8) | −0.001 (5) | −0.002 (6) | −0.007 (5) |
H7 | 0.069 (9) | 0.023 (6) | 0.032 (8) | −0.010 (5) | −0.003 (6) | −0.008 (5) |
H16 | 0.053 (8) | 0.037 (7) | 0.024 (8) | −0.002 (6) | −0.007 (7) | −0.002 (6) |
H18A | 0.063 (8) | 0.080 (9) | 0.071 (11) | −0.015 (7) | 0.036 (7) | −0.023 (8) |
H18B | 0.201 (18) | 0.029 (7) | 0.051 (11) | 0.024 (8) | 0.022 (11) | −0.008 (6) |
H18C | 0.070 (9) | 0.145 (14) | 0.051 (10) | 0.048 (9) | −0.014 (7) | −0.054 (9) |
Cl17—C5 | 1.7373 (6) | O16—C14 | 1.3136 (7) |
C5—C6 | 1.3933 (8) | O16—H16 | 0.983 (14) |
C5—C4 | 1.3850 (9) | C11—C10 | 1.3761 (9) |
C6—C1 | 1.4103 (9) | C11—C12 | 1.3957 (9) |
C6—C18 | 1.4957 (9) | C11—H11 | 1.085 (10) |
C8—C9 | 1.4217 (7) | N7—H7 | 1.019 (10) |
C8—N7 | 1.3679 (8) | C13—C12 | 1.3789 (8) |
C8—C13 | 1.4064 (8) | C13—H13 | 1.089 (9) |
C2—C1 | 1.3965 (9) | O15—C14 | 1.2355 (8) |
C2—C3 | 1.3855 (9) | C10—H10 | 1.088 (9) |
C2—H2 | 1.081 (10) | C3—H3 | 1.098 (10) |
C1—N7 | 1.3985 (7) | C12—H12 | 1.078 (10) |
C4—C3 | 1.3865 (10) | C18—H18A | 1.087 (12) |
C4—H4 | 1.086 (9) | C18—H18B | 1.048 (11) |
C9—C10 | 1.4019 (8) | C18—H18C | 1.052 (11) |
C9—C14 | 1.4625 (8) | ||
C6—C5—Cl17 | 119.20 (5) | C1—N7—C8 | 129.34 (5) |
C4—C5—Cl17 | 117.59 (4) | H7—N7—C8 | 113.1 (7) |
C4—C5—C6 | 123.21 (6) | H7—N7—C1 | 117.5 (7) |
C1—C6—C5 | 117.11 (6) | C12—C13—C8 | 120.91 (5) |
C18—C6—C5 | 121.33 (6) | H13—C13—C8 | 119.5 (6) |
C18—C6—C1 | 121.55 (5) | H13—C13—C12 | 119.6 (6) |
N7—C8—C9 | 120.11 (5) | C11—C10—C9 | 121.44 (5) |
C13—C8—C9 | 117.85 (5) | H10—C10—C9 | 118.6 (6) |
C13—C8—N7 | 122.00 (5) | H10—C10—C11 | 119.9 (6) |
C3—C2—C1 | 120.37 (6) | C4—C3—C2 | 120.55 (6) |
H2—C2—C1 | 118.9 (6) | H3—C3—C2 | 120.6 (6) |
H2—C2—C3 | 120.7 (6) | H3—C3—C4 | 118.8 (6) |
C2—C1—C6 | 120.31 (5) | C13—C12—C11 | 121.20 (6) |
N7—C1—C6 | 117.43 (6) | H12—C12—C11 | 120.0 (5) |
N7—C1—C2 | 122.09 (6) | H12—C12—C13 | 118.7 (5) |
C3—C4—C5 | 118.43 (5) | O16—C14—C9 | 115.61 (5) |
H4—C4—C5 | 119.2 (6) | O15—C14—C9 | 123.51 (5) |
H4—C4—C3 | 122.4 (6) | O15—C14—O16 | 120.88 (6) |
C10—C9—C8 | 119.68 (5) | H18A—C18—C6 | 111.5 (8) |
C14—C9—C8 | 121.91 (5) | H18B—C18—C6 | 113.2 (8) |
C14—C9—C10 | 118.41 (5) | H18B—C18—H18A | 104.1 (13) |
H16—O16—C14 | 110.9 (8) | H18C—C18—C6 | 114.1 (7) |
C12—C11—C10 | 118.83 (6) | H18C—C18—H18A | 106.5 (13) |
H11—C11—C10 | 120.7 (6) | H18C—C18—H18B | 106.8 (13) |
H11—C11—C12 | 120.5 (6) | ||
Cl17—C5—C6—C1 | 179.07 (4) | C6—C1—N7—C8 | −142.97 (5) |
Cl17—C5—C6—C18 | −0.77 (5) | C8—C9—C10—C11 | 1.22 (7) |
Cl17—C5—C4—C3 | −179.13 (4) | C8—C9—C14—O16 | 176.88 (6) |
C5—C6—C1—C2 | −0.01 (6) | C8—C9—C14—O15 | −3.68 (7) |
C5—C6—C1—N7 | −175.43 (5) | C8—N7—C1—C2 | 41.71 (8) |
C5—C4—C3—C2 | 0.17 (7) | C8—C13—C12—C11 | −0.37 (7) |
C6—C1—C2—C3 | 0.94 (6) | C9—C10—C11—C12 | 1.17 (8) |
D—H···A | D—H | H···A | D···A | D—H···A |
N7—H7···O15 | 1.019 (11) | 1.800 (10) | 2.6469 (7) | 138.0 (8) |
O16—H16···O15i | 0.998 (14) | 1.640 (14) | 2.6381 (8) | 179.0 (12) |
Symmetry code: (i) −x+2, −y+1, −z+1. |
Form | D—H···A | D—H | H···A | D···A | D—H···A |
I (KAXXAI01) | N7—H7···O15 | 0.79 | 2.02 | 2.676 | 141 |
O16—H16···O15i | 0.97 | 1.69 | 2.648 | 170 | |
II (KAXXAI) | N7—H7···O15 | 0.84 | 1.96 | 2.653 | 139 |
O16—H16···O15ii | 0.93 | 1.72 | 2.648 | 176 |
Symmetry codes: (i) -x, 1 - y, 1 - z; (ii) 2 - x, 1 - y, 1 - z. |
Acknowledgements
The authors thank David Sage and Philip Muwanga for their assistance in using 4Sight to analyse the structures and prepare the figures.
Funding information
Funding for this research was provided by: Engineering and Physical Sciences Research Council (grant No. EP/K039547/1).
References
Andersen, K. V., Larsen, S., Alhede, B., Gelting, N. & Buchardt, O. (1989). J. Chem. Soc. Perkin Trans. 2, pp. 1443–1447. CSD CrossRef Web of Science Google Scholar
Ang, L. S., Mohamed-Ibrahim, M. I. & Sulaiman, S. (2016). Phys. Res. Int., article ID 3537842. Google Scholar
Blessing, R. H. (1995). Acta Cryst. A51, 33–38. CrossRef CAS Web of Science IUCr Journals Google Scholar
Blundell, C. D., Packer, M. J. & Almond, A. (2013). Bioorg. Med. Chem. 21, 4976–4987. Web of Science CrossRef CAS PubMed Google Scholar
Bouanga Boudiombo, J. S. & Jacobs, A. (2016). Acta Cryst. B72, 836–845. Web of Science CSD CrossRef IUCr Journals Google Scholar
Bourhis, L. J., Dolomanov, O. V., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2015). Acta Cryst. A71, 59–75. Web of Science CrossRef IUCr Journals Google Scholar
Capelli, S. C., Bürgi, H.-B., Dittrich, B., Grabowsky, S. & Jayatilaka, D. (2014). IUCrJ, 1, 361–379. Web of Science CSD CrossRef CAS PubMed IUCr Journals Google Scholar
Case, D. H., Srirambhatla, V. K., Guo, R., Watson, R. E., Price, L. S., Polyzois, H., Cockcroft, J. K., Florence, A. J., Tocher, D. A. & Price, S. L. (2018). Cryst. Growth Des. 18, 5322–5331. Web of Science CSD CrossRef CAS Google Scholar
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Du, W., Cruz-Cabeza, A. J., Woutersen, S., Davey, R. J. & Yin, Q. (2015). Chem. Sci. 6, 3515–3524. Web of Science CrossRef CAS PubMed Google Scholar
Dunning, T. H. (1989). J. Chem. Phys. 90, 1007–1023. CrossRef CAS Web of Science Google Scholar
Fábián, L., Hamill, N., Eccles, K. S., Moynihan, H. A., Maguire, A. R., McCausland, L. & Lawrence, S. E. (2011). Cryst. Growth Des. 11, 3522–3528. Google Scholar
Fugel, M., Jayatilaka, D., Hupf, E., Overgaard, J., Hathwar, V. R., Macchi, P., Turner, M. J., Howard, J. A. K., Dolomanov, O. V., Puschmann, H., Iversen, B. B., Bürgi, H.-B. & Grabowsky, S. (2018). IUCrJ, 5, 32–44. Web of Science CSD CrossRef CAS PubMed IUCr Journals Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Lipsitz, R. S. & Tjandra, N. (2004). Annu. Rev. Biophys. Biomol. Struct. 33, 387–413. Web of Science CrossRef PubMed CAS Google Scholar
López-Mejías, V., Kampf, J. W. & Matzger, A. J. (2009). J. Am. Chem. Soc. 131, 4554–4555. Web of Science PubMed Google Scholar
Mattei, A. & Li, T. (2012). Pharm. Res. 29, 460–470. Web of Science CrossRef CAS PubMed Google Scholar
Mattei, A. & Li, T. (2014). Cryst. Growth Des. 14, 2709–2713. Web of Science CrossRef CAS Google Scholar
Mattei, A., Mei, X., Miller, A. F. & Li, T. (2013). Cryst. Growth Des. 13, 3303–3307. Web of Science CrossRef CAS Google Scholar
Rigaku OD (2017). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England. Google Scholar
Sheldrick, G. M. (1996). SADABS. University of Göttingen, Göttingen, Germany. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Siskos, M. G., Choudhary, M. I. & Gerothanassis, I. P. (2017). Molecules, 22, 415–446. Web of Science CrossRef Google Scholar
Surov, A. O., Simagina, A. A., Manin, N. G., Kuzmina, L. G., Churakov, A. V. & Perlovich, G. L. (2015). Cryst. Growth Des. 15, 228–238. Web of Science CSD CrossRef CAS Google Scholar
Wittering, K. E., Agnew, L. R., Klapwijk, A. R., Robertson, K., Cousen, A. J. P., Cruickshank, D. L. & Wilson, C. C. (2015). CrystEngComm, 17, 3610–3618. Web of Science CSD CrossRef CAS Google Scholar
This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.