2-Chloro-3-nitro-5-(trifluoromethyl)benzoic acid and -benzamide: structural characterization of two precursors for antitubercular benzothiazinones

The crystal and molecular structures of 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid and 2-chloro-3-nitro-5-(trifluoromethyl)benzamide, two precursors for the synthesis of 8-nitro-1,3-benzothiazin-4-ones, a promising class of new antituberculosis drug candidates, are described.

Reaction with the aforementioned secondary amine eventually affords BTZ043.
To the best of our knowledge, Welch et al. (1969) were the first to report the synthesis of the title compounds more than 50 years ago in the course of a study on trifluoromethylbenzamides as anticoccidial agents. Compound 1 is readily obtained from 2-chloro-5-(trifluoromethyl)benzonitrile upon reaction with nitrating acid mixture. Treatment of 1 with thionyl chloride affords the corresponding acid chloride, which is reacted with concentrated ammonia solution to give amide 2 in good yield (Fig. 1). Both compounds form hydrogen-bonded dimers in the solid state, which in the case of 2 is augmented by additional N-HÁ Á ÁO hydrogen bonds to form a catemer (see Section 3). In 1, the plane defined by the carboxy group non-hydrogen atoms (O1, O2 and C7) is twisted out of the mean plane of the benzene ring (C1-C6) by 22.9 (1) . Remarkably, the plane defined by the nitro group (O3, O4 and N1) is oriented nearly perpendicular to the mean plane of the benzene ring with a tilt angle of 85.38 (7) .

Structural commentary
Compound 2 crystallizes with two molecules in the asymmetric unit (Z 0 = 2), one of which exhibits partial rotational disorder of the trifluoromethyl group. With respect to the mean plane of benzene ring (C1-C6), the plane defined by the non-hydrogen atoms of the amide group (O1, N1 and C7) is inclined at 49.0 (2) and 43.4 (2) in molecule 1 and 2, respectively. The tilt angle between the plane of the nitro group (O2, Figure 2 Hydrogen-bonded dimers of 1 (a) and 2 (b) in the crystal. Displacement ellipsoids are drawn at the 50% probability level. The site of the disordered trifluoromethyl group in 2 with minor occupancy (ca 12%) in the crystal is shown by empty ellipsoids. Hydrogen atoms are represented by small spheres of arbitrary radius and hydrogen bonds are shown by dashed lines. Symmetry code: (i) Àx + 2, Ày + 1, Àz + 1.

Figure 1
Conversion of 1 to 2 in two steps and schematic illustration of two representative syntheses of BTZ043 starting from 1 (Makarov et al., 2007) or 2 (Makarov, 2011). O3 and N2) and the benzene ring mean plane is 46.1 (1) in molecule 1 and 46.7 (1) in molecule 2, which is significantly smaller than in 1.
The 1 H NMR spectrum of 2 in DMSO-d 6 at room temperature shows two distinct broad singlets for the amide hydrogen atoms (see supporting information), indicating restricted rotation about the C-N bond due to partial doublebond character (Wiberg, 2003). In the IR spectrum of solid 2 (see supporting information), two characteristic N-H stretching bands at 3356 and 3178 cm À1 are present (Parker, 1971).

Supramolecular features
The supramolecular structures of 1 and 2 feature carboxylic acid-carboxylic acid and amide-amide homosynthons (Desiraju, 1995;Thakuria et al., 2017), respectively. The hydrogen-bond motif is R 2 2 (8) (Bernstein et al., 1995) in both cases. Geometric parameters of the O-HÁ Á ÁO hydrogen bonds in 1 (Table 1) and the N-HÁ Á ÁO hydrogen bonds in 2 ( Table 2) are within expected ranges (Thakuria et al., 2017). In 1 two molecules related by crystallographic inversion symmetry form a carboxylic acid dimer, whereas in 2 two crystallographically unique molecules related by approximate local inversion symmetry form a carboxamide dimer. The second amide hydrogen atom forms a hydrogen bond to the carbonyl oxygen atom of an adjacent dimer. The additional R 2 4 (8) hydrogen-bond motif thus formed about a crystallographic centre of symmetry extends the N-HÁ Á ÁO hydrogen-bonding pattern in 2 into typical primary amide tapes (Leiserowitz & Schmidt, 1969) parallel to the [101] direction (Fig. 3a).
In addition to classical O-HÁ Á ÁO and N-HÁ Á ÁO intermolecular hydrogen bonds in 1 and 2, respectively, the solidstate supramolecular structures of both compounds feature a number of possible weak interactions (Tables 1 and 2). In 1 the C4-H4 moiety forms a short contact to a fluorine atom of the trifluoromethyl group of a neighbouring molecule (Fig. S1 in the supporting information) and the nitro group appears to accept a donating bifurcated weak C-HÁ Á ÁO hydrogen bond from the C6-H6 moiety (Fig. S2 in the supporting information). The latter interaction links the molecules into chains in the [110] direction and may be discussed in connection with the remarkable twist of the nitro group out of the plane of the benzene ring. A packing index for 1 of 74.3%, as calculated with PLATON (Spek, 2020), indicates a fairly dense crystal packing for a molecular compound (Kitaigorodskii, 1973 (001), showing short C-HÁ Á ÁO contacts in addition to classical N-HÁ Á ÁO hydrogen bonds (both represented by dashed lines). The number after the underscore indicate unique molecule 1 or 2 (Fig. 2). The minor disorder part of the trifluoromethyl group in molecule 2 and carbon-bound hydrogen atoms are omitted for clarity in (a). Symmetry codes: (i) Àx + 2, Ày + 1; (ii) Àx + 1, Ày + 1, -z; (iii) x + 1, y, z; (iv) x À 1, y, z. Table 1 Hydrogen-bond geometry (Å , ) for 1. Symmetry codes: (i) Àx þ 2; Ày þ 1; Àz þ 1; (ii) Àx þ 1; Ày þ 2; Àz; (iii) x À 1; y À 1; z.
In the crystal structure of 2, short fluorine-fluorine contacts between the non-disordered trifluoromethyl groups of adjacent molecules 1 can be identified ( Fig. S3 in the supporting information). Based on the corresponding C-FÁ Á ÁF angles of 152.1 (1) at F1 and 168.6 (1) at F3, these contacts may be classified as type I fluorine-fluorine interactions (Baker et al., 2012). As in 1, the C6-H6 moieties in 2 form short C-HÁ Á ÁO contacts to nitro oxygen atoms of adjacent molecules (Fig. 3b). The electron-withdrawing effect exerted by the ring substituents in both 1 and 2 should activate the C-H moieties for weak hydrogen bonding (Thakuria et al., 2017) to some extent. Notably, the packing index for 2 of 70.0%, as calculated only for the major disorder part of the trifluoromethyl group in molecule 2, is markedly smaller than for 1.

Synthesis and crystallization
General: Starting materials and reagents were obtained from chemical suppliers and used as received. Solvents were of reagent grade and were distilled before use. NMR spectra were measured on an Agilent Technologies VNMRS 400 MHz spectrometer. Chemical shifts are reported relative to the residual solvent peak of DMSO-d 6 ( H = 2.50 ppm, C = 39.5 ppm). Abbreviations: s = singlet, d = doublet, q = quartet. IR spectra were measured on a Bruker ALPHA Platinum ATR-FT-IR spectrometer. Mass spectra were recorded on a Thermo Fisher Q Exactive TM Plus Orbitrap mass spectrometer for 1 and on an Advion expression S compact mass spectrometer for 2, using methanol as solvent.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. Diffraction data for 1 were measured at the P11 beamline at PETRA III at DESY (Meents et al., 2013;Burkhardt et al., 2016). Rotational disorder of a trifluoromethyl group in 2 was refined using a split model with similar distance restraints on the 1,2-and 1,3distances and equal atomic displacement parameters for opposite fluorine atoms belonging to different disorder sites. Refinement of the ratio of occupancies by means of a free variable resulted in 0.876 (3):0.124 (3). Carbon-bound H atoms were placed in geometrically calculated positions with C-H = 0.95 Å , and refined with the appropriate riding model and U iso (H) = 1.2 U eq (C). The carboxy hydrogen atom in 1 was located in a difference-Fourier map and refined freely. The amide H atoms in 2 were also located in difference-Fourier maps and refined semi-freely with the N-H distances restrained to a target value of 0.88 (2) Å and with U iso (H) = 1.2 U eq (N).
Acta Cryst. (2021). E77, 142-147 research communications Table 3 Experimental details.  SAINT (Bruker, 2004) for (2). For both structures, program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg, 2018); software used to prepare material for publication: enCIFer (Allen et al., 2004) and publCIF (Westrip, 2010). 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.

2-Chloro-3-nitro-5-(trifluoromethyl)benzamide (2)
Crystal data 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.