Synthesis and crystal structures of 1-benzoyl-4-(4-nitrophenyl)piperazine and 1-(4-bromobenzoyl)-4-phenylpiperazine at 90 K

The syntheses and low-temperature (90 K) crystal structures of 1-benzoyl-4-(4-nitrophenyl)piperazine and 1-(4-bromobenzoyl)phenylpiperazine are presented.


Chemical context
Piperazines are important pharmacophores that are found in many biologically active compounds across a number of different therapeutic areas (Berkheij et al., 2005;Brockunier et al., 2004;Bogatcheva et al., 2006) such as antifungal (Upadhayaya et al., 2004), anti-bacterial, anti-malarial and antipsychotic agents (Chaudhary et al., 2006). The pharmacological properties of phenylpiperazines and their derivatives have been described by Cohen et al. (1982), Conrado et al. (2008), Neves et al. (2003), and by Hanano et al. (2000). The design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer have been described by Demirci et al. (2019). Many pharmaceutical compounds are derived from 1-phenylpiperazine, viz., oxypertine, trazodone, nefazodone, etc. Valuable insights into recent advances in antimicrobial activity of piperazine derivatives have been provided by Kharb et al. (2012). A review of current pharmacological and toxicological information for piperazine derivatives was conducted by Elliott (2011).
4-Nitrophenylpiperazinium chloride monohydrate has been used as an intermediate in the synthesis of anticancer drugs, transcriptase inhibitors and antifungal reagents, and is also an important reagent for potassium channel openers, which show considerable biomolecular current-voltage rectification characteristics (Lu, 2007). The inclusion behaviours of 4-sulfonatocalix[n]arenes (SCXn) (n = 4, 6, 8) with 1-(4nitrophenyl)piperazine (NPP) were investigated by UV and fluorescence spectroscopies at different pH values (Zhang et al., 2014). The design, synthesis and biological profiling of aryl piperazine-based scaffolds for the management of androgensensitive prostatic disorders has also been reported by Gupta et al. (2016). 4-Nitrophenylpiperazine was the starting material in the synthesis and biological evaluation of novel piperazine containing hydrazone derivatives (Kaya et al., 2016).

Structural commentary
There are no unusual bond distances or angles in either I or II. The asymmetric unit of I (see scheme) contains two molecules, suffixed 'A' and 'B' in Fig. 1. Each consists of a central piperazine ring in a chair conformation, with a benzoyl and nitrophenyl group attached to different nitrogen atoms. The nitro groups are almost coplanar with their attached benzene rings, forming dihedral angles of 4.4 (2) and 3.0 (2) for molecules A and B, respectively. The phenyl rings are twisted out of planarity with the carbonyl group and its linkage to the piperazine rings, giving N1-C11-C12-C13 torsion angles of À46.8 (3) and 45.4 (3) for A and B, respectively. The dihedral angles between the phenyl and nitrobenzene rings are 51.52 (6) in A and 57.23 (7) in B. Compound II on the other hand has just one molecule in its asymmetric unit (Fig. 2). The piperazine ring is also in a chair conformation and the brominated ring is torsioned [N1-C11-C12-C13 = 46.4 (4) ] to a similar degree to that in I, but the dihedral angle between the phenyl and brominated benzene rings is larger, at 86.6 (1) .

Supramolecular features
There are no conventional hydrogen bonds in either I or II, but there are weaker C-HÁ Á ÁO contacts (Table 1). For I, SHELXL identifies a number of 'potential' hydrogen-bonding interactions, but most of these have poor geometry for hydrogen bonds. The shortest donor-acceptor distances occur for the bifurcated pair C6B-H6BÁ Á ÁO1A and C7B-H7BÁ Á ÁO1A within the chosen asymmetric unit. A similar bifurcated pair of contacts C6A-H6AÁ Á ÁO1B i and C7A-H7AÁ Á ÁO1B i [symmetry code: (i) x, y, z + 1] occur between the A and B molecules in adjacent (along c) asymmetric units. In combination, these interactions lead to double chains that extend parallel to [001] (Fig. 3). In contrast to I, SHELXL identifies no 'potential' hydrogen bonds for II. Mercury (Macrae et al., 2020) on the other hand, which has different default parameters for flagging hydrogen bonds, identifies a bifurcated pair, C13-H13Á Á ÁO1 ii and C14-H14Á Á ÁO1 ii [symmetry code: (ii) x, y + 1, z] (Table 1). A clearer picture of this interaction is provided by a view of the Hirshfeld surface plotted over d norm , as calculated by CrystalExplorer (Spackman et al., 2021), which highlights contacts shorter than the van der Waals radius sum as red blobs (Fig. 4) An ellipsoid plot (50% probability) of II. A partial packing plot of II, showing the Hirshfeld surface of the central molecule, highlighting (red blobs) the bifurcated close contacts (dashed lines) that join the molecules into chains parallel to the b-axis.

Figure 3
A partial packing plot of I, showing close contacts (dashed lines) that connect the molecules into chains parallel to the c-axis.
(5 ml) was then added and stirring was continued overnight at ambient temperature. Reaction schemes are summarized in Fig. 7. When the reactions were confirmed to be complete using thin-layer chromatography, each mixture was quenched with water (10 ml) and extracted with ethyl acetate (20 ml). Each organic fraction was separated and washed successively with an aqueous hydrochloric acid solution (1 mol dm À3 ), a saturated solution of sodium hydrogencarbonate, and lastly with brine. The organic phases were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Crystals suitable for single-crystal X-ray diffraction were grown by slow evaporation, at ambient temperature and in the presence of air, of solutions in ethyl acetate (I: yield 81%, m.p. 428-430 K; II: yield 75%, m.p. 394-396 K).

Data collection and structure refinement
For I, an orange, irregular block-shaped crystal was mounted using polyisobutene oil on the tip of a fine glass fibre in a copper mounting pin. Cu K radiation was chosen to facilitate setting the correct absolute structure, which was definitively established by variants of Flack's parameter (Flack & Bernardinelli, 1999;Hooft et al., 2008;Parsons et al., 2013). For II, the available sample consisted of colourless plates, none of which were single crystals. A suitable specimen was mounted in the same way as for I. Diffraction data collected at 90 K showed two slightly mis-aligned, but sharp and distinct reciprocal lattices. These were not related by any rational twin operation, but by a seemingly arbitrary $4 rotation, presumably due to mis-stacking of aggregated plates. Nevertheless, for data acquisition and processing, facilities for handling twinning by non-merohedry were used. For a brief discussion of true twins vs aggregates, see Parkin (2021). The absolute structure was again determined unambiguously via the Flack parameter and related methods. Crystal data, data collection and refinement statistics are summarized in Table 2. For both structures, hydrogen atoms were included using riding models, with constrained distances set to 0.95 Å (Csp 2 H) and 0.99 Å (R 2 CH 2 ). U iso (H) parameters were set to 1.2U eq of the attached atom. For both structures, data collection: APEX3 (Bruker, 2016); cell refinement: APEX3 (Bruker, 2016); data reduction: APEX3 (Bruker, 2016); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2019/2 (Sheldrick, 2015b); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010).   (5) 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. Refinement. Refinement progress was checked using Platon (Spek, 2020) and by an R-tensor (Parkin, 2000). The final model was further checked with the IUCr utility checkCIF.

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. Refinement. Refinement progress was checked using Platon (Spek, 2020) and by an R-tensor (Parkin, 2000