Crystal structure of 4-[4-(ethoxycarbonyl)piperazin-1-yl]benzoic acid

4-[4-(Ethoxycarbonyl)piperazin-1-yl]benzoic acid (EPBA) is the product of a reaction between ethyl 1-piperazinecarboxylate and 4-fluorobenzoic acid. The conformation of the two independent molecules (A and B) in the asymmetric unit is similar. The piperazine ring adopts a chair conformation in both molecules. The dihedral angles formed by the four approximately planar C atoms of the piperazine ring and the benzene ring is 30.8 (5)° in molecule A and 30.6 (5)% in molecule B.


Chemical context
Piperazines are among the most important building blocks in drug discovery today. The piperazine nucleus is capable of binding to multiple receptors with high affinity and therefore piperazine has been classified as a privileged structure (Dinsmore & Beshore, 2002). Piperazine and its derivatives are important pharmacores that can be found in biologically active compounds across a number of different therapeutic areas (Berkheij et al., 2005), such as antifungal (Upadhayaya et al., 2004), anti-bacterial, antimalarial, anti-psychotic agents (Chaudhary et al., 2006), HIV protease inhibitors (Dorsey et al., 1994), anti-depressant and anti-tumour activity against colon, prostate, breast, lung and leukemia tumors (Hulme & Cherrier, 1999). A review on the current pharmacological and toxicological information for piperazine derivatives is given by Elliott (2011). The title compound also contains a carboxylic group, which has been widely used in various fields such as coordination chemistry (Rueff et al., 2001), pharmaceutical chemistry (Strachan et al., 2007) and supramolecular chemistry (Desiraju, 2002). Recently, the main focus for carboxylic acids has been in crystal engineering via hydrogen-bonded assembly of organic acids and organic bases (Grossel et al., 2006). In an attempt to further synthesis piperazine derivatives, the title compound was synthesized and the crystal structure is reported herein.

Structural commentary
The molecular structure of the asymmetric unit is shown in Fig. 1. The conformation of the two molecules (A and B) is essentially the same. The piperazine rings are in chair conformations with the N atoms (N1A/N2A and N1B/N2B) ISSN 2056-9890 out of plane of the essentially planar C atoms. The dihedral angles formed by the four approximately planar C atoms of the piperazine ring (C8A-C11A and C8B-C11B) and the benzene ring (C2A-C7A and C2B-C7B) is 30.8 (5) in molecule A and 30.6 (5) in molecule B.

Synthesis and crystallization
The title compound was prepared by a mixture of ethyl 1-piperazinecarboxylate (2.0 g, 12.6 mmol), 4-fluorobenzoic acid (1.7 g, 12.6 mmol), and K 2 CO 3 (2.6 g, 18.9 mmol) in 10 mL of dry acetonitrile which was heated at 353 K for 12 h with constant stirring under a nitrogen atmosphere. After cooling to room temperature, the mixture was poured slowly onto ice-cold water (100 ml) and acidified with glacial acetic acid (AcOH) to pH 3-5. After filtration, the product was obtained as a pale-white crystalline solid (70%). Crystals of the title compound used for X-ray analysis were obtained within three days by slow evaporation of the acetonitrile solvent.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms were placed in calculated positions with C-H = 0.95-0.99 Å , O-H = 0.84 Å and included in the refinement in a riding-motion approximation with U iso (H) = 1.2U eq (C) or 1.5U eq (O, C methyl ). The crystal quality was generally poor and although the best crystal available was selected, the precision of the structure has been affected by the crystal quality. The molecular structures of the two crystallographically independent molecules (A and B) in the asymmetric unit of the title compound. Displacement ellipsoids are drawn at the 40% probability level. Hydrogen bonds are shown as dashed lines. Table 1 Hydrogen-bond geometry (Å , ).    (Sheldrick, 2015), PLATON (Spek, 2009) and DIAMOND (Brandenburg, 2006). program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: PLATON (Spek, 2009) and DIAMOND (Brandenburg, 2006); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015).

4-[4-(Ethoxycarbonyl)piperazin-1-yl]benzoic acid
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.