The Synthesis and New Crystal Structures of Three Arylpiperazine Compounds

The structure of arylpiperazine moieties as an important pharmacophore could generate wide pharmacological activities.Arylpiperazine derivatives referred in this paper possessed antitumor activity. The title compounds were crystallized by slow evaporation. 2-(4-(2-(4-Phenylpiperazin-1-yl)ethyl)benzyl)isoindoline-1,3-dione(1), 2-(4-(2-(4-(4-Bromophenyl)piperazin-1-yl)ethyl)benzyl)isoindoline-1,3-dione (2) and 2-(4-(2-(4-(4-Chlorophenyl)piperazin-1-yl)ethyl)benzyl)isoindoline-1,3-dione (3) crystallizes in the triclinic space group P-1 with two molecules in the unit cell. The unit cell parameters for 1 are a = 6.9159(14) Å, b = 9.999(2) Å, c = 16.925(3) Å, α = 88.25(3)°, β = 85.14(3) °, γ = 79.22(3) °. The unit cell parameters for 2 are a = 6.9995(14) Å, b = 9.919(2) Å, c = 17.671(4) Å, α= 97.55(3)°, β = 92.19(3) °, γ = 102.23(3) °. The unit cell parameters for 1 are a = 6.9872(14) Å, b = 9.863(2) Å, c = 17.557(4) Å, α=96.81(3)°, β = 91.89(3) °, γ = 101.74(3) °. Pi-pi interactions were observed between molecules, and compound 2 and 3 showed halogen interactions between molecules nearby, which was different from compound 1.


Introduction
The structure of arylpiperazine moieties as an important pharmacophore could generate wide pharmacological activities [1][2][3]．Compounds with arylpiperazine moieties have anti-proliferative properties [4][5].Naftopidil, an arylpiperazine ether derivative, is a specific a1d-adrenergic receptor antagonist [6,7], and it is one of the most widely used a1-adrenergic receptor antagonists in Japan for the treatment of benign prostatic hyperplasia (BPH) [8,9].Recent studies have shown that naftopidil could possibly exert an anticancer effect and inhibit prostate cancer cell growth by arresting the G1 cell cycle phase [10,11], as well as inducing apoptosis in malignant mesothelioma cell lines [12].Arylpiperazine derivatives referred in this paper possessed antitumor activity.
The halogen bond is a noncovalent interaction involving polarizable chlorine, bromine, or iodine molecular substituents.It is easily observed in small molecule packing [13,14], and is now being exploited to control the assembly of small molecules in the design of supramolecular complexes and new materials [15,16].In this study, arylpiperazine halogen derivatives were synthesized to observe if the packing mode was affected by halogen bonds.

Description of Structures
Single-crystal X-ray diffraction reveals that all the three compounds crystallized in the triclinic space group P-1.The molecular structures and unit cell of three compounds are shown in Fig. 1 and Fig. 2, respectively.All asymmetrical units contain only one independent molecule.The chemical structures of these three compounds were similar, except the substituent groups at ring 1 (C1-C2-C3-C4-C5-C6).Compared with compound 1, compound 2 and 3 were substituted by Cl and Br, respectively.All three compounds contained three benzene rings, a six-membered ring, apyrrole ring.Ring 4 and ring 5 are coplanar.In compound 1, the dihedral angles made by the planes of the ring1 and ring2, ring 1 and ring 3, ring 1 and ring 4are3.9(2)˚,110.5(2)˚and 67.5(2)˚, respectively.In compound 2, the dihedral angles made by the planes of the ring1 and ring 2, ring 1 and ring 3, ring 1 and ring 4are16.9(2)˚,92.0(1)˚and 101.0(1)˚, respectively.In compound 3, the dihedral angles made by the planes of the ring1 and ring 2, ring 1 and ring 3, ring 1 and ring 4are17.4(2)˚, 91.4(2)˚and 99.5(2)˚, respectively.The bond lengths of these 3 compounds were same, which indicated that substitution of halogen didn't affect the configuration of the molecules.The dihedral angle values indicated the conformation of compound 2 and 3 were similar, which was a little different from that of compound 1 due to the effect of the halogen atoms.All these compounds expanded into 3D-network via the intermolecular weak hydrogen bonds.Compound 2 and 3 showed halogen interactions between molecules nearby different from compound 1, which resulted in the large difference of cell parameter of compound 1 (Figure 4).In summary, the dihedral angle values, the bond lengths and the parameters demonstrated that involvement of halogen atoms did affect the conformation and the packing mode of compounds.

Materials and Instrumentation
NMR spectra were recorded on a Brucker ADVANCE 400MHz spectrometer (Bruker, Billerica, MA, USA) and chemical shifts of the 1H, and 13C spectra were reported in parts per million (ppm) using the solvent shifts for 1H and 13C as internal standard (CDCl3: 1H d = 7.26, 13C d = 77.0).MS spectra were determined by electron spray ionization using an Electron Finnigan MAT 95-XP mass spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).X-ray single crystal experiments were performed on a Bruker P4 diffractometer (Bruker, Billerica, MA, USA).

Crystal Structure Determination
Crystals suitable for diffraction experiment were collected from solutions.The data were collected by Crystal data, data collection and structure refinement details are summarized in Table 1.The structure was solved and refined using the OLEX2 program suite [17], equipped with ShelXT and ShelXL program [18].All non-hydrogen atoms were located from Fourier map directly by ShelXT and refined anisotropically.Hydrogen atoms on all non-hydrogen atoms were placed in calculated positions, and their coordinates and displacement parameters were constrained to ride on the carrier atoms.All the CIF files could be downloaded from http://www.ccdc.cam.ac.uk.   3) were synthesized via classical synthesis method.Their structures were determined via NMR, MS and X-ray single crystal diffraction analysis.Pi-pi interactions were observed between molecules, and compound 2 and 3 showed halogen interactions between molecules nearby, which was different from compound1.The dihedral angle values, the bond lengths and the parameters demonstrated that involvement of halogen atoms did affect the conformation and the packing mode of the compounds.