4-[Bis(4-fluorophenyl)methyl]piperazin-1-ium 2-(2-phenylethyl)benzoate

Richard Betz; Thomas Gerber; Eric Hosten; Alaloor S Dayananda; Hemmige S Yathirajan

doi:10.1107/S160053681103902X

. 2011 Sep 30;67(Pt 10):o2783–o2784. doi: 10.1107/S160053681103902X

4-[Bis(4-fluorophenyl)methyl]piperazin-1-ium 2-(2-phenylethyl)benzoate

Richard Betz ^a,^*, Thomas Gerber ^a, Eric Hosten ^a, Alaloor S Dayananda ^b, Hemmige S Yathirajan ^b

PMCID: PMC3201291 PMID: 22064768

Abstract

The asymmetric unit of the title salt, C₁₇H₁₉F₂N₂ ^+.C₁₅H₁₃O₂ ⁻, derived from a 1,4-diazacyclohexane derivative and a carboxylic acid, contains two formula units. The cation is protonated at the secondary amine functionality. The six-membered heterocycles adopt chair conformations. The fluorophenyl rings in the two cations make dihedral angles of 77.21 (19) and 78.8 (2)° while the aromatic rings in the anions enclose angles of 69.5 (2) and 69.9 (2)°. In the crystal, classical N—H⋯O hydrogen bonds as well as C—H⋯F and C—H⋯O contacts connect the entities into layers parallel to ac.

Related literature

For the biological activity of piperazines, see: Brockunier et al. (2004 ▶); Bogatcheva et al. (2006 ▶). For related structures, see: Anilkumar et al. (2005 ▶); Betz et al. (2011 ▶); Fun et al. (2011 ▶); Jasinski et al. (2010 ▶, 2011 ▶); Dutkiewicz et al. (2011 ▶). For graph-set analysis of hydrogen bonds, see: Etter et al. (1990 ▶); Bernstein et al. (1995 ▶). For puckering analysis, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

C₁₇H₁₉F₂N₂ ⁺·C₁₅H₁₃O₂ ⁻
M _r = 514.60
Monoclinic,
a = 8.2330 (2) Å
b = 35.5366 (10) Å
c = 10.1505 (3) Å
β = 112.925 (1)°
V = 2735.19 (13) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 200 K
0.52 × 0.34 × 0.31 mm

Data collection

Bruker APEXII CCD diffractometer
24852 measured reflections
6889 independent reflections
6401 reflections with I > 2σ(I)
R _int = 0.033

Refinement

R[F ² > 2σ(F ²)] = 0.050
wR(F ²) = 0.129
S = 1.07
6889 reflections
701 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.29 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: APEX2 (Bruker, 2010 ▶); cell refinement: SAINT (Bruker, 2010 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEPIII (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S160053681103902X/bt5651sup1.cif

e-67-o2783-sup1.cif^{(40.1KB, cif)}

Supplementary material file. DOI: 10.1107/S160053681103902X/bt5651Isup2.cdx

Structure factors: contains datablock(s) I. DOI: 10.1107/S160053681103902X/bt5651Isup3.hkl

e-67-o2783-Isup3.hkl^{(337.1KB, hkl)}

Supplementary material file. DOI: 10.1107/S160053681103902X/bt5651Isup4.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H721⋯O22	0.89 (4)	1.81 (4)	2.691 (3)	173 (4)
N2—H722⋯O12ⁱ	0.99 (4)	1.70 (4)	2.688 (3)	174 (4)
N4—H741⋯O21ⁱⁱ	0.94 (3)	1.75 (3)	2.683 (3)	174 (3)
N4—H742⋯O11ⁱⁱⁱ	0.98 (4)	1.71 (4)	2.688 (3)	174 (3)
C23—H23⋯F1^iv	0.95	2.41	3.281 (6)	153
C55—H55⋯F3^iv	0.95	2.46	3.374 (5)	161
C3—H3A⋯O21^iv	0.99	2.61	3.576 (3)	165
C5—H5B⋯O12^v	0.99	2.60	3.564 (3)	164

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) .

Acknowledgments

ASD thanks the University of Mysore for research facilities. HSY thanks R. L. Fine Chem., Bengaluru, for the gift sample of the title compound.

supplementary crystallographic information

Comment

4,4'-Difluorobenzhydryl piperazine is an intermediate for the preparation of flunarizine which is a calcium channel blocker. Piperazines are among the most important building blocks in today's drug discovery. They are found in biologically active compounds across a number of different therapeutic areas such as antifungal, antibacterial, antimalarial, antipsychotic, antidepressant and antitumour activity against colon, prostate, breast, lung and leukemia tumors (Brockunier et al., 2004; Bogatcheva et al., 2006). The crystal structures of some related compounds, viz., 2-(2-phenylethyl)benzoic acid (Anilkumar et al., 2005), levocetirizinium dipicrate (Jasinski et al., 2010), cinnarizinium dipicrate (Jasinski et al., 2011), 1-methylpiperazine-1,4- diium dipicrate (Dutkiewicz et al., 2011) and 4-(4-chlorophenyl)-4-hydroxypipe ridinium 2-(2-phenylethyl)benzoate (Fun et al., 2011) have been reported. Recently, we have reported the crystal structure of 4-[bis(4-fluorophenyl) methyl]piperazin-1-ium picrate (Betz et al., 2011). In the course of our studies on the salts of piperazines and in view of the importance of piperazines, the paper reports the crystal and molecular structure of the title salt.

In both cations present in the asymmetric unit protonation occurred on the secondary amine functionality. According to a conformational analysis (Cremer & Pople, 1975), both diazacyclohexane moieties adopt a ⁴C₁chair conformation. The least-squares planes defined by the carbon atoms of the para-fluorophenyl moieties in the respective cations intersect at angles of 77.21 (19) ° and 78.8 (2) °. The aromatic systems in the anions enclose angles of 69.5 (2) ° and 69.9 (2) °, respectively (Fig. 1).

In the crystal, classical hydrogen bonds as well as C–H···F contacts and C–H···O contacts whose range falls by more than 0.1 Å below the sum of van-der-Waals radii of the atoms participating are observed. The classical hydrogen bonds are apparent between the protonated amine functionality and both oxygen atoms of the carboxylic acid and give rise to the formation of cyclic patterns involving both symmetry-independent cations and anions of the asymmetric unit. While the C–H···F contacts exclusively involve hydrogen atoms in ortho-position to the fluorine atoms on the para-fluorophenyl moieties and connect only one of the cations with its symmetry-generated equivalents, the C–H···O contacts appear between hydrogen atoms of the methylene groups in the carboxylates and "dimerize" the two independent anions present in the asymmetric unit. In terms of graph-set analysis (Etter et al., 1990; Bernstein et al., 1995), the descriptor for the classical hydrogen bonds is DDDD on the unitary level while a R⁴₄(12) descriptor on the quartenary level emphasizes the presence of the cyclic patterns illustrated in Figure 2. For the C–H···F contacts, a C¹₁(10)C¹₁(10) descriptor on the unitary level shows the presence of two homodromic chains as depicted in Figure 3 while a R²₂(12) descriptor on the binary level is indicative for the cyclization of the two anions present in the asymmetric unit on grounds of C–H···O contacts (Fig. 4). In total, the entities of the title compound are connected to planes parallel to ac. The shortest intercentroid distance between two centers of gravity was found at 4.615 (3) Å.

The packing of the title compound in the crystal is shown in Figure 5.

Experimental

4,4'-Difluorobenzhydryl piperazine was obtained from R. L. Fine Chem., Bengaluru, India. 4,4'-Difluorobenzhydryl piperazine (2.88 g, 0.01 mol) was dissolved in 10 ml of methanol and 2-(2-phenylethyl)benzoic acid (2.26 g, 0.01 mol) was also dissolved in 10 ml of methanol. Both the solutions were mixed and stirred in a beaker at 333 K for 60 minutes. The mixture was kept aside for a day at room temperature. The salt formed was filtered & dried in vaccum desiccator over phosphorous pentoxide. X-ray quality crystals of the title compound were obtained from ethanol by slow evaporation.