1-[Bis(4-fluoro­phen­yl)meth­yl]-4-[(2Z)-3-phenyl­prop-2-en-1-yl]piperazine-1,4-diium dichloride hemihydrate

S Shivaprakash; G Chandrasekara Reddy; Jerry P Jasinski

doi:10.1107/S1600536814011064

. 2014 May 21;70(Pt 6):o694–o695. doi: 10.1107/S1600536814011064

1-[Bis(4-fluorophenyl)methyl]-4-[(2Z)-3-phenylprop-2-en-1-yl]piperazine-1,4-diium dichloride hemihydrate

S Shivaprakash ^a, G Chandrasekara Reddy ^a, Jerry P Jasinski ^b,^*

PMCID: PMC4051083 PMID: 24940270

Abstract

The asymmetric unit of the title monohydrated salt, 2C₂₆H₂₈F₂N₂ ²⁺·4Cl^−.H₂O, consists of a 1-[bis(4-fluorophenyl)methyl]-4-[(2Z)-3-phenylprop-2-en-1-yl]piperazine-1,4-diium cation with a diprotonated piperizine ring in close proximity to two chloride anions and a single water molecule that lies on a twofold rotation axis. In the cation, the piperazine ring adopts a slightly distorted chair conformation. The dihedral angles between the phenyl ring and the 4-fluorophenyl rings are 89.3 (9) and 35.0 (5)°. The two fluorophenyl rings are inclined at 65.0 (5)° to one another. In the crystal, N—H⋯Cl hydrogen bonds and weak C—H⋯Cl intermolecular interactions link the molecules into chains along [010]. In addition, weak C—H⋯O interactions between the piperizine and prop-2-en-1-yl groups with the water molecule, along with weak C—H⋯Cl interactions between the prop-2en-1-yl and methyl groups with the chloride ions, weak C—H⋯F interactions between the two fluorophenyl groups and weak O—H⋯Cl interactions between the water molecule and chloride ions form a three-dimensional supramolecular network.

Related literature

For the use of flunarizine {systematic name: (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine} as an antihistamine and vasodilator, see: Agnoli et al. (1988 ▶); Prasanna & Row (2001 ▶). For the synthesis of (E)-isomers of 1-benzhydryl-4-cinnamyl piperazines, see: Cignarella & Testa (1968 ▶) and that of the Z-isomer of cinnerizine, [systematic name: (E)-1-(diphenylmethyl)-4-(3-phenylprop-2-enyl)piperazine], see; Shivaprakash & Chandrasekara Reddy (2014 ▶). For puckering parameters, see Cremer & Pople (1975 ▶). For standard bond lengths, see: Allen et al. (1987 ▶).

Experimental

Crystal data

2C₂₆H₂₈F₂N₂ ²⁺·4Cl⁻·H₂O
M _r = 972.82
Monoclinic,
a = 18.2973 (6) Å
b = 7.02041 (14) Å
c = 20.1554 (6) Å
β = 104.601 (3)°
V = 2505.44 (13) Å³
Z = 2
Mo Kα radiation
μ = 0.29 mm⁻¹
T = 173 K
0.44 × 0.38 × 0.16 mm

Data collection

Agilent Eos Gemini diffractometer
Absorption correction: multi-scan (CrysAlis PRO and CrysAlis RED; Agilent, 2012 ▶) T _min = 0.914, T _max = 1.000
32975 measured reflections
8607 independent reflections
6582 reflections with I > 2σ(I)
R _int = 0.034

Refinement

R[F ² > 2σ(F ²)] = 0.057
wR(F ²) = 0.153
S = 1.09
8607 reflections
306 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.65 e Å⁻³
Δρ_min = −0.41 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2012 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis RED (Agilent, 2012 ▶); program(s) used to solve structure: SUPERFLIP (Palatinus & Chapuis, 2007 ▶; Palatinus & van der Lee, 2008 ▶; Palatinus et al., 2012 ▶); program(s) used to refine structure: SHELXL2012 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: OLEX2.

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536814011064/sj5400sup1.cif

e-70-0o694-sup1.cif^{(32KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814011064/sj5400Isup2.hkl

e-70-0o694-Isup2.hkl^{(471.4KB, hkl)}

Click here for additional data file.^{(9.1KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814011064/sj5400Isup3.cml

CCDC reference: 1002927

Additional supporting information: crystallographic information; 3D view; checkCIF report

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯Cl1ⁱ	0.84 (2)	2.14 (2)	2.9782 (13)	176 (2)
N2—H2⋯Cl2ⁱⁱ	0.86 (3)	2.17 (3)	3.0248 (13)	174 (2)
C1—H1A⋯O1W ⁱ	0.99	2.68	3.512 (2)	142
C5—H5A⋯O1W ⁱ	0.99	2.67	3.470 (2)	138
C5—H5B⋯Cl1ⁱⁱ	0.99	2.51	3.4934 (16)	176
C14—H14⋯Cl2ⁱ	1.00	2.49	3.4735 (15)	168
C19—H19⋯F2ⁱⁱⁱ	0.95	2.46	3.244 (2)	140
O1W—H1W⋯Cl1	0.80 (3)	2.48 (3)	3.2603 (12)	163 (3)

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

Acknowledgments

We express our sincere thanks to Dr Anil Kush, Director, VMSRF for his keen interest and support throughout this work. JPJ acknowledges the NSF–MRI program (grant No. CHE-1039027) for funds to purchase the X-ray diffractometer.

supplementary crystallographic information

1. Comment

Flunarizine, (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2- propenyl)piperazine, is a clinically useful drug used as an antihistamine and vasodilator (Agnoli et al. (1988), Prasanna & Row (2001). Because the greater biological importance of (E)-isomers of 1-benzhydryl-4-cinnamyl piperazines has been recognised, several synthetic methods for these isomers have been described (Cignarella & Testa, 1968). However, the synthesis of (Z)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine has only recently been reported (Shivaprakash & Chandrasekara Reddy, 2014).

The title compound, 2(C₂₆H₂₈F₂N₂), 4(Cl), H₂O, (I), is a close analogue of the existing drug, flunarizine, which has an (E) configuration. The crystal structure of flunarizine has been reported (Prasanna & Row, 2001). We have prepared the (Z) isomer (I) for the first time as the crystalline hydrochloride salt to study structure activity relationships and we report its structure here.

The asymmetric unit of the title monohydrated salt, 2(C₂₆H₂₈F₂N₂²⁺), 4(Cl^-), H₂O, (I), consists of a [(Z)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine] cation with a diprotonated piperizine ring in close proximity to two chloride anions and a single water molecule that lies on a two-fold rotation axis (Fig. 1). The piperazine group adopts a slightly distorted chair conformation (puckering parameters Q, θ, and φ = 0.5911 (15)Å, 0.95 (15)° and 154 (8)°, respectively (Cremer & Pople, 1975). Bond lengths are within normal ranges (Allen et al., 1987). In the cation, the dihedral angles between the mean planes of the two 4-fluorophenyl rings with that of the phenyl ring are 89.3 (9)° and 35.0 (5)°, respectively. The two fluorophenyl groups are inclined at 65.0 (5)° to one another. In the crystal, N—H···Cl hydrogen bonds and weak C—H···Cl intermolecular interactions link the molecules into chains along [010] (Fig. 2). In addition, weak C—H···O interactions between the piperizine and prop-2-en-1-yl groups with the water molecule along with weak C—H···Cl interactions between the prop-2en-1-yl and methyl groups with the chloride ions and weak C—H···F interactions between the two fluorophenyl groups and weak O—H···Cl interactions between the water molecule and chloride ions (Table 1) form a 3-D supramolecular network.

2. Experimental

To a solution of 1-(4, 4'-difluoro phenylmethyl)-4-(2-acetaldehyde) piperazine (5.6 g, 17.0 mmol) in dichloromethane (50 ml) under a nitrogen atmosphere was added benzyltriphenyl phosphonium chloride, (6.9 g, 17.9 mmol). The mixture was cooled to 278 °K and t-BuOK (4.6 g, 41.3 mmol) was added with stirring. After completion, the reaction mass was quenched into water (100 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The solution was then subjected to column chromatography over silica gel with an EtOAc/Hexane (1:9) elutant mixture to afford (Z)-1-[bis-(4-fluorophenyl)-methyl]-4-(cinnamyl) piperazine as a viscous liquid. This was then converted into the hydrochloride salt using ethanolic HCl and crystallized from acetone/ethanol (2:8) mp 473-475°K.