2-Chloro-1-[4-(2,4-difluoro­benz­yl)piperazin-1-yl]ethanone

Zhang, B.; Damu, G.L.V.; Lv, J.-S.; Zhou, C.-H.

doi:10.1107/S1600536811052597

organic compounds

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ISSN: 2056-9890

Volume 68| Part 1| January 2012| Page o70

doi:10.1107/S1600536811052597

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2-Chloro-1-[4-(2,4-difluorobenzyl)piperazin-1-yl]ethanone

Bo Zhang,^a Guri L. V. Damu,^a Jing-Song Lv ^a and Cheng-He Zhou ^a ^*

^aLaboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Republic of China
^*Correspondence e-mail: zhouch@swu.edu.cn

(Received 30 November 2011; accepted 6 December 2011; online 10 December 2011)

In the title molecule, C₁₃H₁₅ClF₂N₂O, the piperazine ring is in a chair conformation with the 2,4-difluorobenzyl and chloroacetyl substituents in equatorial positions.

Related literature

For the synthesis, see: Gan et al. (2010 ). For applications of piperazine derivatives, see: Gan, Cai & Zhou (2009 ); Cai et al. (2009 ); Gan, Lu, & Zhou (2009 ).

Experimental

Crystal data

C₁₃H₁₅ClF₂N₂O
M_r = 288.72
Orthorhombic, P 2₁ 2₁ 2₁
a = 7.895 (2) Å
b = 8.512 (2) Å
c = 19.884 (5) Å
V = 1336.2 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.30 mm⁻¹
T = 296 K
0.30 × 0.25 × 0.24 mm

Data collection

Bruker SMART CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ) T_min = 0.915, T_max = 0.931
5743 measured reflections
2324 independent reflections
2238 reflections with I > 2σ(I)
R_int = 0.026

Refinement

R[F² > 2σ(F²)] = 0.031
wR(F²) = 0.086
S = 1.07
2324 reflections
220 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.18 e Å⁻³
Absolute structure: Flack (1983 ), 938 Friedel pairs
Flack parameter: 0.05 (7)

Data collection: SMART (Bruker, 2001 ); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009 ); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811052597/lh5389sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536811052597/lh5389Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536811052597/lh5389Isup3.cml

checkCIF report

Comment top

The piperazine ring is present in many clinical drugs (Cai et al., 2009). The incorporation of a piperazine moiety gernerally improves physicochemical properties, and thereby enhances biological activities (Gan, Cai & Zhou, 2009). The piperazine moiety is extensively employed to construct various bioactive molecules (Gan, Lu & Zhou, 2009). Our interest is to develop azole-containing piperazine derivatives as medicinal agents (Gan et al., 2010). Herein we report the crystal structure of the title compound (I).

In the molecular structure (Fig. 1) of (I) the piperazine ring is in a chair conformation, in which the 2,4-difluorobenzyl and chloroacetyl groups are located in equatorial positions.

Related literature top

For the synthesis, see: Gan et al. (2010). For applications of piperazine derivatives, see: Gan, Cai & Zhou (2009); Cai et al. (2009); Gan, Lu, & Zhou (2009).

Experimental top

Compound (I) was synthesized according to the procedure of Gan et al. (2010). Single crystals suitable for X-ray diffraction analysis were grown in a mixed solution petroleum ether and ethyl acetate by slow evaporation at room temperature.

Computing details top

Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

Fig. 1. The molecular structure of the title compound showing 50% ellipsoids.

2-Chloro-1-[4-(2,4-difluorobenzyl)piperazin-1-yl]ethanone top

Crystal data top

C₁₃H₁₅ClF₂N₂O	F(000) = 600
M_r = 288.72	D_x = 1.435 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 4078 reflections
a = 7.895 (2) Å	θ = 3.2–27.4°
b = 8.512 (2) Å	µ = 0.30 mm⁻¹
c = 19.884 (5) Å	T = 296 K
V = 1336.2 (6) Å³	Block, colorless
Z = 4	0.30 × 0.25 × 0.24 mm

Data collection top

Bruker SMART CCD diffractometer	2324 independent reflections
Radiation source: fine-focus sealed tube	2238 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.026
ϕ and ω scans	θ_max = 25.0°, θ_min = 2.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −9→8
T_min = 0.915, T_max = 0.931	k = −8→10
5743 measured reflections	l = −21→23

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.031	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.086	w = 1/[σ²(F_o²) + (0.0501P)² + 0.1826P] where P = (F_o² + 2F_c²)/3
S = 1.07	(Δ/σ)_max < 0.001
2324 reflections	Δρ_max = 0.37 e Å⁻³
220 parameters	Δρ_min = −0.18 e Å⁻³
0 restraints	Absolute structure: Flack (1983), 938 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.05 (7)

Crystal data top

C₁₃H₁₅ClF₂N₂O	V = 1336.2 (6) Å³
M_r = 288.72	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 7.895 (2) Å	µ = 0.30 mm⁻¹
b = 8.512 (2) Å	T = 296 K
c = 19.884 (5) Å	0.30 × 0.25 × 0.24 mm

Data collection top

Bruker SMART CCD diffractometer	2324 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	2238 reflections with I > 2σ(I)
T_min = 0.915, T_max = 0.931	R_int = 0.026
5743 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.031	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.086	Δρ_max = 0.37 e Å⁻³
S = 1.07	Δρ_min = −0.18 e Å⁻³
2324 reflections	Absolute structure: Flack (1983), 938 Friedel pairs
220 parameters	Absolute structure parameter: 0.05 (7)
0 restraints

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
Cl1	0.26806 (8)	1.41412 (7)	0.14714 (3)	0.06679 (19)
N1	0.53726 (18)	0.88254 (16)	0.14628 (8)	0.0392 (3)
F1	0.86597 (19)	0.62487 (19)	0.15098 (7)	0.0786 (4)
N2	0.25240 (19)	1.04611 (18)	0.20166 (8)	0.0441 (4)
C7	0.6577 (3)	0.8543 (2)	0.09087 (11)	0.0466 (4)
C2	0.1248 (2)	1.1492 (2)	0.19486 (9)	0.0397 (4)
C4	0.3630 (2)	0.8503 (2)	0.12429 (10)	0.0437 (4)
C6	0.5486 (2)	1.0480 (2)	0.16685 (11)	0.0458 (4)
O1	−0.01636 (16)	1.11102 (17)	0.17464 (8)	0.0559 (4)
C3	0.2357 (3)	0.8832 (2)	0.17911 (11)	0.0482 (4)
F2	0.6783 (2)	0.21756 (16)	0.01314 (7)	0.0834 (5)
C1	0.1573 (3)	1.3191 (2)	0.21356 (10)	0.0474 (4)
C13	0.7660 (2)	0.5758 (2)	0.10072 (9)	0.0477 (4)
C9	0.5670 (3)	0.6280 (2)	0.01646 (10)	0.0504 (5)
H9	0.4984	0.6980	−0.0070	0.061*
C5	0.4260 (2)	1.0821 (3)	0.22316 (11)	0.0509 (5)
C8	0.6638 (2)	0.6844 (2)	0.06941 (8)	0.0416 (4)
C10	0.5682 (3)	0.4712 (3)	−0.00294 (10)	0.0539 (5)
H10	0.5005	0.4354	−0.0380	0.065*
C11	0.6726 (3)	0.3717 (2)	0.03146 (10)	0.0540 (5)
C12	0.7734 (3)	0.4185 (2)	0.08374 (10)	0.0576 (5)
H12	0.8430	0.3483	0.1066	0.069*
H2M	0.219 (3)	1.327 (3)	0.2523 (10)	0.049 (6)*
H1M	0.049 (3)	1.374 (3)	0.2171 (10)	0.048 (5)*
H9M	0.451 (3)	1.011 (3)	0.2616 (12)	0.056 (6)*
H5M	0.328 (2)	0.920 (2)	0.0833 (9)	0.038 (5)*
H4M	0.265 (3)	0.814 (3)	0.2201 (11)	0.064 (6)*
H10M	0.432 (3)	1.185 (3)	0.2347 (12)	0.064 (7)*
H7M	0.665 (3)	1.071 (2)	0.1839 (9)	0.045 (5)*
H6M	0.362 (3)	0.745 (3)	0.1093 (11)	0.062 (7)*
H8M	0.524 (3)	1.123 (2)	0.1293 (10)	0.048 (5)*
H3M	0.134 (3)	0.868 (3)	0.1630 (11)	0.057 (6)*
H11M	0.761 (3)	0.886 (3)	0.1060 (10)	0.051 (5)*
H12M	0.619 (3)	0.919 (3)	0.0531 (13)	0.061 (6)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0769 (4)	0.0526 (3)	0.0708 (3)	−0.0112 (3)	0.0027 (3)	0.0112 (2)
N1	0.0336 (7)	0.0325 (7)	0.0514 (8)	0.0009 (6)	0.0024 (6)	−0.0012 (6)
F1	0.0775 (9)	0.0846 (10)	0.0737 (8)	0.0243 (8)	−0.0276 (7)	−0.0206 (8)
N2	0.0328 (7)	0.0415 (8)	0.0581 (8)	0.0027 (7)	−0.0002 (7)	−0.0081 (7)
C7	0.0422 (10)	0.0400 (10)	0.0577 (11)	−0.0014 (8)	0.0096 (9)	0.0031 (9)
C2	0.0351 (8)	0.0415 (9)	0.0424 (8)	0.0014 (8)	0.0052 (7)	0.0008 (7)
C4	0.0375 (9)	0.0323 (9)	0.0611 (11)	−0.0029 (8)	−0.0004 (8)	−0.0060 (8)
C6	0.0321 (9)	0.0385 (10)	0.0667 (12)	−0.0006 (7)	−0.0065 (8)	−0.0067 (9)
O1	0.0328 (6)	0.0533 (8)	0.0815 (9)	0.0013 (6)	−0.0034 (6)	−0.0032 (7)
C3	0.0361 (9)	0.0376 (9)	0.0710 (12)	−0.0001 (8)	0.0047 (9)	−0.0024 (9)
F2	0.1251 (14)	0.0440 (7)	0.0812 (9)	0.0043 (8)	0.0120 (9)	−0.0143 (7)
C1	0.0461 (10)	0.0431 (10)	0.0532 (11)	0.0057 (9)	0.0024 (9)	−0.0072 (9)
C13	0.0456 (9)	0.0524 (11)	0.0451 (9)	0.0064 (10)	−0.0002 (8)	−0.0044 (8)
C9	0.0508 (10)	0.0531 (12)	0.0474 (10)	0.0074 (9)	−0.0017 (8)	0.0041 (9)
C5	0.0394 (10)	0.0492 (12)	0.0643 (12)	0.0064 (9)	−0.0108 (9)	−0.0151 (10)
C8	0.0386 (9)	0.0418 (10)	0.0444 (9)	0.0017 (8)	0.0096 (7)	0.0030 (8)
C10	0.0562 (12)	0.0567 (12)	0.0487 (10)	−0.0027 (10)	0.0024 (9)	−0.0083 (9)
C11	0.0689 (13)	0.0396 (10)	0.0535 (10)	−0.0009 (10)	0.0147 (9)	−0.0055 (9)
C12	0.0688 (13)	0.0498 (11)	0.0542 (11)	0.0208 (11)	0.0009 (10)	0.0031 (9)

Geometric parameters (Å, º) top

Cl1—C1	1.778 (2)	C6—H8M	1.00 (2)
N1—C4	1.469 (2)	C3—H4M	1.03 (2)
N1—C6	1.469 (2)	C3—H3M	0.88 (3)
N1—C7	1.475 (2)	F2—C11	1.362 (2)
F1—C13	1.340 (2)	C1—H2M	0.91 (2)
N2—C2	1.343 (2)	C1—H1M	0.98 (2)
N2—C3	1.463 (2)	C13—C8	1.376 (3)
N2—C5	1.468 (2)	C13—C12	1.382 (3)
C7—C8	1.509 (3)	C9—C8	1.387 (3)
C7—H11M	0.91 (2)	C9—C10	1.389 (3)
C7—H12M	0.98 (3)	C9—H9	0.9300
C2—O1	1.228 (2)	C5—H9M	1.00 (2)
C2—C1	1.516 (3)	C5—H10M	0.90 (3)
C4—C3	1.509 (3)	C10—C11	1.365 (3)
C4—H5M	1.046 (19)	C10—H10	0.9300
C4—H6M	0.94 (3)	C11—C12	1.368 (3)
C6—C5	1.508 (3)	C12—H12	0.9300
C6—H7M	1.00 (2)

C4—N1—C6	108.60 (14)	H4M—C3—H3M	114 (2)
C4—N1—C7	110.54 (15)	C2—C1—Cl1	109.57 (13)
C6—N1—C7	108.94 (14)	C2—C1—H2M	111.4 (14)
C2—N2—C3	121.37 (16)	Cl1—C1—H2M	109.4 (13)
C2—N2—C5	126.42 (16)	C2—C1—H1M	108.8 (13)
C3—N2—C5	111.78 (15)	Cl1—C1—H1M	105.6 (12)
N1—C7—C8	112.82 (15)	H2M—C1—H1M	111.9 (18)
N1—C7—H11M	106.6 (13)	F1—C13—C8	118.23 (17)
C8—C7—H11M	110.3 (14)	F1—C13—C12	117.35 (17)
N1—C7—H12M	106.2 (14)	C8—C13—C12	124.42 (18)
C8—C7—H12M	109.6 (14)	C8—C9—C10	122.64 (19)
H11M—C7—H12M	111.4 (19)	C8—C9—H9	118.7
O1—C2—N2	122.76 (17)	C10—C9—H9	118.7
O1—C2—C1	119.10 (16)	N2—C5—C6	110.06 (16)
N2—C2—C1	118.14 (16)	N2—C5—H9M	106.3 (14)
N1—C4—C3	111.97 (16)	C6—C5—H9M	109.0 (13)
N1—C4—H5M	112.1 (10)	N2—C5—H10M	108.9 (16)
C3—C4—H5M	106.2 (10)	C6—C5—H10M	109.9 (16)
N1—C4—H6M	106.0 (15)	H9M—C5—H10M	113 (2)
C3—C4—H6M	113.6 (14)	C13—C8—C9	115.72 (18)
H5M—C4—H6M	106.9 (17)	C13—C8—C7	122.34 (17)
N1—C6—C5	110.60 (17)	C9—C8—C7	121.95 (17)
N1—C6—H7M	109.5 (12)	C11—C10—C9	117.5 (2)
C5—C6—H7M	107.6 (11)	C11—C10—H10	121.3
N1—C6—H8M	112.9 (11)	C9—C10—H10	121.3
C5—C6—H8M	107.8 (12)	F2—C11—C10	118.9 (2)
H7M—C6—H8M	108.2 (17)	F2—C11—C12	117.6 (2)
N2—C3—C4	109.69 (15)	C10—C11—C12	123.4 (2)
N2—C3—H4M	106.1 (13)	C11—C12—C13	116.28 (19)
C4—C3—H4M	108.3 (14)	C11—C12—H12	121.9
N2—C3—H3M	109.5 (15)	C13—C12—H12	121.9
C4—C3—H3M	108.7 (15)

C4—N1—C7—C8	−64.7 (2)	N1—C6—C5—N2	−58.6 (2)
C6—N1—C7—C8	176.09 (16)	F1—C13—C8—C9	178.12 (17)
C3—N2—C2—O1	6.0 (3)	C12—C13—C8—C9	−1.7 (3)
C5—N2—C2—O1	177.8 (2)	F1—C13—C8—C7	−1.6 (3)
C3—N2—C2—C1	−174.52 (18)	C12—C13—C8—C7	178.66 (19)
C5—N2—C2—C1	−2.7 (3)	C10—C9—C8—C13	1.8 (3)
C6—N1—C4—C3	−58.6 (2)	C10—C9—C8—C7	−178.50 (18)
C7—N1—C4—C3	−178.10 (15)	N1—C7—C8—C13	−85.7 (2)
C4—N1—C6—C5	59.1 (2)	N1—C7—C8—C9	94.6 (2)
C7—N1—C6—C5	179.51 (16)	C8—C9—C10—C11	−1.3 (3)
C2—N2—C3—C4	117.63 (19)	C9—C10—C11—F2	−179.20 (19)
C5—N2—C3—C4	−55.3 (2)	C9—C10—C11—C12	0.5 (3)
N1—C4—C3—N2	56.8 (2)	F2—C11—C12—C13	179.39 (19)
O1—C2—C1—Cl1	−101.22 (18)	C10—C11—C12—C13	−0.4 (3)
N2—C2—C1—Cl1	79.24 (19)	F1—C13—C12—C11	−178.81 (18)
C2—N2—C5—C6	−115.8 (2)	C8—C13—C12—C11	1.0 (3)
C3—N2—C5—C6	56.7 (2)

Experimental details

Crystal data
Chemical formula	C₁₃H₁₅ClF₂N₂O
M_r	288.72
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	296
a, b, c (Å)	7.895 (2), 8.512 (2), 19.884 (5)
V (Å³)	1336.2 (6)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.30
Crystal size (mm)	0.30 × 0.25 × 0.24

Data collection
Diffractometer	Bruker SMART CCD diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick, 1996)
T_min, T_max	0.915, 0.931
No. of measured, independent and observed [I > 2σ(I)] reflections	5743, 2324, 2238
R_int	0.026
(sin θ/λ)_max (Å⁻¹)	0.594

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.031, 0.086, 1.07
No. of reflections	2324
No. of parameters	220
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.37, −0.18
Absolute structure	Flack (1983), 938 Friedel pairs
Absolute structure parameter	0.05 (7)

Computer programs: SMART (Bruker, 2001), SAINT (Bruker, 2001), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009), SHELXTL (Sheldrick, 2008).

Acknowledgements

This work was partially supported by the Natural Science Foundation of China (21172181), the Specialized Research Fund for the Doctoral Program of Higher Education of China (SRFDP 20110182110007) and the Fundamental Research Funds for the Central Universities (XDJK2011D007).

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