(2,6-Difluoro­phen­yl)(4-methyl­piperidin-1-yl)methanone

Al-Dajani, M.T.M.; Adballah, H.H.; Mohamed, N.; Hemamalini, M.; Fun, H.-K.

doi:10.1107/S1600536811033848

organic compounds

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ISSN: 2056-9890

Volume 67| Part 9| September 2011| Page o2409

doi:10.1107/S1600536811033848

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(2,6-Difluorophenyl)(4-methylpiperidin-1-yl)methanone

Mohammad T. M. Al-Dajani,^a Hassan H. Adballah,^b Nornisah Mohamed,^a Madhukar Hemamalini ^c and Hoong-Kun Fun ^c ^*‡

^aSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia, ^bSchool of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia, and ^cX-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
^*Correspondence e-mail: hkfun@usm.my

(Received 5 August 2011; accepted 19 August 2011; online 27 August 2011)

In the title compound, C₁₃H₁₅F₂NO, the piperidine ring adopts a chair conformation. The dihedral angle between the least-squares plane of the piperidine ring and the benzene ring is 48.75 (7)°. In the crystal structure, the molecules are connected via C—H⋯O hydrogen bonds, forming a zigzag chain along the b axis.

Related literature

For the biological applications of piperidine derivatives, see: Waelbroeck et al. (1992 ); El Hadri et al. (1995 ). For puckering parameters, see: Cremer & Pople (1975 ).

Experimental

Crystal data

C₁₃H₁₅F₂NO
M_r = 239.26
Monoclinic, P 2₁ /c
a = 9.1807 (7) Å
b = 10.9910 (8) Å
c = 13.2477 (8) Å
β = 115.582 (4)°
V = 1205.71 (15) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 296 K
0.43 × 0.38 × 0.19 mm

Data collection

Bruker APEXII DUO CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2009 ) T_min = 0.956, T_max = 0.981
11030 measured reflections
3513 independent reflections
2617 reflections with I > 2σ(I)
R_int = 0.018

Refinement

R[F² > 2σ(F²)] = 0.045
wR(F²) = 0.136
S = 1.06
3513 reflections
155 parameters
H-atom parameters constrained
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C3—H3A⋯O1ⁱ	0.93	2.35	3.2646 (18)	168
Symmetry code: (i) $[-x, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009 ).

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811033848/is2763sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536811033848/is2763Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536811033848/is2763Isup3.cml

checkCIF report

Comment top

The piperidine nucleus is present in a wide range of biologically active compounds. For example, the binding properties of 4-diphenyl acetoxy-N-methylpiperidine methiodide (4-DAMP) and its analogs have been evaluated on muscarinic receptors in human neuroblastoma NB-OK1 cells (M1 receptor subtype), rat heart (M2 subtype), rat pancreas (M3 subtype) and the putative M4 receptor subtype in striatum (Waelbroeck et al., 1992). NMDA receptor antagonist properties of piperidine-2-carboxylic acid derivatives have also been reported (El Hadri et al., 1995). Due to their biological importance of piperidine derivatives, herein, we have present the crystal structure of the title compound (I).

The molecular structure of the title compound is shown in Fig. 1. The piperidine (N1/C8–C12) ring adopts a chair conformation [puckering parameters: Q = 0.5569 (14) Å, θ = 2.24 (14)° and ϕ = 132 (4)° (Cremer & Pople, 1975)] with atoms C8 and C10 deviating by 0.230 (1) and 0.238 (1) Å from the least-squares plane defined by the remaining atoms (N1/C9/C11–C12) in the ring. The dihedral angle between the least-squares plane of the piperidine (N1/C8–C12) ring and the fluoro-subsituted benzene (C1–C6) ring is 48.75 (7)°.

In the crystal structure, the molecules are connected via C—H···O hydrogen bonds (Table 1) forming one-dimensional supramolecular chains along the b axis (Fig. 2).

Related literature top

For the biological applications of piperidine derivatives, see: Waelbroeck et al. (1992); El Hadri et al. (1995). For puckering parameters, see: Cremer & Pople (1975).

Experimental top

In a round bottom flask, 25ml of toluene was mixed with 4-methylpiperidine (0.01 mol, 1.0 g) with stirring. Drops of 2,6-difluorobenzylchloride (0.01 mol, 1.7g) dissolved in toluene was then added. The reaction mixture was refluxed for 30 min. The yellow precipitate formed was washed with chloroform and with water. The precipitate was then dissolved in methanol at room temperature. After few days, colourless needle-shaped crystals were formed by slow evaporation.

Computing details top

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top

	Fig. 1. The molecular structure of the title compound, showing 50% probability displacement ellipsoids and the atom-numbering scheme.
	Fig. 2. The crystal packing of the title compound, viewed along the c axis. Dashed lines represent C—H···O hydrogen bonds.

(2,6-Difluorophenyl)(4-methylpiperidin-1-yl)methanone top

Crystal data top

C₁₃H₁₅F₂NO	F(000) = 504
M_r = 239.26	D_x = 1.318 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 4002 reflections
a = 9.1807 (7) Å	θ = 2.5–29.6°
b = 10.9910 (8) Å	µ = 0.10 mm⁻¹
c = 13.2477 (8) Å	T = 296 K
β = 115.582 (4)°	Block, colourless
V = 1205.71 (15) Å³	0.43 × 0.38 × 0.19 mm
Z = 4

Data collection top

Bruker APEXII DUO CCD area-detector diffractometer	3513 independent reflections
Radiation source: fine-focus sealed tube	2617 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.018
ϕ and ω scans	θ_max = 30.1°, θ_min = 2.5°
Absorption correction: multi-scan (SADABS; Bruker, 2009)	h = −12→12
T_min = 0.956, T_max = 0.981	k = −13→15
11030 measured reflections	l = −18→18

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.045	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.136	H-atom parameters constrained
S = 1.06	w = 1/[σ²(F_o²) + (0.0678P)² + 0.1308P] where P = (F_o² + 2F_c²)/3
3513 reflections	(Δ/σ)_max = 0.001
155 parameters	Δρ_max = 0.23 e Å⁻³
0 restraints	Δρ_min = −0.20 e Å⁻³

Crystal data top

C₁₃H₁₅F₂NO	V = 1205.71 (15) Å³
M_r = 239.26	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 9.1807 (7) Å	µ = 0.10 mm⁻¹
b = 10.9910 (8) Å	T = 296 K
c = 13.2477 (8) Å	0.43 × 0.38 × 0.19 mm
β = 115.582 (4)°

Data collection top

Bruker APEXII DUO CCD area-detector diffractometer	3513 independent reflections
Absorption correction: multi-scan (SADABS; Bruker, 2009)	2617 reflections with I > 2σ(I)
T_min = 0.956, T_max = 0.981	R_int = 0.018
11030 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.045	0 restraints
wR(F²) = 0.136	H-atom parameters constrained
S = 1.06	Δρ_max = 0.23 e Å⁻³
3513 reflections	Δρ_min = −0.20 e Å⁻³
155 parameters

Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'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 > 2σ(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
F1	0.26788 (12)	0.67786 (9)	0.26565 (7)	0.0733 (3)
F2	0.16103 (13)	0.89859 (9)	0.52606 (7)	0.0835 (3)
O1	0.23349 (12)	0.59626 (9)	0.48443 (8)	0.0697 (3)
N1	0.46198 (12)	0.70862 (9)	0.55150 (9)	0.0528 (3)
C1	0.19420 (13)	0.77289 (11)	0.28922 (9)	0.0476 (3)
C2	0.10112 (15)	0.85157 (14)	0.20507 (10)	0.0600 (4)
H2A	0.0896	0.8407	0.1324	0.072*
C3	0.02604 (15)	0.94608 (15)	0.23065 (12)	0.0638 (4)
H3A	−0.0384	0.9992	0.1744	0.077*
C4	0.04459 (16)	0.96375 (14)	0.33859 (12)	0.0625 (4)
H4A	−0.0058	1.0283	0.3562	0.075*
C5	0.13981 (15)	0.88297 (12)	0.41937 (10)	0.0517 (3)
C6	0.21693 (12)	0.78571 (10)	0.39862 (8)	0.0413 (2)
C7	0.30603 (14)	0.68901 (10)	0.48395 (9)	0.0455 (3)
C8	0.54606 (14)	0.82462 (12)	0.56603 (10)	0.0526 (3)
H8A	0.4746	0.8839	0.5139	0.063*
H8B	0.6391	0.8145	0.5502	0.063*
C9	0.60040 (14)	0.86998 (11)	0.68488 (10)	0.0504 (3)
H9A	0.5064	0.8871	0.6981	0.060*
H9B	0.6604	0.9451	0.6946	0.060*
C10	0.70612 (14)	0.77668 (11)	0.76970 (10)	0.0503 (3)
H10A	0.8025	0.7636	0.7570	0.060*
C11	0.61572 (15)	0.65643 (11)	0.74973 (11)	0.0563 (3)
H11A	0.6864	0.5953	0.7997	0.068*
H11B	0.5238	0.6660	0.7670	0.068*
C12	0.55722 (17)	0.61347 (11)	0.62987 (11)	0.0631 (4)
H12A	0.6493	0.5925	0.6156	0.076*
H12B	0.4915	0.5411	0.6185	0.076*
C13	0.7612 (2)	0.82022 (17)	0.88950 (12)	0.0781 (5)
H13A	0.8241	0.8931	0.9009	0.117*
H13B	0.8258	0.7583	0.9402	0.117*
H13C	0.6686	0.8368	0.9031	0.117*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0883 (6)	0.0761 (6)	0.0598 (5)	0.0042 (5)	0.0360 (4)	−0.0189 (4)
F2	0.1137 (8)	0.0920 (7)	0.0538 (5)	0.0326 (6)	0.0448 (5)	0.0010 (4)
O1	0.0689 (6)	0.0515 (5)	0.0607 (6)	−0.0175 (4)	0.0017 (4)	0.0058 (4)
N1	0.0477 (5)	0.0406 (5)	0.0503 (5)	0.0007 (4)	0.0025 (4)	0.0013 (4)
C1	0.0445 (5)	0.0567 (7)	0.0384 (5)	−0.0074 (5)	0.0147 (4)	−0.0065 (4)
C2	0.0545 (7)	0.0820 (9)	0.0331 (5)	−0.0143 (6)	0.0091 (5)	0.0061 (5)
C3	0.0429 (6)	0.0752 (9)	0.0575 (7)	0.0000 (6)	0.0069 (5)	0.0263 (7)
C4	0.0511 (6)	0.0641 (8)	0.0702 (8)	0.0153 (6)	0.0243 (6)	0.0146 (6)
C5	0.0520 (6)	0.0601 (7)	0.0439 (6)	0.0077 (5)	0.0214 (5)	0.0032 (5)
C6	0.0380 (5)	0.0456 (5)	0.0350 (5)	−0.0021 (4)	0.0107 (4)	−0.0002 (4)
C7	0.0495 (6)	0.0409 (5)	0.0364 (5)	−0.0022 (4)	0.0093 (4)	−0.0035 (4)
C8	0.0447 (5)	0.0528 (7)	0.0501 (6)	−0.0060 (5)	0.0110 (5)	0.0037 (5)
C9	0.0463 (6)	0.0418 (6)	0.0578 (7)	−0.0074 (5)	0.0175 (5)	−0.0042 (5)
C10	0.0443 (5)	0.0553 (7)	0.0446 (6)	−0.0016 (5)	0.0130 (4)	−0.0039 (5)
C11	0.0523 (6)	0.0473 (6)	0.0547 (7)	0.0042 (5)	0.0094 (5)	0.0074 (5)
C12	0.0613 (7)	0.0417 (6)	0.0580 (7)	0.0084 (5)	−0.0009 (6)	−0.0013 (5)
C13	0.0974 (12)	0.0762 (10)	0.0507 (8)	−0.0106 (9)	0.0224 (8)	−0.0110 (7)

Geometric parameters (Å, º) top

F1—C1	1.3522 (15)	C8—H8A	0.9700
F2—C5	1.3518 (14)	C8—H8B	0.9700
O1—C7	1.2192 (15)	C9—C10	1.5213 (17)
N1—C7	1.3381 (14)	C9—H9A	0.9700
N1—C8	1.4595 (16)	C9—H9B	0.9700
N1—C12	1.4671 (15)	C10—C13	1.5200 (18)
C1—C2	1.3777 (18)	C10—C11	1.5218 (18)
C1—C6	1.3795 (15)	C10—H10A	0.9800
C2—C3	1.368 (2)	C11—C12	1.5153 (19)
C2—H2A	0.9300	C11—H11A	0.9700
C3—C4	1.379 (2)	C11—H11B	0.9700
C3—H3A	0.9300	C12—H12A	0.9700
C4—C5	1.3747 (17)	C12—H12B	0.9700
C4—H4A	0.9300	C13—H13A	0.9600
C5—C6	1.3739 (17)	C13—H13B	0.9600
C6—C7	1.5094 (15)	C13—H13C	0.9600
C8—C9	1.5159 (17)

C7—N1—C8	125.53 (10)	C8—C9—C10	111.36 (10)
C7—N1—C12	119.81 (10)	C8—C9—H9A	109.4
C8—N1—C12	114.19 (9)	C10—C9—H9A	109.4
F1—C1—C2	119.69 (11)	C8—C9—H9B	109.4
F1—C1—C6	117.24 (11)	C10—C9—H9B	109.4
C2—C1—C6	123.06 (12)	H9A—C9—H9B	108.0
C3—C2—C1	118.63 (12)	C13—C10—C9	112.18 (12)
C3—C2—H2A	120.7	C13—C10—C11	111.45 (12)
C1—C2—H2A	120.7	C9—C10—C11	109.32 (9)
C2—C3—C4	120.94 (12)	C13—C10—H10A	107.9
C2—C3—H3A	119.5	C9—C10—H10A	107.9
C4—C3—H3A	119.5	C11—C10—H10A	107.9
C5—C4—C3	117.94 (13)	C12—C11—C10	111.88 (12)
C5—C4—H4A	121.0	C12—C11—H11A	109.2
C3—C4—H4A	121.0	C10—C11—H11A	109.2
F2—C5—C6	117.00 (10)	C12—C11—H11B	109.2
F2—C5—C4	119.21 (12)	C10—C11—H11B	109.2
C6—C5—C4	123.79 (12)	H11A—C11—H11B	107.9
C5—C6—C1	115.62 (10)	N1—C12—C11	110.65 (10)
C5—C6—C7	123.88 (10)	N1—C12—H12A	109.5
C1—C6—C7	120.14 (10)	C11—C12—H12A	109.5
O1—C7—N1	124.08 (11)	N1—C12—H12B	109.5
O1—C7—C6	118.17 (10)	C11—C12—H12B	109.5
N1—C7—C6	117.69 (10)	H12A—C12—H12B	108.1
N1—C8—C9	110.03 (10)	C10—C13—H13A	109.5
N1—C8—H8A	109.7	C10—C13—H13B	109.5
C9—C8—H8A	109.7	H13A—C13—H13B	109.5
N1—C8—H8B	109.7	C10—C13—H13C	109.5
C9—C8—H8B	109.7	H13A—C13—H13C	109.5
H8A—C8—H8B	108.2	H13B—C13—H13C	109.5

F1—C1—C2—C3	179.14 (11)	C8—N1—C7—C6	13.13 (19)
C6—C1—C2—C3	−0.79 (19)	C12—N1—C7—C6	−175.26 (11)
C1—C2—C3—C4	0.9 (2)	C5—C6—C7—O1	94.43 (15)
C2—C3—C4—C5	−0.5 (2)	C1—C6—C7—O1	−78.49 (15)
C3—C4—C5—F2	179.55 (13)	C5—C6—C7—N1	−88.19 (15)
C3—C4—C5—C6	−0.2 (2)	C1—C6—C7—N1	98.90 (13)
F2—C5—C6—C1	−179.40 (11)	C7—N1—C8—C9	115.22 (13)
C4—C5—C6—C1	0.35 (19)	C12—N1—C8—C9	−56.81 (15)
F2—C5—C6—C7	7.40 (18)	N1—C8—C9—C10	56.43 (13)
C4—C5—C6—C7	−172.86 (12)	C8—C9—C10—C13	−179.72 (12)
F1—C1—C6—C5	−179.77 (10)	C8—C9—C10—C11	−55.56 (14)
C2—C1—C6—C5	0.16 (17)	C13—C10—C11—C12	178.83 (12)
F1—C1—C6—C7	−6.30 (16)	C9—C10—C11—C12	54.25 (14)
C2—C1—C6—C7	173.64 (11)	C7—N1—C12—C11	−116.98 (13)
C8—N1—C7—O1	−169.65 (13)	C8—N1—C12—C11	55.54 (17)
C12—N1—C7—O1	2.0 (2)	C10—C11—C12—N1	−53.71 (16)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3A···O1ⁱ	0.93	2.35	3.2646 (18)	168

Symmetry code: (i) −x, y+1/2, −z+1/2.

Experimental details

Crystal data
Chemical formula	C₁₃H₁₅F₂NO
M_r	239.26
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	296
a, b, c (Å)	9.1807 (7), 10.9910 (8), 13.2477 (8)
β (°)	115.582 (4)
V (Å³)	1205.71 (15)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.10
Crystal size (mm)	0.43 × 0.38 × 0.19

Data collection
Diffractometer	Bruker APEXII DUO CCD area-detector diffractometer
Absorption correction	Multi-scan (SADABS; Bruker, 2009)
T_min, T_max	0.956, 0.981
No. of measured, independent and observed [I > 2σ(I)] reflections	11030, 3513, 2617
R_int	0.018
(sin θ/λ)_max (Å⁻¹)	0.705

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.045, 0.136, 1.06
No. of reflections	3513
No. of parameters	155
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.23, −0.20

Computer programs: APEX2 (Bruker, 2009), SAINT (Bruker, 2009), SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3A···O1ⁱ	0.9300	2.3500	3.2646 (18)	168.00

Symmetry code: (i) −x, y+1/2, −z+1/2.

Footnotes

‡Thomson Reuters ResearcherID: A-3561-2009

Acknowledgements

NM gratefully acknowledges funding from the Malaysian Ministry of Science, Technology and Innovation, through the Malaysian Institute of Pharmaceutical and Nutraceutical R&D Initiative Grant (grant Nos. 09-05-IFN-MEB 004 and 304/PFARMASI/650512/I121). HKF and MH thank the Malaysian Government and USM for the Research University Grant (No. 1001/PFIZIK/811160). MH also thanks USM for a post-doctoral research fellowship.

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