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Acta Cryst. (2008). E64, o564    [ doi:10.1107/S1600536808003590 ]

N-(3,4-Difluorophenyl)-2-(3,4-dimethoxyphenyl)acetamide

W. K. Hong, Y.-S. Lee, B. H. Han, S. K. Kang and C. K. Sung

Abstract top

In the title amide, C16H15F2NO3, the dihedral angle between the benzene rings is 53.7 (1)°. Molecules are linked in the crystal structure by an intermolecular N-H...O hydrogen bond involving N-H and C=O functionalities of the amide group. A one-dimensional network is thus formed along the [001] direction. No significant interchain contacts are observed.

Comment top

Tyrosinase is the key enzyme (Ha et al., 2007) that converts tyrosine to melanin, and its inhibitors are the target molecules to develop and research anti-pigmentation agents for application to skin. The melanin formation is also accelerated by exposure under sunlight, especially U.V. (Ha et al., 2007; Yan et al., 2007). Therefore, treatments using potent inhibitory agents on tyrosinase and melanin formation may be cosmetically useful. Most of the whitening agents (Maeda et al., 1991; Dawley et al., 1993; Nerya et al., 2003) contain hydroxyl (Hong et al., 2008; Lee et al., 2007), aromatic, alkene, carbonyl, and ether groups in their structure, and act as a specific functional group to make the skin white by inhibiting the production of melanin.

During our work on developing potent whiting agents, in order to prevent the inadequacies of current whitening agents (poor skin penetration and toxicity) and maximize the inhibitory effects of melanin creation, we synthesized the title compound, (I), via a general chemical reaction, and studied its X-ray crystal structure.

The 3,4-dimethoxyphenyl moiety and 3,4-difluoroaniline group are essentially planar, with a mean deviation of 0.005 and 0.006 Å, respectively, from the corresponding least-squares planes. The dihedral angle between the benzene rings is 53.7 (1)°. The intermolecular N7—H7···O9i (symmetry code: (i) x, -y + 3/2, z - 1/2) hydrogen bond (involving the H atom of the amine and O atom of carbonyl) allows to form an extensive one-dimensional network along the c-axis, which stabilizes the crystal structure.

Related literature top

For general background see: Maeda et al. (1991); Dawley et al. (1993); Nerya et al. (2003); Lee et al. (2007); Ha et al. (2007); Hong et al. (2008); Yan et al. (2007).

Experimental top

3,4-Difluoroaniline and 3,4-dimethoxy phenyl acetyl chloride were purchased from Sigma Chemicals Co. Solvents used for organic synthesis were distilled before use. All other chemicals and solvents were of analytical grade and used without further purification. The title compound was prepared from the reaction of 3,4-difluoroaniline (1 mmol) and 3,4-dimethoxy phenyl acetyl chloride (1.2 mmol) by simple substitution (nucleophilic addition-elimination on carbonyl C atom) in THF. Removal of solvent gave a white solid. The solid was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to give the title compound (92% yield). Colourless crystals (m.p. 393 K) were obtained by slow evaporation of an ethyl acetate solution at 298 K.

Refinement top

Although diffraction data were collected using optimized parameters, a poor quality pattern resulted, which is reflected in the high final residuals. Atom H7 of the NH group was located in a differnce map and refined freely. Other H atoms were positioned geometrically and refined using a riding model, with C—H = 0.93–0.97 Å, and with Uiso(H) = 1.2Ueq(carrier C) for aromatic and CH2 groups, and 1.5Ueq(carrier C) for methyl H atoms.

Computing details top

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994); cell refinement: CAD-4 EXPRESS (Enraf–Nonius, 1994); data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound, showing the atom-numbering scheme and 30% probability ellipsoids.
N-(3,4-Difluorophenyl)-2-(3,4-dimethoxyphenyl)acetamide top
Crystal data top
C16H15F2NO3F000 = 640
Mr = 307.29Dx = 1.414 Mg m−3
Monoclinic, P21/cMelting point: 393 K
Hall symbol: -P 2ybcMo Kα radiation
λ = 0.71073 Å
a = 8.6440 (11) ÅCell parameters from 25 reflections
b = 18.867 (6) Åθ = 10.0–13.5º
c = 9.4827 (13) ŵ = 0.12 mm−1
β = 111.019 (11)ºT = 295 (2) K
V = 1443.6 (5) Å3Block, colourless
Z = 40.26 × 0.26 × 0.23 mm
Data collection top
Enraf–Nonius CAD-4
diffractometer		θmin = 2.2º
non–profiled ω/2θ scansh = −10→9
Absorption correction: nonek = 0→22
2855 measured reflectionsl = 0→11
2689 independent reflections3 standard reflections
1089 reflections with I > 2σ(I) every 400 reflections
Rint = 0.050 intensity decay: 3%
θmax = 25.5º
Refinement top
Refinement on F2H atoms treated by a mixture of
independent and constrained refinement
Least-squares matrix: full  w = 1/[σ2(Fo2) + (0.0403P)2]
where P = (Fo2 + 2Fc2)/3
R[F2 > 2σ(F2)] = 0.076(Δ/σ)max < 0.001
wR(F2) = 0.161Δρmax = 0.19 e Å−3
S = 1.00Δρmin = −0.19 e Å−3
2689 reflectionsExtinction correction: none
203 parameters
Crystal data top
C16H15F2NO3V = 1443.6 (5) Å3
Mr = 307.29Z = 4
Monoclinic, P21/cMo Kα
a = 8.6440 (11) ŵ = 0.12 mm−1
b = 18.867 (6) ÅT = 295 (2) K
c = 9.4827 (13) Å0.26 × 0.26 × 0.23 mm
β = 111.019 (11)º
Data collection top
Enraf–Nonius CAD-4
diffractometer		Rint = 0.050
Absorption correction: none3 standard reflections
2855 measured reflections every 400 reflections
2689 independent reflections intensity decay: 3%
1089 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.076203 parameters
wR(F2) = 0.161H atoms treated by a mixture of
independent and constrained refinement
S = 1.00Δρmax = 0.19 e Å−3
2689 reflectionsΔρmin = −0.19 e Å−3
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.1632 (6)0.6519 (2)−0.2444 (5)0.0423 (12)
C20.0544 (6)0.6516 (3)−0.3939 (5)0.0492 (13)
H20.05780.6871−0.46060.059*
C3−0.0570 (7)0.5976 (3)−0.4396 (6)0.0581 (15)
C4−0.0637 (7)0.5447 (3)−0.3452 (6)0.0593 (15)
C50.0438 (7)0.5443 (3)−0.1995 (6)0.0671 (17)
H50.04070.5079−0.13460.081*
C60.1575 (6)0.5985 (3)−0.1487 (5)0.0531 (14)
H60.23060.5988−0.04890.064*
F1−0.1663 (4)0.59760 (17)−0.5842 (3)0.0941 (12)
F2−0.1777 (4)0.49215 (17)−0.3968 (4)0.0917 (12)
N70.2760 (5)0.7098 (2)−0.2001 (4)0.0446 (11)
H70.304 (6)0.729 (3)−0.273 (5)0.08 (2)*
C80.3307 (6)0.7408 (3)−0.0639 (5)0.0418 (12)
O90.2978 (4)0.71902 (17)0.0431 (3)0.0608 (11)
C100.4341 (6)0.8066 (3)−0.0549 (5)0.0566 (15)
H10A0.50550.7986−0.11220.068*
H10B0.36070.8457−0.10190.068*
C110.5399 (6)0.8276 (3)0.1044 (5)0.0464 (13)
C120.5239 (6)0.8935 (3)0.1612 (5)0.0502 (14)
H120.44630.92540.10070.06*
C130.6219 (6)0.9127 (3)0.3069 (5)0.0490 (14)
C140.7395 (6)0.8654 (3)0.3968 (5)0.0498 (13)
C150.7552 (6)0.8002 (3)0.3398 (5)0.0611 (16)
H150.83340.76820.39930.073*
C160.6557 (6)0.7815 (3)0.1945 (6)0.0599 (15)
H160.66770.7370.15750.072*
O170.6123 (4)0.97621 (19)0.3725 (4)0.0741 (12)
C180.4880 (7)1.0251 (3)0.2884 (6)0.0797 (19)
H18A0.49461.06710.34740.12*
H18B0.38071.00390.26430.12*
H18C0.5051.03730.19680.12*
O190.8299 (4)0.88921 (18)0.5388 (4)0.0679 (11)
C200.9656 (6)0.8464 (3)0.6292 (5)0.0686 (17)
H20A1.01950.8690.72510.103*
H20B1.04310.84080.57860.103*
H20C0.92520.80080.64460.103*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.047 (3)0.043 (3)0.037 (3)0.001 (3)0.015 (2)−0.006 (2)
C20.054 (3)0.045 (3)0.039 (3)0.000 (3)0.006 (3)0.006 (2)
C30.060 (4)0.062 (4)0.040 (3)0.001 (3)0.004 (3)−0.013 (3)
C40.061 (4)0.053 (4)0.060 (4)−0.007 (3)0.018 (3)−0.010 (3)
C50.092 (5)0.043 (4)0.066 (4)−0.010 (3)0.028 (4)0.001 (3)
C60.067 (4)0.047 (3)0.040 (3)0.002 (3)0.012 (3)0.006 (3)
F10.087 (3)0.103 (3)0.062 (2)−0.025 (2)−0.0110 (18)−0.010 (2)
F20.093 (3)0.073 (2)0.103 (3)−0.036 (2)0.028 (2)−0.024 (2)
N70.047 (3)0.053 (3)0.030 (2)−0.004 (2)0.010 (2)−0.003 (2)
C80.041 (3)0.053 (3)0.029 (3)−0.002 (3)0.010 (2)−0.003 (3)
O90.078 (3)0.073 (3)0.0360 (19)−0.027 (2)0.0258 (18)−0.0142 (18)
C100.056 (3)0.066 (4)0.045 (3)−0.009 (3)0.015 (3)−0.003 (3)
C110.045 (3)0.051 (3)0.041 (3)−0.004 (3)0.012 (2)−0.003 (3)
C120.044 (3)0.056 (4)0.044 (3)−0.001 (3)0.009 (3)0.004 (3)
C130.050 (3)0.049 (3)0.041 (3)0.000 (3)0.007 (3)−0.011 (3)
C140.041 (3)0.058 (4)0.041 (3)−0.001 (3)0.004 (2)−0.006 (3)
C150.056 (3)0.057 (4)0.054 (3)0.011 (3)0.000 (3)−0.014 (3)
C160.060 (4)0.059 (4)0.057 (3)0.000 (3)0.018 (3)−0.009 (3)
O170.069 (3)0.062 (3)0.062 (2)0.020 (2)−0.012 (2)−0.008 (2)
C180.074 (4)0.059 (4)0.083 (4)0.016 (3)0.000 (3)−0.006 (3)
O190.062 (2)0.070 (3)0.048 (2)0.019 (2)−0.0085 (19)−0.0103 (19)
C200.054 (3)0.078 (4)0.051 (3)0.010 (3)−0.009 (3)0.000 (3)
Geometric parameters (Å, °) top
C1—C61.368 (6)C11—C161.369 (6)
C1—C21.392 (6)C11—C121.381 (6)
C1—N71.423 (6)C12—C131.386 (6)
C2—C31.362 (6)C12—H120.93
C2—H20.93C13—O171.367 (5)
C3—C41.356 (7)C13—C141.390 (6)
C3—F11.357 (5)C14—O191.368 (5)
C4—F21.359 (5)C14—C151.370 (6)
C4—C51.361 (6)C15—C161.383 (6)
C5—C61.380 (6)C15—H150.93
C5—H50.93C16—H160.93
C6—H60.93O17—C181.423 (5)
N7—C81.340 (5)C18—H18A0.96
N7—H70.89 (5)C18—H18B0.96
C8—O91.219 (5)C18—H18C0.96
C8—C101.515 (6)O19—C201.428 (5)
C10—C111.511 (6)C20—H20A0.96
C10—H10A0.97C20—H20B0.96
C10—H10B0.97C20—H20C0.96
C6—C1—C2120.0 (5)C16—C11—C10120.2 (5)
C6—C1—N7123.6 (4)C12—C11—C10121.0 (4)
C2—C1—N7116.4 (4)C11—C12—C13120.9 (5)
C3—C2—C1118.0 (5)C11—C12—H12119.6
C3—C2—H2121C13—C12—H12119.6
C1—C2—H2121O17—C13—C12124.6 (4)
C4—C3—F1119.2 (5)O17—C13—C14115.7 (4)
C4—C3—C2122.2 (5)C12—C13—C14119.7 (5)
F1—C3—C2118.5 (5)O19—C14—C15125.5 (4)
C3—C4—F2119.8 (5)O19—C14—C13115.3 (4)
C3—C4—C5119.9 (5)C15—C14—C13119.2 (4)
F2—C4—C5120.4 (5)C14—C15—C16120.5 (5)
C4—C5—C6119.5 (5)C14—C15—H15119.7
C4—C5—H5120.2C16—C15—H15119.7
C6—C5—H5120.2C11—C16—C15120.9 (5)
C1—C6—C5120.3 (5)C11—C16—H16119.5
C1—C6—H6119.9C15—C16—H16119.5
C5—C6—H6119.9C13—O17—C18118.1 (4)
C8—N7—C1125.9 (4)O17—C18—H18A109.5
C8—N7—H7118 (3)O17—C18—H18B109.5
C1—N7—H7116 (3)H18A—C18—H18B109.5
O9—C8—N7123.3 (5)O17—C18—H18C109.5
O9—C8—C10122.6 (4)H18A—C18—H18C109.5
N7—C8—C10114.1 (4)H18B—C18—H18C109.5
C11—C10—C8113.8 (4)C14—O19—C20117.5 (4)
C11—C10—H10A108.8O19—C20—H20A109.5
C8—C10—H10A108.8O19—C20—H20B109.5
C11—C10—H10B108.8H20A—C20—H20B109.5
C8—C10—H10B108.8O19—C20—H20C109.5
H10A—C10—H10B107.7H20A—C20—H20C109.5
C16—C11—C12118.8 (4)H20B—C20—H20C109.5
C6—C1—C2—C30.8 (7)C8—C10—C11—C1659.3 (6)
N7—C1—C2—C3−178.9 (4)C8—C10—C11—C12−121.7 (5)
C1—C2—C3—C4−0.6 (8)C16—C11—C12—C13−0.6 (7)
C1—C2—C3—F1178.5 (4)C10—C11—C12—C13−179.5 (4)
F1—C3—C4—F20.8 (8)C11—C12—C13—O17−178.9 (5)
C2—C3—C4—F2179.9 (5)C11—C12—C13—C140.8 (7)
F1—C3—C4—C5−179.3 (5)O17—C13—C14—O19−0.2 (7)
C2—C3—C4—C5−0.2 (9)C12—C13—C14—O19−180.0 (4)
C3—C4—C5—C60.8 (8)O17—C13—C14—C15179.1 (5)
F2—C4—C5—C6−179.3 (5)C12—C13—C14—C15−0.6 (8)
C2—C1—C6—C5−0.2 (7)O19—C14—C15—C16179.4 (5)
N7—C1—C6—C5179.5 (5)C13—C14—C15—C160.2 (8)
C4—C5—C6—C1−0.6 (8)C12—C11—C16—C150.1 (8)
C6—C1—N7—C8−34.1 (7)C10—C11—C16—C15179.1 (5)
C2—C1—N7—C8145.6 (5)C14—C15—C16—C110.1 (8)
C1—N7—C8—O95.3 (8)C12—C13—O17—C183.0 (7)
C1—N7—C8—C10−173.2 (4)C14—C13—O17—C18−176.8 (5)
O9—C8—C10—C1120.3 (7)C15—C14—O19—C208.1 (8)
N7—C8—C10—C11−161.2 (4)C13—C14—O19—C20−172.6 (4)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N7—H7···O9i0.89 (5)1.98 (5)2.846 (5)163 (5)
Symmetry codes: (i) x, −y+3/2, z−1/2.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N7—H7···O9i0.89 (5)1.98 (5)2.846 (5)163 (5)
Symmetry codes: (i) x, −y+3/2, z−1/2.
Acknowledgements top

The X-ray data were collected at the Center for Research Facilities, Chungnam National University. This work was partially supported by the fund of New University for Regional Innovation (grant No. 05-Na—A-01) from the Ministry of Education and Human Resources Department, Republic of Korea.

references
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