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Acta Crystallogr Sect E Struct Rep Online. 2010 September 1; 66(Pt 9): o2320.
Published online 2010 August 18. doi:  10.1107/S1600536810032095
PMCID: PMC3007869

N-(3,4-Difluoro­phen­yl)-N′-(2,5-di­methoxy­phen­yl)urea

Abstract

In the title compound, C15H14F2N2O3, the dihedral angle between the benzene rings is 64.5 (1)°. One F atom is disordered over two meta positions, with occupancy factors of 0.72 and 0.28. In the crystal, mol­ecules are linked by N—H(...)O hydrogen bonds involving two N—H and one C=O groups of the urea central fragment, leading to a supra­molecular chain along [011].

Related literature

For general background to the development of potent inhib­itory agents of tyrosinase and melanin formation used as whitening agents, see: Cabanes et al. (1994 [triangle]); Choi et al. (2010 [triangle]); Criton & Le Mellay-Hamon (2008 [triangle]); Germanas et al. (2007 [triangle]); Dawley & Flurkey (1993 [triangle]); Ha et al. (2007 [triangle]); Hong et al. (2008 [triangle]); Kwak et al. (2010 [triangle]); Lee et al. (2007 [triangle]); Nerya et al. (2003 [triangle]); Yi et al. (2009 [triangle], 2010 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o2320-scheme1.jpg

Experimental

Crystal data

  • C15H14F2N2O3
  • M r = 308.28
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o2320-efi1.jpg
  • a = 13.209 (2) Å
  • b = 12.0887 (18) Å
  • c = 9.0740 (12) Å
  • β = 104.990 (4)°
  • V = 1399.6 (4) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.12 mm−1
  • T = 174 K
  • 0.09 × 0.04 × 0.02 mm

Data collection

  • Bruker SMART CCD area-detector diffractometer
  • 10104 measured reflections
  • 2433 independent reflections
  • 1211 reflections with I > 2σ(I)
  • R int = 0.120

Refinement

  • R[F 2 > 2σ(F 2)] = 0.061
  • wR(F 2) = 0.145
  • S = 0.96
  • 2433 reflections
  • 218 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.25 e Å−3
  • Δρmin = −0.26 e Å−3

Data collection: SMART (Bruker, 2002 [triangle]); cell refinement: SAINT (Bruker, 2002 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]); software used to prepare material for publication: WinGX (Farrugia, 1999 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810032095/bh2300sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810032095/bh2300Isup2.hkl

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

Acknowledgments

We wish to thank the DBIO Company for partial support of this work.

supplementary crystallographic information

Comment

Melanin is the pigment responsible for the color of human skin and it is formed through a series of oxidative reaction in the presence of key enzyme tyrosinase (Ha et al., 2007) that converts tyrosine into melanin. It is secreted by melanocyte cells distributed in the basal layer of the dermis. Its role is to protect the skin from ultraviolet (UV) damage by absorbing the ultraviolet sunlight and removing reactive oxygen species. Therefore these inhibitors are target molecules for developing anti-pigmentation agents. Common tyrosinase inhibitors (Dawley & Flurkey, 1993; Nerya et al., 2003) are hydroquinone, ascorbic acid, kojic acid and arbutin (Cabanes et al., 1994). Recently, numerous reports have focused on the inhibition of tyrosinase. They are containing aromatic, methoxy, hydroxyl (Hong et al., 2008; Lee et al., 2007), aldehyde (Yi et al., 2010), amide (Kwak et al., 2010; Choi et al., 2010), thiosemicarbazone (Yi et al., 2009), thiazole (Germanas et al., 2007), thiourea (Criton & Le Mellay-Hamon, 2008) groups in their structures, and act as a specific functional group to make the skin white by inhibiting the production of melanin. However, most of them are not potent enough to put into practical use due to their weak individual activities, poor skin penetration, and low stability of formulations, as well as toxicity or safety concerns. Consequently, there is still need to search and develop novel tyrosinase inhibitors with better activities together with lower side effects. To complement the inadequacy of current whitening agent above mentioned and maximize the effect of inhabitation of melanin creation, we have synthesized the title compound, (I), from the reaction of 3,4-difluoroaniline with 2,5-dimethoxyphenyl isocyanate, under ambient conditions. Herein, the crystal sturucture of (I) is described (Fig. 1).

The 3,4-difluoroaniline group and 2,5-dimethoxyphenyl moiety are essentially planar, with a mean deviations of 0.007 Å and 0.016 Å, respectively, from the corresponding least-squares planes defined by each nine constituent atoms. The dihedral angle between the benzene rings is 64.5 (1) °. The presence of intermolecular N—H···O hydrogen bonds lead to the formation a supramolecular chain along [011].

Experimental

2,5-Dimethoxyphenyl isocyanate and 3,4-difluoroaniline were purchased from Sigma Chemical Co. Solvents used for synthesis were redistilled 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 (0.28 ml, 3 mmol) and 2,5-dimethoxyphenyl isocyanate (0.5 g, 3 mmol) in acetonitrile (6 ml). The mixture was refluxed for 8 h at 353 K, and then treated with water and extracted with methylene chloride (2 × 50 mL). The combined extracts were dried over anhydrous magnesium sulfate. Removal of solvent gave a white solid (90%, m.p. 454 K). Single crystals were obtained by slow evaporation of a methylene chloride solution at room temperature.

Refinement

The amide H atoms were located in a difference map and refined freely. The remaining H atoms were positioned geometrically and refined using a riding model with C—H = 0.93–0.96 Å, and with Uiso(H) = 1.2Ueq (C) for aromatic and 1.5Ueq(C) for methyl H atoms. Atom F7 is disordered over two positions and the two split atoms are designated by having the suffix A after the atom number. The final occupancy factors are F7 0.72 and F7A 0.28. The measured diffraction fraction is relatively low of 95.5% due to a tiny single-crystal for data collection. This single-crystal was the largest one we could produce as described in the experimental section.

Figures

Fig. 1.
Molecular structure of (l), showing the atom-numbering scheme and 50% probability ellipsoids.

Crystal data

C15H14F2N2O3F(000) = 640
Mr = 308.28Dx = 1.463 Mg m3
Monoclinic, P21/cMelting point: 454 K
Hall symbol: -P 2ybcMo Kα radiation, λ = 0.71073 Å
a = 13.209 (2) ÅCell parameters from 398 reflections
b = 12.0887 (18) Åθ = 3.0–18.6°
c = 9.0740 (12) ŵ = 0.12 mm1
β = 104.990 (4)°T = 174 K
V = 1399.6 (4) Å3Needle, colourless
Z = 40.09 × 0.04 × 0.02 mm

Data collection

Bruker SMART CCD area-detector diffractometerRint = 0.120
Radiation source: fine-focus sealed tubeθmax = 25.3°, θmin = 1.6°
[var phi] and ω scansh = −15→14
10104 measured reflectionsk = −12→14
2433 independent reflectionsl = −4→10
1211 reflections with I > 2σ(I)

Refinement

Refinement on F20 restraints
Least-squares matrix: full0 constraints
R[F2 > 2σ(F2)] = 0.061H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.145w = 1/[σ2(Fo2) + (0.0573P)2] where P = (Fo2 + 2Fc2)/3
S = 0.96(Δ/σ)max < 0.001
2433 reflectionsΔρmax = 0.25 e Å3
218 parametersΔρmin = −0.26 e Å3

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

xyzUiso*/UeqOcc. (<1)
C10.6480 (3)0.4327 (3)0.4129 (4)0.0243 (9)
C20.5993 (3)0.4687 (3)0.2657 (4)0.0278 (10)
H20.59910.42450.18180.033*
C30.5517 (3)0.5705 (4)0.2464 (4)0.0351 (11)
H30.51890.59490.14840.042*0.28
C40.5517 (3)0.6365 (3)0.3683 (5)0.0354 (11)
C50.5984 (3)0.6018 (4)0.5137 (4)0.0336 (11)
H50.59730.64680.59640.04*0.72
C60.6469 (3)0.5008 (3)0.5371 (4)0.0278 (10)
H60.67910.47750.63580.033*
F70.5055 (3)0.6079 (3)0.1088 (3)0.0597 (11)0.72
F7A0.6007 (6)0.6720 (7)0.6227 (8)0.041 (2)0.28
F80.5028 (2)0.7365 (2)0.3447 (3)0.0586 (8)
N90.6969 (2)0.3289 (3)0.4443 (3)0.0274 (9)
H90.706 (3)0.302 (3)0.533 (4)0.038 (12)*
C100.7429 (3)0.2699 (3)0.3512 (4)0.0271 (10)
O110.74653 (19)0.3012 (2)0.2231 (2)0.0301 (7)
N120.7839 (3)0.1710 (3)0.4127 (4)0.0315 (9)
H120.775 (3)0.151 (3)0.492 (4)0.036 (13)*
C130.8518 (3)0.1019 (3)0.3556 (4)0.0259 (10)
C140.8499 (3)−0.0108 (4)0.3854 (4)0.0295 (10)
C150.9184 (3)−0.0817 (4)0.3393 (4)0.0347 (11)
H150.9177−0.15690.36040.042*
C160.9883 (3)−0.0401 (4)0.2614 (4)0.0346 (11)
H161.0341−0.08750.22990.042*
C170.9893 (3)0.0715 (4)0.2313 (4)0.0317 (10)
C180.9216 (3)0.1432 (3)0.2788 (4)0.0295 (10)
H180.92330.21860.2590.035*
O190.7767 (2)−0.0423 (2)0.4625 (3)0.0381 (7)
C200.7657 (4)−0.1587 (4)0.4843 (5)0.0496 (13)
H20A0.7476−0.19510.3870.074*
H20B0.7114−0.17090.53530.074*
H20C0.8307−0.18790.54530.074*
O211.0554 (2)0.1220 (2)0.1555 (3)0.0414 (8)
C221.1393 (3)0.0546 (4)0.1310 (4)0.0423 (12)
H22A1.180.02650.22710.063*
H22B1.18330.09840.08460.063*
H22C1.1107−0.0060.06510.063*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.029 (2)0.018 (2)0.0284 (19)−0.0011 (19)0.0118 (16)0.0004 (16)
C20.030 (2)0.024 (3)0.0296 (19)−0.001 (2)0.0088 (17)−0.0009 (17)
C30.034 (3)0.034 (3)0.036 (2)0.004 (2)0.0063 (19)0.007 (2)
C40.034 (3)0.016 (3)0.055 (3)0.010 (2)0.010 (2)0.004 (2)
C50.030 (3)0.028 (3)0.045 (2)0.000 (2)0.0121 (19)−0.006 (2)
C60.030 (2)0.027 (3)0.0278 (19)−0.003 (2)0.0082 (16)−0.0031 (17)
F70.077 (3)0.052 (3)0.0428 (18)0.022 (2)0.0015 (17)0.0155 (18)
F7A0.050 (6)0.031 (5)0.050 (4)0.006 (5)0.025 (4)−0.016 (4)
F80.066 (2)0.0366 (18)0.0715 (16)0.0211 (15)0.0138 (14)0.0024 (13)
N90.039 (2)0.025 (2)0.0191 (16)0.0072 (18)0.0103 (14)0.0042 (15)
C100.025 (3)0.031 (3)0.0251 (19)−0.001 (2)0.0065 (16)−0.0030 (18)
O110.0381 (17)0.0301 (18)0.0248 (12)0.0040 (14)0.0133 (11)0.0004 (11)
N120.043 (2)0.025 (2)0.0300 (18)0.0083 (18)0.0158 (16)0.0063 (16)
C130.029 (3)0.021 (3)0.0270 (19)0.004 (2)0.0059 (17)0.0016 (17)
C140.035 (3)0.026 (3)0.0265 (19)−0.003 (2)0.0066 (18)0.0019 (18)
C150.046 (3)0.020 (3)0.037 (2)0.003 (2)0.008 (2)−0.0021 (18)
C160.042 (3)0.027 (3)0.036 (2)0.011 (2)0.0121 (19)−0.0048 (19)
C170.033 (3)0.024 (3)0.039 (2)0.007 (2)0.0094 (19)0.0010 (19)
C180.037 (3)0.018 (3)0.034 (2)0.001 (2)0.0105 (18)0.0033 (17)
O190.0450 (19)0.0241 (19)0.0492 (15)−0.0003 (15)0.0193 (14)0.0043 (13)
C200.066 (3)0.028 (3)0.057 (3)−0.012 (3)0.019 (2)0.003 (2)
O210.0436 (19)0.035 (2)0.0553 (16)0.0122 (15)0.0299 (14)0.0078 (14)
C220.043 (3)0.041 (3)0.050 (2)0.012 (2)0.024 (2)0.003 (2)

Geometric parameters (Å, °)

C1—C21.394 (5)C13—C141.390 (5)
C1—C61.400 (5)C14—O191.385 (4)
C1—N91.406 (5)C14—C151.387 (5)
C2—C31.371 (5)C15—C161.394 (5)
C2—H20.93C15—H150.93
C3—C41.365 (5)C16—C171.377 (5)
C3—F71.320 (5)C16—H160.93
C4—F81.361 (4)C17—O211.386 (5)
C4—C51.369 (5)C17—C181.391 (5)
C5—C61.369 (5)C18—H180.93
C5—H50.93O19—C201.434 (5)
C6—H60.93C20—H20A0.96
N9—C101.362 (4)C20—H20B0.96
N9—H90.84 (4)C20—H20C0.96
C10—O111.235 (4)O21—C221.439 (4)
C10—N121.370 (5)C22—H22A0.96
N12—C131.418 (5)C22—H22B0.96
N12—H120.80 (4)C22—H22C0.96
C13—C181.385 (5)
C2—C1—C6119.3 (4)C14—C13—N12117.5 (4)
C2—C1—N9123.2 (3)O19—C14—C15125.3 (4)
C6—C1—N9117.5 (3)O19—C14—C13114.7 (4)
C3—C2—C1119.0 (3)C15—C14—C13120.1 (4)
C3—C2—H2120.5C14—C15—C16120.0 (4)
C1—C2—H2120.5C14—C15—H15120
F7—C3—C4118.0 (4)C16—C15—H15120
F7—C3—C2120.9 (4)C17—C16—C15119.7 (4)
C4—C3—C2121.1 (4)C17—C16—H16120.2
C4—C3—H3119.4C15—C16—H16120.2
C2—C3—H3119.4C16—C17—O21124.7 (4)
F8—C4—C3119.4 (4)C16—C17—C18120.7 (4)
F8—C4—C5120.1 (4)O21—C17—C18114.6 (4)
C3—C4—C5120.5 (4)C13—C18—C17119.7 (4)
C6—C5—C4119.9 (4)C13—C18—H18120.1
C6—C5—H5120C17—C18—H18120.1
C4—C5—H5120C14—O19—C20116.7 (3)
C5—C6—C1120.1 (4)O19—C20—H20A109.5
C5—C6—H6119.9O19—C20—H20B109.5
C1—C6—H6119.9H20A—C20—H20B109.5
C10—N9—C1126.7 (3)O19—C20—H20C109.5
C10—N9—H9115 (3)H20A—C20—H20C109.5
C1—N9—H9118 (3)H20B—C20—H20C109.5
O11—C10—N9123.7 (4)C17—O21—C22115.9 (3)
O11—C10—N12122.9 (4)O21—C22—H22A109.5
N9—C10—N12113.4 (3)O21—C22—H22B109.5
C10—N12—C13125.9 (3)H22A—C22—H22B109.5
C10—N12—H12120 (3)O21—C22—H22C109.5
C13—N12—H12114 (3)H22A—C22—H22C109.5
C18—C13—C14119.9 (4)H22B—C22—H22C109.5
C18—C13—N12122.6 (4)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N9—H9···O11i0.84 (4)2.09 (4)2.907 (4)163 (4)
N12—H12···O11i0.80 (4)2.30 (4)3.002 (4)147 (4)

Symmetry codes: (i) x, −y+1/2, z+1/2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BH2300).

References

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