PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of actaeInternational Union of Crystallographysearchopen accessarticle submissionjournal home pagethis article
 
Acta Crystallogr Sect E Struct Rep Online. 2010 May 1; 66(Pt 5): o1142.
Published online 2010 April 24. doi:  10.1107/S1600536810013796
PMCID: PMC2979189

N-(3,4-Difluoro­phen­yl)-3,4,5-trimethoxy­benzamide

Abstract

In the title amide, C16H15F2NO4, the dihedral angle between the benzene rings is 2.33 (15)°. Mol­ecules are linked in the crystal structure by N—H(...)O hydrogen bonding involving N—H and C=O groups of the amide function, leading to a supra­molecular chain along [100].

Related literature

For background to the development of potent inhibitory agents of tyrosinase and melanin formation as whitening agents, see: Cabanes et al. (1994 [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]); Park et al. (2010 [triangle]); Sung & Samyang Genex (2001 [triangle]); Yi et al. (2009 [triangle], 2010 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o1142-scheme1.jpg

Experimental

Crystal data

  • C16H15F2NO4
  • M r = 323.29
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1142-efi1.jpg
  • a = 5.0031 (3) Å
  • b = 8.8986 (5) Å
  • c = 32.726 (2) Å
  • β = 93.896 (4)°
  • V = 1453.59 (15) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.12 mm−1
  • T = 174 K
  • 0.12 × 0.05 × 0.04 mm

Data collection

  • Bruker SMART CCD area-detector diffractometer
  • 10828 measured reflections
  • 2634 independent reflections
  • 1522 reflections with I > 2σ(I)
  • R int = 0.080

Refinement

  • R[F 2 > 2σ(F 2)] = 0.065
  • wR(F 2) = 0.185
  • S = 1.05
  • 2634 reflections
  • 216 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.32 e Å−3
  • Δρmin = −0.31 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/S1600536810013796/tk2658sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810013796/tk2658Isup2.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 synthesis is principally responsible for skin color and plays a key role in the prevention of UV-induced skin damages. Tyrosinase is the key enzyme (Ha et al., 2007) that converts tyrosine to melanin and its inhibitors are target molecules for developing anti-pigmentation agents. Therefore, treatments using potent inhibitory agents on tyrosinase and melanin formation may be cosmetically useful. Common tyrosinase inhibitors (Dawley & Flurkey, 1993; Nerya et al., 2003) are hydroquinone, ascorbic acid, kojic acid and arbutin (Cabanes et al., 1994). Recently, a number of reports have focused on the development of new agents for the inhibition of tyrosinase. They contain aromatic, methoxy, hydroxyl (Hong et al., 2008; Lee et al., 2007), aldehyde (Yi et al., 2010), amide (Kwak et al., 2010), thiosemicarbazone (Yi et al., 2009) groups in their respective molecule structure. The application of natural products as a melanin synthesis inhibitors has also attracted interest (Park et al., 2010; Sung et al., 2001). However, most of these are not sufficiently potent for practical use owing to their weak individual activities or due to safety concerns. Undoubtedly, significant research and development into novel tyrosinase inhibitors is required to generate molecules with better activities and reduced side-effects. In continuation of our program aimed to develop tyrosinase inhibitors, we have synthesized the title compound, N-(3,4-difluorophenyl)-3,4,5-trimethoxybenzamide, (I), from the reaction of 3,4-difluoroaniline with 3,4,5-trimethoxybenzoyl chloride under ambient condition. Herein, the crystal structure of (I) is described (Fig. 1).

The 3,4,5-trimethoxybenzoic acid moiety (except for the C10 methyl group) and 3,4-difluoroaniline group are essentially planar, with a mean deviations of 0.027 Å and 0.006 Å, respectively, from the corresponding least-squares plane defined by the ten and nine, respectively, constituent atoms. The dihedral angle between the benzene rings is 2.33 (15) °. The presence of intermolecular N15—H15···O14i (symmetry code: (i) x-1, y, z) hydrogen bonds lead to the formation an 1-D supramolecular chain along the a axis, Table 1.

Experimental

3,4,5-Trimethoxybenzoyl chloride 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 3,4,5-trimethoxybenzoyl chloride (1.078 g, 5 mmol) and 3,4-difluoroaniline (0.5 g, 4 mmol) in THF with TEA (15 ml) as a catalyst. After being stirred for 5 h at 298 K, the mixture was treated with water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. Removal of solvent gave a white solid (90%, m.pt. 428 K). Single crystals were obtained by slow evaporation of a methylene chloride and ethyl alcohol solution of (I) held at room temperature.

Refinement

The amide-H atom was located in a difference Fourier 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 (carrier C) for aromatic and 1.5Ueq(carrier C) for methyl H atoms.

Figures

Fig. 1.
The molecular structure of (I), showing displacement ellipsoids drawn at the 30% probability level.

Crystal data

C16H15F2NO4F(000) = 672
Mr = 323.29Dx = 1.477 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ynCell parameters from 761 reflections
a = 5.0031 (3) Åθ = 2.6–19.9°
b = 8.8986 (5) ŵ = 0.12 mm1
c = 32.726 (2) ÅT = 174 K
β = 93.896 (4)°Needle, colourless
V = 1453.59 (15) Å30.12 × 0.05 × 0.04 mm
Z = 4

Data collection

Bruker SMART CCD area-detector diffractometerRint = 0.080
[var phi] and ω scansθmax = 25.5°, θmin = 2.4°
10828 measured reflectionsh = −4→6
2634 independent reflectionsk = −10→6
1522 reflections with I > 2σ(I)l = −39→34

Refinement

Refinement on F2H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: fullw = 1/[σ2(Fo2) + (0.0682P)2 + 1.4724P] where P = (Fo2 + 2Fc2)/3
R[F2 > 2σ(F2)] = 0.065(Δ/σ)max < 0.001
wR(F2) = 0.185Δρmax = 0.32 e Å3
S = 1.05Δρmin = −0.31 e Å3
2634 reflectionsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
216 parametersExtinction coefficient: 0.014 (2)
0 restraints

Special details

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

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

xyzUiso*/Ueq
C10.6607 (7)0.3453 (4)0.11117 (12)0.0287 (9)
C20.4753 (7)0.2630 (5)0.13169 (11)0.0295 (9)
H20.35690.19880.11720.035*
C30.4671 (7)0.2766 (4)0.17375 (12)0.0290 (9)
C40.6362 (7)0.3786 (4)0.19522 (11)0.0269 (9)
C50.8177 (7)0.4651 (4)0.17433 (12)0.0308 (10)
C60.8325 (7)0.4471 (4)0.13255 (12)0.0297 (9)
H60.95580.50220.11870.036*
O70.3015 (5)0.1970 (3)0.19728 (8)0.0361 (7)
C80.1331 (8)0.0851 (5)0.17712 (13)0.0387 (11)
H8A0.00820.13280.15770.058*
H8B0.03680.03230.19710.058*
H8C0.24160.01540.16320.058*
O90.6159 (5)0.3968 (3)0.23691 (8)0.0372 (8)
C100.8440 (8)0.3424 (5)0.26132 (13)0.0436 (12)
H10A0.86040.23590.25750.065*
H10B0.82180.36330.28970.065*
H10C1.00270.39150.25310.065*
O110.9674 (5)0.5622 (3)0.19817 (8)0.0402 (8)
C121.1391 (8)0.6627 (5)0.17819 (14)0.0445 (12)
H12A1.28180.60680.16720.067*
H12B1.21290.73510.19760.067*
H12C1.03810.71380.15640.067*
C130.6990 (7)0.3258 (4)0.06673 (12)0.0317 (10)
O140.9186 (5)0.3442 (3)0.05305 (8)0.0409 (8)
N150.4757 (6)0.2891 (4)0.04286 (10)0.0299 (8)
H150.313 (8)0.294 (4)0.0547 (11)0.029 (10)*
C160.4673 (7)0.2563 (5)0.00065 (12)0.0305 (9)
C170.2768 (8)0.1532 (5)−0.01466 (13)0.0389 (11)
H170.16330.10690.00280.047*
C180.2571 (9)0.1203 (5)−0.05565 (13)0.0426 (11)
C190.4247 (9)0.1857 (5)−0.08182 (12)0.0415 (11)
C200.6105 (9)0.2881 (6)−0.06747 (13)0.0493 (13)
H200.72280.3337−0.08530.059*
C210.6312 (8)0.3240 (5)−0.02595 (12)0.0402 (11)
H210.75710.3944−0.01610.048*
F220.0737 (6)0.0196 (3)−0.07070 (8)0.0697 (9)
F230.3998 (5)0.1491 (3)−0.12188 (7)0.0625 (9)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0233 (19)0.032 (2)0.030 (2)0.0051 (18)−0.0008 (16)−0.0001 (18)
C20.0215 (18)0.035 (2)0.032 (2)−0.0027 (17)0.0031 (16)−0.0032 (18)
C30.0236 (19)0.030 (2)0.034 (2)0.0022 (17)0.0048 (17)0.0008 (19)
C40.0277 (19)0.032 (2)0.021 (2)0.0052 (18)0.0021 (16)−0.0014 (18)
C50.028 (2)0.028 (2)0.035 (3)0.0000 (18)−0.0016 (17)−0.0020 (19)
C60.027 (2)0.030 (2)0.031 (2)−0.0011 (18)0.0014 (16)0.0047 (18)
O70.0376 (15)0.0399 (18)0.0314 (16)−0.0088 (14)0.0071 (12)0.0033 (13)
C80.039 (2)0.033 (2)0.045 (3)−0.005 (2)0.008 (2)0.007 (2)
O90.0331 (15)0.0477 (19)0.0311 (17)0.0038 (14)0.0041 (12)−0.0016 (14)
C100.037 (2)0.060 (3)0.034 (3)0.008 (2)0.0027 (19)0.005 (2)
O110.0464 (17)0.0383 (17)0.0351 (18)−0.0121 (14)−0.0030 (13)−0.0064 (14)
C120.042 (2)0.040 (3)0.051 (3)−0.007 (2)−0.004 (2)0.001 (2)
C130.025 (2)0.035 (2)0.035 (2)0.0000 (18)0.0010 (17)−0.0018 (19)
O140.0242 (14)0.066 (2)0.0332 (17)−0.0050 (14)0.0079 (12)−0.0011 (15)
N150.0239 (17)0.041 (2)0.025 (2)0.0001 (16)0.0027 (14)−0.0020 (16)
C160.0235 (19)0.036 (2)0.032 (2)0.0010 (18)0.0012 (16)−0.0018 (19)
C170.038 (2)0.044 (3)0.034 (3)−0.005 (2)0.0042 (19)−0.004 (2)
C180.046 (3)0.039 (3)0.041 (3)0.000 (2)−0.003 (2)−0.008 (2)
C190.047 (3)0.056 (3)0.021 (2)0.013 (2)0.0002 (19)−0.005 (2)
C200.044 (3)0.074 (4)0.031 (3)−0.001 (3)0.006 (2)0.011 (3)
C210.038 (2)0.051 (3)0.032 (3)−0.007 (2)0.0018 (19)0.001 (2)
F220.085 (2)0.072 (2)0.0507 (18)−0.0236 (18)−0.0041 (15)−0.0209 (16)
F230.0721 (18)0.087 (2)0.0284 (16)0.0145 (16)0.0001 (13)−0.0119 (14)

Geometric parameters (Å, °)

C1—C21.390 (5)O11—C121.429 (5)
C1—C61.402 (5)C12—H12A0.96
C1—C131.490 (5)C12—H12B0.96
C2—C31.385 (5)C12—H12C0.96
C2—H20.93C13—O141.226 (4)
C3—O71.367 (4)C13—N151.358 (5)
C3—C41.397 (5)N15—C161.410 (5)
C4—O91.384 (4)N15—H150.93 (4)
C4—C51.403 (5)C16—C211.375 (5)
C5—O111.355 (4)C16—C171.392 (5)
C5—C61.383 (5)C17—C181.370 (6)
C6—H60.93C17—H170.93
O7—C81.436 (5)C18—F221.352 (5)
C8—H8A0.96C18—C191.368 (6)
C8—H8B0.96C19—F231.348 (5)
C8—H8C0.96C19—C201.362 (6)
O9—C101.432 (4)C20—C211.393 (6)
C10—H10A0.96C20—H200.93
C10—H10B0.96C21—H210.93
C10—H10C0.96
C2—C1—C6120.4 (4)C5—O11—C12117.5 (3)
C2—C1—C13123.0 (4)O11—C12—H12A109.5
C6—C1—C13116.6 (3)O11—C12—H12B109.5
C3—C2—C1120.0 (4)H12A—C12—H12B109.5
C3—C2—H2120O11—C12—H12C109.5
C1—C2—H2120H12A—C12—H12C109.5
O7—C3—C2125.1 (3)H12B—C12—H12C109.5
O7—C3—C4115.0 (3)O14—C13—N15123.0 (4)
C2—C3—C4119.9 (3)O14—C13—C1121.3 (3)
O9—C4—C3119.3 (3)N15—C13—C1115.7 (3)
O9—C4—C5120.6 (3)C13—N15—C16125.6 (3)
C3—C4—C5120.1 (3)C13—N15—H15118 (2)
O11—C5—C6125.3 (4)C16—N15—H15117 (2)
O11—C5—C4114.8 (3)C21—C16—C17119.0 (4)
C6—C5—C4119.8 (4)C21—C16—N15123.4 (4)
C5—C6—C1119.7 (4)C17—C16—N15117.6 (3)
C5—C6—H6120.1C18—C17—C16119.7 (4)
C1—C6—H6120.1C18—C17—H17120.2
C3—O7—C8117.4 (3)C16—C17—H17120.2
O7—C8—H8A109.5F22—C18—C19118.9 (4)
O7—C8—H8B109.5F22—C18—C17120.0 (4)
H8A—C8—H8B109.5C19—C18—C17121.1 (4)
O7—C8—H8C109.5F23—C19—C20120.8 (4)
H8A—C8—H8C109.5F23—C19—C18119.1 (4)
H8B—C8—H8C109.5C20—C19—C18120.1 (4)
C4—O9—C10113.7 (3)C19—C20—C21119.6 (4)
O9—C10—H10A109.5C19—C20—H20120.2
O9—C10—H10B109.5C21—C20—H20120.2
H10A—C10—H10B109.5C16—C21—C20120.6 (4)
O9—C10—H10C109.5C16—C21—H21119.7
H10A—C10—H10C109.5C20—C21—H21119.7
H10B—C10—H10C109.5

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N15—H15···O14i0.93 (4)2.02 (4)2.872 (4)152 (3)

Symmetry codes: (i) x−1, y, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: TK2658).

References

  • Bruker (2002). SADABS, SAINT and SMART Bruker AXS Inc., Madison, Wisconsin, USA.
  • Cabanes, J., Chazarra, S. & Garcia-Carmona, F. (1994). J. Pharm. Pharmacol.46, 982–985. [PubMed]
  • Dawley, R. M. & Flurkey, W. H. (1993). J. Food Sci.58, 609–610
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Farrugia, L. J. (1999). J. Appl. Cryst.32, 837–838.
  • Ha, Y. M., Chang, S. W., Song, S. H. & Lee, H. J. (2007). Biol. Pharm. Bull.30, 1711–1715. [PubMed]
  • Hong, W. K., Heo, J. Y., Han, B. H., Sung, C. K. & Kang, S. K. (2008). Acta Cryst. E64, o49. [PMC free article] [PubMed]
  • Kwak, S. Y., Noh, J. M., Park, S. H., Byun, J. W. & Choi, H. R. (2010). Bioorg. Med. Chem. Lett.20, 738–742. [PubMed]
  • Lee, C. W., Son, E. M., Kim, H. S. & Xu, P. (2007). Bioorg. Med. Chem. Lett.17, 5462–5464. [PubMed]
  • Nerya, O., Vaya, J., Musa, R., Izrael, S., Ben-Arie, R. & Tamir, S. (2003). J. Agric. Food Chem.51, 1201–1207. [PubMed]
  • Park, J. S., Kim, D. H., Lee, J. K., Lee, J. Y., Kim, D. H., Kim, H. K., Lee, H. J. & Kim, H. C. (2010). Bioorg. Med. Chem. Lett.20, 1162–1164. [PubMed]
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Sung, C. K. & Samyang Genex. (2001). US Patent WO 01/41778.
  • Yi, W., Cao, R. H., Chen, Z. Y. Yu. L. Ma. L. & Song, H. C. (2009). Chem. Pharm. Bull.7, 1273–1277. [PubMed]
  • Yi, W., Cao, R., Peng, W., Wen, H., Yan, Q., Zhou, B., Ma, L. & Song, H. (2010). Eur. J. Med. Chem.45, 639–646. [PubMed]

Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography