Acta Cryst. (2010). E66, o1142 [ doi:10.1107/S1600536810013796 ]
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].
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.
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.
Data collection: SMART (Bruker, 2002); cell refinement: SAINT (Bruker, 2002); data reduction: SAINT (Bruker, 2002); 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).
![[Figure 1]](./tk2658fig1thm.gif)
| Fig. 1. The molecular structure of (I), showing displacement ellipsoids drawn at the 30% probability level. |
| C16H15F2NO4 | F(000) = 672 |
| Mr = 323.29 | Dx = 1.477 Mg m−3 |
| Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
| Hall symbol: -P 2yn | Cell parameters from 761 reflections |
| a = 5.0031 (3) Å | θ = 2.6–19.9° |
| b = 8.8986 (5) Å | µ = 0.12 mm−1 |
| c = 32.726 (2) Å | T = 174 K |
| β = 93.896 (4)° | Needle, colourless |
| V = 1453.59 (15) Å3 | 0.12 × 0.05 × 0.04 mm |
| Z = 4 |
| Bruker SMART CCD area-detector diffractometer | Rint = 0.080 |
| φ and ω scans | θmax = 25.5°, θmin = 2.4° |
| 10828 measured reflections | h = −4→6 |
| 2634 independent reflections | k = −10→6 |
| 1522 reflections with I > 2σ(I) | l = −39→34 |
| Refinement on F2 | H atoms treated by a mixture of independent and constrained refinement |
| Least-squares matrix: full | w = 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) = 0.185 | Δρmax = 0.32 e Å−3 |
| S = 1.05 | Δρmin = −0.31 e Å−3 |
| 2634 reflections | Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
| 216 parameters | Extinction coefficient: 0.014 (2) |
| 0 restraints |
| C16H15F2NO4 | V = 1453.59 (15) Å3 |
| Mr = 323.29 | Z = 4 |
| Monoclinic, P21/n | Mo Kα radiation |
| a = 5.0031 (3) Å | µ = 0.12 mm−1 |
| b = 8.8986 (5) Å | T = 174 K |
| c = 32.726 (2) Å | 0.12 × 0.05 × 0.04 mm |
| β = 93.896 (4)° |
| Bruker SMART CCD area-detector diffractometer | 1522 reflections with I > 2σ(I) |
| 10828 measured reflections | Rint = 0.080 |
| 2634 independent reflections | θmax = 25.5° |
| R[F2 > 2σ(F2)] = 0.065 | H atoms treated by a mixture of independent and constrained refinement |
| wR(F2) = 0.185 | Δρmax = 0.32 e Å−3 |
| S = 1.05 | Δρmin = −0.31 e Å−3 |
| 2634 reflections | Absolute structure: ? |
| 216 parameters | Flack parameter: ? |
| 0 restraints | Rogers parameter: ? |
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. |
| x | y | z | Uiso*/Ueq | ||
| C1 | 0.6607 (7) | 0.3453 (4) | 0.11117 (12) | 0.0287 (9) | |
| C2 | 0.4753 (7) | 0.2630 (5) | 0.13169 (11) | 0.0295 (9) | |
| H2 | 0.3569 | 0.1988 | 0.1172 | 0.035* | |
| C3 | 0.4671 (7) | 0.2766 (4) | 0.17375 (12) | 0.0290 (9) | |
| C4 | 0.6362 (7) | 0.3786 (4) | 0.19522 (11) | 0.0269 (9) | |
| C5 | 0.8177 (7) | 0.4651 (4) | 0.17433 (12) | 0.0308 (10) | |
| C6 | 0.8325 (7) | 0.4471 (4) | 0.13255 (12) | 0.0297 (9) | |
| H6 | 0.9558 | 0.5022 | 0.1187 | 0.036* | |
| O7 | 0.3015 (5) | 0.1970 (3) | 0.19728 (8) | 0.0361 (7) | |
| C8 | 0.1331 (8) | 0.0851 (5) | 0.17712 (13) | 0.0387 (11) | |
| H8A | 0.0082 | 0.1328 | 0.1577 | 0.058* | |
| H8B | 0.0368 | 0.0323 | 0.1971 | 0.058* | |
| H8C | 0.2416 | 0.0154 | 0.1632 | 0.058* | |
| O9 | 0.6159 (5) | 0.3968 (3) | 0.23691 (8) | 0.0372 (8) | |
| C10 | 0.8440 (8) | 0.3424 (5) | 0.26132 (13) | 0.0436 (12) | |
| H10A | 0.8604 | 0.2359 | 0.2575 | 0.065* | |
| H10B | 0.8218 | 0.3633 | 0.2897 | 0.065* | |
| H10C | 1.0027 | 0.3915 | 0.2531 | 0.065* | |
| O11 | 0.9674 (5) | 0.5622 (3) | 0.19817 (8) | 0.0402 (8) | |
| C12 | 1.1391 (8) | 0.6627 (5) | 0.17819 (14) | 0.0445 (12) | |
| H12A | 1.2818 | 0.6068 | 0.1672 | 0.067* | |
| H12B | 1.2129 | 0.7351 | 0.1976 | 0.067* | |
| H12C | 1.0381 | 0.7138 | 0.1564 | 0.067* | |
| C13 | 0.6990 (7) | 0.3258 (4) | 0.06673 (12) | 0.0317 (10) | |
| O14 | 0.9186 (5) | 0.3442 (3) | 0.05305 (8) | 0.0409 (8) | |
| N15 | 0.4757 (6) | 0.2891 (4) | 0.04286 (10) | 0.0299 (8) | |
| H15 | 0.313 (8) | 0.294 (4) | 0.0547 (11) | 0.029 (10)* | |
| C16 | 0.4673 (7) | 0.2563 (5) | 0.00065 (12) | 0.0305 (9) | |
| C17 | 0.2768 (8) | 0.1532 (5) | −0.01466 (13) | 0.0389 (11) | |
| H17 | 0.1633 | 0.1069 | 0.0028 | 0.047* | |
| C18 | 0.2571 (9) | 0.1203 (5) | −0.05565 (13) | 0.0426 (11) | |
| C19 | 0.4247 (9) | 0.1857 (5) | −0.08182 (12) | 0.0415 (11) | |
| C20 | 0.6105 (9) | 0.2881 (6) | −0.06747 (13) | 0.0493 (13) | |
| H20 | 0.7228 | 0.3337 | −0.0853 | 0.059* | |
| C21 | 0.6312 (8) | 0.3240 (5) | −0.02595 (12) | 0.0402 (11) | |
| H21 | 0.7571 | 0.3944 | −0.0161 | 0.048* | |
| F22 | 0.0737 (6) | 0.0196 (3) | −0.07070 (8) | 0.0697 (9) | |
| F23 | 0.3998 (5) | 0.1491 (3) | −0.12188 (7) | 0.0625 (9) |
| U11 | U22 | U33 | U12 | U13 | U23 | |
| C1 | 0.0233 (19) | 0.032 (2) | 0.030 (2) | 0.0051 (18) | −0.0008 (16) | −0.0001 (18) |
| C2 | 0.0215 (18) | 0.035 (2) | 0.032 (2) | −0.0027 (17) | 0.0031 (16) | −0.0032 (18) |
| C3 | 0.0236 (19) | 0.030 (2) | 0.034 (2) | 0.0022 (17) | 0.0048 (17) | 0.0008 (19) |
| C4 | 0.0277 (19) | 0.032 (2) | 0.021 (2) | 0.0052 (18) | 0.0021 (16) | −0.0014 (18) |
| C5 | 0.028 (2) | 0.028 (2) | 0.035 (3) | 0.0000 (18) | −0.0016 (17) | −0.0020 (19) |
| C6 | 0.027 (2) | 0.030 (2) | 0.031 (2) | −0.0011 (18) | 0.0014 (16) | 0.0047 (18) |
| O7 | 0.0376 (15) | 0.0399 (18) | 0.0314 (16) | −0.0088 (14) | 0.0071 (12) | 0.0033 (13) |
| C8 | 0.039 (2) | 0.033 (2) | 0.045 (3) | −0.005 (2) | 0.008 (2) | 0.007 (2) |
| O9 | 0.0331 (15) | 0.0477 (19) | 0.0311 (17) | 0.0038 (14) | 0.0041 (12) | −0.0016 (14) |
| C10 | 0.037 (2) | 0.060 (3) | 0.034 (3) | 0.008 (2) | 0.0027 (19) | 0.005 (2) |
| O11 | 0.0464 (17) | 0.0383 (17) | 0.0351 (18) | −0.0121 (14) | −0.0030 (13) | −0.0064 (14) |
| C12 | 0.042 (2) | 0.040 (3) | 0.051 (3) | −0.007 (2) | −0.004 (2) | 0.001 (2) |
| C13 | 0.025 (2) | 0.035 (2) | 0.035 (2) | 0.0000 (18) | 0.0010 (17) | −0.0018 (19) |
| O14 | 0.0242 (14) | 0.066 (2) | 0.0332 (17) | −0.0050 (14) | 0.0079 (12) | −0.0011 (15) |
| N15 | 0.0239 (17) | 0.041 (2) | 0.025 (2) | 0.0001 (16) | 0.0027 (14) | −0.0020 (16) |
| C16 | 0.0235 (19) | 0.036 (2) | 0.032 (2) | 0.0010 (18) | 0.0012 (16) | −0.0018 (19) |
| C17 | 0.038 (2) | 0.044 (3) | 0.034 (3) | −0.005 (2) | 0.0042 (19) | −0.004 (2) |
| C18 | 0.046 (3) | 0.039 (3) | 0.041 (3) | 0.000 (2) | −0.003 (2) | −0.008 (2) |
| C19 | 0.047 (3) | 0.056 (3) | 0.021 (2) | 0.013 (2) | 0.0002 (19) | −0.005 (2) |
| C20 | 0.044 (3) | 0.074 (4) | 0.031 (3) | −0.001 (3) | 0.006 (2) | 0.011 (3) |
| C21 | 0.038 (2) | 0.051 (3) | 0.032 (3) | −0.007 (2) | 0.0018 (19) | 0.001 (2) |
| F22 | 0.085 (2) | 0.072 (2) | 0.0507 (18) | −0.0236 (18) | −0.0041 (15) | −0.0209 (16) |
| F23 | 0.0721 (18) | 0.087 (2) | 0.0284 (16) | 0.0145 (16) | 0.0001 (13) | −0.0119 (14) |
| C1—C2 | 1.390 (5) | O11—C12 | 1.429 (5) |
| C1—C6 | 1.402 (5) | C12—H12A | 0.96 |
| C1—C13 | 1.490 (5) | C12—H12B | 0.96 |
| C2—C3 | 1.385 (5) | C12—H12C | 0.96 |
| C2—H2 | 0.93 | C13—O14 | 1.226 (4) |
| C3—O7 | 1.367 (4) | C13—N15 | 1.358 (5) |
| C3—C4 | 1.397 (5) | N15—C16 | 1.410 (5) |
| C4—O9 | 1.384 (4) | N15—H15 | 0.93 (4) |
| C4—C5 | 1.403 (5) | C16—C21 | 1.375 (5) |
| C5—O11 | 1.355 (4) | C16—C17 | 1.392 (5) |
| C5—C6 | 1.383 (5) | C17—C18 | 1.370 (6) |
| C6—H6 | 0.93 | C17—H17 | 0.93 |
| O7—C8 | 1.436 (5) | C18—F22 | 1.352 (5) |
| C8—H8A | 0.96 | C18—C19 | 1.368 (6) |
| C8—H8B | 0.96 | C19—F23 | 1.348 (5) |
| C8—H8C | 0.96 | C19—C20 | 1.362 (6) |
| O9—C10 | 1.432 (4) | C20—C21 | 1.393 (6) |
| C10—H10A | 0.96 | C20—H20 | 0.93 |
| C10—H10B | 0.96 | C21—H21 | 0.93 |
| C10—H10C | 0.96 | ||
| C2—C1—C6 | 120.4 (4) | C5—O11—C12 | 117.5 (3) |
| C2—C1—C13 | 123.0 (4) | O11—C12—H12A | 109.5 |
| C6—C1—C13 | 116.6 (3) | O11—C12—H12B | 109.5 |
| C3—C2—C1 | 120.0 (4) | H12A—C12—H12B | 109.5 |
| C3—C2—H2 | 120 | O11—C12—H12C | 109.5 |
| C1—C2—H2 | 120 | H12A—C12—H12C | 109.5 |
| O7—C3—C2 | 125.1 (3) | H12B—C12—H12C | 109.5 |
| O7—C3—C4 | 115.0 (3) | O14—C13—N15 | 123.0 (4) |
| C2—C3—C4 | 119.9 (3) | O14—C13—C1 | 121.3 (3) |
| O9—C4—C3 | 119.3 (3) | N15—C13—C1 | 115.7 (3) |
| O9—C4—C5 | 120.6 (3) | C13—N15—C16 | 125.6 (3) |
| C3—C4—C5 | 120.1 (3) | C13—N15—H15 | 118 (2) |
| O11—C5—C6 | 125.3 (4) | C16—N15—H15 | 117 (2) |
| O11—C5—C4 | 114.8 (3) | C21—C16—C17 | 119.0 (4) |
| C6—C5—C4 | 119.8 (4) | C21—C16—N15 | 123.4 (4) |
| C5—C6—C1 | 119.7 (4) | C17—C16—N15 | 117.6 (3) |
| C5—C6—H6 | 120.1 | C18—C17—C16 | 119.7 (4) |
| C1—C6—H6 | 120.1 | C18—C17—H17 | 120.2 |
| C3—O7—C8 | 117.4 (3) | C16—C17—H17 | 120.2 |
| O7—C8—H8A | 109.5 | F22—C18—C19 | 118.9 (4) |
| O7—C8—H8B | 109.5 | F22—C18—C17 | 120.0 (4) |
| H8A—C8—H8B | 109.5 | C19—C18—C17 | 121.1 (4) |
| O7—C8—H8C | 109.5 | F23—C19—C20 | 120.8 (4) |
| H8A—C8—H8C | 109.5 | F23—C19—C18 | 119.1 (4) |
| H8B—C8—H8C | 109.5 | C20—C19—C18 | 120.1 (4) |
| C4—O9—C10 | 113.7 (3) | C19—C20—C21 | 119.6 (4) |
| O9—C10—H10A | 109.5 | C19—C20—H20 | 120.2 |
| O9—C10—H10B | 109.5 | C21—C20—H20 | 120.2 |
| H10A—C10—H10B | 109.5 | C16—C21—C20 | 120.6 (4) |
| O9—C10—H10C | 109.5 | C16—C21—H21 | 119.7 |
| H10A—C10—H10C | 109.5 | C20—C21—H21 | 119.7 |
| H10B—C10—H10C | 109.5 |
| D—H···A | D—H | H···A | D···A | D—H···A |
| N15—H15···O14i | 0.93 (4) | 2.02 (4) | 2.872 (4) | 152 (3) |
| Symmetry codes: (i) x−1, y, z. |
| D—H···A | D—H | H···A | D···A | D—H···A |
| N15—H15···O14i | 0.93 (4) | 2.02 (4) | 2.872 (4) | 152 (3) |
| Symmetry codes: (i) x−1, y, z. |
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.
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.
Hong, W. K., Heo, J. Y., Han, B. H., Sung, C. K. & Kang, S. K. (2008). Acta Cryst. E64, o49.
Kwak, S. Y., Noh, J. M., Park, S. H., Byun, J. W. & Choi, H. R. (2010). Bioorg. Med. Chem. Lett. 20, 738–742.
Lee, C. W., Son, E. M., Kim, H. S. & Xu, P. (2007). Bioorg. Med. Chem. Lett. 17, 5462–5464.
Nerya, O., Vaya, J., Musa, R., Izrael, S., Ben-Arie, R. & Tamir, S. (2003). J. Agric. Food Chem. 51, 1201–1207.
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.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.
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.
Yi, W., Cao, R., Peng, W., Wen, H., Yan, Q., Zhou, B., Ma, L. & Song, H. (2010). Eur. J. Med. Chem. 45, 639–646.
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.