N-(3,4-Difluoro­phen­yl)-3,4-dimethoxy­benzene­sulfonamide

In the title sulfonamide derivative, C₁₄H₁₃F₂NO₄S, the dihedral angle between the benzene rings is 66.05 (9)°. The crystal structure is stabilized by weak inter­molecular N—H...O hydrogen bonds involving the amine and meth­oxy groups, which link the mol­ecules into a one-dimensional chain. No significant inter­chain contacts are observed.

Key indicators

• Single-crystal X-ray study
• T = 295 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.044
• wR factor = 0.127
• Data-to-parameter ratio = 16.2

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT241_ALERT_2_C Check High      Ueq as Compared to Neighbors for         C5
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for         C3
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for         C4
PLAT480_ALERT_4_C Long H...A H-Bond Reported H7     ..  O19     ..       2.61 Ang.

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   3 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Most skin whitening agents currently on the market (Dawley & Flurkey, 1993; Nerya et al., 2003) contain hydroquinone, ascorbic acid, kojic acid (Juana et al., 1994), arbutin, azealic acid, and glycyrrhetinic acid. They include aromatic, methoxy, hydroxyl and carbonyl functional groups in their structures. They are acting as a direct inhibitors of tyrosinase, the enzyme in the skin pigment cells (melanocytes) producing melanin.

Tyrosinase is the key enzyme converting the amino acid L-tyrosine to melanin, and its inhibitors are target molecules to develop anti-pigmentation agents for skin treatment after sunburn (Briganti et al. 2003). The melanin formation by the tyrosinase activity after sunlight exposure causes some dermatological disorders associated with freckles and melasma. Therefore, potent inhibitory agents on melanin formation and tyrosinase should be cosmetically useful for treatment of dermatological disorders.

However, most skin whitening agents have some problems, due to toxicity, low stability of formulation and poor skin permeation. In our work on the development of new whitening agents to complement the inadequacy of current whitening agents and maximize the inhibitory effects of melanin creation, we synthesized the title compound (Fig. 1), via a general chemical reaction (Hussain et al., 2003) of 3,4-difluoroaniline with aromatic sulfonyl chloride, and studied its X-ray crystal structure.

The 3,4-dimethoxybenzenesulfonyl and 3,4-difluoroaniline moieties are essentially planar, with a mean deviation of 0.004 Å and 0.010 Å, respectively, from the corresponding least-squares planes. The dihedral angle between benzene rings is 66.05 (9)°. The intermolecular N7—H7···O17ⁱ and O19ⁱ [symmetry code: (i) -x + 2, y + 1/2, -z + 1/2] hydrogen bonds (involving the H atom of the amine and O atoms of methoxy groups) allow to form an extensive one-dimensional network along the b axis, which stabilizes the crystal structure.

Related literature

For a general background on skin whitening agents, see: Dawley & Flurkey (1993); Nerya et al. (2003); Juana et al. (1994); Briganti et al. (2003). For the synthesis, see: Hussain et al. (2003).

S2. Experimental

3,4-difluoroaniline and 3,4-dimethoxy benzenesulfonyl chloride were purchased from Sigma Chemical Co. Solvents used for organic synthesis were redistilled before used. All other chemicals and solvents were of analytical grade and used without further purification. The title compound was prepared by the reaction of 3,4-difluoroaniline (1 mmol) with aromatic sulfonyl chloride (1.2 mmol) in triethylamine as a solvent, under stirring. Evaporation of solvent, treatment with water, extraction with methylene chloride and chromatography of the dried solution (MgSO₄) on silica gel column (2 / 1 = hexane / ethyl acetate) gave the title compound in 56% yield. Colourless single crystals were obtained by slow evaporation from an ethyl acetate solution, at room temperature.

S3. Refinement

The amine H atom H7 was located in a difference map and refined freely. The other H atoms were positioned geometrically and refined using a riding model, with C—H = 0.93 Å for aromatic H atoms and 0.96 Å for methyl H atoms, and with U_iso(H) = 1.2U_eq(C) for aromatic and 1.5U_eq(C) for methyl H atoms.

Computing details

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).

Figures

Fig. 1. The molecular structure of the title compound, showing the atom-numbering scheme and 30% probability ellipsoids.

N-(3,4-Difluorophenyl)-3,4-dimethoxybenzenesulfonamide

Crystal data

C14H13F2NO4S	F(000) = 680
Mr = 329.31	Dx = 1.516 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 1598 reflections
a = 12.2886 (10) Å	θ = 2.8–23.5°
b = 8.5662 (7) Å	µ = 0.26 mm^−1
c = 14.5546 (12) Å	T = 295 K
β = 109.655 (2)°	Block, colourless
V = 1442.8 (2) Å^3	0.25 × 0.18 × 0.15 mm
Z = 4

Data collection

Bruker SMART CCD area-detector diffractometer	1700 reflections with I > 2σ(I)
ϕ and ω scans	Rint = 0.042
Absorption correction: multi-scan (SADABS; Bruker, 2002)	θmax = 27.5°, θmin = 1.8°
Tmin = 0.928, Tmax = 0.957	h = −15→14
9690 measured reflections	k = −11→9
3308 independent reflections	l = −18→18

Refinement

Refinement on F^2	H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.0426P)^2 + 0.5561P] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.044	(Δ/σ)max = 0.001
wR(F^2) = 0.126	Δρmax = 0.19 e Å^−3
S = 0.99	Δρmin = −0.21 e Å^−3
3308 reflections	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
204 parameters	Extinction coefficient: 0.0349 (19)
0 restraints

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

	x	y	z	Uiso*/Ueq
F1	0.37106 (16)	0.1400 (3)	−0.04021 (13)	0.0975 (7)
F2	0.3788 (2)	0.0318 (3)	0.13264 (17)	0.1271 (9)
C1	0.6212 (2)	0.3457 (3)	0.11332 (19)	0.0492 (7)
C2	0.5338 (2)	0.2966 (3)	0.0306 (2)	0.0584 (8)
H2	0.5288	0.3352	−0.0304	0.07*
C3	0.4554 (2)	0.1914 (4)	0.0395 (2)	0.0609 (8)
C4	0.4593 (3)	0.1366 (4)	0.1281 (2)	0.0753 (10)
C5	0.5430 (3)	0.1849 (5)	0.2102 (2)	0.0885 (12)
H5	0.5454	0.1475	0.2708	0.106*
C6	0.6248 (2)	0.2906 (4)	0.2030 (2)	0.0692 (9)
H6	0.6826	0.3245	0.2591	0.083*
N7	0.7042 (2)	0.4591 (3)	0.1068 (2)	0.0595 (7)
H7	0.738 (2)	0.489 (4)	0.158 (2)	0.062 (10)*
S8	0.78080 (6)	0.43912 (9)	0.03547 (5)	0.0595 (3)
O9	0.84833 (17)	0.5777 (2)	0.04834 (17)	0.0802 (7)
O10	0.70295 (15)	0.3991 (3)	−0.05866 (13)	0.0709 (6)
C11	0.8750 (2)	0.2809 (3)	0.07756 (18)	0.0490 (7)
C12	0.9910 (2)	0.3073 (3)	0.13211 (17)	0.0478 (6)
H12	1.0184	0.4087	0.1468	0.057*
C13	1.0644 (2)	0.1829 (3)	0.16380 (17)	0.0472 (6)
C14	1.0231 (2)	0.0296 (3)	0.14189 (18)	0.0480 (6)
C15	0.9086 (2)	0.0050 (3)	0.0875 (2)	0.0559 (7)
H15	0.8809	−0.0962	0.0724	0.067*
C16	0.8350 (2)	0.1300 (3)	0.0554 (2)	0.0566 (7)
H16	0.7579	0.1128	0.0187	0.068*
O17	1.17904 (15)	0.1936 (2)	0.21844 (13)	0.0614 (5)
C18	1.2333 (2)	0.3419 (4)	0.2277 (2)	0.0669 (9)
H18A	1.3129	0.3326	0.2681	0.1*
H18B	1.1949	0.4141	0.2569	0.1*
H18C	1.2288	0.3792	0.1643	0.1*
O19	1.10296 (15)	−0.0832 (2)	0.17753 (14)	0.0599 (5)
C20	1.0682 (3)	−0.2409 (3)	0.1507 (2)	0.0668 (8)
H20A	1.132	−0.3098	0.1805	0.1*
H20B	1.0441	−0.2514	0.0811	0.1*
H20C	1.005	−0.2674	0.1727	0.1*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0780 (12)	0.1205 (18)	0.0749 (12)	−0.0470 (12)	0.0005 (10)	−0.0069 (11)
F2	0.1139 (17)	0.160 (2)	0.1037 (16)	−0.0684 (17)	0.0321 (14)	0.0185 (15)
C1	0.0374 (13)	0.0490 (16)	0.0540 (17)	0.0026 (12)	0.0060 (12)	−0.0074 (13)
C2	0.0499 (16)	0.0634 (19)	0.0522 (17)	−0.0065 (14)	0.0044 (13)	0.0047 (14)
C3	0.0480 (16)	0.069 (2)	0.0555 (18)	−0.0104 (15)	0.0037 (14)	−0.0058 (15)
C4	0.0615 (19)	0.088 (3)	0.075 (2)	−0.0210 (18)	0.0223 (17)	0.0036 (19)
C5	0.074 (2)	0.134 (4)	0.057 (2)	−0.015 (2)	0.0207 (18)	0.008 (2)
C6	0.0520 (17)	0.096 (3)	0.0530 (19)	−0.0028 (17)	0.0093 (14)	−0.0121 (17)
N7	0.0462 (13)	0.0581 (16)	0.0618 (17)	−0.0029 (12)	0.0019 (12)	−0.0102 (13)
S8	0.0460 (4)	0.0573 (5)	0.0647 (5)	−0.0070 (4)	0.0048 (3)	0.0101 (4)
O9	0.0582 (12)	0.0579 (14)	0.1098 (18)	−0.0137 (10)	0.0090 (12)	0.0198 (12)
O10	0.0543 (11)	0.0896 (17)	0.0556 (12)	−0.0054 (10)	0.0009 (9)	0.0153 (11)
C11	0.0422 (14)	0.0530 (17)	0.0480 (15)	−0.0059 (13)	0.0102 (12)	0.0031 (13)
C12	0.0480 (14)	0.0453 (16)	0.0459 (15)	−0.0115 (12)	0.0102 (12)	−0.0005 (12)
C13	0.0420 (14)	0.0526 (17)	0.0427 (14)	−0.0059 (13)	0.0084 (11)	0.0005 (12)
C14	0.0469 (14)	0.0473 (17)	0.0482 (15)	−0.0036 (13)	0.0138 (12)	0.0015 (12)
C15	0.0509 (16)	0.0509 (17)	0.0643 (18)	−0.0130 (14)	0.0171 (14)	−0.0060 (14)
C16	0.0418 (14)	0.062 (2)	0.0598 (18)	−0.0137 (14)	0.0092 (13)	−0.0027 (15)
O17	0.0470 (10)	0.0523 (12)	0.0707 (13)	−0.0082 (9)	0.0010 (9)	0.0051 (10)
C18	0.0486 (16)	0.061 (2)	0.078 (2)	−0.0199 (14)	0.0042 (14)	0.0031 (16)
O19	0.0563 (11)	0.0441 (12)	0.0732 (13)	−0.0037 (9)	0.0138 (10)	−0.0016 (9)
C20	0.0727 (19)	0.0473 (18)	0.081 (2)	−0.0054 (16)	0.0270 (17)	−0.0061 (16)

Geometric parameters (Å, º)

F1—C3	1.343 (3)	C11—C12	1.398 (3)
F2—C4	1.354 (3)	C12—C13	1.372 (4)
C1—C6	1.375 (4)	C12—H12	0.93
C1—C2	1.382 (3)	C13—O17	1.369 (3)
C1—N7	1.434 (4)	C13—C14	1.405 (4)
C2—C3	1.357 (4)	C14—O19	1.350 (3)
C2—H2	0.93	C14—C15	1.379 (3)
C3—C4	1.359 (4)	C15—C16	1.378 (4)
C4—C5	1.352 (4)	C15—H15	0.93
C5—C6	1.383 (4)	C16—H16	0.93
C5—H5	0.93	O17—C18	1.420 (3)
C6—H6	0.93	C18—H18A	0.96
N7—S8	1.628 (3)	C18—H18B	0.96
N7—H7	0.76 (3)	C18—H18C	0.96
S8—O10	1.424 (2)	O19—C20	1.431 (3)
S8—O9	1.424 (2)	C20—H20A	0.96
S8—C11	1.754 (3)	C20—H20B	0.96
C11—C16	1.381 (4)	C20—H20C	0.96
C6—C1—C2	119.3 (3)	C13—C12—C11	119.6 (2)
C6—C1—N7	119.9 (2)	C13—C12—H12	120.2
C2—C1—N7	120.7 (3)	C11—C12—H12	120.2
C3—C2—C1	119.2 (3)	O17—C13—C12	125.1 (2)
C3—C2—H2	120.4	O17—C13—C14	114.6 (2)
C1—C2—H2	120.4	C12—C13—C14	120.3 (2)
F1—C3—C2	120.1 (3)	O19—C14—C15	125.5 (2)
F1—C3—C4	118.5 (3)	O19—C14—C13	114.9 (2)
C2—C3—C4	121.4 (3)	C15—C14—C13	119.6 (3)
C5—C4—F2	120.7 (3)	C16—C15—C14	120.1 (3)
C5—C4—C3	120.4 (3)	C16—C15—H15	119.9
F2—C4—C3	118.9 (3)	C14—C15—H15	119.9
C4—C5—C6	119.3 (3)	C15—C16—C11	120.5 (2)
C4—C5—H5	120.3	C15—C16—H16	119.8
C6—C5—H5	120.3	C11—C16—H16	119.8
C1—C6—C5	120.3 (3)	C13—O17—C18	118.3 (2)
C1—C6—H6	119.8	O17—C18—H18A	109.5
C5—C6—H6	119.8	O17—C18—H18B	109.5
C1—N7—S8	123.2 (2)	H18A—C18—H18B	109.5
C1—N7—H7	109 (2)	O17—C18—H18C	109.5
S8—N7—H7	115 (2)	H18A—C18—H18C	109.5
O10—S8—O9	120.03 (13)	H18B—C18—H18C	109.5
O10—S8—N7	107.04 (13)	C14—O19—C20	117.3 (2)
O9—S8—N7	105.36 (14)	O19—C20—H20A	109.5
O10—S8—C11	107.51 (13)	O19—C20—H20B	109.5
O9—S8—C11	108.15 (12)	H20A—C20—H20B	109.5
N7—S8—C11	108.29 (13)	O19—C20—H20C	109.5
C16—C11—C12	119.9 (2)	H20A—C20—H20C	109.5
C16—C11—S8	120.0 (2)	H20B—C20—H20C	109.5
C12—C11—S8	120.0 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N7—H7···O17^i	0.76 (3)	2.48 (3)	3.180 (3)	155 (3)
N7—H7···O19^i	0.76 (3)	2.61 (3)	3.256 (3)	144 (3)

Symmetry code: (i) −x+2, y+1/2, −z+1/2.