FJ6, N-methyl-N-(4-nitro-2-phenoxy­phenyl)­methanesulfon­amide

FJ6, N-methyl-N-(4-nitro-2-phenoxy­phenyl)­methanesulfon­amide, C₁₄H₁₄N₂O₅S, is an analogue of nimesulide, a selective inhibitor of cyclo­oxy­genase-2. The structure of the title compound has been characterized to understand its inactivity towards cyclo­oxy­genase-2.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.041
• wR factor = 0.118
• Data-to-parameter ratio = 14.5

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

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S1. Comment

The crystal structure of N-(4-nitro-2-phenoxyphenyl)methanesulfonamide, nimesulide, (I), has been previously described (Dupont et al., 1995). It is reported as a selective inhibitor of cyclooxygenase-2 (COX-2) (Tavares & Bishai, 1995). In order to study the importance of the NH proton, an analogue of nimesulide, N-methyl-N-(4-nitro-2-phenoxyphenyl)methanesulfonamide, (FJ6), (II), was synthesized and its structure solved (Fig. 1). FJ6 appeared to be inactive as a COX inhibitor (Julémont, 2001). The sole difference between the two compounds is that the sulfonamide N atom is protonated in nimesulide, while it is methylated in FJ6. The molecular conformation of nimesulide is stabilized by an intramolecular N17—H···O7 hydrogen bond, not available in FJ6. As a result, the orientation of the sulfonamide group differs from that in nimesulide, while the position of the phenoxy group remains unchanged. This can be seen in the superposition of the two compounds (Fig. 2). The inactivity of FJ6 could be partly explained by this change in orientation. Indeed, the displacement of one of the O atoms of the sulfonamide group (O20) could prevent the formation of an hydrogen bond inside the COX-2 active site and consequently yield a less stable enzyme–ligand complex. Furthermore, the two methyl groups in FJ6 could lead to steric clashes in the COX-2 enzyme. Moreover, S—O bond lengths are observed to be longer in nimesulide [1.431 (2) Å] than in FJ6 [1.418 (2) Å]. This suggests that electronic delocalization is more important for the O atoms of the sulfonamide group in nimesulide than in FJ6. Thus, O atoms of nimesulide will be able to form stronger hydrogen bonds with COX-2 residues, increasing the interaction between the inhibitor and the enzyme. In conclusion, the COX inactivity of the title compound could be partially related to its sulfonamide conformation and electronic properties, different from those observed in nimesulide.

S2. Experimental

Crystal source: slow evaporation of a solution of FJ6 with methanol at 277 K gave colorless crystals suitable for X-ray analysis.

Computing details

Data collection: CAD-4 EXPRESS (Enraf-Nonius, 1992); cell refinement: CAD-4 EXPRESS; data reduction: PLATON (Spek, 2001); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON; software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. Displacement ellipsoid (50% probability) representation of FJ6.
	Fig. 2. Superposition of nimesulide (in black) and FJ6 (in grey).

N-methyl-N-(4-nitro-2-phenoxyphenyl)methanesulfonamide

Crystal data

C14H14N2O5S	F(000) = 672
Mr = 322.33	Dx = 1.423 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54178 Å
a = 14.522 (1) Å	Cell parameters from 24 reflections
b = 10.439 (1) Å	θ = 32–40°
c = 10.523 (1) Å	µ = 2.16 mm^−1
β = 109.460 (4)°	T = 293 K
V = 1504.1 (2) Å^3	Polyhedral, colorless
Z = 4	0.46 × 0.36 × 0.15 mm

Data collection

Nonius diffractometer	2747 reflections with I > 2σ(I)
Radiation source: long fine-focus sealed tube	Rint = 0.034
Graphite monochromator	θmax = 71.9°, θmin = 3.2°
ω/θ scans	h = −17→0
Absorption correction: analytical (de Meulenaer & Tompa, 1965)	k = −11→12
Tmin = 0.411, Tmax = 0.743	l = −12→12
5119 measured reflections	3 standard reflections every 200 reflections
2951 independent reflections	intensity decay: 5%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.041	H-atom parameters constrained
wR(F^2) = 0.118	w = 1/[σ^2(Fo^2) + (0.061P)^2 + 0.373P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max = 0.005
2951 reflections	Δρmax = 0.23 e Å^−3
203 parameters	Δρmin = −0.31 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0139 (8)

Special details

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

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
S19	0.09820 (3)	0.39270 (5)	0.16659 (4)	0.05765 (19)
O21	0.04416 (12)	0.27815 (16)	0.12467 (17)	0.0850 (5)
O7	0.22028 (10)	0.50640 (18)	0.50900 (13)	0.0797 (5)
O16	0.51319 (13)	0.77639 (18)	0.56081 (16)	0.0869 (5)
O15	0.55160 (14)	0.7375 (2)	0.38477 (18)	0.0973 (6)
O20	0.12730 (11)	0.4642 (2)	0.07183 (15)	0.0857 (5)
N17	0.19856 (10)	0.35423 (14)	0.28886 (15)	0.0552 (4)
N14	0.50130 (11)	0.71966 (16)	0.45550 (16)	0.0618 (4)
C10	0.42369 (11)	0.62339 (16)	0.41260 (16)	0.0491 (4)
C12$	0.33644 (13)	0.46585 (18)	0.25715 (17)	0.0542 (4)
C8	0.28922 (11)	0.52039 (17)	0.44807 (16)	0.0504 (4)
C13	0.27459 (11)	0.44752 (16)	0.33146 (15)	0.0469 (3)
C9	0.36518 (12)	0.60666 (17)	0.49095 (16)	0.0521 (4)
H9	0.3766	0.6523	0.5706	0.063*
C11	0.41069 (13)	0.55540 (19)	0.29531 (17)	0.0563 (4)
H11	0.4507	0.5695	0.2436	0.068*
C3	0.31187 (16)	0.4931 (2)	0.7455 (2)	0.0681 (5)
H3	0.3537	0.4333	0.7283	0.082*
C4	0.23891 (13)	0.54821 (19)	0.64109 (17)	0.0567 (4)
C22	0.03142 (16)	0.4925 (3)	0.2367 (3)	0.0801 (6)
H22A	0.0673	0.5701	0.2678	0.120*
H22B	0.0205	0.4496	0.3112	0.120*
H22C	−0.0302	0.5125	0.1697	0.120*
C1	0.26067 (18)	0.6124 (2)	0.9017 (2)	0.0724 (6)
H1	0.2673	0.6329	0.9903	0.087*
C2	0.32242 (18)	0.5271 (2)	0.8760 (2)	0.0719 (5)
H2	0.3724	0.4913	0.9471	0.086*
C5	0.17718 (15)	0.6381 (2)	0.6648 (2)	0.0714 (5)
H5	0.1291	0.6777	0.5942	0.086*
C6	0.18948 (18)	0.6677 (2)	0.7993 (3)	0.0796 (6)
H6	0.1478	0.7266	0.8184	0.095*
C18	0.18954 (18)	0.2569 (2)	0.3867 (3)	0.0826 (7)
H18A	0.2531	0.2380	0.4498	0.124*
H18B	0.1613	0.1801	0.3395	0.124*
H18C	0.1485	0.2894	0.4343	0.124*
H12	0.3296	0.4224	0.1782	0.071 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S19	0.0491 (3)	0.0693 (3)	0.0530 (3)	−0.00738 (17)	0.01497 (18)	−0.00689 (18)
O21	0.0707 (9)	0.0824 (10)	0.0943 (11)	−0.0200 (7)	0.0170 (8)	−0.0286 (8)
O7	0.0535 (7)	0.1426 (14)	0.0514 (7)	−0.0261 (8)	0.0286 (6)	−0.0203 (8)
O16	0.0821 (10)	0.1003 (12)	0.0759 (9)	−0.0309 (9)	0.0229 (8)	−0.0212 (8)
O15	0.0878 (11)	0.1210 (14)	0.0976 (11)	−0.0441 (10)	0.0503 (9)	−0.0093 (10)
O20	0.0648 (8)	0.1299 (14)	0.0572 (8)	−0.0108 (9)	0.0132 (6)	0.0203 (8)
N17	0.0506 (7)	0.0555 (8)	0.0597 (8)	−0.0035 (6)	0.0187 (6)	0.0047 (6)
N14	0.0523 (8)	0.0684 (9)	0.0625 (9)	−0.0063 (7)	0.0164 (7)	0.0074 (7)
C10	0.0408 (7)	0.0566 (9)	0.0484 (8)	0.0006 (6)	0.0131 (6)	0.0084 (6)
C12$	0.0517 (9)	0.0661 (10)	0.0493 (8)	0.0004 (7)	0.0227 (7)	−0.0039 (7)
C8	0.0428 (8)	0.0678 (10)	0.0434 (8)	0.0027 (7)	0.0183 (6)	0.0053 (7)
C13	0.0421 (7)	0.0529 (8)	0.0461 (8)	0.0039 (6)	0.0150 (6)	0.0061 (6)
C9	0.0467 (8)	0.0653 (10)	0.0445 (8)	0.0025 (7)	0.0155 (6)	−0.0002 (7)
C11	0.0491 (8)	0.0751 (11)	0.0511 (8)	−0.0015 (8)	0.0253 (7)	0.0046 (8)
C3	0.0701 (12)	0.0756 (12)	0.0620 (11)	0.0078 (9)	0.0268 (9)	−0.0037 (9)
C4	0.0529 (9)	0.0754 (11)	0.0493 (8)	−0.0099 (8)	0.0271 (7)	−0.0036 (8)
C22	0.0548 (11)	0.0934 (15)	0.0839 (14)	0.0104 (10)	0.0122 (10)	−0.0186 (12)
C1	0.0928 (15)	0.0701 (12)	0.0627 (11)	−0.0159 (11)	0.0371 (11)	−0.0128 (9)
C2	0.0870 (14)	0.0734 (12)	0.0548 (10)	−0.0037 (10)	0.0229 (10)	0.0033 (9)
C5	0.0615 (11)	0.0752 (12)	0.0790 (13)	0.0038 (9)	0.0254 (10)	0.0055 (10)
C6	0.0859 (15)	0.0712 (13)	0.0953 (16)	0.0028 (11)	0.0484 (13)	−0.0201 (12)
C18	0.0760 (13)	0.0714 (13)	0.0967 (16)	−0.0074 (10)	0.0239 (12)	0.0275 (11)

Geometric parameters (Å, º)

S19—O21	1.4177 (15)	C11—H11	0.9300
S19—O20	1.4183 (16)	C3—C4	1.373 (3)
S19—N17	1.6405 (15)	C3—C2	1.376 (3)
S19—C22	1.745 (2)	C3—H3	0.9300
O7—C8	1.3647 (19)	C4—C5	1.377 (3)
O7—C4	1.395 (2)	C22—H22A	0.9600
O16—N14	1.217 (2)	C22—H22B	0.9600
O15—N14	1.218 (2)	C22—H22C	0.9600
N17—C13	1.428 (2)	C1—C6	1.349 (3)
N17—C18	1.484 (2)	C1—C2	1.353 (3)
N14—C10	1.465 (2)	C1—H1	0.9300
C10—C9	1.378 (2)	C2—H2	0.9300
C10—C11	1.381 (3)	C5—C6	1.400 (3)
C12$—C11	1.382 (3)	C5—H5	0.9300
C12$—C13	1.387 (2)	C6—H6	0.9300
C12$—H12	0.9229	C18—H18A	0.9600
C8—C9	1.378 (2)	C18—H18B	0.9600
C8—C13	1.399 (2)	C18—H18C	0.9600
C9—H9	0.9300
O21—S19—O20	119.28 (11)	C4—C3—C2	119.3 (2)
O21—S19—N17	107.01 (9)	C4—C3—H3	120.3
O20—S19—N17	106.58 (8)	C2—C3—H3	120.3
O21—S19—C22	107.87 (12)	C3—C4—C5	121.05 (18)
O20—S19—C22	108.71 (13)	C3—C4—O7	120.55 (18)
N17—S19—C22	106.74 (10)	C5—C4—O7	118.18 (18)
C8—O7—C4	120.37 (13)	S19—C22—H22A	109.5
C13—N17—C18	119.16 (15)	S19—C22—H22B	109.5
C13—N17—S19	118.12 (11)	H22A—C22—H22B	109.5
C18—N17—S19	116.83 (13)	S19—C22—H22C	109.5
O16—N14—O15	123.36 (17)	H22A—C22—H22C	109.5
O16—N14—C10	118.41 (15)	H22B—C22—H22C	109.5
O15—N14—C10	118.22 (16)	C6—C1—C2	120.3 (2)
C9—C10—C11	122.79 (16)	C6—C1—H1	119.8
C9—C10—N14	117.85 (15)	C2—C1—H1	119.8
C11—C10—N14	119.35 (15)	C1—C2—C3	120.5 (2)
C11—C12$—C13	121.26 (16)	C1—C2—H2	119.7
C11—C12$—H12	115.7	C3—C2—H2	119.7
C13—C12$—H12	123.0	C4—C5—C6	117.5 (2)
O7—C8—C9	123.26 (16)	C4—C5—H5	121.2
O7—C8—C13	115.68 (15)	C6—C5—H5	121.2
C9—C8—C13	120.91 (14)	C1—C6—C5	121.2 (2)
C12$—C13—C8	118.82 (15)	C1—C6—H6	119.4
C12$—C13—N17	119.71 (15)	C5—C6—H6	119.4
C8—C13—N17	121.46 (14)	N17—C18—H18A	109.5
C10—C9—C8	118.21 (15)	N17—C18—H18B	109.5
C10—C9—H9	120.9	H18A—C18—H18B	109.5
C8—C9—H9	120.9	N17—C18—H18C	109.5
C10—C11—C12$	117.94 (15)	H18A—C18—H18C	109.5
C10—C11—H11	121.0	H18B—C18—H18C	109.5
C12$—C11—H11	121.0
O21—S19—N17—C13	168.05 (13)	C18—N17—C13—C8	−51.1 (2)
O20—S19—N17—C13	39.39 (16)	S19—N17—C13—C8	101.08 (16)
C22—S19—N17—C13	−76.65 (16)	C11—C10—C9—C8	−1.6 (3)
O21—S19—N17—C18	−39.15 (18)	N14—C10—C9—C8	177.13 (15)
O20—S19—N17—C18	−167.82 (17)	O7—C8—C9—C10	−172.45 (16)
C22—S19—N17—C18	76.14 (18)	C13—C8—C9—C10	2.9 (2)
O16—N14—C10—C9	3.0 (2)	C9—C10—C11—C12$	−0.9 (3)
O15—N14—C10—C9	−178.01 (18)	N14—C10—C11—C12$	−179.59 (16)
O16—N14—C10—C11	−178.23 (17)	C13—C12$—C11—C10	2.2 (3)
O15—N14—C10—C11	0.7 (3)	C2—C3—C4—C5	0.9 (3)
C4—O7—C8—C9	−20.3 (3)	C2—C3—C4—O7	−173.58 (18)
C4—O7—C8—C13	164.13 (17)	C8—O7—C4—C3	−63.9 (3)
C11—C12$—C13—C8	−0.9 (3)	C8—O7—C4—C5	121.5 (2)
C11—C12$—C13—N17	179.91 (16)	C6—C1—C2—C3	−1.8 (3)
O7—C8—C13—C12$	173.96 (16)	C4—C3—C2—C1	1.1 (3)
C9—C8—C13—C12$	−1.7 (2)	C3—C4—C5—C6	−2.2 (3)
O7—C8—C13—N17	−6.9 (2)	O7—C4—C5—C6	172.44 (19)
C9—C8—C13—N17	177.49 (15)	C2—C1—C6—C5	0.4 (4)
C18—N17—C13—C12$	128.11 (19)	C4—C5—C6—C1	1.5 (3)
S19—N17—C13—C12$	−79.74 (18)