N-(4-Meth­oxy-2-nitro­phen­yl)acetamide

In the title compound, the pendant groups differ in their divergence from coplanarity with the central ring.

Abstract

In the title compound, C₉H₁₀N₂O₄, the three substituents vary in the degree of lack of planarity with the central phenyl ring. The meth­oxy group is nearest to being coplanar, with a C—C—O—C torsion angle of 6.1 (5)°. The nitro group is less coplanar, with a 12.8 (5)° twist about the C—N bond and the acetamido group is considerably less coplanar with the central ring, having a 25.4 (5)° twist about the C—N bond to the ring. The NH group forms an intra­molecular N—H⋯O hydrogen bond to a nitro-group O atom.

Structure description

The analgesic use of 4-alk­oxy­acetanilides, in particular 4-eth­oxy­acetanilide or 4-EA, predates the First World War. 4-Hy­droxy­acetanilide (popularly known as Tylenol or acetamino­phen) and 4-EA were introduced into the markets at around the same time; however, 4-EA was withdrawn from sale some decades ago due to its carcinogenic and kidney-damaging properties (Dubach et al., 1983 ▸; Nakanishi et al., 1982 ▸). Although there has been extensive information on phase I and phase II biotransformation of 4-alk­oxy­acetanilides (Hinson, 1983 ▸; Kapetanović et al., 1979 ▸; Mulder et al., 1984 ▸; Veronese et al., 1985 ▸), little or no information is available on nitrated or other oxidation products that could be formed in reactions with cellular oxidants, such as hypochlorite (⁻OCl)/hypo­chlorous acid (HOCl; pK _a ≃ 7.53) and per­oxy­nitrite (ONOO⁻)/per­oxy­nitrous acid (ONOOH; pK _a ≃ 6.2; ONOOH and ONOO⁻ are collectively referred to as per­oxy­nitrite or PN). We have shown, for instance, that 4-hy­droxy­acetanilide forms nitrated and chlorinated products along with varying amounts of dimers when reacted with HOCl/⁻OCl and PN/CO₂ under physiologically relevant conditions (Uppu & Martin, 2005 ▸; Deere et al., 2022 ▸). We suspect that similar products (or their positional isomers) may be formed in the reactions of 4-alk­oxy­acetanilides with the cellular oxidants referenced above. Towards a better understanding of this and to shed light on mol­ecular targets (Bertolini et al., 2006 ▸), we have synthesized the title compound, C₉H₁₀N₂O₄: single crystals grown from aqueous solution were analyzed by X-ray diffraction.

The title compound is shown in Fig. 1 ▸. It is significantly non-planar, and its deviation from planarity may be described by torsion angles about bonds from the central C1–C6 phenyl ring to the three substituents. The meth­oxy group is nearest to being coplanar, with a C9—O2—C4–C3 torsion angle of 6.1 (5)°. The nitro group deviates more from coplanarity with the central ring, with the O3—N2—C2—C1 torsion angle being −12.8 (5)°. The acetamido group is considerably less coplanar with the central ring, with a C7—N1—C1—C6 torsion angle of 25.4 (5)°. These deviations are similar to those seen in the analogous 4-eth­oxy compound (Uppu et al., 2020 ▸), in which the corresponding torsion angles are 0.56 (12), −14.94 (13) and 18.23 (15)°, respectively. N-(4-Hy­droxy-2-nitro­phen­yl)acetamide (Hines et al., 2022 ▸) is considerably more planar, with torsion angles to the nitro group and to the acetamido group being −0.79 (19) and 3.1 (2)°, respectively, likely as a result of inter­molecular hydrogen bonding by the OH group. The structure of N-(4-hy­droxy-3-nitro­phen­yl)acetamide, in which the OH group likewise participates in inter­molecular hydrogen bonding, has also been reported (Salahifar et al., 2015 ▸; Deere et al., 2019 ▸). It is also more planar than the title compound, with a torsion angle of −11.8 (2)° for the nitro group and 9.0 (2)° for the acetamido group. An intra­molecular N1—H1N⋯O3 hydrogen bond (Table 1 ▸) is observed in the title compound.

Figure 1.

The title mol­ecule with 50% displacement ellipsoids with the intra­molecular N—H⋯O hydrogen bond shown as a blue dashed line.

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1N⋯O3	0.87 (5)	1.92 (5)	2.632 (4)	137 (4)
C5—H5⋯O2i	0.95	2.48	3.418 (4)	171
C6—H6⋯O1	0.95	2.30	2.864 (4)	117
C8—H8B⋯O3ii	0.98	2.64	3.578 (4)	160
C8—H8C⋯O4iii	0.98	2.63	3.546 (4)	156

Symmetry codes: (i) ; (ii) ; (iii) .

The unit cell of the title compound is shown in Figs. 2 ▸ and 3 ▸. The closest inter­molecular contact is C5—H5⋯O2 (at 1 − x, −y, 1 − z), forming dimers about inversion centers with a C⋯O distance of 3.418 (4) Å and 171° angle about H. Mol­ecules form a herringbone pattern in the [101] direction with alternate phenyl rings forming a dihedral angle of 65.7 (2)°.

Figure 2.

The unit cell, viewed down the [010] direction, showing intra­molecular hydrogen bonds.

Figure 3.

The unit cell, viewed down the [101] direction. H atoms are not shown.

Synthesis and crystallization

N-(4-Meth­oxy-2-nitro­phen­yl)acetamide was synthesized by acetyl­ation of 4-meth­oxy-2-nitro­aniline using acetic anhydride in acetic acid solvent: 3.36 g (20 mmol) of 4-meth­oxy-2-nitro­aniline in 30 ml of glacial acetic was allowed to react with 2.46 g (24 mmol) of acetic anhydride for 18 h at room temperature. The reaction mixture was stirred continuously during the reaction. In the end, the mixture was dried under vacuum, and the N-(4-meth­oxy-2-nitro­phen­yl)acetamide in the residue was purified by recrystallization twice from aqueous solution. Single crystals in the form of yellow laths were grown in water by slow cooling of a hot and nearly saturated solution of the title compound.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸.

Table 2. Experimental details.

Crystal data
Chemical formula	C9H10N2O4
M r	210.19
Crystal system, space group	Monoclinic, P21/n
Temperature (K)	90
a, b, c (Å)	14.8713 (7), 3.9563 (2), 17.2057 (9)
β (°)	114.051 (3)
V (Å3)	924.42 (8)
Z	4
Radiation type	Cu Kα
μ (mm−1)	1.03
Crystal size (mm)	0.42 × 0.06 × 0.01
Data collection
Diffractometer	Bruker Kappa APEXII DUO CCD
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 ▸)
T min, T max	0.692, 0.990
No. of measured, independent and observed [I > 2σ(I)] reflections	11516, 1638, 1211
R int	0.122
(sin θ/λ)max (Å−1)	0.595
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.071, 0.203, 1.09
No. of reflections	1638
No. of parameters	141
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.24, −0.27

Computer programs: APEX2 and SAINT (Bruker, 2016 ▸), SHELXT2014/5 (Sheldrick, 2008 ▸), SHELXL2017/1 (Sheldrick, 2015 ▸), Mercury (Macrae et al., 2020 ▸), and publCIF (Westrip, 2010 ▸).

Supplementary Material

CCDC reference: 2157748

Additional supporting information: crystallographic information; 3D view; checkCIF report

full crystallographic data

Crystal data

C9H10N2O4	F(000) = 440
Mr = 210.19	Dx = 1.510 Mg m−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54184 Å
a = 14.8713 (7) Å	Cell parameters from 2102 reflections
b = 3.9563 (2) Å	θ = 3.3–66.3°
c = 17.2057 (9) Å	µ = 1.03 mm−1
β = 114.051 (3)°	T = 90 K
V = 924.42 (8) Å3	Lath, yellow
Z = 4	0.42 × 0.06 × 0.01 mm

Data collection

Bruker Kappa APEXII DUO CCD diffractometer	1638 independent reflections
Radiation source: IµS microfocus	1211 reflections with I > 2σ(I)
QUAZAR multilayer optics monochromator	Rint = 0.122
φ and ω scans	θmax = 66.7°, θmin = 3.3°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −17→17
Tmin = 0.692, Tmax = 0.990	k = −4→4
11516 measured reflections	l = −20→20

Refinement

Refinement on F2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.071	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.203	w = 1/[σ2(Fo2) + 0.298P] where P = (Fo2 + 2Fc2)/3
S = 1.09	(Δ/σ)max < 0.001
1638 reflections	Δρmax = 0.24 e Å−3
141 parameters	Δρmin = −0.27 e Å−3

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.

Refinement. All H atoms were located in difference maps and those on C were thereafter treated as riding in geometrically idealized positions with C—H distances 0.95 Å for phenyl and 0.98 Å for methyl. Coordinates of the N—H hydrogen atom were refined. Uiso(H) values were assigned as 1.2Ueq for the attached atom (1.5 for methyl).

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

	x	y	z	Uiso*/Ueq
O1	0.58485 (18)	0.7604 (7)	0.81731 (16)	0.0512 (7)
O2	0.36866 (18)	0.2368 (6)	0.43490 (15)	0.0455 (6)
O3	0.23210 (18)	0.9412 (7)	0.67288 (16)	0.0529 (7)
O4	0.16683 (18)	0.9595 (6)	0.53559 (16)	0.0480 (7)
N1	0.4165 (2)	0.7462 (7)	0.75182 (18)	0.0447 (7)
H1N	0.363 (4)	0.830 (11)	0.753 (3)	0.054*
N2	0.2326 (2)	0.8718 (7)	0.60286 (18)	0.0416 (7)
C1	0.4018 (3)	0.6185 (9)	0.6716 (2)	0.0428 (8)
C2	0.3144 (2)	0.6751 (8)	0.5992 (2)	0.0420 (8)
C3	0.3005 (2)	0.5555 (8)	0.5182 (2)	0.0415 (8)
H3A	0.241073	0.602472	0.470197	0.050*
C4	0.3736 (3)	0.3699 (8)	0.5092 (2)	0.0417 (8)
C5	0.4605 (3)	0.3057 (8)	0.5806 (2)	0.0431 (8)
H5	0.511084	0.176401	0.574482	0.052*
C6	0.4740 (3)	0.4264 (9)	0.6593 (2)	0.0442 (8)
H6	0.533915	0.378381	0.706654	0.053*
C7	0.5054 (3)	0.8178 (8)	0.8187 (2)	0.0435 (8)
C8	0.4928 (3)	0.9743 (9)	0.8926 (2)	0.0475 (8)
H8A	0.473964	0.799894	0.923540	0.071*
H8B	0.441299	1.147414	0.872021	0.071*
H8C	0.554993	1.078496	0.930706	0.071*
C9	0.2843 (3)	0.3245 (9)	0.3589 (2)	0.0488 (9)
H9A	0.224837	0.228708	0.361637	0.073*
H9B	0.292327	0.233462	0.309172	0.073*
H9C	0.278101	0.571021	0.354165	0.073*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.0331 (14)	0.0634 (15)	0.0497 (14)	0.0015 (10)	0.0093 (11)	−0.0066 (11)
O2	0.0413 (14)	0.0494 (13)	0.0439 (13)	−0.0005 (10)	0.0154 (10)	−0.0013 (10)
O3	0.0419 (14)	0.0706 (16)	0.0434 (14)	0.0026 (12)	0.0145 (11)	−0.0053 (11)
O4	0.0361 (13)	0.0553 (14)	0.0444 (13)	0.0047 (10)	0.0079 (10)	0.0026 (10)
N1	0.0398 (17)	0.0513 (16)	0.0424 (15)	0.0000 (12)	0.0162 (13)	0.0006 (12)
N2	0.0308 (15)	0.0463 (15)	0.0425 (16)	−0.0030 (11)	0.0097 (13)	−0.0028 (12)
C1	0.0376 (18)	0.0453 (17)	0.0429 (18)	−0.0019 (13)	0.0140 (15)	0.0030 (13)
C2	0.0354 (18)	0.0430 (17)	0.0458 (19)	−0.0024 (13)	0.0148 (15)	0.0032 (13)
C3	0.0342 (17)	0.0411 (17)	0.0432 (17)	−0.0037 (13)	0.0095 (14)	0.0033 (13)
C4	0.0381 (18)	0.0425 (17)	0.0446 (18)	−0.0025 (13)	0.0170 (15)	−0.0011 (13)
C5	0.0331 (18)	0.0454 (17)	0.0469 (19)	−0.0008 (13)	0.0125 (15)	−0.0009 (14)
C6	0.0366 (18)	0.0437 (17)	0.0495 (19)	0.0007 (13)	0.0146 (15)	0.0033 (14)
C7	0.0342 (19)	0.0449 (17)	0.0452 (18)	−0.0005 (13)	0.0099 (15)	0.0039 (13)
C8	0.0412 (19)	0.0501 (19)	0.0462 (18)	0.0005 (15)	0.0126 (15)	−0.0017 (15)
C9	0.045 (2)	0.0517 (19)	0.0416 (18)	0.0030 (15)	0.0089 (16)	−0.0008 (14)

Geometric parameters (Å, º)

O1—C7	1.214 (4)	C3—H3A	0.9500
O2—C4	1.357 (4)	C4—C5	1.395 (5)
O2—C9	1.438 (4)	C5—C6	1.371 (5)
O3—N2	1.239 (4)	C5—H5	0.9500
O4—N2	1.222 (4)	C6—H6	0.9500
N1—C7	1.383 (5)	C7—C8	1.492 (5)
N1—C1	1.401 (5)	C8—H8A	0.9800
N1—H1N	0.87 (5)	C8—H8B	0.9800
N2—C2	1.467 (4)	C8—H8C	0.9800
C1—C6	1.400 (5)	C9—H9A	0.9800
C1—C2	1.405 (5)	C9—H9B	0.9800
C2—C3	1.404 (5)	C9—H9C	0.9800
C3—C4	1.372 (5)
C4—O2—C9	117.1 (3)	C6—C5—H5	119.5
C7—N1—C1	127.4 (3)	C4—C5—H5	119.5
C7—N1—H1N	118 (3)	C5—C6—C1	121.7 (3)
C1—N1—H1N	113 (3)	C5—C6—H6	119.1
O4—N2—O3	122.6 (3)	C1—C6—H6	119.1
O4—N2—C2	117.9 (3)	O1—C7—N1	123.6 (3)
O3—N2—C2	119.6 (3)	O1—C7—C8	123.8 (3)
C6—C1—N1	121.6 (3)	N1—C7—C8	112.7 (3)
C6—C1—C2	116.2 (3)	C7—C8—H8A	109.5
N1—C1—C2	122.2 (3)	C7—C8—H8B	109.5
C3—C2—C1	122.4 (3)	H8A—C8—H8B	109.5
C3—C2—N2	115.6 (3)	C7—C8—H8C	109.5
C1—C2—N2	122.0 (3)	H8A—C8—H8C	109.5
C4—C3—C2	119.2 (3)	H8B—C8—H8C	109.5
C4—C3—H3A	120.4	O2—C9—H9A	109.5
C2—C3—H3A	120.4	O2—C9—H9B	109.5
O2—C4—C3	124.9 (3)	H9A—C9—H9B	109.5
O2—C4—C5	115.7 (3)	O2—C9—H9C	109.5
C3—C4—C5	119.4 (3)	H9A—C9—H9C	109.5
C6—C5—C4	121.0 (3)	H9B—C9—H9C	109.5
C7—N1—C1—C6	25.4 (5)	C9—O2—C4—C3	6.1 (5)
C7—N1—C1—C2	−154.6 (3)	C9—O2—C4—C5	−174.3 (3)
C6—C1—C2—C3	−1.8 (5)	C2—C3—C4—O2	179.1 (3)
N1—C1—C2—C3	178.2 (3)	C2—C3—C4—C5	−0.4 (5)
C6—C1—C2—N2	180.0 (3)	O2—C4—C5—C6	−179.9 (3)
N1—C1—C2—N2	−0.1 (5)	C3—C4—C5—C6	−0.3 (5)
O4—N2—C2—C3	−10.9 (4)	C4—C5—C6—C1	−0.1 (5)
O3—N2—C2—C3	168.8 (3)	N1—C1—C6—C5	−178.9 (3)
O4—N2—C2—C1	167.5 (3)	C2—C1—C6—C5	1.1 (5)
O3—N2—C2—C1	−12.8 (5)	C1—N1—C7—O1	−3.9 (6)
C1—C2—C3—C4	1.5 (5)	C1—N1—C7—C8	175.8 (3)
N2—C2—C3—C4	179.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O3	0.87 (5)	1.92 (5)	2.632 (4)	137 (4)
C5—H5···O2i	0.95	2.48	3.418 (4)	171
C6—H6···O1	0.95	2.30	2.864 (4)	117
C8—H8B···O3ii	0.98	2.64	3.578 (4)	160
C8—H8C···O4iii	0.98	2.63	3.546 (4)	156

Symmetry codes: (i) −x+1, −y, −z+1; (ii) −x+1/2, y+1/2, −z+3/2; (iii) x+1/2, −y+5/2, z+1/2.

Funding Statement

The authors acknowledge the support from the National Institutes of Health (NIH) through the National Institute of General Medical Science (NIGMS) grant No. 5 P2O GM103424–17 and the US Department of Education (US DoE; Title III, HBGI Part B grant No. P031B040030). Its contents are solely the responsibility of authors and do not represent the official views of NIH, NIGMS, or US DoE. The upgrade of the diffractometer was made possible by grant No. LEQSF(2011–12)-ENH-TR-01, administered by the Louisiana Board of Regents