N-(4-Meth­oxy-3-nitro­phen­yl)acetamide

The title compound crystallizes with a disordered nitro group in twinned crystals. In the crystal, the N—H group donates a hydrogen bond to a nitro oxygen atom, generating chains propagating in the [101] direction. The amide carbonyl oxygen atom is not involved in the hydrogen bonding.

Abstract

The title compound, C₉H₁₀N₂O₄, crystallizes with a disordered nitro group in twinned crystals. Both the meth­oxy group and the acetamide groups are nearly coplanar with the phenyl ring, and the C—N—C—O torsion angle [0.2 (4)°] is also insignificantly different from zero. Overall, the 12-atom meth­oxy­phenyl­acetamide group is nearly planar, with an r.m.s. deviation of 0.042 Å. The nitro group is twisted out of this plane by about 30°, disordered into two orientations with opposite senses of twist. In the crystal, the N—H group donates a hydrogen bond to a nitro oxygen atom, generating chains propagating in the [101] direction. The amide carbonyl oxygen atom is not involved in the hydrogen bonding.

Structure description

Belonging to the class of 4-alk­oxy­acetanilides (4-AAs), phenacetin [N-(4-eth­oxy­phen­yl)acetamide] was the first synthetic fever reducer and non-opioid analgesic to go on the market worldwide as early as the 1890s. It is generally believed that the analgesic effects of 4-AAs are due to their actions on the sensory tracts of the spinal cord, while the anti­pyretic actions arise from their actions on the brain where the temperature set point is lowered (Dalmann et al., 2015 ▸; Flower & Vane, 1972 ▸). In vivo, 4-AAs mostly undergo oxidative O-de­alkyl­ation to give N-(4-hydroxphen­yl)acetamide (Brodie & Axelrod, 1948 ▸; Kapetanović & Mieyal, 1979 ▸), the clinically relevant analgesic, while small portions may undergo de­acyl­ation, producing carcinogenic, kidney-damaging 4-alk­oxy­anilines and/or their N-oxidation products, namely, N-(4-alk­oxy­phen­yl)hydroxyl­amine and 1-alk­oxy-4-nitroso­benzene (Prescott, 1980 ▸).

There has been extensive information on phase I and phase II biotransformation of 4-AAs (Estus & Mieyal, 1983 ▸; Hinson, 1983 ▸; Kapetanović & Mieyal, 1979 ▸; Taxak et al., 2013 ▸), but little is known about their biotransformation by non-enzymatic mechanisms, including those mediated by nitric oxide-derived free radical and non-free radical oxidants (viz., nitro­gen dioxide, carbonate radical, and per­oxy­nitrous acid). Studies from our laboratory have shown, for instance, that N-(4-hy­droxy­phen­yl)acetamide forms nitrated products along with varying amounts of dimers when reacted with the said nitric oxide-derived oxidants under physiologically relevant conditions (Deere et al., 2023 ▸; Uppu & Martin, 2004 ▸). We reason that similar products (or their positional isomers) may be formed in the reactions of 4-AAs with nitric oxide-derived oxidants or other cellular oxidants like the hypochlorite/hypo­chlorous acid conjugate acid/base system (pH ≃ 7.53).

Towards better understanding of these possibilities and to shed light on mol­ecular targets, we have synthesized the title compound, C₉H₁₀N₂O₄ [N-(4-meth­oxy-3-nitro­phen­yl)acetamide]: crystals grown in water were analyzed by X-ray diffraction. Combined with the recent revelations of mechanisms of action of N-(4-hy­droxy­phen­yl)acetamide through indirect activation of CB1 receptors by 4-amino­phenol [hydrolysis product of N-(4-hy­droxy­phen­yl)acetamide] and endocannabinoid reuptake inhibitor AM404 (Bertolini et al., 2006 ▸; Zygmunt et al., 2000 ▸), the information presented here may provide useful insights into mol­ecular targets for 4-AAs and their nitrated metabolites.

The title compound, shown in Fig. 1 ▸, crystallizes with a disordered nitro group in twinned crystals. Both the meth­oxy group and the acetamide groups are nearly coplanar with the phenyl ring, with respective torsion angles 0.0 (4)° for C9—O2—C4—C5 and 4.9 (4)° for C7—N1—C1—C2. The C1—N1—C7—O1 torsion angle is also insignificantly different from zero, 0.2 (4)°. Overall, the atoms of the 12-atom meth­oxy­phenyl­acetamide group are almost coplanar with an r.m.s. deviation of 0.042 Å. The nitro group is twisted out of this plane by 23.5 (2) and 35.6 (2)°, disordered into two orientations with opposite senses of twist. The dihedral angle between the two disordered C—NO₂ planes is 59.2 (2)°. The N—H group donates inter­molecular hydrogen bonds to the nitro oxygen atom at x −  ,  − y, z −  , with an N1⋯O3A distance of 3.122 (4) Å (Table 1 ▸), thereby forming chains propagating in the [101] direction, as shown in Fig. 2 ▸. The unit cell is shown in Fig. 3 ▸. Inter­estingly, the amide carbonyl oxygen atom is not involved in the hydrogen bonding.

Figure 1.

The title mol­ecule with displacement ellipsoids drawn at the 50% probability level.

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1N⋯O3i	0.87 (3)	2.59 (3)	3.410 (5)	157 (2)
N1—H1N⋯O3A i	0.87 (3)	2.37 (3)	3.122 (4)	145 (3)

Symmetry code: (i) .

Figure 2.

The hydrogen-bonding scheme. Only one orientation of the disordered NO₂ group is shown.

Figure 3.

The unit-cell packing. Only one orientation of the disordered NO₂ group is shown.

Synthesis and crystallization

N-(4-Meth­oxy-3-nitro­phen­yl)acetamide was synthesized by the acetyl­ation of 4-meth­oxy-3-nitro­aniline using acetic anhydride. Typically, 20 mmol (3.36 g) of 4-meth­oxy-3-nitro­aniline in 30 ml of glacial acetic acid was refluxed for 2 h with 20% molar excess (24 mmol; 2.46 g) of acetic anhydride. The reaction mixture was stirred continuously during the reaction. In the end, the mixture was dried under vacuum, and the residue was purified by recrystallization twice from deionized water. Single crystals of the title compound were grown from an aqueous solution by slow cooling of a hot and nearly saturated solution.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The crystal chosen for data collection was found to be a three-component nonmerohedral twin with approximate fractions of 0.962: 0.024: 0.014. Refinement was against a twin4.hkl file prepared by TWINABS and the twin fractions were not refined.

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)	10.8740 (8), 7.0136 (6), 12.2891 (12)
β (°)	92.313 (5)
V (Å3)	936.48 (14)
Z	4
Radiation type	Cu Kα
μ (mm−1)	1.02
Crystal size (mm)	0.32 × 0.09 × 0.04
Data collection
Diffractometer	Bruker Kappa APEXII DUO CCD
Absorption correction	Multi-scan (TWINABS; Bruker, 2016 ▸)
T min, T max	0.742, 0.961
No. of measured, independent and observed [I > 2σ(I)] reflections	2937, 1675, 1360
R int	0.047
(sin θ/λ)max (Å−1)	0.607
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.059, 0.176, 1.08
No. of reflections	1675
No. of parameters	160
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.28, −0.35

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: 2253001

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

full crystallographic data

Crystal data

C9H10N2O4	F(000) = 440
Mr = 210.19	Dx = 1.491 Mg m−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54184 Å
a = 10.8740 (8) Å	Cell parameters from 3893 reflections
b = 7.0136 (6) Å	θ = 5.3–69.2°
c = 12.2891 (12) Å	µ = 1.02 mm−1
β = 92.313 (5)°	T = 90 K
V = 936.48 (14) Å3	Needle, yellow
Z = 4	0.32 × 0.09 × 0.04 mm

Data collection

Bruker Kappa APEXII DUO CCD diffractometer	1675 independent reflections
Radiation source: IµS microfocus	1360 reflections with I > 2σ(I)
QUAZAR multilayer optics monochromator	Rint = 0.047
φ and ω scans	θmax = 69.4°, θmin = 5.3°
Absorption correction: multi-scan (TWINABS; Bruker, 2016)	h = −13→13
Tmin = 0.742, Tmax = 0.961	k = −8→8
2937 measured reflections	l = −14→14

Refinement

Refinement on F2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.059	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.176	w = 1/[σ2(Fo2) + (0.0926P)2 + 0.7816P] where P = (Fo2 + 2Fc2)/3
S = 1.08	(Δ/σ)max < 0.001
1675 reflections	Δρmax = 0.28 e Å−3
160 parameters	Δρmin = −0.35 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. Twinned crystal. Refinement was vs. an HKLF4 file prepared by TWINABS. 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 of 0.95 Å for phenyl and 0.98 Å for methyl. The coordinates of the amide H atom were refined. Uiso(H) values were constrained to be 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	Occ. (<1)
O1	0.29551 (15)	0.2148 (3)	0.64386 (16)	0.0309 (5)
O2	0.84160 (14)	0.4030 (3)	0.47776 (15)	0.0291 (5)
O3	0.6667 (4)	0.4337 (10)	0.7443 (4)	0.0382 (13)	0.500 (6)
O4	0.8325 (3)	0.3096 (8)	0.6813 (4)	0.0450 (16)	0.500 (6)
O3A	0.6722 (4)	0.3056 (10)	0.7606 (3)	0.0377 (13)	0.500 (6)
O4A	0.8073 (3)	0.4813 (6)	0.6859 (3)	0.0366 (13)	0.500 (6)
N1	0.34765 (17)	0.1800 (3)	0.46794 (18)	0.0246 (5)
H1N	0.323 (3)	0.145 (4)	0.403 (3)	0.030*
N2	0.72034 (18)	0.3692 (3)	0.67532 (19)	0.0314 (6)
C1	0.4726 (2)	0.2346 (3)	0.4747 (2)	0.0248 (6)
C2	0.5355 (2)	0.2771 (3)	0.5717 (2)	0.0248 (6)
H2	0.495195	0.269873	0.638738	0.030*
C3	0.6593 (2)	0.3309 (4)	0.5696 (2)	0.0249 (6)
C4	0.7224 (2)	0.3447 (3)	0.4729 (2)	0.0252 (6)
C5	0.6570 (2)	0.2991 (4)	0.3768 (2)	0.0278 (6)
H5	0.696789	0.305718	0.309488	0.033*
C6	0.5349 (2)	0.2441 (3)	0.3779 (2)	0.0255 (6)
H6	0.492590	0.212081	0.311263	0.031*
C7	0.2676 (2)	0.1729 (3)	0.5507 (2)	0.0260 (6)
C8	0.1392 (2)	0.1083 (4)	0.5162 (2)	0.0316 (6)
H8A	0.102811	0.039286	0.576348	0.047*
H8B	0.143220	0.024068	0.452865	0.047*
H8C	0.088432	0.219750	0.497165	0.047*
C9	0.9015 (2)	0.4168 (4)	0.3751 (2)	0.0308 (6)
H9A	0.906509	0.289913	0.342208	0.046*
H9B	0.984699	0.468291	0.387608	0.046*
H9C	0.854022	0.501614	0.325949	0.046*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.0196 (9)	0.0424 (11)	0.0312 (12)	−0.0022 (7)	0.0055 (7)	0.0013 (8)
O2	0.0149 (8)	0.0369 (11)	0.0359 (11)	−0.0033 (6)	0.0060 (7)	0.0021 (8)
O3	0.036 (2)	0.052 (4)	0.027 (2)	−0.003 (2)	0.0027 (17)	−0.009 (2)
O4	0.0188 (19)	0.078 (4)	0.037 (3)	−0.0051 (18)	−0.0031 (15)	0.010 (2)
O3A	0.033 (2)	0.052 (4)	0.027 (2)	−0.0082 (19)	−0.0026 (16)	0.002 (2)
O4A	0.0236 (19)	0.048 (3)	0.039 (2)	−0.0111 (16)	0.0014 (15)	−0.0081 (18)
N1	0.0163 (10)	0.0324 (12)	0.0251 (12)	−0.0046 (7)	0.0012 (8)	−0.0011 (9)
N2	0.0188 (10)	0.0402 (13)	0.0349 (14)	−0.0045 (9)	−0.0023 (9)	0.0080 (11)
C1	0.0164 (11)	0.0231 (12)	0.0348 (15)	0.0006 (8)	0.0023 (9)	0.0026 (10)
C2	0.0172 (11)	0.0254 (13)	0.0320 (15)	−0.0010 (8)	0.0048 (9)	0.0030 (10)
C3	0.0196 (12)	0.0275 (13)	0.0276 (14)	0.0002 (9)	0.0015 (9)	0.0024 (10)
C4	0.0156 (11)	0.0237 (12)	0.0368 (16)	−0.0005 (8)	0.0061 (9)	0.0038 (10)
C5	0.0229 (12)	0.0311 (14)	0.0299 (15)	0.0003 (9)	0.0081 (10)	0.0019 (11)
C6	0.0223 (12)	0.0283 (13)	0.0261 (14)	0.0009 (9)	0.0029 (9)	−0.0028 (10)
C7	0.0177 (12)	0.0259 (13)	0.0346 (16)	0.0002 (9)	0.0019 (10)	0.0038 (10)
C8	0.0177 (12)	0.0337 (14)	0.0433 (17)	−0.0034 (9)	0.0016 (10)	−0.0016 (12)
C9	0.0192 (12)	0.0397 (15)	0.0343 (15)	−0.0022 (10)	0.0087 (10)	0.0011 (11)

Geometric parameters (Å, º)

O1—C7	1.209 (3)	C2—H2	0.9500
O2—C4	1.358 (3)	C3—C4	1.399 (3)
O2—C9	1.446 (3)	C4—C5	1.391 (4)
O3—N2	1.142 (5)	C5—C6	1.383 (3)
O4—N2	1.288 (5)	C5—H5	0.9500
O3A—N2	1.271 (5)	C6—H6	0.9500
O4A—N2	1.233 (4)	C7—C8	1.511 (3)
N1—C7	1.366 (3)	C8—H8A	0.9800
N1—C1	1.411 (3)	C8—H8B	0.9800
N1—H1N	0.87 (3)	C8—H8C	0.9800
N2—C3	1.459 (3)	C9—H9A	0.9800
C1—C2	1.383 (4)	C9—H9B	0.9800
C1—C6	1.394 (3)	C9—H9C	0.9800
C2—C3	1.400 (3)
C4—O2—C9	116.4 (2)	C6—C5—C4	120.9 (2)
C7—N1—C1	127.4 (2)	C6—C5—H5	119.5
C7—N1—H1N	119.2 (19)	C4—C5—H5	119.5
C1—N1—H1N	113.4 (19)	C5—C6—C1	121.4 (2)
O4A—N2—O3A	118.5 (3)	C5—C6—H6	119.3
O3—N2—O4	126.7 (4)	C1—C6—H6	119.3
O3—N2—C3	120.4 (3)	O1—C7—N1	123.6 (2)
O4A—N2—C3	122.0 (3)	O1—C7—C8	122.2 (2)
O3A—N2—C3	118.8 (3)	N1—C7—C8	114.3 (2)
O4—N2—C3	112.7 (3)	C7—C8—H8A	109.5
C2—C1—C6	119.0 (2)	C7—C8—H8B	109.5
C2—C1—N1	123.4 (2)	H8A—C8—H8B	109.5
C6—C1—N1	117.6 (2)	C7—C8—H8C	109.5
C1—C2—C3	119.0 (2)	H8A—C8—H8C	109.5
C1—C2—H2	120.5	H8B—C8—H8C	109.5
C3—C2—H2	120.5	O2—C9—H9A	109.5
C4—C3—C2	122.6 (2)	O2—C9—H9B	109.5
C4—C3—N2	121.5 (2)	H9A—C9—H9B	109.5
C2—C3—N2	115.9 (2)	O2—C9—H9C	109.5
O2—C4—C5	124.1 (2)	H9A—C9—H9C	109.5
O2—C4—C3	118.9 (2)	H9B—C9—H9C	109.5
C5—C4—C3	117.0 (2)
C7—N1—C1—C2	4.9 (4)	C9—O2—C4—C5	0.0 (4)
C7—N1—C1—C6	−175.6 (2)	C9—O2—C4—C3	−179.3 (2)
C6—C1—C2—C3	0.9 (4)	C2—C3—C4—O2	178.2 (2)
N1—C1—C2—C3	−179.6 (2)	N2—C3—C4—O2	−2.8 (4)
C1—C2—C3—C4	0.4 (4)	C2—C3—C4—C5	−1.1 (4)
C1—C2—C3—N2	−178.6 (2)	N2—C3—C4—C5	177.9 (2)
O3—N2—C3—C4	147.7 (4)	O2—C4—C5—C6	−178.8 (2)
O4A—N2—C3—C4	29.0 (4)	C3—C4—C5—C6	0.5 (4)
O3A—N2—C3—C4	−160.7 (4)	C4—C5—C6—C1	0.8 (4)
O4—N2—C3—C4	−37.3 (4)	C2—C1—C6—C5	−1.5 (4)
O3—N2—C3—C2	−33.3 (5)	N1—C1—C6—C5	179.0 (2)
O4A—N2—C3—C2	−152.0 (3)	C1—N1—C7—O1	0.2 (4)
O3A—N2—C3—C2	18.4 (5)	C1—N1—C7—C8	179.9 (2)
O4—N2—C3—C2	141.8 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O3i	0.87 (3)	2.59 (3)	3.410 (5)	157 (2)
N1—H1N···O3Ai	0.87 (3)	2.37 (3)	3.122 (4)	145 (3)

Symmetry code: (i) x−1/2, −y+1/2, 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.