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

Hines III, J.E.; Agu, O.A.; Deere, C.J.; Fronczek, F.R.; Uppu, R.M.

doi:10.1107/S2414314623002985

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 8| Part 4| April 2023| x230298

https://doi.org/10.1107/S2414314623002985

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

James E. Hines III,^a Ogad A. Agu,^a Curtistine J. Deere,^a Frank R. Fronczek ^b and Rao M. Uppu ^a ^*

^aDepartment of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA 70813, USA, and ^bDepartment of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
^*Correspondence e-mail: rao_uppu@subr.edu

Edited by W. T. A. Harrison, University of Aberdeen, United Kingdom (Received 29 March 2023; accepted 30 March 2023; online 4 April 2023)

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.

Keywords: N-alkoxyacetanilides; phenacetin congeners; nitro products; crystal structure; hydrogen bonding.

CCDC reference: 2253001

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 − $[{1\over 2}]$ , $[{1\over 2}]$ − y, z − $[{1\over 2}]$ , 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.

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⋯O3Aⁱ	0.87 (3)	2.37 (3)	3.122 (4)	145 (3)
Symmetry code: (i) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

Figure 1
The title molecule with displacement ellipsoids drawn at the 50% probability level.

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[F² > 2σ(F²)], wR(F²), 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
Δρ_max, Δρ_min (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 ).

Structural data

CCDC reference: 2253001

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314623002985/hb4429sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314623002985/hb4429Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314623002985/hb4429Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014/5 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2017/1 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2020); software used to prepare material for publication: publCIF (Westrip, 2010).

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

Crystal data top

C₉H₁₀N₂O₄	F(000) = 440
M_r = 210.19	D_x = 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 top

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

Refinement top

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(F_o²) + (0.0926P)² + 0.7816P] where P = (F_o² + 2F_c²)/3
S = 1.08	(Δ/σ)_max < 0.001
1675 reflections	Δρ_max = 0.28 e Å⁻³
160 parameters	Δρ_min = −0.35 e Å⁻³

Special details top

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. U_iso(H) values were constrained to be 1.2U_eq for the attached atom (1.5 for methyl).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq	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 (Å²) top

	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) top

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) top

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 information

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.

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