N-(4-Eth­oxy-2,5-di­nitro­phen­yl)acetamide

Uppu, S.N.; Agu, O.A.; Deere, C.J.; Fronczek, F.R.

doi:10.1107/S2414314620011219

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 5| Part 8| August 2020| x201121

https://doi.org/10.1107/S2414314620011219

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N-(4-Ethoxy-2,5-dinitrophenyl)acetamide

Sannihith N. Uppu,^a,^b ^* Ogad A. Agu,^b Curtistine J. Deere ^b and Frank R. Fronczek ^c

^aDepartment of Biological Engineering, Louisiana State University, Baton Rouge, LA, 70803, USA, ^bDepartment of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA, and ^cDepartment of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
^*Correspondence e-mail: suppu3@lsu.edu

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 6 August 2020; accepted 16 August 2020; online 28 August 2020)

In the title compound, C₁₀H₁₁N₃O₆, the torsion angles about the bonds to the benzene ring are less than 4°, except for the nitro groups, which are twisted out of the ring plane by 25.27 (3) and 43.63 (2)°. The N—H group forms a bifurcated hydrogen bond, with an intramolecular component to a nitro group O atom and an intermolecular component to the other nitro group, thereby forming chains propagating in the [010] direction. Several weak C—H⋯O interactions are also present.

Keywords: crystal structure; nitrated phenacetin; hydrogen bonding.

CCDC reference: 2023527

Structure description

The analgesic use of 4-acetamidophenetole (4-AcP) predates the First World War. 4-AcP was likely the first synthetic chemical to go on the market as a fever reducer, but was withdrawn from global markets three decades ago due to its carcinogenic and kidney-damaging properties (Zeman, 1963 ; Carrociampi, 1978 ; Leistenschneider et al., 1983 ; Holmäng et al., 2013 ). However, in view of 4-AcP's physical appearance and textural similarities to cocaine, in recent years, there have been several instances of 4-AcP being used as an adulterant or cutting agent (Broséus et al., 2016 ). Thus, phenacetin is still in use, however, now in the form of an illicit drug. We believe that 4-AcP, like its putative major metabolite, 4-acetamidophenol (4-AP) (Hinson, 1983 ; Lakshmi et al., 2000 ; Liu et al., 2019 ), undergoes oxidative transformation by cellular oxidants such as hypochlorite/hypochlorous acid and peroxynitrite/peroxynitrous acid and forms chlorinated and nitrated products. Towards understanding this and to shed light on molecular targets, we have synthesized the title compound 2,5-dinitro-4-AcP, C₁₀H₁₁N₃O₆, and we now report its structure. The results of the present study, together with the recent understanding of the mechanisms of action of 4-acetamidophenol (4-AP), which proceeds through hydrolysis and subsequent formation of arachidonic acid conjugates and their binding cannabinoid receptors, may be useful in providing insights into molecular targets for 4-AcP and its metabolites.

The ethoxy group is nearly coplanar with the phenyl ring, having a C2—C1—O1—C7 torsion angle of 1.43 (8)° and C1—O1—C7—C8(Me) torsion angle of 174.56 (5)°, as shown in Fig. 1. The acetamido group is also nearly coplanar with the phenyl ring, having a C5—C4—N2—C9 torsion angle of 3.18 (9)°. The N1/O2/O3 nitro group adjacent to the acetamido substituent is twisted out of the phenyl plane by 25.27 (3)°, and the N3/O5/O6 group adjacent to the ethoxy group forms a dihedral angle of 43.63 (2)° with respect to the C1–C6 ring.

Figure 1
The title molecule showing 50% displacement ellipsoids.

The N2—H2N group forms a bifurcated hydrogen bond (Table 1), with an intramolecular component to the adjacent nitro group [N2⋯O3 = 2.6875 (6) Å] and a longer intermolecular component to the other nitro group [N2⋯O6ⁱ = 3.4308 (6) Å; symmetry code: (i) x, y + 1, z], forming chains propagating in the [010] direction, as shown in Fig. 2. Several C—H⋯O interactions are also present (Table 1), which together with the N—H⋯O hydrogen bond lead to (100) sheets.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2N⋯O3	0.900 (10)	2.015 (10)	2.6875 (6)	130.5 (8)
N2—H2N⋯O6ⁱ	0.900 (10)	2.618 (10)	3.4308 (6)	150.5 (8)
C5—H5A⋯O4	0.95	2.20	2.8386 (7)	123
C8—H8A⋯O2ⁱⁱ	0.98	2.63	3.3768 (9)	133
C10—H10A⋯O2ⁱⁱⁱ	0.98	2.37	3.3367 (7)	171
C10—H10B⋯O5ⁱ	0.98	2.65	3.5677 (8)	155
Symmetry codes: (i) x, y+1, z; (ii) x, y-1, z; (iii) x, y, z+1.

Figure 2
The unit cell viewed down [100], showing hydrogen bonds as blue lines. C—H hydrogen atoms are not shown.

Synthesis and crystallization

2,5-Dinitro-4-AcP was synthesized by nitration of 4-AcP using nitric acid–sulfuric acid mixtures (0–5°C) and subsequent purification by column chromatography on alumina or silica gel as described by Russell et al. (1990 ). Yellow needles were grown by slow evaporation from methanol solution.

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₁₀H₁₁N₃O₆
M_r	269.22
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	90
a, b, c (Å)	6.7463 (3), 9.0360 (4), 9.3954 (4)
α, β, γ (°)	81.005 (2), 85.099 (2), 88.700 (2)
V (Å³)	563.60 (4)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.13
Crystal size (mm)	0.30 × 0.10 × 0.09

Data collection
Diffractometer	Bruker Kappa APEXII DUO CCD
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.920, 0.988
No. of measured, independent and observed [I > 2σ(I)] reflections	29518, 7110, 5824
R_int	0.043
(sin θ/λ)_max (Å⁻¹)	0.911

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.111, 1.04
No. of reflections	7110
No. of parameters	177
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.76, −0.28
Computer programs: APEX3 and SAINT (Bruker, 2016 ), SHELXS97 (Sheldrick, 2008 ), SHELXL2017/1 (Sheldrick, 2015 ), Mercury (Macrae et al., 2020 ) and publCIF (Westrip, 2010 ).

Structural data

CCDC reference: 2023527

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314620011219/hb4359sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314620011219/hb4359Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314620011219/hb4359Isup3.cml

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXS97 (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-Ethoxy-2,5-dinitrophenyl)acetamide top

Crystal data top

C₁₀H₁₁N₃O₆	Z = 2
M_r = 269.22	F(000) = 280
Triclinic, P1	D_x = 1.586 Mg m⁻³
a = 6.7463 (3) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.0360 (4) Å	Cell parameters from 9965 reflections
c = 9.3954 (4) Å	θ = 3.0–40.2°
α = 81.005 (2)°	µ = 0.13 mm⁻¹
β = 85.099 (2)°	T = 90 K
γ = 88.700 (2)°	Needle, yellow
V = 563.60 (4) Å³	0.30 × 0.10 × 0.09 mm

Data collection top

Bruker Kappa APEXII DUO CCD diffractometer	7110 independent reflections
Radiation source: fine-focus sealed tube	5824 reflections with I > 2σ(I)
TRIUMPH curved graphite monochromator	R_int = 0.043
φ and ω scans	θ_max = 40.4°, θ_min = 2.2°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −11→12
T_min = 0.920, T_max = 0.988	k = −15→16
29518 measured reflections	l = −17→15

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.038	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.111	w = 1/[σ²(F_o²) + (0.0597P)² + 0.0585P] where P = (F_o² + 2F_c²)/3
S = 1.04	(Δ/σ)_max = 0.001
7110 reflections	Δρ_max = 0.76 e Å⁻³
177 parameters	Δρ_min = −0.28 e Å⁻³
0 restraints

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. 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, 0.99 Å for CH₂ and 0.98 Å for methyl. Coordinates of the N—H hydrogen atom were refined. U_iso(H) values were assigned as 1.2U_eq for the attached C or N atom (1.5 for methyl).

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

	x	y	z	U_iso*/U_eq
O1	0.69178 (7)	0.25306 (4)	0.22213 (4)	0.01208 (7)
O2	0.80562 (9)	0.79863 (5)	0.13502 (5)	0.02166 (10)
O3	0.94649 (7)	0.84282 (5)	0.32212 (5)	0.01549 (8)
O4	0.74286 (8)	0.55569 (5)	0.80156 (5)	0.01579 (8)
O5	0.54980 (7)	0.15057 (5)	0.63040 (5)	0.01655 (9)
O6	0.76371 (8)	0.07153 (5)	0.47211 (5)	0.01675 (9)
N1	0.84988 (7)	0.76273 (5)	0.25917 (5)	0.01119 (8)
N2	0.78930 (7)	0.69046 (5)	0.57358 (5)	0.01020 (7)
H2N	0.8235 (15)	0.7816 (11)	0.5253 (10)	0.012*
N3	0.66942 (7)	0.17087 (5)	0.52301 (5)	0.01052 (7)
C1	0.72020 (8)	0.36104 (5)	0.30173 (5)	0.00923 (8)
C2	0.76108 (8)	0.50980 (6)	0.24458 (5)	0.00986 (8)
H2A	0.768693	0.540555	0.142853	0.012*
C3	0.79085 (8)	0.61374 (5)	0.33497 (5)	0.00893 (8)
C4	0.77060 (7)	0.58036 (5)	0.48682 (5)	0.00857 (8)
C5	0.72406 (7)	0.43112 (5)	0.54384 (5)	0.00912 (8)
H5A	0.705143	0.401790	0.645627	0.011*
C6	0.70546 (7)	0.32621 (5)	0.45315 (5)	0.00893 (8)
C7	0.71005 (9)	0.29652 (6)	0.06650 (6)	0.01309 (9)
H7A	0.840288	0.344280	0.034497	0.016*
H7B	0.603451	0.368885	0.036447	0.016*
C8	0.69258 (11)	0.15636 (7)	0.00051 (7)	0.01860 (11)
H8A	0.799779	0.086200	0.030043	0.028*
H8B	0.702903	0.181958	−0.105121	0.028*
H8C	0.563670	0.109681	0.033650	0.028*
C9	0.77619 (8)	0.67490 (6)	0.72252 (5)	0.01021 (8)
C10	0.80679 (9)	0.81975 (6)	0.77720 (6)	0.01351 (9)
H10A	0.805013	0.800989	0.882891	0.020*
H10B	0.699950	0.890571	0.748418	0.020*
H10C	0.935357	0.862121	0.735925	0.020*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.01876 (18)	0.00903 (15)	0.00891 (14)	−0.00178 (12)	−0.00191 (12)	−0.00211 (11)
O2	0.0418 (3)	0.01400 (18)	0.00889 (16)	−0.00649 (18)	−0.00647 (17)	0.00250 (13)
O3	0.0220 (2)	0.01191 (16)	0.01286 (16)	−0.00698 (14)	−0.00066 (14)	−0.00239 (13)
O4	0.0251 (2)	0.01173 (16)	0.00957 (15)	−0.00162 (14)	−0.00047 (14)	0.00104 (12)
O5	0.01628 (19)	0.01397 (17)	0.01650 (18)	−0.00063 (14)	0.00464 (14)	0.00348 (14)
O6	0.0270 (2)	0.00892 (16)	0.01395 (17)	0.00363 (14)	0.00026 (15)	−0.00213 (13)
N1	0.01583 (19)	0.00887 (16)	0.00837 (15)	−0.00144 (13)	0.00098 (13)	−0.00063 (12)
N2	0.01441 (18)	0.00899 (16)	0.00720 (15)	−0.00176 (13)	−0.00061 (13)	−0.00115 (12)
N3	0.01234 (18)	0.00852 (16)	0.01048 (16)	−0.00062 (13)	−0.00219 (13)	−0.00006 (12)
C1	0.01055 (18)	0.00821 (17)	0.00896 (17)	−0.00029 (13)	−0.00101 (13)	−0.00125 (13)
C2	0.01238 (19)	0.00864 (17)	0.00846 (17)	−0.00046 (14)	−0.00077 (14)	−0.00106 (13)
C3	0.01064 (18)	0.00772 (16)	0.00810 (16)	−0.00083 (13)	−0.00041 (13)	−0.00031 (13)
C4	0.00907 (17)	0.00864 (17)	0.00797 (16)	−0.00039 (13)	−0.00065 (13)	−0.00115 (13)
C5	0.01008 (18)	0.00848 (17)	0.00854 (17)	−0.00012 (13)	−0.00084 (13)	−0.00044 (13)
C6	0.00947 (18)	0.00756 (17)	0.00939 (17)	−0.00010 (13)	−0.00098 (13)	−0.00012 (13)
C7	0.0193 (2)	0.01123 (19)	0.00900 (18)	−0.00058 (16)	−0.00162 (16)	−0.00213 (14)
C8	0.0270 (3)	0.0157 (2)	0.0145 (2)	−0.0029 (2)	−0.0004 (2)	−0.00697 (18)
C9	0.01131 (19)	0.01111 (18)	0.00811 (17)	0.00027 (14)	−0.00081 (13)	−0.00121 (14)
C10	0.0185 (2)	0.0127 (2)	0.00990 (18)	−0.00142 (16)	−0.00154 (16)	−0.00304 (15)

Geometric parameters (Å, º) top

O1—C1	1.3451 (6)	C2—H2A	0.9500
O1—C7	1.4489 (7)	C3—C4	1.4068 (7)
O2—N1	1.2214 (6)	C4—C5	1.4031 (7)
O3—N1	1.2327 (6)	C5—C6	1.3845 (7)
O4—C9	1.2225 (7)	C5—H5A	0.9500
O5—N3	1.2299 (6)	C7—C8	1.5058 (8)
O6—N3	1.2228 (6)	C7—H7A	0.9900
N1—C3	1.4677 (7)	C7—H7B	0.9900
N2—C9	1.3798 (7)	C8—H8A	0.9800
N2—C4	1.3953 (6)	C8—H8B	0.9800
N2—H2N	0.900 (10)	C8—H8C	0.9800
N3—C6	1.4698 (7)	C9—C10	1.5035 (8)
C1—C2	1.3918 (7)	C10—H10A	0.9800
C1—C6	1.4036 (7)	C10—H10B	0.9800
C2—C3	1.3895 (7)	C10—H10C	0.9800

C1—O1—C7	116.70 (4)	C5—C6—C1	123.59 (4)
O2—N1—O3	123.54 (5)	C5—C6—N3	116.61 (4)
O2—N1—C3	117.91 (5)	C1—C6—N3	119.79 (4)
O3—N1—C3	118.51 (4)	O1—C7—C8	107.33 (4)
C9—N2—C4	128.40 (4)	O1—C7—H7A	110.2
C9—N2—H2N	116.4 (6)	C8—C7—H7A	110.2
C4—N2—H2N	115.0 (6)	O1—C7—H7B	110.2
O6—N3—O5	124.77 (5)	C8—C7—H7B	110.2
O6—N3—C6	117.66 (4)	H7A—C7—H7B	108.5
O5—N3—C6	117.55 (4)	C7—C8—H8A	109.5
O1—C1—C2	124.44 (5)	C7—C8—H8B	109.5
O1—C1—C6	119.56 (4)	H8A—C8—H8B	109.5
C2—C1—C6	115.99 (4)	C7—C8—H8C	109.5
C3—C2—C1	120.59 (4)	H8A—C8—H8C	109.5
C3—C2—H2A	119.7	H8B—C8—H8C	109.5
C1—C2—H2A	119.7	O4—C9—N2	123.41 (5)
C2—C3—C4	123.56 (4)	O4—C9—C10	123.63 (5)
C2—C3—N1	114.48 (4)	N2—C9—C10	112.96 (4)
C4—C3—N1	121.95 (4)	C9—C10—H10A	109.5
N2—C4—C5	122.78 (4)	C9—C10—H10B	109.5
N2—C4—C3	121.68 (4)	H10A—C10—H10B	109.5
C5—C4—C3	115.50 (4)	C9—C10—H10C	109.5
C6—C5—C4	120.61 (4)	H10A—C10—H10C	109.5
C6—C5—H5A	119.7	H10B—C10—H10C	109.5
C4—C5—H5A	119.7

C7—O1—C1—C2	1.43 (8)	N2—C4—C5—C6	179.44 (5)
C7—O1—C1—C6	−179.73 (5)	C3—C4—C5—C6	1.54 (7)
O1—C1—C2—C3	−179.20 (5)	C4—C5—C6—C1	−3.56 (8)
C6—C1—C2—C3	1.92 (8)	C4—C5—C6—N3	176.11 (5)
C1—C2—C3—C4	−3.97 (8)	O1—C1—C6—C5	−177.20 (5)
C1—C2—C3—N1	174.85 (5)	C2—C1—C6—C5	1.74 (8)
O2—N1—C3—C2	23.69 (7)	O1—C1—C6—N3	3.14 (7)
O3—N1—C3—C2	−154.05 (5)	C2—C1—C6—N3	−177.92 (5)
O2—N1—C3—C4	−157.47 (6)	O6—N3—C6—C5	−136.01 (5)
O3—N1—C3—C4	24.79 (8)	O5—N3—C6—C5	42.40 (7)
C9—N2—C4—C5	3.18 (9)	O6—N3—C6—C1	43.67 (7)
C9—N2—C4—C3	−179.04 (5)	O5—N3—C6—C1	−137.92 (5)
C2—C3—C4—N2	−175.80 (5)	C1—O1—C7—C8	174.56 (5)
N1—C3—C4—N2	5.47 (8)	C4—N2—C9—O4	−0.69 (9)
C2—C3—C4—C5	2.13 (8)	C4—N2—C9—C10	179.41 (5)
N1—C3—C4—C5	−176.60 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2N···O3	0.900 (10)	2.015 (10)	2.6875 (6)	130.5 (8)
N2—H2N···O6ⁱ	0.900 (10)	2.618 (10)	3.4308 (6)	150.5 (8)
C5—H5A···O4	0.95	2.20	2.8386 (7)	123
C8—H8A···O2ⁱⁱ	0.98	2.63	3.3768 (9)	133
C10—H10A···O2ⁱⁱⁱ	0.98	2.37	3.3367 (7)	171
C10—H10B···O5ⁱ	0.98	2.65	3.5677 (8)	155

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

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 purchase of the diffractometer was made possible by grant No. LEQSF (1999–2000)-ENH-TR-13, administered by the Louisiana Board of Regents.

References

Broséus, J., Gentile, N. & Esseiva, P. (2016). Forensic Sci. Int. 262, 73–83. PubMed Google Scholar
Bruker (2016). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Carrociampi, G. (1978). Toxicology, 10, 311–339. CAS PubMed Google Scholar
Hinson, J. A. (1983). Environ. Health Perspect. 49, 71–79. CrossRef CAS PubMed Google Scholar
Holmäng, S., Holmberg, E. & Johansson, S. L. (2013). Scand. J. Urol. 47, 491–496. PubMed Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
Lakshmi, V. M., Hsu, F. F., Davis, B. B. & Zenser, T. V. (2000). Chem. Res. Toxicol. 13, 891–899. CrossRef PubMed CAS Google Scholar
Leistenschneider, W., Nagel, R. & Steffens, J. (1983). Aktuel. Urol. 14, 15–20. CrossRef Google Scholar
Liu, Y. J., Liu, H. S., Hu, C. Y. & Lo, S. L. (2019). Water Res. 155, 56–65. CrossRef CAS PubMed Google Scholar
Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226–235. Web of Science CrossRef CAS IUCr Journals Google Scholar
Russell, R. A., Switzer, R. W., Longmore, R. W., Dutton, B. H. & Harland, L. (1990). J. Chem. Educ. 67, 168–169. CrossRef CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar
Zeman, F. D. (1963). J. Chronic Dis. 16, 1085–1098. CrossRef PubMed CAS Google Scholar

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