organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2414-3146

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

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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.

3D view (loading...)
[Scheme 3D1]
Chemical scheme
[Scheme 1]

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the First World War. 4-AcP was likely the first synthetic chemical to go on the market as a fever reducer, but was withdrawn from global markets three decades ago due to its carcinogenic and kidney-damaging properties (Zeman, 1963[Zeman, F. D. (1963). J. Chronic Dis. 16, 1085-1098.]; Carrociampi, 1978[Carrociampi, G. (1978). Toxicology, 10, 311-339.]; Leistenschneider et al., 1983[Leistenschneider, W., Nagel, R. & Steffens, J. (1983). Aktuel. Urol. 14, 15-20.]; Holmäng et al., 2013[Holmäng, S., Holmberg, E. & Johansson, S. L. (2013). Scand. J. Urol. 47, 491-496.]). 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[Broséus, J., Gentile, N. & Esseiva, P. (2016). Forensic Sci. Int. 262, 73-83.]). 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[Hinson, J. A. (1983). Environ. Health Perspect. 49, 71-79.]; Lakshmi et al., 2000[Lakshmi, V. M., Hsu, F. F., Davis, B. B. & Zenser, T. V. (2000). Chem. Res. Toxicol. 13, 891-899.]; Liu et al., 2019[Liu, Y. J., Liu, H. S., Hu, C. Y. & Lo, S. L. (2019). Water Res. 155, 56-65.]), 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[link]. 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]
Figure 1
The title mol­ecule showing 50% displacement ellipsoids.

The N2—H2N group forms a bifurcated hydrogen bond (Table 1[link]), 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[link]. Several C—H⋯O inter­actions are also present (Table 1[link]), 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 DA 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]
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[Russell, R. A., Switzer, R. W., Longmore, R. W., Dutton, B. H. & Harland, L. (1990). J. Chem. Educ. 67, 168-169.]). Yellow needles were grown by slow evaporation from methanol solution.

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula C10H11N3O6
Mr 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)
V3) 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[Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3-10.])
Tmin, Tmax 0.920, 0.988
No. of measured, independent and observed [I > 2σ(I)] reflections 29518, 7110, 5824
Rint 0.043
(sin θ/λ)max−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
Δρmax, Δρmin (e Å−3) 0.76, −0.28
Computer programs: APEX3 and SAINT (Bruker, 2016[Bruker (2016). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), SHELXL2017/1 (Sheldrick, 2015[Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.]), Mercury (Macrae et al., 2020[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.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Structural data


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
C10H11N3O6Z = 2
Mr = 269.22F(000) = 280
Triclinic, P1Dx = 1.586 Mg m3
a = 6.7463 (3) ÅMo Kα radiation, λ = 0.71073 Å
b = 9.0360 (4) ÅCell parameters from 9965 reflections
c = 9.3954 (4) Åθ = 3.0–40.2°
α = 81.005 (2)°µ = 0.13 mm1
β = 85.099 (2)°T = 90 K
γ = 88.700 (2)°Needle, yellow
V = 563.60 (4) Å30.30 × 0.10 × 0.09 mm
Data collection top
Bruker Kappa APEXII DUO CCD
diffractometer
7110 independent reflections
Radiation source: fine-focus sealed tube5824 reflections with I > 2σ(I)
TRIUMPH curved graphite monochromatorRint = 0.043
φ and ω scansθmax = 40.4°, θmin = 2.2°
Absorption correction: multi-scan
(SADABS; Krause et al., 2015)
h = 1112
Tmin = 0.920, Tmax = 0.988k = 1516
29518 measured reflectionsl = 1715
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.038H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.111 w = 1/[σ2(Fo2) + (0.0597P)2 + 0.0585P]
where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max = 0.001
7110 reflectionsΔρmax = 0.76 e Å3
177 parametersΔρmin = 0.28 e Å3
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. Uiso(H) values were assigned as 1.2Ueq for the attached C or N atom (1.5 for methyl).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.69178 (7)0.25306 (4)0.22213 (4)0.01208 (7)
O20.80562 (9)0.79863 (5)0.13502 (5)0.02166 (10)
O30.94649 (7)0.84282 (5)0.32212 (5)0.01549 (8)
O40.74286 (8)0.55569 (5)0.80156 (5)0.01579 (8)
O50.54980 (7)0.15057 (5)0.63040 (5)0.01655 (9)
O60.76371 (8)0.07153 (5)0.47211 (5)0.01675 (9)
N10.84988 (7)0.76273 (5)0.25917 (5)0.01119 (8)
N20.78930 (7)0.69046 (5)0.57358 (5)0.01020 (7)
H2N0.8235 (15)0.7816 (11)0.5253 (10)0.012*
N30.66942 (7)0.17087 (5)0.52301 (5)0.01052 (7)
C10.72020 (8)0.36104 (5)0.30173 (5)0.00923 (8)
C20.76108 (8)0.50980 (6)0.24458 (5)0.00986 (8)
H2A0.7686930.5405550.1428530.012*
C30.79085 (8)0.61374 (5)0.33497 (5)0.00893 (8)
C40.77060 (7)0.58036 (5)0.48682 (5)0.00857 (8)
C50.72406 (7)0.43112 (5)0.54384 (5)0.00912 (8)
H5A0.7051430.4017900.6456270.011*
C60.70546 (7)0.32621 (5)0.45315 (5)0.00893 (8)
C70.71005 (9)0.29652 (6)0.06650 (6)0.01309 (9)
H7A0.8402880.3442800.0344970.016*
H7B0.6034510.3688850.0364470.016*
C80.69258 (11)0.15636 (7)0.00051 (7)0.01860 (11)
H8A0.7997790.0862000.0300430.028*
H8B0.7029030.1819580.1051210.028*
H8C0.5636700.1096810.0336500.028*
C90.77619 (8)0.67490 (6)0.72252 (5)0.01021 (8)
C100.80679 (9)0.81975 (6)0.77720 (6)0.01351 (9)
H10A0.8050130.8009890.8828910.020*
H10B0.6999500.8905710.7484180.020*
H10C0.9353570.8621210.7359250.020*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.01876 (18)0.00903 (15)0.00891 (14)0.00178 (12)0.00191 (12)0.00211 (11)
O20.0418 (3)0.01400 (18)0.00889 (16)0.00649 (18)0.00647 (17)0.00250 (13)
O30.0220 (2)0.01191 (16)0.01286 (16)0.00698 (14)0.00066 (14)0.00239 (13)
O40.0251 (2)0.01173 (16)0.00957 (15)0.00162 (14)0.00047 (14)0.00104 (12)
O50.01628 (19)0.01397 (17)0.01650 (18)0.00063 (14)0.00464 (14)0.00348 (14)
O60.0270 (2)0.00892 (16)0.01395 (17)0.00363 (14)0.00026 (15)0.00213 (13)
N10.01583 (19)0.00887 (16)0.00837 (15)0.00144 (13)0.00098 (13)0.00063 (12)
N20.01441 (18)0.00899 (16)0.00720 (15)0.00176 (13)0.00061 (13)0.00115 (12)
N30.01234 (18)0.00852 (16)0.01048 (16)0.00062 (13)0.00219 (13)0.00006 (12)
C10.01055 (18)0.00821 (17)0.00896 (17)0.00029 (13)0.00101 (13)0.00125 (13)
C20.01238 (19)0.00864 (17)0.00846 (17)0.00046 (14)0.00077 (14)0.00106 (13)
C30.01064 (18)0.00772 (16)0.00810 (16)0.00083 (13)0.00041 (13)0.00031 (13)
C40.00907 (17)0.00864 (17)0.00797 (16)0.00039 (13)0.00065 (13)0.00115 (13)
C50.01008 (18)0.00848 (17)0.00854 (17)0.00012 (13)0.00084 (13)0.00044 (13)
C60.00947 (18)0.00756 (17)0.00939 (17)0.00010 (13)0.00098 (13)0.00012 (13)
C70.0193 (2)0.01123 (19)0.00900 (18)0.00058 (16)0.00162 (16)0.00213 (14)
C80.0270 (3)0.0157 (2)0.0145 (2)0.0029 (2)0.0004 (2)0.00697 (18)
C90.01131 (19)0.01111 (18)0.00811 (17)0.00027 (14)0.00081 (13)0.00121 (14)
C100.0185 (2)0.0127 (2)0.00990 (18)0.00142 (16)0.00154 (16)0.00304 (15)
Geometric parameters (Å, º) top
O1—C11.3451 (6)C2—H2A0.9500
O1—C71.4489 (7)C3—C41.4068 (7)
O2—N11.2214 (6)C4—C51.4031 (7)
O3—N11.2327 (6)C5—C61.3845 (7)
O4—C91.2225 (7)C5—H5A0.9500
O5—N31.2299 (6)C7—C81.5058 (8)
O6—N31.2228 (6)C7—H7A0.9900
N1—C31.4677 (7)C7—H7B0.9900
N2—C91.3798 (7)C8—H8A0.9800
N2—C41.3953 (6)C8—H8B0.9800
N2—H2N0.900 (10)C8—H8C0.9800
N3—C61.4698 (7)C9—C101.5035 (8)
C1—C21.3918 (7)C10—H10A0.9800
C1—C61.4036 (7)C10—H10B0.9800
C2—C31.3895 (7)C10—H10C0.9800
C1—O1—C7116.70 (4)C5—C6—C1123.59 (4)
O2—N1—O3123.54 (5)C5—C6—N3116.61 (4)
O2—N1—C3117.91 (5)C1—C6—N3119.79 (4)
O3—N1—C3118.51 (4)O1—C7—C8107.33 (4)
C9—N2—C4128.40 (4)O1—C7—H7A110.2
C9—N2—H2N116.4 (6)C8—C7—H7A110.2
C4—N2—H2N115.0 (6)O1—C7—H7B110.2
O6—N3—O5124.77 (5)C8—C7—H7B110.2
O6—N3—C6117.66 (4)H7A—C7—H7B108.5
O5—N3—C6117.55 (4)C7—C8—H8A109.5
O1—C1—C2124.44 (5)C7—C8—H8B109.5
O1—C1—C6119.56 (4)H8A—C8—H8B109.5
C2—C1—C6115.99 (4)C7—C8—H8C109.5
C3—C2—C1120.59 (4)H8A—C8—H8C109.5
C3—C2—H2A119.7H8B—C8—H8C109.5
C1—C2—H2A119.7O4—C9—N2123.41 (5)
C2—C3—C4123.56 (4)O4—C9—C10123.63 (5)
C2—C3—N1114.48 (4)N2—C9—C10112.96 (4)
C4—C3—N1121.95 (4)C9—C10—H10A109.5
N2—C4—C5122.78 (4)C9—C10—H10B109.5
N2—C4—C3121.68 (4)H10A—C10—H10B109.5
C5—C4—C3115.50 (4)C9—C10—H10C109.5
C6—C5—C4120.61 (4)H10A—C10—H10C109.5
C6—C5—H5A119.7H10B—C10—H10C109.5
C4—C5—H5A119.7
C7—O1—C1—C21.43 (8)N2—C4—C5—C6179.44 (5)
C7—O1—C1—C6179.73 (5)C3—C4—C5—C61.54 (7)
O1—C1—C2—C3179.20 (5)C4—C5—C6—C13.56 (8)
C6—C1—C2—C31.92 (8)C4—C5—C6—N3176.11 (5)
C1—C2—C3—C43.97 (8)O1—C1—C6—C5177.20 (5)
C1—C2—C3—N1174.85 (5)C2—C1—C6—C51.74 (8)
O2—N1—C3—C223.69 (7)O1—C1—C6—N33.14 (7)
O3—N1—C3—C2154.05 (5)C2—C1—C6—N3177.92 (5)
O2—N1—C3—C4157.47 (6)O6—N3—C6—C5136.01 (5)
O3—N1—C3—C424.79 (8)O5—N3—C6—C542.40 (7)
C9—N2—C4—C53.18 (9)O6—N3—C6—C143.67 (7)
C9—N2—C4—C3179.04 (5)O5—N3—C6—C1137.92 (5)
C2—C3—C4—N2175.80 (5)C1—O1—C7—C8174.56 (5)
N1—C3—C4—N25.47 (8)C4—N2—C9—O40.69 (9)
C2—C3—C4—C52.13 (8)C4—N2—C9—C10179.41 (5)
N1—C3—C4—C5176.60 (5)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2N···O30.900 (10)2.015 (10)2.6875 (6)130.5 (8)
N2—H2N···O6i0.900 (10)2.618 (10)3.4308 (6)150.5 (8)
C5—H5A···O40.952.202.8386 (7)123
C8—H8A···O2ii0.982.633.3768 (9)133
C10—H10A···O2iii0.982.373.3367 (7)171
C10—H10B···O5i0.982.653.5677 (8)155
Symmetry codes: (i) x, y+1, z; (ii) x, y1, 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

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