organic compounds
N-(4-Ethoxy-2,5-dinitrophenyl)acetamide
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
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the First World War. 4-AcP was likely the first synthetic chemical to go on the market as a fever reducer, but was withdrawn from global markets three decades ago due to its carcinogenic and kidney-damaging properties (Zeman, 1963; Carrociampi, 1978; Leistenschneider et al., 1983;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.
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.
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 et al. (1990). Yellow needles were grown by slow evaporation from methanol solution.
on alumina or silica gel as described by RussellRefinement
Crystal data, data collection and structure .
details are summarized in Table 2
|
Structural data
CCDC reference: 2023527
https://doi.org/10.1107/S2414314620011219/hb4359sup1.cif
contains datablock I. DOI: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
Data collection: APEX3 (Bruker, 2016); cell
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).C10H11N3O6 | Z = 2 |
Mr = 269.22 | F(000) = 280 |
Triclinic, P1 | Dx = 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 |
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 | Rint = 0.043 |
φ and ω scans | θmax = 40.4°, θmin = 2.2° |
Absorption correction: multi-scan (SADABS; Krause et al., 2015) | h = −11→12 |
Tmin = 0.920, Tmax = 0.988 | k = −15→16 |
29518 measured reflections | l = −17→15 |
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(Fo2) + (0.0597P)2 + 0.0585P] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max = 0.001 |
7110 reflections | Δρmax = 0.76 e Å−3 |
177 parameters | Δρmin = −0.28 e Å−3 |
0 restraints |
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). |
x | y | z | Uiso*/Ueq | ||
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* |
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) |
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) |
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.
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