N-(4-Hy­droxy-2-nitro­phen­yl)acetamide

The title compound is more planar than its 3-nitro isomer in the solid state and differs in its hydrogen-bonding pattern.

Abstract

The title compound, C₈H₈N₂O₄, differs in its degree of planarity from the 3-nitro isomer and also in its hydrogen-bonding pattern. Its NH group forms an intra­molecular hydrogen bond to a nitro oxygen atom, and its OH group forms an inter­molecular hydrogen bond to an amide oxygen atom, generating [10 ] chains in the crystal.

Structure description

The putative free-radical products of the per­oxy­nitrite anion (PN)—CO₂ reaction (^.NO₂ and CO₃ ^.–) have long been thought to constitute an important source of non-CYP450-mediated oxidative biotransformation of N-(4-hy­droxy­phen­yl)acetamide (4-HPA; acetamino­phen or paracetamol) and other xenobiotics (Babu et al., 2012 ▸; Dou et al., 2017 ▸; Gernapudi et al., 2009 ▸; Rangan et al., 2006 ▸; Uppu et al., 2005 ▸). In reactions of 4-HPA/PN/CO₂, we find that N-(4-hy­droxy-3-nitro­phen­yl)acetamide is one of the major products formed along with N,N′-(6,6′-dihy­droxy[1,1′-biphen­yl]-3,3′-di­yl)bis­acetamide (dimer of 4-HPA) and a metastable N-acetyl-1,4-benzo­quinone (NBQI; demonstrated through its binding to N-acetyl-l-cysteine; Uppu & Martin, 2005 ▸; Deere et al., 2022 ▸). It was shown that NBQI can react with electrophiles such as the nitrite ion and form yet another nitro product, N-(4-hy­droxy-2-nitro­phen­yl)acetamide (Matsuno et al., 1989 ▸). Although we did not find evidence for the formation of this 2-nitro isomer in 4-HPA/PN/CO₂ reactions, we believe that this isomer along with other oxidation products of 4-HPA may play a role in the pharmacology and toxicology of 4-HPA (4-HPA overdose, either unintentional or intentional, is the most common cause of hepatic failure in the USA and elsewhere).

Towards a better understanding of this chemistry, we have synthesized N-(4-hy­droxy-2-nitro­phen­yl)acetamide and N-(4-hy­droxy-3-nitro­phen­yl)acetamide and determined their single-crystal structures. Interestingly, the 2-nitro and 3-nitro isomers have significantly different degrees of mol­ecular planarity in the solid-state and also differ in their hydrogen bonding patterns.

In N-(4-hy­droxy-2-nitro­phen­yl)acetamide, Fig. 1 ▸, the mol­ecule is nearly planar, with an r.m.s. deviation of 0.035 Å for the non-hydrogen atoms. The acetamido group has the largest deviation, with a 5.1 (2)° twist about its central C7—N2 bond. The N—H group forms an intra­molecular hydrogen bond (Table 1 ▸) to O3 (part of the nitro group) having an N⋯O distance of 2.6363 (15) Å and N—H⋯O angle of 139.6 (15)°. The hy­droxy group forms an inter­molecular hydrogen bond to acetamido atom O4 with O⋯O = 2.7183 (14) Å and O—H⋯O = 172.0 (18)°, thereby forming chains propagating in the [10 ] direction (Figs. 2 ▸ and 3 ▸).

Figure 1.

The mol­ecular structure of the title mol­ecule with 50% displacement ellipsoids.

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1O⋯O4i	0.84 (2)	1.88 (2)	2.7183 (14)	172.0 (18)
N2—H2N⋯O3	0.883 (19)	1.901 (17)	2.6363 (15)	139.6 (15)

Symmetry code: (i) .

Figure 2.

The hydrogen-bonded chain.

Figure 3.

The unit cell of the title compound.

The crystal structure of N-(4-hy­droxy-3-nitro­phen­yl)acetamide has been reported (Salahifar et al., 2015 ▸; Deere et al., 2019 ▸). It is significantly less planar than the title compound, with the acetamido group twisted out of the plane of the phenyl group by 9.0 (2)° and the nitro group twisted out of the phenyl plane by 11.8 (2)°. Its hydrogen-bonding pattern also differs, with the N—H group forming an inter­molecular hydrogen bond to the acetamido O atom [N⋯O = 2.9079 (17) Å; N—H⋯O = 176.6 (19)°]. Its OH group forms a bifurcated O—H⋯(O,O) hydrogen bond, with intra­molecular component to the adjacent nitro group [O⋯O = 2.6093 (17) Å] and a longer inter­molecular component to a nitro oxygen atom of an adjacent mol­ecule [O⋯O = 3.1421 (17) Å; Deere et al., 2019 ▸].

Synthesis and crystallization

The title compound was synthesized by the acetyl­ation of 4-hy­droxy-2-nitro­aniline using acetic anhydride as described by Naik et al. (2004 ▸) with some minor modification (Fig. 4 ▸). Briefly, 4-hy­droxy-2-nitro­aniline (3.08 g; 20 mmol) in its hydro­chloride form (prepared by addition of a slight molar excess of HCl; 26 mmol) was dissolved in 125 ml of aceto­nitrile/water (1/4, v/v). The solution was cooled in an ice bath, followed by addition of acetic anhydride (2.43 ml; 24 mmol). Then, sodium bicarbonate (3.36–5.04 g; 40–60 mmol) was added to the mixture with the contents being constantly stirred. Care was taken to maintain that the pH of the final reaction mixture was between 5.5 and 6.5. The yellow precipitate of N-(4-hy­droxy-2-nitro­phen­yl)acetamide was separ­ated by filtration and purified by recrystallization twice from aqueous solution. Single crystals were grown from methanol solution.

Figure 4.

Schematic representation of the synthesis of the title compound.

Refinement

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

Table 2. Experimental details.

Crystal data
Chemical formula	C8H8N2O4
M r	196.16
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	90
a, b, c (Å)	9.6643 (3), 18.5534 (5), 9.3072 (2)
β (°)	95.5075 (14)
V (Å3)	1661.13 (8)
Z	8
Radiation type	Cu Kα
μ (mm−1)	1.10
Crystal size (mm)	0.21 × 0.07 × 0.02
Data collection
Diffractometer	Bruker Kappa APEXII DUO CCD
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 ▸)
T min, T max	0.872, 0.978
No. of measured, independent and observed [I > 2σ(I)] reflections	6856, 1543, 1486
R int	0.028
(sin θ/λ)max (Å−1)	0.607
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.035, 0.095, 1.13
No. of reflections	1543
No. of parameters	134
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.29, −0.24

Computer programs: APEX3 and SAINT (Bruker, 2016 ▸), SHELXS97 (Sheldrick, 2008 ▸), SHELXL2014/7 (Sheldrick, 2015 ▸), Mercury (Macrae et al., 2020 ▸); ORTEP-3 (Farrugia, 2012 ▸) and publCIF (Westrip, 2010 ▸).

Supplementary Material

CCDC reference: 2153454

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

full crystallographic data

Crystal data

C8H8N2O4	F(000) = 816
Mr = 196.16	Dx = 1.569 Mg m−3
Monoclinic, C2/c	Cu Kα radiation, λ = 1.54184 Å
a = 9.6643 (3) Å	Cell parameters from 5235 reflections
b = 18.5534 (5) Å	θ = 4.8–69.3°
c = 9.3072 (2) Å	µ = 1.10 mm−1
β = 95.5075 (14)°	T = 90 K
V = 1661.13 (8) Å3	Lath, yellow
Z = 8	0.21 × 0.07 × 0.02 mm

Data collection

Bruker Kappa APEXII DUO CCD diffractometer	1543 independent reflections
Radiation source: IµS microfocus	1486 reflections with I > 2σ(I)
QUAZAR multilayer optics monochromator	Rint = 0.028
φ and ω scans	θmax = 69.3°, θmin = 4.8°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −11→7
Tmin = 0.872, Tmax = 0.978	k = −22→20
6856 measured reflections	l = −11→10

Refinement

Refinement on F2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.035	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.095	w = 1/[σ2(Fo2) + (0.0487P)2 + 1.5639P] where P = (Fo2 + 2Fc2)/3
S = 1.13	(Δ/σ)max < 0.001
1543 reflections	Δρmax = 0.29 e Å−3
134 parameters	Δρmin = −0.23 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. 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 and 0.98 Å for methyl. The coordinates of the N—H and O—H hydrogen atoms were refined. Uiso(H) values were assigned as 1.2Ueq for the attached atom (1.5 for OH and methyl).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.49965 (11)	0.11112 (5)	0.49610 (11)	0.0180 (2)
H1O	0.435 (2)	0.1126 (10)	0.551 (2)	0.027*
O2	0.36347 (11)	0.35035 (5)	0.64809 (11)	0.0240 (3)
O3	0.47807 (11)	0.43019 (5)	0.53985 (12)	0.0239 (3)
O4	0.79942 (10)	0.37109 (5)	0.17917 (10)	0.0208 (3)
N1	0.44852 (12)	0.36642 (6)	0.56392 (12)	0.0163 (3)
N2	0.65588 (12)	0.39184 (6)	0.35604 (12)	0.0149 (3)
H2N	0.6134 (17)	0.4246 (10)	0.4050 (18)	0.018*
C1	0.53400 (14)	0.18008 (7)	0.46502 (14)	0.0143 (3)
C2	0.47727 (13)	0.23927 (7)	0.52723 (13)	0.0146 (3)
H2	0.4113	0.2327	0.5955	0.018*
C3	0.51647 (13)	0.30877 (7)	0.49012 (13)	0.0138 (3)
C4	0.61410 (13)	0.32179 (7)	0.39015 (13)	0.0137 (3)
C5	0.66952 (13)	0.26010 (7)	0.32904 (13)	0.0140 (3)
H5	0.7356	0.2659	0.2606	0.017*
C6	0.63082 (13)	0.19119 (7)	0.36548 (13)	0.0143 (3)
H6	0.6708	0.1509	0.3220	0.017*
C7	0.74622 (13)	0.41291 (7)	0.25993 (14)	0.0152 (3)
C8	0.77664 (15)	0.49227 (7)	0.26014 (16)	0.0211 (3)
H8A	0.8474	0.5036	0.3395	0.032*
H8B	0.6914	0.5192	0.2729	0.032*
H8C	0.8109	0.5058	0.1681	0.032*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.0214 (5)	0.0120 (5)	0.0220 (5)	−0.0007 (4)	0.0096 (4)	0.0002 (4)
O2	0.0279 (6)	0.0189 (5)	0.0287 (6)	0.0003 (4)	0.0202 (4)	0.0005 (4)
O3	0.0298 (6)	0.0121 (5)	0.0327 (6)	−0.0014 (4)	0.0180 (5)	−0.0002 (4)
O4	0.0256 (5)	0.0158 (5)	0.0234 (5)	0.0000 (4)	0.0141 (4)	−0.0013 (4)
N1	0.0175 (6)	0.0143 (6)	0.0182 (6)	0.0003 (4)	0.0073 (4)	−0.0003 (4)
N2	0.0148 (6)	0.0129 (5)	0.0179 (6)	0.0009 (4)	0.0061 (4)	−0.0006 (4)
C1	0.0142 (6)	0.0132 (6)	0.0155 (6)	−0.0010 (5)	0.0005 (5)	0.0010 (5)
C2	0.0143 (6)	0.0159 (7)	0.0143 (6)	−0.0002 (5)	0.0041 (5)	0.0001 (5)
C3	0.0140 (6)	0.0141 (7)	0.0136 (6)	0.0017 (5)	0.0026 (5)	−0.0019 (5)
C4	0.0124 (6)	0.0153 (6)	0.0133 (6)	−0.0002 (5)	0.0004 (5)	0.0004 (5)
C5	0.0122 (6)	0.0165 (7)	0.0138 (6)	0.0003 (5)	0.0031 (5)	−0.0003 (5)
C6	0.0134 (6)	0.0152 (6)	0.0145 (6)	0.0016 (5)	0.0025 (5)	−0.0013 (5)
C7	0.0142 (6)	0.0143 (6)	0.0173 (6)	0.0006 (5)	0.0028 (5)	0.0010 (5)
C8	0.0245 (7)	0.0142 (7)	0.0266 (7)	−0.0006 (5)	0.0125 (6)	−0.0002 (5)

Geometric parameters (Å, º)

O1—C1	1.3599 (16)	C2—C3	1.3966 (18)
O1—H1O	0.84 (2)	C2—H2	0.9500
O2—N1	1.2255 (15)	C3—C4	1.4081 (18)
O3—N1	1.2424 (15)	C4—C5	1.4067 (18)
O4—C7	1.2270 (17)	C5—C6	1.3835 (18)
N1—C3	1.4608 (17)	C5—H5	0.9500
N2—C7	1.3657 (18)	C6—H6	0.9500
N2—C4	1.4063 (17)	C7—C8	1.5014 (18)
N2—H2N	0.883 (19)	C8—H8A	0.9800
C1—C2	1.3795 (18)	C8—H8B	0.9800
C1—C6	1.3938 (19)	C8—H8C	0.9800
C1—O1—H1O	108.0 (12)	N2—C4—C3	122.20 (12)
O2—N1—O3	121.80 (11)	C5—C4—C3	115.65 (12)
O2—N1—C3	118.79 (11)	C6—C5—C4	122.03 (12)
O3—N1—C3	119.41 (11)	C6—C5—H5	119.0
C7—N2—C4	128.89 (12)	C4—C5—H5	119.0
C7—N2—H2N	119.9 (11)	C5—C6—C1	120.94 (12)
C4—N2—H2N	111.2 (11)	C5—C6—H6	119.5
O1—C1—C2	123.01 (12)	C1—C6—H6	119.5
O1—C1—C6	118.27 (12)	O4—C7—N2	123.52 (12)
C2—C1—C6	118.72 (12)	O4—C7—C8	121.83 (12)
C1—C2—C3	120.20 (12)	N2—C7—C8	114.66 (11)
C1—C2—H2	119.9	C7—C8—H8A	109.5
C3—C2—H2	119.9	C7—C8—H8B	109.5
C2—C3—C4	122.46 (12)	H8A—C8—H8B	109.5
C2—C3—N1	114.51 (11)	C7—C8—H8C	109.5
C4—C3—N1	123.02 (12)	H8A—C8—H8C	109.5
N2—C4—C5	122.14 (12)	H8B—C8—H8C	109.5
O1—C1—C2—C3	−179.68 (11)	N1—C3—C4—N2	1.39 (19)
C6—C1—C2—C3	0.19 (19)	C2—C3—C4—C5	0.31 (18)
C1—C2—C3—C4	−0.29 (19)	N1—C3—C4—C5	180.00 (11)
C1—C2—C3—N1	180.00 (11)	N2—C4—C5—C6	178.36 (11)
O2—N1—C3—C2	−1.17 (17)	C3—C4—C5—C6	−0.25 (18)
O3—N1—C3—C2	178.91 (11)	C4—C5—C6—C1	0.18 (19)
O2—N1—C3—C4	179.12 (12)	O1—C1—C6—C5	179.74 (11)
O3—N1—C3—C4	−0.79 (19)	C2—C1—C6—C5	−0.13 (19)
C7—N2—C4—C5	3.1 (2)	C4—N2—C7—O4	5.1 (2)
C7—N2—C4—C3	−178.38 (12)	C4—N2—C7—C8	−174.86 (12)
C2—C3—C4—N2	−178.30 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O4i	0.84 (2)	1.88 (2)	2.7183 (14)	172.0 (18)
N2—H2N···O3	0.883 (19)	1.901 (17)	2.6363 (15)	139.6 (15)

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.