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

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

doi:10.1107/S2414314622002012

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 7| Part 2| February 2022| x220201

https://doi.org/10.1107/S2414314622002012

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

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

^aDepartment of Environmental Toxicology, College of Agriculture, 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, Scotland (Received 27 January 2022; accepted 20 February 2022; online 25 February 2022)

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 $[\overline{1}]$ ] chains in the crystal.

Keywords: crystal structure; hydrogen bonding.

CCDC reference: 2153454

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 $[\overline{1}]$ ] direction (Figs. 2 and 3).

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) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]$ .

Figure 1
The molecular structure of the title molecule with 50% displacement ellipsoids.

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

Structural data

CCDC reference: 2153454

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314622002012/hb4400sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314622002012/hb4400Isup3.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314622002012/hb4400Isup3.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: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2020); ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: publCIF (Westrip, 2010).

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

Crystal data top

C₈H₈N₂O₄	F(000) = 816
M_r = 196.16	D_x = 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 top

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

Refinement top

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(F_o²) + (0.0487P)² + 1.5639P] where P = (F_o² + 2F_c²)/3
S = 1.13	(Δ/σ)_max < 0.001
1543 reflections	Δρ_max = 0.29 e Å⁻³
134 parameters	Δρ_min = −0.23 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. 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. U_iso(H) values were assigned as 1.2U_eq for the attached atom (1.5 for OH and methyl).

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

	x	y	z	U_iso*/U_eq
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 (Å²) top

	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) top

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) top

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 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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