N-(3-Chloro-4-hy­droxy­phen­yl)acetamide

Uppu, R.M.; Fronczek, F.R.

doi:10.1107/S2414314625006959

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 10| Part 8| August 2025| x250695

https://doi.org/10.1107/S2414314625006959

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N-(3-Chloro-4-hydroxyphenyl)acetamide

Rao M. Uppu ^a ^* and Frank R. Fronczek ^b

^aDepartment of Environmental Toxicology, Southern University and A&M College, Baton Rouge, Louisiana 70813, USA, and ^bDepartment of Chemistry, Louisiana State University, Baton Rouge, Louisiana, 70803, USA
^*Correspondence e-mail: [email protected]

Edited by W. T. A. Harrison, University of Aberdeen, United Kingdom (Received 31 July 2025; accepted 2 August 2025; online 5 August 2025)

In the title compound, C₈H₈ClNO₂, the acetamide substituent is twisted out of the phenyl plane, forming a dihedral angle of 58.61 (7)°. In the extended structure, each molecule donates two hydrogen bonds [N—H⋯O(carbonyl) and O—H⋯O(carbonyl)] and thus also accepts two such hydrogen bonds. The chlorine atom is not involved in the hydrogen bonding.

Keywords: crystal structure; acetaminophen; acetaminophen impurity C; cellular oxidants; non-enzymatic biotransformation.

CCDC reference: 2478003

Structure description

The title compound, C₈H₈ClNO₂, is one of several products formed when acetaminophen [N-(4-hydroxyphenyl)acetamide; C₈H₉NO₂] reacts with hypochlorous acid/hypochlorite (HOCl/⁻OCl; pK_a ≃7.5) under mildly oxidative, near-neutral pH conditions (Bedner & MacCrehan, 2006 ). Ring-chlorination products such as N-(3-chloro-4-hydroxyphenyl)acetamide have been detected when wastewater and surface water samples were spiked with environmentally relevant concentrations of acetaminophen and then subjected to chlorine-based disinfection (Cao et al., 2016 ; Kolpin et al., 2002 ; Paíga et al., 2025 ). Although trichlorinated acetaminophen does not form under these conditions, chlorination predominantly yields mono- and dichlorinated congeners together with 1,4-benzoquinoneimine, 1,4-benzoquinone, and some high-molecular-weight products with m/z values between 320 and 610 (Bedner & MacCrehan, 2006; Glassmeyer & Shoemaker, 2005 ; Li et al., 2022 ). These products possess greater toxicological potency or environmental persistence, prompting researchers to adopt combined and advanced oxidation processes for more efficient removal and reduced toxicity in treated waters (Dahlin & Nelson, 1982 ; Postigo & Richardson, 2014 ; Qutob et al., 2022 ; Vo et al., 2019 ; Wang et al., 2020 ).

Besides, N-(3-chloro-4-hydroxyphenyl)acetamide can appear in acetaminophen produced via the thionyl chloride/SO₂ Beckmann route, but its formation is effectively suppressed by adding iodide scavengers such as 0.2% KI (Bevan, 1989 ) or by using non-chlorinated syntheses followed by double recrystallization of the bulk drug (Abdelmonem et al., 2004 ). Because aromatic chloro-acetanilides carry toxicological alerts, pharmacopeias and ICH guidelines limit N-(3-chloro-4-hydroxyphenyl)acetamide to < 0.05% and the genotoxic N-(4-chlorophenyl)acetamide to ≤ 0.001% in finished products (Eur Ph, 2024 ; USP, 2024 ).

Acetaminophen is the active ingredient in more than 600 over-the-counter analgesic–antipyretic products, with about 25 billion doses sold annually in the United States (Uppu & Fronczek, 2025 ; Yoon et al., 2016 ). To clarify the molecular structure of its chlorinated impurity, N-(3-chloro-4-hydroxyphenyl)acetamide, and to guide studies of its potential biological interactions, we grew single crystals of the impurity from water and analyzed them by single-crystal X-ray diffraction.

The molecular structure (Fig. 1) shows that the hydroxy oxygen atom O1, the chloro substituent, and the acetamide nitrogen atom are essentially coplanar with the C1–C6 aromatic ring, having a mean deviation of 0.026 Å. The five-atom acetamide group forms a dihedral angle of 58.61 (7)° with the phenyl group, with the C2—C1—N1—C7 torsion angle being −56.10 (14)° and C1—N1—C7—O1 = −4.77 (15)°.

Figure 1
The asymmetric unit of the title compound with 50% displacement ellipsoids.

Intermolecular interactions (Table 1) are dominated by nearly linear O—H⋯O and N—H⋯O hydrogen bonds from both donors to the acetanilide carbonyl oxygen atom O2. Thus, each molecule donates two hydrogen bonds and accepts two, as shown in Fig. 2. The O1—H⋯O2( $[{1\over 2}]$ − x, y − $[{1\over 2}]$ , $[{1\over 2}]$ + z) hydrogen bond has an O⋯O distance of 2.644 (2) Å and forms chains in the [01 $[\overline{1}]$ ] direction with graph-set motif C₁¹(9). The N1—H⋯O2(x + $[{1\over 2}]$ , $[{3\over 2}]$ − y, z) hydrogen bond has an N⋯O distance of 2.866 (2) Å and forms chains in the [100] direction with graph set C₁¹(4). Thus, the overall strong hydrogen bonding pattern is three-dimensional. The chlorine atom is not involved in the hydrogen bonding, as shown in Fig. 3. A weaker C8—H8C⋯O1( $[{1\over 2}]$ + x, $[{3\over 2}]$ − y, 1 − z) interaction exists with C⋯O = 3.250 (2) Å.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1O⋯O2ⁱ	0.88 (3)	1.77 (3)	2.644 (2)	172 (4)
N1—H1N⋯O2ⁱⁱ	0.86 (3)	2.02 (3)	2.866 (2)	168 (3)
Symmetry codes: (i) $[-x+{\script{1\over 2}}, y-{\script{1\over 2}}, z+{\script{1\over 2}}]$ ; (ii) $[x+{\script{1\over 2}}, -y+{\script{3\over 2}}, z]$ .

Figure 2
The hydrogen bonding. Only N—H and O—H hydrogen atoms are shown.

Figure 3
The unit cell. Only N—H and O—H hydrogen atoms are shown.

Synthesis and crystallization

N-(3-Chloro-4-hydroxyphenyl)]acetamide, C₈H₈ClNO₂ (CAS 3964–54-3) was obtained from AmBeed (Arlington Heights, IL) and was used without further purification. Crystals in the form of yellow needles were prepared by slow cooling of a nearly saturated solution of the title compound in boiling deionized water (resistance ca. 18 MΩ.cm⁻¹).

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₈H₈ClNO₂
M_r	185.60
Crystal system, space group	Orthorhombic, Pna2₁
Temperature (K)	100
a, b, c (Å)	8.0264 (4), 11.6750 (6), 9.1911 (5)
V (Å³)	861.28 (8)
Z	4
Radiation type	Ag Kα, λ = 0.56086 Å
μ (mm⁻¹)	0.21
Crystal size (mm)	0.39 × 0.14 × 0.14

Data collection
Diffractometer	Bruker D8 Venture DUO with Photon III C14
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.841, 0.971
No. of measured, independent and observed [I > 2σ(I)] reflections	39597, 3610, 3269
R_int	0.141
(sin θ/λ)_max (Å⁻¹)	0.794

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.090, 1.05
No. of reflections	3610
No. of parameters	116
No. of restraints	1
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.41, −0.20
Absolute structure	Flack x determined using 1397 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	0.13 (6)
Computer programs: APEX5 and SAINT (Bruker, 2016 ), SHELXT2018/2 (Sheldrick, 2015 a), SHELXL2019/1 (Sheldrick, 2015b), Mercury (Macrae et al., 2020 ) and publCIF (Westrip, 2010 ).

Structural data

CCDC reference: 2478003

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314625006959/hb4530sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314625006959/hb4530Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314625006959/hb4530Isup3.cml

checkCIF report

Computing details top

N-(3-Chloro-4-hydroxyphenyl)acetamide top

Crystal data top

C₈H₈ClNO₂	D_x = 1.431 Mg m⁻³
M_r = 185.60	Ag Kα radiation, λ = 0.56086 Å
Orthorhombic, Pna2₁	Cell parameters from 4651 reflections
a = 8.0264 (4) Å	θ = 3.0–26.3°
b = 11.6750 (6) Å	µ = 0.21 mm⁻¹
c = 9.1911 (5) Å	T = 100 K
V = 861.28 (8) Å³	Needle, colourless
Z = 4	0.39 × 0.14 × 0.14 mm
F(000) = 384

Data collection top

Bruker D8 Venture DUO with Photon III C14 diffractometer	3269 reflections with I > 2σ(I)
Radiation source: IµS 3.0 microfocus	R_int = 0.141
φ and ω scans	θ_max = 26.4°, θ_min = 2.2°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −12→12
T_min = 0.841, T_max = 0.971	k = −18→18
39597 measured reflections	l = −14→14
3610 independent reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.035	w = 1/[σ²(F_o²) + (0.0412P)² + 0.050P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.090	(Δ/σ)_max < 0.001
S = 1.05	Δρ_max = 0.41 e Å⁻³
3610 reflections	Δρ_min = −0.20 e Å⁻³
116 parameters	Absolute structure: Flack x determined using 1397 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: 0.13 (6)

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 of 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 methyl and OH). A torsional parameter was refined for the methyl group. The absolute structure (Parsons et al., 2013) was determined using 1397 quotients, x = 0.13 (6).

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

	x	y	z	U_iso*/U_eq
Cl1	0.27874 (6)	0.82350 (4)	0.83454 (6)	0.02458 (11)
O1	0.20435 (18)	0.58074 (12)	0.81799 (15)	0.0226 (3)
H1O	0.171 (4)	0.510 (3)	0.800 (4)	0.034*
O2	0.40669 (17)	0.86881 (12)	0.28796 (16)	0.0216 (2)
N1	0.59913 (19)	0.74091 (13)	0.36310 (16)	0.0180 (3)
H1N	0.697 (4)	0.712 (2)	0.352 (4)	0.022*
C1	0.5004 (2)	0.69771 (15)	0.47984 (18)	0.0169 (3)
C2	0.4449 (2)	0.77256 (15)	0.58827 (19)	0.0174 (3)
H2	0.473800	0.851413	0.584791	0.021*
C3	0.3474 (2)	0.73088 (15)	0.70076 (17)	0.0171 (3)
C4	0.3030 (2)	0.61509 (15)	0.70743 (17)	0.0176 (3)
C5	0.3617 (2)	0.54145 (15)	0.5997 (2)	0.0200 (3)
H5	0.334517	0.462332	0.604003	0.024*
C6	0.4598 (2)	0.58210 (15)	0.48598 (19)	0.0195 (3)
H6	0.498652	0.531098	0.412947	0.023*
C7	0.5491 (2)	0.82626 (14)	0.27705 (18)	0.0166 (3)
C8	0.6697 (2)	0.86814 (17)	0.1643 (2)	0.0235 (3)
H8A	0.771327	0.821706	0.167850	0.035*
H8B	0.697519	0.948435	0.183612	0.035*
H8C	0.618996	0.861631	0.067608	0.035*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0317 (2)	0.02167 (17)	0.02040 (16)	−0.00217 (15)	0.00738 (17)	−0.00433 (16)
O1	0.0280 (6)	0.0215 (5)	0.0184 (6)	−0.0049 (5)	0.0069 (5)	0.0013 (5)
O2	0.0180 (5)	0.0217 (6)	0.0250 (6)	0.0028 (5)	0.0016 (5)	0.0043 (5)
N1	0.0144 (6)	0.0198 (6)	0.0197 (6)	0.0009 (5)	0.0036 (4)	0.0022 (5)
C1	0.0145 (6)	0.0198 (7)	0.0163 (6)	0.0012 (6)	0.0016 (5)	0.0021 (5)
C2	0.0161 (6)	0.0183 (7)	0.0177 (6)	−0.0010 (5)	0.0019 (5)	0.0009 (5)
C3	0.0183 (7)	0.0175 (6)	0.0155 (6)	−0.0002 (5)	0.0019 (5)	−0.0013 (5)
C4	0.0199 (7)	0.0176 (6)	0.0152 (6)	−0.0005 (6)	0.0010 (5)	0.0023 (5)
C5	0.0241 (7)	0.0166 (6)	0.0194 (7)	−0.0010 (6)	0.0036 (6)	0.0013 (5)
C6	0.0221 (8)	0.0175 (7)	0.0190 (6)	0.0007 (6)	0.0037 (6)	−0.0004 (5)
C7	0.0170 (7)	0.0172 (6)	0.0156 (6)	−0.0013 (5)	0.0015 (5)	−0.0005 (5)
C8	0.0248 (8)	0.0238 (8)	0.0220 (7)	−0.0008 (7)	0.0071 (6)	0.0040 (6)

Geometric parameters (Å, º) top

Cl1—C3	1.7276 (17)	C2—H2	0.9500
O1—C4	1.349 (2)	C3—C4	1.399 (2)
O1—H1O	0.88 (3)	C4—C5	1.393 (2)
O2—C7	1.251 (2)	C5—C6	1.392 (2)
N1—C7	1.334 (2)	C5—H5	0.9500
N1—C1	1.426 (2)	C6—H6	0.9500
N1—H1N	0.86 (3)	C7—C8	1.500 (3)
C1—C6	1.390 (2)	C8—H8A	0.9800
C1—C2	1.398 (2)	C8—H8B	0.9800
C2—C3	1.385 (2)	C8—H8C	0.9800

C4—O1—H1O	108 (2)	C6—C5—C4	120.97 (16)
C7—N1—C1	122.91 (15)	C6—C5—H5	119.5
C7—N1—H1N	120 (2)	C4—C5—H5	119.5
C1—N1—H1N	117 (2)	C1—C6—C5	119.63 (16)
C6—C1—C2	120.20 (16)	C1—C6—H6	120.2
C6—C1—N1	120.31 (16)	C5—C6—H6	120.2
C2—C1—N1	119.49 (16)	O2—C7—N1	121.61 (16)
C3—C2—C1	119.51 (16)	O2—C7—C8	121.04 (16)
C3—C2—H2	120.2	N1—C7—C8	117.34 (15)
C1—C2—H2	120.2	C7—C8—H8A	109.5
C2—C3—C4	121.07 (15)	C7—C8—H8B	109.5
C2—C3—Cl1	119.45 (13)	H8A—C8—H8B	109.5
C4—C3—Cl1	119.49 (13)	C7—C8—H8C	109.5
O1—C4—C5	123.39 (16)	H8A—C8—H8C	109.5
O1—C4—C3	118.01 (15)	H8B—C8—H8C	109.5
C5—C4—C3	118.60 (15)

Cl1—C3—C2—C1	−179.95 (9)	C1—C2—C3—C4	−0.25 (14)
Cl1—C3—C4—O1	1.31 (12)	C1—C6—C5—C4	0.30 (16)
Cl1—C3—C4—C5	−179.02 (10)	C2—C1—N1—C7	−56.10 (14)
O1—C4—C3—C2	−178.39 (11)	C2—C1—C6—C5	0.77 (15)
O1—C4—C5—C6	178.35 (13)	C2—C3—C4—C5	1.29 (15)
O2—C7—N1—C1	−4.77 (15)	C3—C2—C1—C6	−0.79 (15)
N1—C1—C2—C3	179.25 (11)	C3—C4—C5—C6	−1.31 (15)
N1—C1—C6—C5	−179.27 (12)	C6—C1—N1—C7	123.94 (13)
C1—N1—C7—C8	176.31 (12)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O2ⁱ	0.88 (3)	1.77 (3)	2.644 (2)	172 (4)
N1—H1N···O2ⁱⁱ	0.86 (3)	2.02 (3)	2.866 (2)	168 (3)

Symmetry codes: (i) −x+1/2, y−1/2, z+1/2; (ii) x+1/2, −y+3/2, z.

Funding information

The authors acknowledge support from the National Institute of General Medical Sciences of the National Institutes of Health (P20 GM103424–21), the US Department of Education (P031B040030), and the National Science Foundation (2418415 RII FEC and CHE-2215262). The contents of this manuscript are solely the responsibility of the authors and do not represent the official views of these funding agencies.

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