4-Acetamido-3-chloro­phenyl acetate

Bai, S.V.; Li, G.; Mensah, P.F.; Fronczek, F.R.; Uppu, R.M.

doi:10.1107/S2414314626000763

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 11| Part 1| January 2026| x260076

https://doi.org/10.1107/S2414314626000763

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4-Acetamido-3-chlorophenyl acetate

Sindhu V. Bai,^a Guoqiang Li,^b Patrick F. Mensah,^c Frank R. Fronczek ^d and Rao M. Uppu ^a ^*

^aDepartment of Environmental Toxicology, Southern University and A&M College, Baton Rouge, Louisiana 70813, USA, ^bDepartment of Mechanical & Industrial Engineering, Louisiana State University, Baton Rouge, Louisiana 70803, USA, ^cDepartment of Mechanical Engineering, Southern University and A&M College, Baton Rouge, Louisiana 70813, USA, and ^dDepartment 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 22 January 2026; accepted 25 January 2026; online 29 January 2026)

In the title compound, C₁₀H₁₀ClNO₃, the dihedral angles between the chlorobenzene ring and the acetamide and acetate planes are 40.70 (8) and 88.07 (8)°, respectively; the acetamide and acetate planes make a dihedral angle of 51.39 (9)°. In the extended structure, the molecules are linked by N—H⋯O hydrogen bonds involving the acetamide group, forming C(4) chains propagating along the [010] direction.

Keywords: crystal structure; chlorinated acetaminophen; hypochlorite–hypochlorous acid oxidation.

CCDC reference: 2492307

Structure description

With approximately 25 billion doses sold annually in the United States, acetaminophen, C₈H₉NO₂ (also known as paracetamol; brand names in different countries include Tylenol, Panadol and many others) is among the most widely used analgesic and antipyretic agents (Uppu & Fronczek, 2025 ; Yoon et al., 2016 ). Its metabolism is dominated by sulfation and glucuronidation, with a smaller contribution from CYP2E1-mediated oxidation (Mazaleuskaya et al., 2015 ). In addition, non-enzymatic transformations mediated by cellular oxidants, including the peroxynitrite–CO₂ system and the myeloperoxidase–H₂O₂–Cl⁻ pathway that generates HOCl/ClO⁻ (pK_a ≃ 7.53), warrant consideration (Bedner & MacCrehan, 2006 ; Hines et al., 2025 ; Hines et al., 2026 ; Uppu & Martin, 2005 ). While CYP2E1 and related oxidants are implicated in overdose-level formation of N-acetyl-1,4-benzoquinone imine (NBQI), the present work focuses on low-level in vivo NBQI formation and the identification of chemically tractable transformation products (Manyike et al., 2000 ).

Given the high intracellular abundance of chloride ions (ca. 150 mM), N-(4-hydroxy-2-chlorophenyl)acetamide (the 2-chloro isomer; Matsuno et al., 1989 ) has been proposed as a chemically plausible product of NBQI–Cl⁻ chemistry. Recognizing that O-acetylation can facilitate cellular uptake, we synthesized the title compound, C₁₀H₁₀ClNO₃ (I), the O-acetylated derivative of N-(4-hydroxy-2-chlorophenyl)acetamide, and determined its crystal structure (Bai et al., 2025 ).

Compound (I) crystallizes as a neutral molecular species in space group I2/a with one molecule in the asymmetric unit (Fig. 1). The dihedral angles between the central C1–C6 aromatic ring and the pendant acetamide (C9/C10/N1/O3) and acetate (C7/C8/O1/O2) mean planes are 40.70 (8) and 88.07 (8)°, respectively: the two substituents are displaced on opposite sides of the central ring. The masking of the phenolic O—H group as an ester in (I) suppresses phenol-based hydrogen bonding and shifts the supramolecular assembly to an amide-centered hydrogen-bonding network in which N1—H1N⋯O3 hydrogen bonds link the molecules into C(4) chains propagating in the [010] direction with adjacent molecules in the chain related by simple translation (Table 1, Fig. 2). Weak C—H⋯Cl and C—H⋯O interactions consolidate the structure (Fig. 3). This solid-state behavior is consistent with an ester that is poised for enzymatic O-deacetylation to N-(4-hydroxy-2-chlorophenyl)acetamide (Soloviev et al., 2022 ). The molecular geometry and packing parameters reported here provide a crystallographic reference for comparison with related acetaminophen derivatives and their functionalized analogues.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1N⋯O3ⁱ	0.87 (2)	2.01 (2)	2.8335 (17)	157.5 (17)
C8—H8A⋯Cl1ⁱⁱ	0.98	2.90	3.8279 (16)	159
C8—H8C⋯Cl1ⁱⁱⁱ	0.98	2.97	3.6541 (16)	128
C10—H10A⋯O3ⁱ	0.98	2.46	3.2796 (18)	141
Symmetry codes: (i) ; (ii) $[x+{\script{1\over 2}}, -y+2, z]$ ; (iii) .

Figure 1
The molecular structure of (I) with displacement ellipsoids drawn at the 50% probability level.

Figure 2
Fragment of a [010] hydrogen-bonded chain in (I).

Figure 3
The unit cell of (I) viewed approximately down [010].

Synthesis and crystallization

The title compound was synthesized by acetylation of 4-amino-3-chlorophenol with acetic anhydride following Naik et al. (2004 ) with minor modifications: 4-amino-3-chlorophenol hydrochloride (1.8 g, 10 mmol) was dissolved in ∼50–75 ml water and adjusted to pH 1.5–1.7 with 1.0 N HCl. The cooled solution (ice bath) was treated with acetic anhydride (1.21 ml, 12 mmol), then sodium bicarbonate (2.16–3.02 g, 25–35 mmol) was added with continuous stirring, maintaining the reaction pH between 5.5 and 6.5. The off-white precipitate was collected by filtration. Crystals were grown from a hot, near-saturated ethanolic aqueous solution by slow cooling and evaporation to form colorless needles of (I).

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₁₀H₁₀ClNO₃
M_r	227.64
Crystal system, space group	Monoclinic, I2/a
Temperature (K)	100
a, b, c (Å)	19.2482 (7), 4.7223 (2), 24.3718 (11)
β (°)	111.222 (2)
V (Å³)	2065.06 (15)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	3.19
Crystal size (mm)	0.40 × 0.03 × 0.02

Data collection
Diffractometer	Bruker D8 Venture DUO with Photon III C14
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.795, 0.939
No. of measured, independent and observed [I > 2σ(I)] reflections	20794, 2190, 1953
R_int	0.049
(sin θ/λ)_max (Å⁻¹)	0.638

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.031, 0.079, 1.06
No. of reflections	2190
No. of parameters	141
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.28, −0.31
Computer programs: APEX5 and SAINT (Bruker, 2016 ), SHELXT2018/2 (Sheldrick, 2015a ), SHELXL2019/1 (Sheldrick, 2015b ) and Mercury (Macrae et al., 2020 ).

Structural data

CCDC reference: 2492307

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314626000763/hb4554sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314626000763/hb4554Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314626000763/hb4554Isup3.cml

checkCIF report

Computing details top

4-Acetamido-3-chlorophenyl acetate top

Crystal data top

C₁₀H₁₀ClNO₃	F(000) = 944
M_r = 227.64	D_x = 1.464 Mg m⁻³
Monoclinic, I2/a	Cu Kα radiation, λ = 1.54184 Å
a = 19.2482 (7) Å	Cell parameters from 7338 reflections
b = 4.7223 (2) Å	θ = 5.1–78.8°
c = 24.3718 (11) Å	µ = 3.19 mm⁻¹
β = 111.222 (2)°	T = 100 K
V = 2065.06 (15) Å³	Needle, colourless
Z = 8	0.40 × 0.03 × 0.02 mm

Data collection top

Bruker D8 Venture DUO with Photon III C14 diffractometer	1953 reflections with I > 2σ(I)
Radiation source: IµS 3.0 microfocus	R_int = 0.049
φ and ω scans	θ_max = 79.5°, θ_min = 3.9°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −23→24
T_min = 0.795, T_max = 0.939	k = −5→5
20794 measured reflections	l = −30→30
2190 independent reflections

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.031	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.079	w = 1/[σ²(F_o²) + (0.0352P)² + 2.3982P] where P = (F_o² + 2F_c²)/3
S = 1.06	(Δ/σ)_max = 0.001
2190 reflections	Δρ_max = 0.28 e Å⁻³
141 parameters	Δρ_min = −0.31 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. The N-bound H atom was located in a difference map and its positon was freely refined. The C-bound H atoms were geometrically placed (C—H = 0.95–0.98 Å) and refined as riding atoms. The constraint U_iso(H) = 1.2U_eq(C) or 1.5U_eq(methyl C or N) was applied in all cases.

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

	x	y	z	U_iso*/U_eq
Cl1	0.29945 (2)	1.05930 (8)	0.43887 (2)	0.02274 (12)
O1	0.51347 (6)	0.4581 (2)	0.42785 (5)	0.0234 (2)
O2	0.54882 (6)	0.7934 (3)	0.37753 (5)	0.0311 (3)
O3	0.16631 (6)	0.3467 (2)	0.29322 (5)	0.0240 (2)
N1	0.21473 (7)	0.7825 (3)	0.32425 (5)	0.0166 (3)
H1N	0.2050 (11)	0.961 (4)	0.3252 (8)	0.025*
C1	0.29024 (8)	0.6998 (3)	0.34951 (6)	0.0164 (3)
C2	0.33611 (8)	0.8169 (3)	0.40297 (6)	0.0175 (3)
C3	0.41082 (8)	0.7434 (3)	0.42888 (6)	0.0193 (3)
H3	0.441580	0.827008	0.464947	0.023*
C4	0.43917 (8)	0.5462 (3)	0.40099 (6)	0.0198 (3)
C5	0.39561 (8)	0.4239 (3)	0.34806 (7)	0.0206 (3)
H5	0.416175	0.287458	0.329626	0.025*
C6	0.32145 (8)	0.5039 (3)	0.32240 (6)	0.0189 (3)
H6	0.291440	0.423692	0.285717	0.023*
C7	0.56449 (8)	0.5943 (3)	0.41004 (6)	0.0196 (3)
C8	0.63895 (8)	0.4550 (4)	0.43598 (7)	0.0236 (3)
H8A	0.675565	0.561234	0.424852	0.035*
H8B	0.635720	0.260647	0.421143	0.035*
H8C	0.654427	0.451599	0.478961	0.035*
C9	0.15738 (8)	0.6016 (3)	0.29791 (6)	0.0169 (3)
C10	0.08112 (8)	0.7331 (3)	0.27509 (6)	0.0203 (3)
H10A	0.084987	0.934742	0.285256	0.031*
H10B	0.049155	0.638463	0.292905	0.031*
H10C	0.059499	0.711821	0.232210	0.031*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.02477 (19)	0.0215 (2)	0.01999 (18)	0.00295 (13)	0.00569 (13)	−0.00444 (13)
O1	0.0159 (5)	0.0289 (6)	0.0251 (5)	0.0034 (4)	0.0071 (4)	0.0090 (4)
O2	0.0261 (6)	0.0313 (6)	0.0364 (6)	0.0010 (5)	0.0119 (5)	0.0116 (5)
O3	0.0240 (5)	0.0134 (5)	0.0315 (6)	0.0002 (4)	0.0063 (4)	−0.0009 (4)
N1	0.0171 (6)	0.0118 (6)	0.0186 (6)	0.0003 (4)	0.0039 (4)	−0.0005 (4)
C1	0.0178 (7)	0.0139 (7)	0.0167 (6)	−0.0007 (5)	0.0051 (5)	0.0030 (5)
C2	0.0203 (7)	0.0148 (7)	0.0173 (7)	−0.0006 (5)	0.0069 (5)	0.0011 (5)
C3	0.0186 (7)	0.0208 (7)	0.0167 (7)	−0.0025 (6)	0.0040 (5)	0.0020 (5)
C4	0.0152 (6)	0.0230 (8)	0.0212 (7)	0.0007 (5)	0.0064 (5)	0.0071 (6)
C5	0.0220 (7)	0.0207 (7)	0.0217 (7)	0.0025 (6)	0.0110 (6)	0.0017 (6)
C6	0.0214 (7)	0.0187 (7)	0.0167 (7)	−0.0003 (5)	0.0071 (5)	0.0001 (5)
C7	0.0198 (7)	0.0221 (7)	0.0173 (7)	−0.0017 (6)	0.0073 (5)	−0.0030 (6)
C8	0.0188 (7)	0.0283 (8)	0.0235 (8)	−0.0005 (6)	0.0076 (6)	−0.0014 (6)
C9	0.0189 (7)	0.0158 (7)	0.0155 (6)	−0.0011 (5)	0.0057 (5)	0.0013 (5)
C10	0.0175 (7)	0.0182 (7)	0.0234 (7)	−0.0001 (5)	0.0050 (5)	0.0004 (6)

Geometric parameters (Å, º) top

Cl1—C2	1.7378 (15)	C4—C5	1.385 (2)
O1—C7	1.3692 (18)	C5—C6	1.388 (2)
O1—C4	1.4033 (17)	C5—H5	0.9500
O2—C7	1.1958 (19)	C6—H6	0.9500
O3—C9	1.2271 (18)	C7—C8	1.494 (2)
N1—C9	1.3592 (18)	C8—H8A	0.9800
N1—C1	1.4129 (17)	C8—H8B	0.9800
N1—H1N	0.87 (2)	C8—H8C	0.9800
C1—C6	1.393 (2)	C9—C10	1.5027 (19)
C1—C2	1.3965 (19)	C10—H10A	0.9800
C2—C3	1.389 (2)	C10—H10B	0.9800
C3—C4	1.376 (2)	C10—H10C	0.9800
C3—H3	0.9500

C7—O1—C4	116.09 (11)	C5—C6—H6	119.4
C9—N1—C1	124.31 (12)	C1—C6—H6	119.4
C9—N1—H1N	118.6 (13)	O2—C7—O1	122.79 (14)
C1—N1—H1N	117.1 (13)	O2—C7—C8	126.87 (14)
C6—C1—C2	118.04 (13)	O1—C7—C8	110.33 (12)
C6—C1—N1	121.95 (12)	C7—C8—H8A	109.5
C2—C1—N1	120.01 (13)	C7—C8—H8B	109.5
C3—C2—C1	121.72 (13)	H8A—C8—H8B	109.5
C3—C2—Cl1	118.56 (11)	C7—C8—H8C	109.5
C1—C2—Cl1	119.72 (11)	H8A—C8—H8C	109.5
C4—C3—C2	118.35 (13)	H8B—C8—H8C	109.5
C4—C3—H3	120.8	O3—C9—N1	122.91 (13)
C2—C3—H3	120.8	O3—C9—C10	121.46 (13)
C3—C4—C5	121.84 (13)	N1—C9—C10	115.63 (13)
C3—C4—O1	119.30 (13)	C9—C10—H10A	109.5
C5—C4—O1	118.81 (13)	C9—C10—H10B	109.5
C4—C5—C6	118.91 (14)	H10A—C10—H10B	109.5
C4—C5—H5	120.5	C9—C10—H10C	109.5
C6—C5—H5	120.5	H10A—C10—H10C	109.5
C5—C6—C1	121.12 (13)	H10B—C10—H10C	109.5

C9—N1—C1—C6	41.6 (2)	C7—O1—C4—C5	86.39 (17)
C9—N1—C1—C2	−138.86 (14)	C3—C4—C5—C6	0.3 (2)
C6—C1—C2—C3	0.2 (2)	O1—C4—C5—C6	177.91 (13)
N1—C1—C2—C3	−179.30 (13)	C4—C5—C6—C1	−1.2 (2)
C6—C1—C2—Cl1	−179.28 (11)	C2—C1—C6—C5	0.9 (2)
N1—C1—C2—Cl1	1.21 (18)	N1—C1—C6—C5	−179.57 (13)
C1—C2—C3—C4	−1.0 (2)	C4—O1—C7—O2	6.4 (2)
Cl1—C2—C3—C4	178.46 (11)	C4—O1—C7—C8	−172.55 (12)
C2—C3—C4—C5	0.8 (2)	C1—N1—C9—O3	−0.6 (2)
C2—C3—C4—O1	−176.80 (12)	C1—N1—C9—C10	178.72 (12)
C7—O1—C4—C3	−95.97 (16)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O3ⁱ	0.87 (2)	2.01 (2)	2.8335 (17)	157.5 (17)
C8—H8A···Cl1ⁱⁱ	0.98	2.90	3.8279 (16)	159
C8—H8C···Cl1ⁱⁱⁱ	0.98	2.97	3.6541 (16)	128
C10—H10A···O3ⁱ	0.98	2.46	3.2796 (18)	141

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

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.

References

Bai, S. V., Mensah, P. F., Li, G., Fronczek, F. R. & Uppu, R. M. (2025). CSD Communication (CCDC 2492307). CCDC, Cambridge, England. Google Scholar
Bedner, M. & MacCrehan, W. A. (2006). Environ. Sci. Technol. 40, 516–522. Web of Science CrossRef PubMed CAS Google Scholar
Bruker (2016). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Hines, J. E. III, Agu, O. A., Deere, C. J. & Uppu, R. M. (2026). American Chemical Society Spring 2026 Meeting, Atlanta, GA, March 22–26. Google Scholar
Hines, J. E. III, Deere, C. J., Ogad, O. A. & Uppu, R. M. (2025). Toxicologist: Late-Breaking Supplement (Supplement to Toxicol. Sci.) 204 (S2), 218–219. Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
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. Web of Science CrossRef CAS IUCr Journals Google Scholar
Manyike, P. T., Kharasch, E. D., Kalhorn, T. F. & Slattery, J. T. (2000). Clin. Pharmacol. Ther. 67, 275–282. CrossRef PubMed CAS Google Scholar
Matsuno, T., Matsukawa, T., Sakuma, Y. & Kunieda, T. (1989). Chem. Pharm. Bull. 37, 1422–1423. CrossRef CAS Google Scholar
Mazaleuskaya, L. L., Sangkuhl, K., Thorn, C. F., FitzGerald, G. A., Altman, R. B. & Klein, T. E. (2015). Pharmacogenet. Genomics 25, 416–426. CrossRef CAS PubMed Google Scholar
Naik, S., Bhattacharjya, G., Kavala, V. R. & Patel, B. K. (2004). Arkivoc pp. 55–63. Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Soloviev, D., Hanna, F., Misuraca, M. & Hunter, C. (2022). Chem. Sci. 13, 11863–11868. CrossRef CAS PubMed Google Scholar
Uppu, R. M. & Fronczek, F. R. (2025). IUCrData 10, x250695. Google Scholar
Uppu, R. M. & Martin, R. J. (2005). Toxicologist (supplement to Toxicol. Sci), p. 319. Google Scholar
Yoon, E., Babar, A., Choudhary, M., Kutner, M. & Pyrsopoulos, N. (2016). J. Clin. Transl. Hepatol. 4, 131–142. PubMed Google Scholar

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