2-Chloro-4-hy­droxy­anilinium chloride

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

doi:10.1107/S2414314625008934

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 10| Part 10| October 2025| x250893

https://doi.org/10.1107/S2414314625008934

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2-Chloro-4-hydroxyanilinium chloride

Sindhu V. Bai,^a Patrick F. Mensah,^b Guoqiang Li,^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 Engineering, Southern University and A&M College, Baton, Rouge, Louisiana 70813, USA, ^cDepartment of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, Louisiana 70803, USA, and ^dDepartment of Chemistry, Louisiana State University, Baton Rouge, Louisiana, 70803, USA
^*Correspondence e-mail: [email protected]

(Received 2 October 2025; accepted 14 October 2025; online 17 October 2025)

The title compound, C₆H₇ClNO⁺·Cl⁻, crystallizes in orthorhombic space group Pnma with both cations and anions lying on a mirror plane in the crystal. The C—Cl distance is 1.7289 (6) Å, the C—N distance is 1.4590 (8) Å, and the C—O distance is 1.3617 (8) Å. Parallel molecules form stacks with interplanar spacing 3.1473 (2) Å, but slipped by 1.97 Å. The NH₃⁺ substituent donates three intermolecular hydrogen bonds to chloride ions having N⋯Cl distances in the range 3.1514 (6)–3.3019 (2) Å, and the OH group donates an intermolecular hydrogen bond to chloride with O⋯Cl distance 3.0671 (6) Å. The chloro substituent and OH group do not accept hydrogen bonds from NH or OH.

Keywords: crystal structure; 4-amino-3-chloroaniline; lenvatinib and tivozanib; tyrosine kinase inhibitors; anticancer drugs and intermediates.

CCDC reference: 2495195

Structure description

4-Hydroxy-2-chloroanilinium chloride is the hydrochloride salt form of the well-established intermediate 4-amino-3-chlorophenol. This compound occupies a central role in pharmaceutical chemistry as a key starting material in the large-scale synthesis of the multikinase inhibitors lenvatinib and tivozanib, which act primarily through potent inhibition of vascular endothelial growth factor receptor (VEGFR) signaling pathways (CN 104326924 A, 2015 ; EP 3620452A1, 2020 ; Nair et al., 2015 ). The simultaneous presence of an aniline amino and a phenolic hydroxyl group renders this scaffold a privileged synthon, particularly suited for the preparation of phenoxy-anilide derivatives. Such derivatives have been widely adopted in kinase inhibitor design and continue to attract attention as versatile structural motifs for next generation anticancer therapeutics (Kumar et al., 2015 ).

Structural biology investigations have demonstrated that the phenoxy-anilide fragment derived from this intermediate is a critical determinant of VEGFR binding. In lenvatinib, this fragment stabilizes occupancy within the ATP-binding site and an adjacent hydrophobic pocket of VEGFR2 (Pan et al., 2021 ; Okamoto et al., 2014 ; Yamamoto et al., 2014 ), thereby enabling potent inhibition across VEGFR1–3 as well as FGFR1–4. Tivozanib employs the same pharmacophore unit to achieve selective kinase blockade (CN 104326924A, 2015). Beyond these clinical examples, the scaffold continues to be featured in discovery libraries and in the design of dual-target inhibitors. Recent advances have further enhanced its industrial relevance, with continuous-flow synthetic routes improving both safety and efficiency (CN 107739313A, 2020 ).

Against this background, it was considered that the crystal structure of 4-amino-3-chlorophenol hydrochloride would provide valuable insights into its molecular conformation, hydrogen-bonding patterns, and supramolecular packing. These structural parameters are expected not only to clarify the stability of the salt form, but also to rationalize its synthetic utility in downstream coupling reactions. In view of its broad applications to mechanistic understanding and its potential for new drug development, we therefore undertook an X-ray diffraction study of the title compound at 100 K.

The ellipsoids and atom numbering are shown in Fig. 1. Both cations and anions lie on a mirror plane, thus, except for two ammonium H atoms related by the mirror, the cation is rigorously planar, and all cations are parallel. This is shown in Fig. 2, a view of the unit cell down the c axis. The interplanar spacing is half the b axial length, 3.1473 (2) Å, but cations related by an inversion center are horizontally slipped by 1.97 Å, as shown in the view down the b axis, Fig. 3.

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

Figure 2
A view of the unit-cell contents, in projection down the c axis.

Figure 3
A view of the unit-cell contents, in projection down the b axis.

Hydrogen bonding from both the NH₃⁺ and OH donors involve chloride only as the acceptor, not the chloro substituent nor the OH group. As shown in Fig. 4, the ammonium group donates to three different chloride ions, and the OH group donates to a fourth. Thus, chloride accepts four hydrogen bonds from NH and OH. There are longer C—H⋯Cl interactions to both chloride and the chloro substituent, as detailed in Table 1.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯Cl2ⁱ	0.82 (1)	2.25 (1)	3.0671 (6)	177 (2)
N1—H1N⋯Cl2ⁱⁱ	0.856 (12)	2.531 (13)	3.3019 (2)	150.4 (10)
N1—H2N⋯Cl2	0.90 (2)	2.25 (2)	3.1514 (6)	176 (1)
C5—H5⋯Cl2ⁱ	0.95	2.90	3.6290 (6)	134
C6—H6⋯Cl1ⁱⁱⁱ	0.95	2.84	3.5519 (6)	132
C6—H6⋯Cl2	0.95	2.84	3.6195 (6)	140
C6—H6⋯Cl1ⁱⁱⁱ	0.95	2.84	3.5519 (6)	132
Symmetry codes: (i) $[x+{\script{1\over 2}}, y, -z+{\script{3\over 2}}]$ ; (ii) $[-x+{\script{1\over 2}}, -y+2, z-{\script{1\over 2}}]$ ; (iii) .

Figure 4
Hydrogen bonding shown as dashed bonds.

Synthesis and crystallization

4-Hydroxy-2-chloroanilinium chloride (CAS 52671–64-4; purity: 98%) was obtained from AmBeed, Buffalo Grove, IL and was used without further purification. Crystallization was performed in ethanol by slow cooling of a hot, nearly saturated solution. The sample was clarified by filtration using Whatman #1 filter paper. Single crystals of the title compound were colorless needles.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. Three reflections were omitted because of beamstop problems.

Table 2
Experimental details

Crystal data
Chemical formula	C₆H₇ClNO⁺·Cl⁻
M_r	180.03
Crystal system, space group	Orthorhombic, Pnma
Temperature (K)	100
a, b, c (Å)	15.5044 (4), 6.2945 (2), 7.5260 (2)
V (Å³)	734.48 (4)
Z	4
Radiation type	Ag Kα, λ = 0.56086 Å
μ (mm⁻¹)	0.41
Crystal size (mm)	0.28 × 0.20 × 0.15

Data collection
Diffractometer	Bruker D8 Venture DUO with Photon III C14
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.881, 0.940
No. of measured, independent and observed [I > 2σ(I)] reflections	41806, 3668, 3193
R_int	0.053
(sin θ/λ)_max (Å⁻¹)	1.042

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.031, 0.089, 1.05
No. of reflections	3668
No. of parameters	68
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)	0.98, −0.50
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: 2495195

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314625008934/tk4119sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314625008934/tk4119Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314625008934/tk4119Isup3.cml

checkCIF report

Computing details top

2-Chloro-4-hydroxyanilinium chloride top

Crystal data top

C₆H₇ClNO⁺·Cl⁻	D_x = 1.628 Mg m⁻³
M_r = 180.03	Ag Kα radiation, λ = 0.56086 Å
Orthorhombic, Pnma	Cell parameters from 9968 reflections
a = 15.5044 (4) Å	θ = 3.0–35.2°
b = 6.2945 (2) Å	µ = 0.41 mm⁻¹
c = 7.5260 (2) Å	T = 100 K
V = 734.48 (4) Å³	Needle fragment, colourless
Z = 4	0.28 × 0.20 × 0.15 mm
F(000) = 368

Data collection top

Bruker D8 Venture DUO with Photon III C14 diffractometer	3193 reflections with I > 2σ(I)
Radiation source: IµS 3.0 microfocus	R_int = 0.053
φ and ω scans	θ_max = 35.8°, θ_min = 3.0°
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	h = −32→32
T_min = 0.881, T_max = 0.940	k = −13→11
41806 measured reflections	l = −14→15
3668 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.031	Hydrogen site location: mixed
wR(F²) = 0.089	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ²(F_o²) + (0.0489P)² + 0.0955P] where P = (F_o² + 2F_c²)/3
3668 reflections	(Δ/σ)_max = 0.001
68 parameters	Δρ_max = 0.98 e Å⁻³
1 restraint	Δρ_min = −0.50 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 of 0.95 Å. The coordinates of the N—H and O—H hydrogen atoms were refined, with the O—H distance restrained to 0.85 Å. U_iso(H) values were assigned as 1.2U_eq for the attached atom (1.5 for NH₃ and OH).

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

	x	y	z	U_iso*/U_eq
Cl1	0.41328 (2)	0.750000	−0.01348 (2)	0.01726 (4)
O1	0.65937 (3)	0.750000	0.42625 (8)	0.01557 (9)
H1	0.6701 (10)	0.750000	0.5329 (19)	0.023*
N1	0.30340 (4)	0.750000	0.30926 (8)	0.01320 (8)
H1N	0.2875 (7)	0.857 (2)	0.2467 (14)	0.020*
H2N	0.2735 (10)	0.750000	0.412 (2)	0.020*
C1	0.39608 (4)	0.750000	0.34282 (8)	0.01067 (8)
C2	0.45356 (4)	0.750000	0.20074 (8)	0.01172 (8)
C3	0.54184 (4)	0.750000	0.22936 (8)	0.01262 (9)
H3	0.580887	0.750000	0.132087	0.015*
C4	0.57223 (4)	0.750000	0.40361 (8)	0.01128 (8)
C5	0.51515 (4)	0.750000	0.54682 (8)	0.01106 (8)
H5	0.536501	0.750000	0.665132	0.013*
C6	0.42714 (4)	0.750000	0.51543 (8)	0.01064 (8)
H6	0.387967	0.750000	0.612496	0.013*
Cl2	0.20751 (2)	0.750000	0.67846 (2)	0.01519 (4)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.01969 (8)	0.02336 (9)	0.00874 (6)	0.000	−0.00069 (4)	0.000
O1	0.00992 (15)	0.0218 (2)	0.01502 (19)	0.000	0.00072 (13)	0.000
N1	0.01106 (17)	0.0165 (2)	0.01204 (18)	0.000	−0.00098 (14)	0.000
C1	0.01023 (17)	0.0120 (2)	0.00982 (18)	0.000	0.00045 (14)	0.000
C2	0.0131 (2)	0.0133 (2)	0.00879 (17)	0.000	0.00073 (15)	0.000
C3	0.0121 (2)	0.0145 (2)	0.01128 (19)	0.000	0.00239 (15)	0.000
C4	0.01043 (17)	0.01161 (19)	0.0118 (2)	0.000	0.00095 (14)	0.000
C5	0.01029 (17)	0.0120 (2)	0.01085 (18)	0.000	0.00049 (14)	0.000
C6	0.01086 (18)	0.0119 (2)	0.00919 (18)	0.000	0.00044 (13)	0.000
Cl2	0.01500 (7)	0.01586 (7)	0.01472 (7)	0.000	0.00405 (4)	0.000

Geometric parameters (Å, º) top

Cl1—C2	1.7289 (6)	C1—C2	1.3919 (8)
O1—C4	1.3617 (8)	C2—C3	1.3856 (9)
O1—H1	0.820 (14)	C3—C4	1.3935 (9)
N1—C1	1.4590 (8)	C3—H3	0.9500
N1—H1N	0.856 (12)	C4—C5	1.3946 (8)
N1—H2N	0.899 (15)	C5—C6	1.3848 (8)
N1—H1Nⁱ	0.856 (12)	C5—H5	0.9500
C1—C6	1.3854 (8)	C6—H6	0.9500

C4—O1—H1	108.8 (12)	C2—C3—C4	118.71 (6)
C1—N1—H1N	112.3 (7)	C2—C3—H3	120.6
C1—N1—H2N	111.1 (10)	C4—C3—H3	120.6
H1N—N1—H2N	108.8 (9)	O1—C4—C3	116.96 (6)
C1—N1—H1Nⁱ	112.3 (7)	O1—C4—C5	122.20 (6)
H1N—N1—H1Nⁱ	103.2 (15)	C3—C4—C5	120.84 (6)
H2N—N1—H1Nⁱ	108.8 (9)	C6—C5—C4	119.57 (6)
C6—C1—C2	119.86 (6)	C6—C5—H5	120.2
C6—C1—N1	120.31 (5)	C4—C5—H5	120.2
C2—C1—N1	119.84 (5)	C5—C6—C1	120.16 (5)
C3—C2—C1	120.86 (6)	C5—C6—H6	119.9
C3—C2—Cl1	120.12 (5)	C1—C6—H6	119.9
C1—C2—Cl1	119.02 (5)

Symmetry code: (i) x, −y+3/2, z.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···Cl2ⁱⁱ	0.82 (1)	2.25 (1)	3.0671 (6)	177 (2)
N1—H1N···Cl2ⁱⁱⁱ	0.856 (12)	2.531 (13)	3.3019 (2)	150.4 (10)
N1—H2N···Cl2	0.90 (2)	2.25 (2)	3.1514 (6)	176 (1)
C5—H5···Cl2ⁱⁱ	0.95	2.90	3.6290 (6)	134
C6—H6···Cl1^iv	0.95	2.84	3.5519 (6)	132
C6—H6···Cl2	0.95	2.84	3.6195 (6)	140
C6—H6···Cl1^iv	0.95	2.84	3.5519 (6)	132

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

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