2-[(3-Chloro-2-methyl­phen­yl)amino]­quinoline-3-carb­oxy­lic acid

Zuo, Y.; Long, S.

doi:10.1107/S2414314626005705

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 11| Part 6| June 2026| x260570

https://doi.org/10.1107/S2414314626005705

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2-[(3-Chloro-2-methylphenyl)amino]quinoline-3-carboxylic acid

Yujie Zuo ^a and Sihui Long ^a ^*

^aSchool of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, Hubei 430205, People's Republic of China
^*Correspondence e-mail: [email protected]

Edited by I. Brito, University of Antofagasta, Chile (Received 27 May 2026; accepted 29 May 2026; online 2 June 2026)

The title compound, C₁₇H₁₃ClN₂O₂, is an analogue of fenamic acid-type non-steroidal anti-inflammatory drugs. It was prepared from 2-chloroquinoline-3-carboxylic acid and 3-chloro-2-methylaniline via palladium-catalysed Buchwald–Hartwig cross-coupling to afford the methyl ester intermediate, followed by alkaline hydrolysis. The molecule adopts a nearly planar conformation with a dihedral angle of 7.17 (5)° between the quinoline ring system and the substituted phenyl ring. Adjacent molecules form centrosymmetric carboxylic acid dimers via pairwise O—H⋯O hydrogen bonds.

Keywords: synthon; hydrogen bond; acid–acid dimer; single crystal.

CCDC reference: 2558014

Structure description

Non-steroidal anti-inflammatory drugs (NSAIDs) are mainstream clinical medicines with anti-inflammatory, analgesic and antipyretic activities. Fenamate-type diarylamine derivatives serve as important lead scaffolds for anti-inflammatory drug discovery (Luan et al. 2017 ). However, traditional fenamate molecules suffer from high conformational flexibility and disordered crystal packing, resulting in poor polymorphic stability and unstable pharmacological performance, which limits their clinical application (Uzoh et al. 2012 ). Replacing the benzene ring with a quinoline fused-ring moiety may enhance molecular conjugation and planarity, thus optimizing the molecular packing characteristics. To further explore the regulatory effects of substituents on molecular structures and solid-state properties, the title quinoline-based fenamate derivative was constructed by introducing a 3-chloro-2-methyl disubstituted group onto the N-aryl ring. The substituent effects on molecular conformations, hydrogen-bonding interactions and crystal packing were investigated, providing theoretical support for structural modification of this class of anti-inflammatory derivatives.

Herein, 2-[(3-chloro-2-methylphenyl)amino]quinoline-3-carboxylic acid (Fig. 1) was synthesized by a two-step route using 2-chloroquinoline-3-carboxylic acid and 3-chloro-2-methylaniline as starting materials. applying the palladium-catalyzed Buchwald–Hartwig cross-coupling, followed by alkaline hydrolysis, acidification and purification (Janke et al. 2019 ). A strong intramolecular N—H⋯O hydrogen bond is present in the molecule (Table 1), with a donor–acceptor distance of 2.6919 (13) Å and a bond angle of 140°. This interaction effectively restricts the free rotation of aromatic rings, yielding an approximately planar molecular conformation with a dihedral angle of 7.17 (5)° between the quinoline ring system and the substituted benzene ring.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O2ⁱ	0.82	1.83	2.6532 (13)	177
N2—H2⋯O2	0.86	1.97	2.6919 (13)	140
Symmetry code: (i) $[-x+{\script{1\over 2}}, -y+{\script{5\over 2}}, -z+1]$ .

Figure 1
Molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level.

In the crystal, adjacent molecules self-assemble into centrosymmetric carboxylic acid dimers through pairwise O—H⋯O hydrogen bonds. The donor–acceptor distance is 2.6532 (13) Å and the bond angle is 177°. These dimers further adopt a layered packing pattern (Fig. 2). The centroid-to-centroid distance between adjacent aromatic rings is 4.9749 (7) Å, hence no effective π–π stacking interactions are observed.

Figure 2
Packing of the molecules in the title compound (for clarity, H atoms not involved in hydrogen bonding are omitted).

Synthesis and crystallization

The title compound was synthesized in two steps using a Buchwald–Hartwig cross-coupling reaction followed by hydrolysis (Fig. 3). The compound was purified by column chromatography. Pale-yellow transparent block-shaped single crystals suitable for single-crystal X-ray diffraction measurements were grown by slow evaporation of an anhydrous ethyl acetate solution at ambient temperature.

Figure 3
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	C₁₇H₁₃ClN₂O₂
M_r	312.74
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	298
a, b, c (Å)	27.6987 (4), 4.97483 (8), 24.2475 (4)
β (°)	97.6652 (14)
V (Å³)	3311.36 (9)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	2.11
Crystal size (mm)	0.22 × 0.17 × 0.13

Data collection
Diffractometer	XtaLAB Synergy R, DW system, HyPix
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2024 )
T_min, T_max	0.747, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	15744, 3303, 2939
R_int	0.020
(sin θ/λ)_max (Å⁻¹)	0.630

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.119, 1.08
No. of reflections	3303
No. of parameters	201
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.35
Computer programs: CrysAlis PRO (Rigaku OD, 2024), SHELXT (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ) and OLEX2 (Dolomanov et al., 2009 ).

Structural data

CCDC reference: 2558014

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2414314626005705/bx4041sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314626005705/bx4041Isup2.hkl

checkCIF report

Computing details top

2-[(3-Chloro-2-methylphenyl)amino]quinoline-3-carboxylic acid top

Crystal data top

C₁₇H₁₃ClN₂O₂	F(000) = 1296
M_r = 312.74	D_x = 1.255 Mg m⁻³
Monoclinic, C2/c	Cu Kα radiation, λ = 1.54184 Å
a = 27.6987 (4) Å	Cell parameters from 11991 reflections
b = 4.97483 (8) Å	θ = 3.7–75.3°
c = 24.2475 (4) Å	µ = 2.11 mm⁻¹
β = 97.6652 (14)°	T = 298 K
V = 3311.36 (9) Å³	Block, clear light yellow
Z = 8	0.22 × 0.17 × 0.13 mm

Data collection top

XtaLAB Synergy R, DW system, HyPix diffractometer	3303 independent reflections
Radiation source: Rotating-anode X-ray tube, Rigaku (Cu) X-ray Source	2939 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.020
Detector resolution: 10.0000 pixels mm^-1	θ_max = 76.4°, θ_min = 4.6°
ω scans	h = −34→34
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2024)	k = −6→6
T_min = 0.747, T_max = 1.000	l = −29→29
15744 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.038	H-atom parameters constrained
wR(F²) = 0.119	w = 1/[σ²(F_o²) + (0.0732P)² + 0.6877P] where P = (F_o² + 2F_c²)/3
S = 1.08	(Δ/σ)_max = 0.001
3303 reflections	Δρ_max = 0.17 e Å⁻³
201 parameters	Δρ_min = −0.35 e Å⁻³
0 restraints

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 position of the H atom in O and the position of the H atom in C are obtained from the differential Fourier diagram. The geometric positioning of the H atom is C—H = 0.93 for the aromatic group.

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

	x	y	z	U_iso*/U_eq
Cl1	0.05724 (2)	0.47003 (12)	0.64179 (2)	0.08519 (19)
O1	0.31240 (3)	1.13616 (19)	0.52322 (4)	0.0517 (2)
H1	0.295888	1.243453	0.503101	0.078*
O2	0.23926 (3)	1.00467 (18)	0.54053 (4)	0.0498 (2)
N1	0.30894 (4)	0.4131 (2)	0.65151 (4)	0.0446 (2)
N2	0.23512 (4)	0.5993 (2)	0.61329 (4)	0.0461 (3)
H2	0.221813	0.709601	0.588480	0.055*
C00H	0.13698 (5)	0.7379 (3)	0.58383 (6)	0.0592 (4)
H00A	0.152806	0.905160	0.594516	0.089*
H00B	0.102309	0.761483	0.580278	0.089*
H00C	0.146033	0.680377	0.548826	0.089*
C1	0.28489 (4)	0.5914 (2)	0.61842 (4)	0.0398 (3)
C2	0.30970 (4)	0.7816 (2)	0.58646 (4)	0.0400 (3)
C3	0.35948 (5)	0.7756 (3)	0.59269 (5)	0.0466 (3)
H3	0.376165	0.895091	0.572572	0.056*
C4	0.38588 (5)	0.5910 (3)	0.62913 (5)	0.0482 (3)
C5	0.43749 (5)	0.5861 (3)	0.63887 (7)	0.0636 (4)
H5	0.455480	0.704892	0.620105	0.076*
C6	0.46074 (6)	0.4060 (4)	0.67600 (7)	0.0699 (4)
H6	0.494581	0.404376	0.682981	0.084*
C7	0.43373 (6)	0.2248 (3)	0.70336 (6)	0.0658 (4)
H7	0.449972	0.101335	0.727994	0.079*
C8	0.38385 (6)	0.2244 (3)	0.69483 (5)	0.0562 (3)
H8	0.366614	0.101220	0.713457	0.067*
C9	0.35855 (5)	0.4118 (2)	0.65761 (5)	0.0445 (3)
C10	0.28369 (4)	0.9822 (2)	0.54854 (5)	0.0405 (3)
C11	0.20208 (5)	0.4583 (2)	0.64160 (5)	0.0436 (3)
C12	0.15239 (5)	0.5282 (3)	0.62760 (5)	0.0462 (3)
C13	0.11928 (5)	0.3953 (3)	0.65606 (6)	0.0541 (3)
C14	0.13227 (6)	0.2027 (3)	0.69635 (6)	0.0614 (4)
H14	0.108869	0.119319	0.714622	0.074*
C15	0.18075 (6)	0.1376 (3)	0.70868 (6)	0.0628 (4)
H15	0.190216	0.007937	0.735593	0.075*
C16	0.21570 (5)	0.2618 (3)	0.68171 (5)	0.0543 (3)
H16	0.248298	0.214214	0.690344	0.065*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0481 (2)	0.1171 (4)	0.0934 (3)	0.0027 (2)	0.0205 (2)	0.0133 (3)
O1	0.0459 (5)	0.0534 (5)	0.0560 (5)	0.0025 (4)	0.0072 (4)	0.0183 (4)
O2	0.0420 (5)	0.0501 (5)	0.0562 (5)	0.0036 (4)	0.0028 (4)	0.0170 (4)
N1	0.0476 (6)	0.0440 (5)	0.0410 (5)	0.0062 (4)	0.0014 (4)	0.0040 (4)
N2	0.0419 (5)	0.0469 (6)	0.0485 (5)	0.0033 (4)	0.0023 (4)	0.0134 (4)
C00H	0.0480 (7)	0.0663 (9)	0.0632 (8)	0.0113 (6)	0.0071 (6)	0.0121 (7)
C1	0.0438 (6)	0.0381 (6)	0.0365 (5)	0.0030 (5)	0.0016 (4)	−0.0006 (4)
C2	0.0428 (6)	0.0384 (6)	0.0379 (5)	0.0037 (5)	0.0019 (4)	0.0000 (4)
C3	0.0438 (6)	0.0478 (7)	0.0480 (6)	0.0021 (5)	0.0050 (5)	0.0023 (5)
C4	0.0442 (7)	0.0505 (7)	0.0484 (6)	0.0084 (5)	0.0002 (5)	−0.0032 (5)
C5	0.0454 (7)	0.0704 (9)	0.0735 (9)	0.0082 (7)	0.0025 (6)	0.0019 (7)
C6	0.0471 (8)	0.0819 (11)	0.0765 (10)	0.0207 (7)	−0.0073 (7)	−0.0049 (8)
C7	0.0661 (9)	0.0672 (9)	0.0585 (8)	0.0262 (8)	−0.0125 (7)	−0.0020 (7)
C8	0.0630 (8)	0.0548 (7)	0.0478 (7)	0.0162 (6)	−0.0034 (6)	0.0019 (6)
C9	0.0497 (7)	0.0442 (6)	0.0376 (5)	0.0092 (5)	−0.0014 (5)	−0.0054 (5)
C10	0.0439 (6)	0.0383 (6)	0.0387 (5)	0.0015 (5)	0.0035 (5)	0.0012 (4)
C11	0.0465 (7)	0.0421 (6)	0.0419 (6)	−0.0016 (5)	0.0056 (5)	0.0008 (5)
C12	0.0475 (7)	0.0466 (6)	0.0448 (6)	0.0009 (5)	0.0074 (5)	−0.0032 (5)
C13	0.0490 (7)	0.0612 (8)	0.0534 (7)	−0.0026 (6)	0.0115 (5)	−0.0063 (6)
C14	0.0648 (9)	0.0666 (9)	0.0558 (8)	−0.0103 (7)	0.0189 (6)	0.0051 (7)
C15	0.0714 (9)	0.0633 (9)	0.0540 (7)	−0.0057 (7)	0.0090 (7)	0.0158 (7)
C16	0.0548 (7)	0.0549 (7)	0.0520 (7)	−0.0016 (6)	0.0029 (6)	0.0131 (6)

Geometric parameters (Å, º) top

Cl1—C13	1.7470 (15)	C4—C5	1.4175 (19)
O1—C10	1.3138 (14)	C4—C9	1.4088 (19)
O2—C10	1.2253 (15)	C5—C6	1.369 (2)
N1—C1	1.3158 (15)	C6—C7	1.395 (3)
N1—C9	1.3623 (16)	C7—C8	1.369 (2)
N2—C1	1.3682 (15)	C8—C9	1.4163 (17)
N2—C11	1.4029 (16)	C11—C12	1.4162 (18)
C00H—C12	1.5087 (18)	C11—C16	1.3952 (17)
C1—C2	1.4525 (16)	C12—C13	1.3867 (19)
C2—C3	1.3674 (17)	C13—C14	1.381 (2)
C2—C10	1.4777 (15)	C14—C15	1.375 (2)
C3—C4	1.4094 (18)	C15—C16	1.384 (2)

C1—N1—C9	119.40 (11)	N1—C9—C8	118.60 (12)
C1—N2—C11	131.02 (10)	C4—C9—C8	118.46 (12)
N1—C1—N2	119.80 (11)	O1—C10—C2	114.17 (10)
N1—C1—C2	121.82 (11)	O2—C10—O1	122.03 (10)
N2—C1—C2	118.38 (10)	O2—C10—C2	123.79 (11)
C1—C2—C10	123.09 (10)	N2—C11—C12	115.89 (11)
C3—C2—C1	117.96 (10)	C16—C11—N2	123.92 (12)
C3—C2—C10	118.95 (11)	C16—C11—C12	120.19 (12)
C2—C3—C4	120.97 (12)	C11—C12—C00H	120.85 (12)
C3—C4—C5	122.89 (13)	C13—C12—C00H	122.41 (12)
C9—C4—C3	116.87 (12)	C13—C12—C11	116.74 (12)
C9—C4—C5	120.22 (12)	C12—C13—Cl1	119.89 (11)
C6—C5—C4	119.76 (16)	C14—C13—Cl1	116.37 (11)
C5—C6—C7	120.05 (15)	C14—C13—C12	123.74 (13)
C8—C7—C6	121.58 (13)	C15—C14—C13	118.15 (13)
C7—C8—C9	119.91 (15)	C14—C15—C16	121.10 (13)
N1—C9—C4	122.94 (11)	C15—C16—C11	120.08 (13)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2ⁱ	0.82	1.83	2.6532 (13)	177
N2—H2···O2	0.86	1.97	2.6919 (13)	140

Symmetry code: (i) −x+1/2, −y+5/2, −z+1.

Acknowledgements

YJZ and SL thank the Graduate Innovation Fund of WIT for financial support.

References

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