2-[(2,5-Di­methyl­phen­yl)amino]­quinoline-3-carb­oxy­lic acid

Ji, X.; Long, S.

doi:10.1107/S2414314626005468

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 11| Part 5| May 2026| x260546

https://doi.org/10.1107/S2414314626005468

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2-[(2,5-Dimethylphenyl)amino]quinoline-3-carboxylic acid

Xiao Ji ^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 12 May 2026; accepted 23 May 2026; online 29 May 2026)

The title compound, C₁₈H₁₆N₂O₂, was synthesized via a two-step route with the Buchwald–Hartwig cross-coupling reaction. The quinoline ring system and phenyl ring of the molecule are nearly coplanar with a dihedral angle of 6.51 (5)°. In the crystal, adjacent molecules form carboxylic acid dimers via intermolecular hydrogen bonding.

Keywords: hydrogen bond; acid-acid dimer; single crystal.

CCDC reference: 2556276

Structure description

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medicines that exert antipyretic, analgesic, and anti-inflammatory effects by inhibiting cyclooxygenase (COX). They are widely used in the treatment of rheumatoid arthritis, osteoarthritis, and acute pain (Vishwakarma & Negi, 2020 ). Classic NSAIDs such as ibuprofen, naproxen, and flurbiprofen all contain an arylpropionic acid or arylacetic acid structure, and their efficacy is closely related to the carboxyl group in the molecule (Astrvatham et al., 2019 ). However, these drugs usually suffer from poor water solubility, variable bioavailability, and gastrointestinal adverse effects. In recent years, studies have shown that the polymorphism of solid drugs directly affects their solubility, dissolution rate, stability, and even biological activity (Bindu et al., 2020 ). For example, different polymorphs of ibuprofen exhibit significantly different dissolution behaviors, which in turn affect in vivo absorption (Zhou et al., 2024 ). Therefore, systematic studies on the polymorphism of NSAIDs are of great significance for optimizing formulation processes, improving therapeutic efficacy, and circumventing patents (Ley et al., 2025 ). Research on drug polymorphism holds promise for discovering new crystal forms of drugs, thereby enhancing their druggability and providing a solid scientific basis for generic drug development. Furthermore, clarifying the polymorphic behavior of intermediates or products can provide key guidance for subsequent formulation screening, helping to select the thermodynamically stable crystal form with the best bioavailability, thereby reducing the risk of efficacy fluctuations caused by crystal form transformation.

In the title compound (Fig. 1), the two aromatic moieties are nearly coplanar with a dihedral angle of 6.51 (5)°. In the crystal (Fig. 2), adjacent molecules form carboxylic acid dimers via intermolecular hydrogen bonding (Table 1).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2⋯O2	0.86	1.96	2.6925 (13)	142
C15—H15⋯N1	0.93	2.30	2.9134 (15)	123
O1—H1⋯O2ⁱ	0.82	1.85	2.6702 (12)	178
Symmetry code: (i) .

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

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 target compound 2-[(2,5-dimethylphenyl)amino]quinoline-3-carboxylic acid was synthesized (Fig. 3) via a two-step route with the Buchwald–Hartwig cross-coupling reaction. In the first step, methyl 2-chloroquinoline-3-carboxylate reacted with 2,5-dimethylaniline in toluene for 24 h using Pd(OAc)₂/BINAP as the catalytic system and Cs₂CO₃ as the base. The intermediate methyl 2-[(2,5-dimethylphenyl)amino]quinoline-3-carboxylate was obtained by extraction followed by column chromatography. In the second step, the above intermediate was hydrolyzed in an aqueous ethanol solution containing KOH for 6 h. After the reaction, the mixture was acidified, and the target product was isolated by extraction and purified by column chromatography. Pure 2-[(2,5-dimethylphenyl)amino]quinoline-3-carboxylic acid was dried for 8 h. Single crystals were obtained by slow evaporation of an ethanol solution at room 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	C₁₈H₁₆N₂O₂
M_r	292.33
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	299
a, b, c (Å)	4.80942 (7), 11.8944 (2), 12.9466 (2)
α, β, γ (°)	88.9803 (13), 85.8751 (12), 84.4910 (12)
V (Å³)	735.24 (2)
Z	2
Radiation type	Cu Kα
μ (mm⁻¹)	0.70
Crystal size (mm)	0.21 × 0.05 × 0.04

Data collection
Diffractometer	XtaLAB Synergy R, DW system, HyPix
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2024 )
T_min, T_max	0.805, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	7863, 2904, 2659
R_int	0.021
(sin θ/λ)_max (Å⁻¹)	0.629

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.039, 0.118, 1.07
No. of reflections	2904
No. of parameters	203
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.22, −0.16
Computer programs: CrysAlis PRO (Rigaku OD, 2024), SHELXT (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ), OLEX2 (Dolomanov et al., 2009 ) and Mercury (Macrae et al., 2020 ).

Structural data

CCDC reference: 2556276

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2414314626005468/bx4040sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314626005468/bx4040Isup2.hkl

checkCIF report

Computing details top

2-[(2,5-Dimethylphenyl)amino]quinoline-3-carboxylic acid top

Crystal data top

C₁₈H₁₆N₂O₂	Z = 2
M_r = 292.33	F(000) = 308
Triclinic, P1	D_x = 1.320 Mg m⁻³
a = 4.80942 (7) Å	Cu Kα radiation, λ = 1.54184 Å
b = 11.8944 (2) Å	Cell parameters from 2760 reflections
c = 12.9466 (2) Å	θ = 3.4–74.8°
α = 88.9803 (13)°	µ = 0.70 mm⁻¹
β = 85.8751 (12)°	T = 299 K
γ = 84.4910 (12)°	Needle, clear dark yellow
V = 735.24 (2) Å³	0.21 × 0.05 × 0.04 mm

Data collection top

XtaLAB Synergy R, DW system, HyPix diffractometer	2904 independent reflections
Radiation source: Rotating-anode X-ray tube, Rigaku (Cu) X-ray Source	2659 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.021
Detector resolution: 10.0000 pixels mm^-1	θ_max = 76.0°, θ_min = 3.4°
ω scans	h = −5→5
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2024)	k = −14→14
T_min = 0.805, T_max = 1.000	l = −16→16
7863 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.039	w = 1/[σ²(F_o²) + (0.0644P)² + 0.1121P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.118	(Δ/σ)_max < 0.001
S = 1.07	Δρ_max = 0.22 e Å⁻³
2904 reflections	Δρ_min = −0.16 e Å⁻³
203 parameters	Extinction correction: SHELXL2018/3 (Sheldrick 2015b), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0035 (12)
Primary atom site location: dual

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 and the geometric positioning of the H atom is O—H = 0.82 for the methyl group.

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

	x	y	z	U_iso*/U_eq
O1	−0.35770 (17)	0.61275 (7)	0.41684 (7)	0.0472 (2)
H1	−0.479882	0.599790	0.461771	0.071*
O2	−0.23465 (17)	0.42979 (7)	0.44090 (6)	0.0456 (2)
N1	0.4312 (2)	0.45264 (8)	0.20624 (7)	0.0415 (3)
N2	0.2069 (2)	0.33488 (8)	0.32298 (8)	0.0437 (3)
H2	0.070482	0.332918	0.369511	0.052*
C1	0.2313 (2)	0.43900 (9)	0.27944 (8)	0.0360 (3)
C2	0.0353 (2)	0.53280 (9)	0.31657 (8)	0.0362 (3)
C3	0.0700 (2)	0.63768 (10)	0.27559 (9)	0.0429 (3)
H3	−0.050859	0.699194	0.298862	0.052*
C4	0.2853 (2)	0.65434 (10)	0.19880 (9)	0.0428 (3)
C5	0.3314 (3)	0.76093 (12)	0.15430 (12)	0.0604 (4)
H5	0.221114	0.825172	0.177780	0.072*
C6	0.5367 (3)	0.77007 (13)	0.07711 (12)	0.0641 (4)
H6	0.565416	0.840374	0.047888	0.077*
C7	0.7041 (3)	0.67368 (13)	0.04186 (11)	0.0585 (4)
H7	0.841604	0.680419	−0.011595	0.070*
C8	0.6686 (3)	0.57010 (12)	0.08475 (10)	0.0510 (3)
H8	0.783743	0.507189	0.061076	0.061*
C9	0.4577 (2)	0.55755 (10)	0.16501 (9)	0.0396 (3)
C10	0.3639 (2)	0.23006 (9)	0.30574 (9)	0.0392 (3)
C11	0.2930 (2)	0.14151 (10)	0.37352 (9)	0.0426 (3)
C12	0.4354 (3)	0.03583 (11)	0.35730 (11)	0.0518 (3)
H12	0.390172	−0.023759	0.400831	0.062*
C13	0.6432 (3)	0.01616 (11)	0.27818 (11)	0.0532 (3)
H13	0.733864	−0.055992	0.269038	0.064*
C14	0.7167 (3)	0.10343 (11)	0.21262 (10)	0.0459 (3)
C15	0.5758 (2)	0.21017 (10)	0.22698 (9)	0.0436 (3)
H15	0.623613	0.269343	0.183389	0.052*
C16	−0.1953 (2)	0.51938 (9)	0.39614 (8)	0.0365 (3)
C17	0.0690 (3)	0.15969 (11)	0.46105 (10)	0.0519 (3)
H17A	0.101986	0.224403	0.500077	0.078*
H17B	0.073923	0.094170	0.505505	0.078*
H17C	−0.111249	0.172065	0.433234	0.078*
C18	0.9457 (3)	0.08438 (12)	0.12718 (11)	0.0586 (4)
H18A	0.919523	0.141436	0.074471	0.088*
H18B	0.938963	0.011242	0.097787	0.088*
H18C	1.124263	0.088331	0.154902	0.088*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0412 (5)	0.0431 (5)	0.0534 (5)	0.0014 (3)	0.0146 (4)	0.0031 (4)
O2	0.0426 (4)	0.0430 (5)	0.0478 (5)	−0.0009 (3)	0.0145 (3)	0.0055 (4)
N1	0.0430 (5)	0.0402 (5)	0.0397 (5)	−0.0053 (4)	0.0101 (4)	0.0021 (4)
N2	0.0438 (5)	0.0379 (5)	0.0460 (5)	−0.0023 (4)	0.0172 (4)	0.0046 (4)
C1	0.0355 (5)	0.0381 (6)	0.0339 (5)	−0.0050 (4)	0.0038 (4)	0.0008 (4)
C2	0.0330 (5)	0.0404 (6)	0.0346 (5)	−0.0040 (4)	0.0019 (4)	0.0015 (4)
C3	0.0399 (6)	0.0404 (6)	0.0466 (6)	0.0001 (4)	0.0037 (5)	0.0042 (5)
C4	0.0410 (6)	0.0431 (6)	0.0440 (6)	−0.0059 (5)	0.0008 (5)	0.0081 (5)
C5	0.0599 (8)	0.0465 (7)	0.0715 (9)	−0.0028 (6)	0.0101 (7)	0.0167 (7)
C6	0.0665 (9)	0.0556 (8)	0.0692 (9)	−0.0152 (7)	0.0087 (7)	0.0243 (7)
C7	0.0580 (8)	0.0679 (9)	0.0493 (7)	−0.0190 (7)	0.0125 (6)	0.0115 (6)
C8	0.0519 (7)	0.0553 (7)	0.0447 (7)	−0.0115 (6)	0.0126 (5)	0.0025 (6)
C9	0.0392 (6)	0.0455 (6)	0.0345 (5)	−0.0091 (5)	0.0012 (4)	0.0031 (5)
C10	0.0391 (6)	0.0359 (6)	0.0418 (6)	−0.0045 (4)	0.0041 (4)	0.0000 (4)
C11	0.0425 (6)	0.0401 (6)	0.0449 (6)	−0.0081 (5)	0.0051 (5)	0.0009 (5)
C12	0.0571 (7)	0.0380 (6)	0.0587 (8)	−0.0062 (5)	0.0067 (6)	0.0071 (5)
C13	0.0554 (7)	0.0382 (6)	0.0630 (8)	0.0034 (5)	0.0068 (6)	−0.0009 (6)
C14	0.0445 (6)	0.0455 (6)	0.0459 (6)	−0.0003 (5)	0.0048 (5)	−0.0044 (5)
C15	0.0450 (6)	0.0400 (6)	0.0439 (6)	−0.0029 (5)	0.0084 (5)	0.0018 (5)
C16	0.0327 (5)	0.0405 (6)	0.0357 (5)	−0.0021 (4)	0.0006 (4)	−0.0004 (4)
C17	0.0580 (8)	0.0431 (7)	0.0526 (7)	−0.0102 (5)	0.0160 (6)	0.0049 (5)
C18	0.0585 (8)	0.0562 (8)	0.0560 (8)	0.0074 (6)	0.0148 (6)	−0.0047 (6)

Geometric parameters (Å, º) top

O1—C16	1.3150 (13)	C5—C6	1.364 (2)
O2—C16	1.2281 (13)	C6—C7	1.400 (2)
N1—C1	1.3199 (14)	C7—C8	1.3631 (19)
N1—C9	1.3621 (15)	C8—C9	1.4149 (15)
N2—C1	1.3633 (14)	C10—C11	1.4102 (16)
N2—C10	1.4070 (14)	C10—C15	1.3954 (15)
C1—C2	1.4549 (15)	C11—C12	1.3844 (18)
C2—C3	1.3672 (16)	C11—C17	1.5099 (16)
C2—C16	1.4765 (14)	C12—C13	1.3855 (19)
C3—C4	1.4087 (16)	C13—C14	1.3852 (18)
C4—C5	1.4135 (17)	C14—C15	1.3894 (17)
C4—C9	1.4095 (17)	C14—C18	1.5078 (17)

C1—N1—C9	119.30 (10)	N1—C9—C8	118.53 (11)
C1—N2—C10	131.81 (9)	C4—C9—C8	118.43 (11)
N1—C1—N2	119.81 (10)	N2—C10—C11	115.75 (10)
N1—C1—C2	121.83 (10)	C15—C10—N2	124.25 (10)
N2—C1—C2	118.36 (9)	C15—C10—C11	120.00 (11)
C1—C2—C16	122.98 (10)	C10—C11—C17	121.81 (11)
C3—C2—C1	117.75 (10)	C12—C11—C10	117.80 (11)
C3—C2—C16	119.27 (10)	C12—C11—C17	120.38 (11)
C2—C3—C4	121.26 (11)	C11—C12—C13	121.98 (11)
C3—C4—C5	123.55 (12)	C14—C13—C12	120.32 (11)
C3—C4—C9	116.75 (11)	C13—C14—C15	118.79 (11)
C9—C4—C5	119.68 (11)	C13—C14—C18	121.21 (11)
C6—C5—C4	120.36 (14)	C15—C14—C18	120.00 (11)
C5—C6—C7	120.03 (12)	C14—C15—C10	121.09 (11)
C8—C7—C6	120.95 (12)	O1—C16—C2	114.30 (9)
C7—C8—C9	120.51 (13)	O2—C16—O1	121.77 (9)
N1—C9—C4	123.04 (10)	O2—C16—C2	123.92 (10)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O2	0.86	1.96	2.6925 (13)	142
C15—H15···N1	0.93	2.30	2.9134 (15)	123
O1—H1···O2ⁱ	0.82	1.85	2.6702 (12)	178

Symmetry code: (i) −x−1, −y+1, −z+1.

Acknowledgements

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

References

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