2-Methyl-4-[(4-methyl­phen­yl)amino]­benzoic acid

He, F.; Long, S.

doi:10.1107/S2414314625004559

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 10| Part 5| May 2025| x250455

https://doi.org/10.1107/S2414314625004559

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2-Methyl-4-[(4-methylphenyl)amino]benzoic acid

Fang He ^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 W. T. A. Harrison, University of Aberdeen, United Kingdom (Received 11 November 2024; accepted 22 May 2025; online 30 May 2025)

In the title compound, C₁₅H₁₅NO₂, which was prepared using a Buchwald–Hartwig cross-coupling reaction followed by ester hydrolysis, the dihedral angle between the aromatic rings is 42.44 (7)°. In the crystal, the molecules associate to form centrosymmetric acid–acid dimers.

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

CCDC reference: 2453294

Structure description

Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of widely used therapeutic drugs in clinical practice for reducing pain and inflammation, and have been shown to protect against many other diseases (Zinellu et al., 2005 ), including cancer and cardiac diseases (Bindu et al., 2020 ). They are among the most commonly used over-the-counter drugs worldwide (Tsutsumi et al., 2004 ). Among the NSAIDs, anthranilic acids are an important branch. For example mefenamic acid can be used to treat mild to moderate postoperative pain and vascular headache, etc., and can be rapidly absorbed by the human body after oral administration (Samie et al., 2017 ). There are currently three known crystal forms of mefenamic acid (Cimolai, 2013 ). As part of our studies in this area, we now report the synthesis and structure of the title compound, (I), which was prepared by a Buchwald–Hartwig cross-coupling reaction between methyl 4-bromo-2-methylbenzoate and 4-methylaniline followed by ester hydrolysis.

The C1–C6 and C9–C14 aromatic rings in (I) are not coplanar (Fig. 1) due to steric repulsion: they subtend a dihedral angle of 42.44 (7)°. In the crystal, the molecules form centrosymmetric carboxylic acid–carboxylic acid hydrogen-bonded dimers linked by pairwise O—H⋯O hydrogen bonds thereby generating R₂²(8) loops (Fig. 2). Weak pairwise N—H⋯π and C—H⋯O interactions also occur (Table 1).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O2ⁱ	0.84	1.81	2.6450 (16)	175
N1—H1A⋯Cg2ⁱⁱ	0.88	2.93	3.5460 (15)	128
C14—H14⋯O1ⁱⁱⁱ	0.95	2.51	3.4368 (18)	165
Symmetry codes: (i) ; (ii) $[-x+{\script{3\over 2}}, -y+{\script{1\over 2}}, -z+1]$ ; (iii) $[-x+{\script{3\over 2}}, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

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

Figure 2
Packing of the molecules of (I) with hydrogen bonds indicated by blue dashed lines (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 and a hydrolysis reaction (Fig. 3). The compound was purified by column chromatography. Single crystals were obtained by slowly evaporating an ethyl acetate solution of the compound.

Figure 3
Synthesis scheme for (I).

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₁₅H₁₅NO₂
M_r	241.28
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	150
a, b, c (Å)	16.4180 (5), 9.9205 (3), 15.2137 (5)
β (°)	95.722 (3)
V (Å³)	2465.58 (12)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	0.69
Crystal size (mm)	0.44 × 0.32 × 0.21

Data collection
Diffractometer	ROD, Synergy Custom system, HyPix
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2024 $[Rigaku OD (2024). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ )
T_min, T_max	0.525, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	8217, 2419, 2168
R_int	0.027
(sin θ/λ)_max (Å⁻¹)	0.629

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.046, 0.133, 1.10
No. of reflections	2419
No. of parameters	167
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.25, −0.21
Computer programs: CrysAlis PRO (Rigaku OD, 2024 $[Rigaku OD (2024). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SHELXT (Sheldrick, 2015a a), SHELXL2018/3 (Sheldrick, 2015b ) and OLEX2 (Dolomanov et al., 2009 ).

Structural data

CCDC reference: 2453294

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2414314625004559/hb4493sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314625004559/hb4493Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314625004559/hb4493Isup3.cml

checkCIF report

Computing details top

2-Methyl-4-[(4-methylphenyl)amino]benzoic acid top

Crystal data top

C₁₅H₁₅NO₂	F(000) = 1024
M_r = 241.28	D_x = 1.300 Mg m⁻³
Monoclinic, C2/c	Cu Kα radiation, λ = 1.54184 Å
a = 16.4180 (5) Å	Cell parameters from 6313 reflections
b = 9.9205 (3) Å	θ = 5.2–75.8°
c = 15.2137 (5) Å	µ = 0.69 mm⁻¹
β = 95.722 (3)°	T = 150 K
V = 2465.58 (12) Å³	Block, colourless
Z = 8	0.44 × 0.32 × 0.21 mm

Data collection top

ROD, Synergy Custom system, HyPix diffractometer	2419 independent reflections
Radiation source: Rotating-anode X-ray tube, Rigaku (Cu) X-ray Source	2168 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.027
Detector resolution: 10.0000 pixels mm^-1	θ_max = 75.8°, θ_min = 5.2°
ω scans	h = −20→20
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2024)	k = −12→8
T_min = 0.525, T_max = 1.000	l = −19→18
8217 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)] = 0.046	w = 1/[σ²(F_o²) + (0.0739P)² + 1.2032P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.133	(Δ/σ)_max < 0.001
S = 1.10	Δρ_max = 0.25 e Å⁻³
2419 reflections	Δρ_min = −0.20 e Å⁻³
167 parameters	Extinction correction: SHELXL2018/3 (Sheldrick, 2015b), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0029 (4)
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 O-bound H atom was located in a difference map and refined in its as-found relative position. The other H atoms were geometrically placed in idealized locations (C—H = 0.95–0.98, N—H = 0.88 Å) and refined as riding atoms.

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

	x	y	z	U_iso*/U_eq
O1	0.53523 (7)	0.57979 (10)	0.90364 (8)	0.0453 (3)
H1	0.513945	0.592474	0.950925	0.068*
O2	0.52812 (7)	0.36584 (11)	0.94716 (7)	0.0467 (3)
N1	0.74595 (8)	0.32437 (14)	0.61998 (9)	0.0445 (4)
H1A	0.758886	0.238319	0.619262	0.053*
C1	0.69439 (8)	0.36056 (15)	0.68229 (10)	0.0369 (4)
C2	0.65895 (8)	0.25743 (14)	0.72803 (10)	0.0366 (3)
H2	0.668889	0.166836	0.711902	0.044*
C3	0.61021 (8)	0.28018 (14)	0.79546 (9)	0.0332 (3)
C4	0.59475 (8)	0.41564 (14)	0.81851 (9)	0.0335 (3)
C5	0.62848 (9)	0.51880 (15)	0.77126 (10)	0.0374 (3)
H5	0.616905	0.609612	0.785434	0.045*
C6	0.67791 (9)	0.49426 (15)	0.70487 (10)	0.0393 (4)
H6	0.700533	0.567010	0.674770	0.047*
C7	0.57618 (9)	0.16081 (14)	0.83972 (10)	0.0397 (4)
H7A	0.599543	0.157063	0.901512	0.059*
H7B	0.590199	0.078181	0.809301	0.059*
H7C	0.516513	0.169078	0.837310	0.059*
C8	0.54936 (8)	0.45005 (14)	0.89410 (9)	0.0348 (3)
C9	0.78086 (9)	0.40470 (16)	0.55745 (10)	0.0385 (4)
C10	0.74147 (9)	0.51372 (17)	0.51438 (10)	0.0436 (4)
H10	0.688559	0.539547	0.528380	0.052*
C11	0.77868 (9)	0.58451 (17)	0.45156 (10)	0.0436 (4)
H11	0.751010	0.659471	0.423548	0.052*
C12	0.85580 (9)	0.54941 (16)	0.42783 (10)	0.0404 (4)
C13	0.89357 (9)	0.43812 (16)	0.47018 (11)	0.0427 (4)
H13	0.945586	0.410170	0.454627	0.051*
C14	0.85766 (9)	0.36754 (15)	0.53389 (11)	0.0423 (4)
H14	0.885419	0.292813	0.562098	0.051*
C15	0.89559 (11)	0.62890 (17)	0.35944 (12)	0.0504 (4)
H15A	0.910292	0.718655	0.382809	0.076*
H15B	0.857318	0.637784	0.306056	0.076*
H15C	0.945053	0.582004	0.344935	0.076*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0555 (7)	0.0317 (6)	0.0516 (7)	0.0040 (5)	0.0205 (5)	−0.0048 (4)
O2	0.0583 (7)	0.0346 (6)	0.0506 (7)	0.0008 (5)	0.0217 (5)	−0.0026 (5)
N1	0.0459 (7)	0.0369 (7)	0.0531 (8)	0.0010 (5)	0.0170 (6)	−0.0082 (6)
C1	0.0315 (7)	0.0391 (8)	0.0403 (7)	−0.0008 (6)	0.0050 (6)	−0.0069 (6)
C2	0.0359 (7)	0.0313 (7)	0.0418 (7)	0.0022 (6)	0.0009 (6)	−0.0071 (6)
C3	0.0301 (6)	0.0308 (7)	0.0380 (7)	−0.0001 (5)	−0.0009 (5)	−0.0027 (5)
C4	0.0310 (6)	0.0307 (7)	0.0386 (7)	0.0013 (5)	0.0021 (5)	−0.0039 (5)
C5	0.0399 (7)	0.0296 (7)	0.0429 (8)	0.0010 (6)	0.0055 (6)	−0.0043 (6)
C6	0.0398 (7)	0.0338 (8)	0.0452 (8)	−0.0028 (6)	0.0089 (6)	−0.0041 (6)
C7	0.0473 (8)	0.0302 (7)	0.0420 (8)	0.0003 (6)	0.0069 (6)	−0.0006 (6)
C8	0.0334 (7)	0.0305 (7)	0.0405 (7)	0.0000 (5)	0.0039 (5)	−0.0026 (6)
C9	0.0354 (7)	0.0395 (8)	0.0416 (8)	−0.0024 (6)	0.0081 (6)	−0.0099 (6)
C10	0.0303 (7)	0.0564 (10)	0.0440 (8)	0.0047 (6)	0.0026 (6)	−0.0070 (7)
C11	0.0399 (8)	0.0494 (9)	0.0407 (8)	0.0069 (7)	0.0000 (6)	−0.0039 (7)
C12	0.0400 (7)	0.0403 (8)	0.0411 (8)	−0.0013 (6)	0.0052 (6)	−0.0112 (6)
C13	0.0376 (7)	0.0399 (8)	0.0523 (9)	0.0024 (6)	0.0137 (6)	−0.0112 (7)
C14	0.0417 (8)	0.0347 (8)	0.0518 (9)	0.0055 (6)	0.0109 (7)	−0.0084 (7)
C15	0.0535 (9)	0.0458 (9)	0.0534 (10)	−0.0032 (7)	0.0126 (8)	−0.0044 (7)

Geometric parameters (Å, º) top

O1—H1	0.8400	C7—H7A	0.9800
O1—C8	1.3184 (18)	C7—H7B	0.9800
O2—C8	1.2358 (18)	C7—H7C	0.9800
N1—H1A	0.8800	C9—C10	1.390 (2)
N1—C1	1.3800 (18)	C9—C14	1.394 (2)
N1—C9	1.406 (2)	C10—H10	0.9500
C1—C2	1.396 (2)	C10—C11	1.377 (2)
C1—C6	1.403 (2)	C11—H11	0.9500
C2—H2	0.9500	C11—C12	1.395 (2)
C2—C3	1.3812 (19)	C12—C13	1.392 (2)
C3—C4	1.4180 (19)	C12—C15	1.506 (2)
C3—C7	1.4977 (19)	C13—H13	0.9500
C4—C5	1.397 (2)	C13—C14	1.375 (2)
C4—C8	1.4715 (19)	C14—H14	0.9500
C5—H5	0.9500	C15—H15A	0.9800
C5—C6	1.379 (2)	C15—H15B	0.9800
C6—H6	0.9500	C15—H15C	0.9800

C8—O1—H1	109.5	O1—C8—C4	114.89 (13)
C1—N1—H1A	115.2	O2—C8—O1	121.59 (13)
C1—N1—C9	129.54 (13)	O2—C8—C4	123.47 (13)
C9—N1—H1A	115.2	C10—C9—N1	123.91 (13)
N1—C1—C2	117.79 (13)	C10—C9—C14	118.33 (14)
N1—C1—C6	124.10 (14)	C14—C9—N1	117.66 (14)
C2—C1—C6	118.07 (13)	C9—C10—H10	119.8
C1—C2—H2	118.3	C11—C10—C9	120.40 (13)
C3—C2—C1	123.46 (13)	C11—C10—H10	119.8
C3—C2—H2	118.3	C10—C11—H11	119.0
C2—C3—C4	118.02 (13)	C10—C11—C12	121.96 (15)
C2—C3—C7	118.33 (12)	C12—C11—H11	119.0
C4—C3—C7	123.65 (13)	C11—C12—C15	121.04 (15)
C3—C4—C8	122.02 (13)	C13—C12—C11	116.87 (14)
C5—C4—C3	118.50 (13)	C13—C12—C15	122.09 (14)
C5—C4—C8	119.34 (13)	C12—C13—H13	119.1
C4—C5—H5	118.6	C14—C13—C12	121.83 (13)
C6—C5—C4	122.70 (14)	C14—C13—H13	119.1
C6—C5—H5	118.6	C9—C14—H14	119.7
C1—C6—H6	120.4	C13—C14—C9	120.59 (15)
C5—C6—C1	119.22 (14)	C13—C14—H14	119.7
C5—C6—H6	120.4	C12—C15—H15A	109.5
C3—C7—H7A	109.5	C12—C15—H15B	109.5
C3—C7—H7B	109.5	C12—C15—H15C	109.5
C3—C7—H7C	109.5	H15A—C15—H15B	109.5
H7A—C7—H7B	109.5	H15A—C15—H15C	109.5
H7A—C7—H7C	109.5	H15B—C15—H15C	109.5
H7B—C7—H7C	109.5

N1—C1—C2—C3	176.07 (13)	C5—C4—C8—O2	−168.92 (14)
N1—C1—C6—C5	−176.83 (14)	C6—C1—C2—C3	−1.5 (2)
N1—C9—C10—C11	−177.63 (14)	C7—C3—C4—C5	−178.68 (13)
N1—C9—C14—C13	177.01 (14)	C7—C3—C4—C8	5.6 (2)
C1—N1—C9—C10	−35.3 (2)	C8—C4—C5—C6	174.02 (13)
C1—N1—C9—C14	148.48 (16)	C9—N1—C1—C2	170.91 (14)
C1—C2—C3—C4	0.8 (2)	C9—N1—C1—C6	−11.6 (2)
C1—C2—C3—C7	−179.65 (13)	C9—C10—C11—C12	0.9 (2)
C2—C1—C6—C5	0.6 (2)	C10—C9—C14—C13	0.6 (2)
C2—C3—C4—C5	0.9 (2)	C10—C11—C12—C13	0.5 (2)
C2—C3—C4—C8	−174.82 (12)	C10—C11—C12—C15	−179.54 (14)
C3—C4—C5—C6	−1.8 (2)	C11—C12—C13—C14	−1.4 (2)
C3—C4—C8—O1	−175.73 (12)	C12—C13—C14—C9	0.9 (2)
C3—C4—C8—O2	6.7 (2)	C14—C9—C10—C11	−1.5 (2)
C4—C5—C6—C1	1.0 (2)	C15—C12—C13—C14	178.66 (14)
C5—C4—C8—O1	8.61 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2ⁱ	0.84	1.81	2.6450 (16)	175
N1—H1A···Cg2ⁱⁱ	0.88	2.93	3.5460 (15)	128
C14—H14···O1ⁱⁱⁱ	0.95	2.51	3.4368 (18)	165

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

Funding information

FH thanks the Graduate Innovation Fund of WIT for financial support (CX2023055).

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