Crystal structure of the pharmaceutical impurity 2-(4-chloro­benzo­yl)pyridine

Singh, K.J.; Tanski, J.M.

doi:10.1107/S2056989026009175

research communications

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Volume 82| Part 10| October 2026|

https://doi.org/10.1107/S2056989026009175

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Crystal structure of the pharmaceutical impurity 2-(4-chlorobenzoyl)pyridine

Karan J. Singh ^a and Joseph M. Tanski ^a ^*

^aDepartment of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA
^*Correspondence e-mail: [email protected]

Edited by W. T. A. Harrison, University of Aberdeen, United Kingdom (Received 31 August 2026; accepted 1 September 2026; online 8 September 2026)

The title compound, C₁₂H₈ClNO, is a pharmaceutical impurity and possible intermediate in the synthesis of carbinoxamine. The aromatic rings of the molecule twist relative to one another resulting in an interplanar angle of 38.1 (1)°. In the extended structure, the molecules are packed into rippled sheets with offset face-to-face stacking of each aromatic ring with the equivalent ring in the neighboring molecule.

Keywords: crystal structure; π-stacking; pharmaceutical impurity; benzophenone derivative.

CCDC reference: 2584887

1. Chemical context

2-(4-Chlorobenzoyl)pyridine, C₁₂H₈ClNO (I), also known as carbinoxamine related compound A, is a known manufacturing impurity of the pharmaceutical ingredient carbinoxamine, 2-[(4-chlorophenyl)-pyridin-2-yl-methoxy]-N,N-dimethyl-ethanamine (C₁₆H₁₉ClN₂O). The compound may be used to synthesize enantiopure alcohols, such as (S)-(4-chlorophenyl)(pyridin-2-yl)methanol, as precursors for the synthesis of carbinoxamine in the fungus Geotrichum candidum using a mutated acetophenone reductase enzyme that catalyzes the reduction of ketones to alcohols (Tang et al., 2024 ). This enzyme belongs to the alcohol dehydrogenase (ADH) class, which catalyzes the reversible interconversion between ketones and alcohols. Carbinoxamine maleate, the maleic acid salt of carbinoxamine, is a first-generation H₁-antihistamine used to treat allergy symptoms and may be synthesized via a Grignard reaction: para-chlorophenylmagnesium bromide, formed by the addition of para-bromochlorobenzene to magnesium in anhydrous ether, is treated with 2-pyridinealdehyde and subsequently with sodium and 2-dimethylaminoethyl chloride to produce an approximate 65% yield of the medication (Mansukhbhai & Das, 2021 ). Carbinoxamine maleate performs by binding to inactive H₁ receptors belonging to G-protein-coupled receptors (GPCRs) found in cells and stabilizing them to remain inactive. This mechanism prevents the binding of the chemical signal histamine to the receptors and inhibits signal transduction pathways leading to allergic reactions (Leurs et al., 2002 ). As part of our studies in this area, we now describe the crystal structure of (I).

2. Structural commentary

Compound (I) crystallizes in space group P2₁/c with one molecule in the asymmetric unit. The molecular structure of (I) (Fig. 1) reveals a 4-chlorobenzoyl group, consisting of a benzene ring bearing a chlorine-atom substituent at the para position relative to the carbonyl group, which is attached to the carbon atom meta to the nitrogen atom of the pyridine ring. Individual molecules of (I) adopt a twisted conformation that minimizes intramolecular repulsion between the benzene and pyridine rings with an interplanar angle of 38.1 (1)° between the C1–C5/N1 and C7–C12 rings. The C5—C6 [1.506 (5) Å] and C6—C7 [1.506 (5) Å] bond lengths are almost identical and the N1—C5—C6—O1 torsion angle is −152.6 (4)°.

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

3. Supramolecular features

In the extended structure, molecules of (I) assemble into rippled (100) sheets via weak C—H⋯O and C—H⋯Cl interactions (Fig. 2, Table 1). As expected, the C11—H11A⋯O1 interaction with a donor–acceptor distance of 3.406 (5) Å is shorter than the C2—H2A⋯Cl1 interaction with a corresponding distance of 3.633 (4) Å. The shortest Cl⋯Cl contact of 3.894 (6) Å is much longer than the sum of the van der Waals radii for chlorine (3.50 Å; Bondi, 1964 ). The sheets stack in such a manner that a slipped face-to-face π-stacking geometrical arrangement of the rings is present between equivalent rings within the molecules (Fig. 3). The π-stacking of the chlorobenzoyl rings is characterized by a centroid–centroid distance of 3.8943 (6) Å (the a unit-cell dimension) and a plane-to-centroid separation of 3.402 (3) Å, resulting in a ring shift of 1.895 (6) Å. The very similar π-stacking of the pyridine rings is characterized by the same centroid–centroid separation and a plane-to-centroid separation of 3.419 (3) Å, resulting in a ring shift of 1.865 (6) Å. In the overall packing (Fig. 4) there is also a longer C—H⋯N interaction (not shown) that interconnects the π-stacked sheets formed by the C—H⋯O and C—H⋯Cl interactions, with a C9—H9A⋯N1 donor–acceptor distance of 3.686 (5) Å.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2A⋯Cl1ⁱ	0.95	2.96	3.633 (4)	129
C11—H11A⋯O1ⁱⁱ	0.95	2.46	3.406 (5)	173
Symmetry codes: (i) $[x+1, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ ; (ii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Figure 2
A view of the weak hydrogen-bonded sheets in (I). Displacement ellipsoids are shown at the 50% probability level. Symmetry codes: (i) x + 1, −y + $[{1\over 2}]$ , z - 1/2; (ii) −x + 1, y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ .

Figure 3
A view of the face-to-face π-stacking geometrical arrangement in (I) with a dashed line indicating the chlorobenzoyl interaction and a solid line indicating the pyridine interaction.

Figure 4
The packing in (I) viewed down [100].

4. Database survey

One similar compound to (I) was found in the CSD version 6.00, April 2025.; Groom et al., 2016 ) with the CSD refcode CEYWOS (Syed et al., 1984 ), which consists of a 4-chlorobenzoyl group attached to a pyridine ring. However, in contrast to (I), the 4-chlorobenzoyl group in CEYWOS is attached to the carbon atom para to the nitrogen atom of the pyridine ring instead of the meta carbon atom. Both CEYWOS (space group P2₁) and (I) display similar weak intermolecular hydrogen bonding as well as π–π stacking interactions between the benzene and pyridine rings in parallel molecules. However, CEYWOS exhibits a greater twist angle of the benzoyl and pyridine rings relative to one another, resulting in an interplanar angle of 52.41° and a shortest Cl⋯Cl contact distance of 3.630 Å that is much closer to the sum of the van der Waals radii for chlorine.

5. Synthesis and crystallization

2-(4-Chlorobenzoyl)pyridine (95%) was purchased from Enamine, USA, and recrystallized by slow evaporation over 48 h at room temperature using a 1:1 solvent mixture of ethyl acetate/hexane.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms were included in calculated positions and refined using a riding model with C—H = 0.95 Å and U_iso(H) = 1.2U_eq(C).

Table 2
Experimental details

Crystal data
Chemical formula	C₁₂H₈ClNO
M_r	217.64
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	125
a, b, c (Å)	3.8943 (6), 10.8402 (15), 23.307 (3)
β (°)	90.573 (2)
V (Å³)	983.9 (2)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.36
Crystal size (mm)	0.30 × 0.17 × 0.04

Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 )
T_min, T_max	0.87, 0.99
No. of measured, independent and observed [I > 2σ(I)] reflections	22981, 3018, 2627
R_int	0.047
(sin θ/λ)_max (Å⁻¹)	0.715

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.087, 0.234, 1.19
No. of reflections	3018
No. of parameters	136
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.63, −0.92
Computer programs: SAINT and SPEX3 (Bruker, 2013 ), SHELXT2018/2 (Sheldrick, 2015a ), SHELXL2017/1 (Sheldrick, 2015b ), SHELXTL2014 (Sheldrick, 2008 ), OLEX2 (Dolomanov et al., 2009 ) and Mercury (Macrae et al., 2020 ).

Supporting information

CCDC reference: 2584887

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2056989026009175/hb8252sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989026009175/hb8252Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989026009175/hb8252Isup3.cml

checkCIF report

Computing details top

2-[(4-Chlorophenyl)carbonyl]pyridine top

Crystal data top

C₁₂H₈ClNO	F(000) = 448
M_r = 217.64	D_x = 1.469 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 3.8943 (6) Å	Cell parameters from 9976 reflections
b = 10.8402 (15) Å	θ = 2.6–30.5°
c = 23.307 (3) Å	µ = 0.36 mm⁻¹
β = 90.573 (2)°	T = 125 K
V = 983.9 (2) Å³	Plate, colourless
Z = 4	0.30 × 0.17 × 0.04 mm

Data collection top

Bruker APEXII CCD diffractometer	3018 independent reflections
Radiation source: sealed X-ray tube, Bruker APEXII CCD	2627 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.047
Detector resolution: 8.3333 pixels mm^-1	θ_max = 30.6°, θ_min = 2.1°
φ and ω scans	h = −5→5
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	k = −15→15
T_min = 0.87, T_max = 0.99	l = −33→33
22981 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.087	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.234	H-atom parameters constrained
S = 1.19	w = 1/[σ²(F_o²) + (0.0373P)² + 7.3622P] where P = (F_o² + 2F_c²)/3
3018 reflections	(Δ/σ)_max < 0.001
136 parameters	Δρ_max = 0.63 e Å⁻³
0 restraints	Δρ_min = −0.91 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.

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

	x	y	z	U_iso*/U_eq
Cl1	0.1218 (3)	0.36829 (10)	0.89790 (4)	0.0240 (3)
O1	0.3127 (10)	0.5625 (3)	0.62865 (14)	0.0306 (8)
N1	0.3630 (9)	0.2415 (3)	0.61545 (14)	0.0182 (6)
C1	0.4401 (11)	0.1573 (4)	0.57571 (17)	0.0209 (8)
H1B	0.375692	0.074018	0.582413	0.025*
C2	0.6100 (11)	0.1851 (4)	0.52497 (18)	0.0220 (8)
H2A	0.66341	0.121867	0.498278	0.026*
C3	0.6995 (11)	0.3065 (4)	0.51413 (19)	0.0247 (8)
H3A	0.810253	0.328332	0.47945	0.03*
C4	0.6246 (11)	0.3954 (4)	0.55481 (17)	0.0209 (8)
H4A	0.687546	0.479185	0.549092	0.025*
C5	0.4537 (10)	0.3588 (4)	0.60456 (16)	0.0167 (7)
C6	0.3522 (11)	0.4574 (4)	0.64667 (17)	0.0186 (7)
C7	0.3001 (10)	0.4297 (3)	0.70928 (16)	0.0159 (7)
C8	0.1338 (10)	0.5204 (3)	0.74168 (17)	0.0165 (7)
H8A	0.055346	0.593758	0.723501	0.02*
C9	0.0826 (10)	0.5041 (4)	0.79999 (17)	0.0193 (7)
H9A	−0.027204	0.566012	0.82209	0.023*
C10	0.1959 (10)	0.3951 (4)	0.82540 (16)	0.0172 (7)
C11	0.3722 (10)	0.3054 (4)	0.79449 (17)	0.0174 (7)
H11A	0.458215	0.233698	0.813115	0.021*
C12	0.4203 (10)	0.3227 (4)	0.73593 (17)	0.0174 (7)
H12A	0.534994	0.261473	0.714114	0.021*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0307 (5)	0.0248 (5)	0.0165 (4)	−0.0023 (4)	0.0050 (3)	0.0009 (4)
O1	0.054 (2)	0.0156 (14)	0.0218 (15)	0.0020 (14)	0.0022 (14)	0.0033 (12)
N1	0.0213 (16)	0.0166 (15)	0.0168 (15)	−0.0006 (12)	−0.0001 (12)	−0.0006 (12)
C1	0.0264 (19)	0.0161 (17)	0.0201 (18)	−0.0016 (15)	0.0015 (15)	−0.0030 (14)
C2	0.0225 (19)	0.025 (2)	0.0184 (18)	0.0022 (16)	0.0024 (14)	−0.0043 (15)
C3	0.024 (2)	0.029 (2)	0.0208 (19)	0.0014 (17)	0.0040 (15)	0.0023 (16)
C4	0.0223 (18)	0.0207 (19)	0.0198 (18)	−0.0013 (15)	0.0011 (14)	0.0029 (15)
C5	0.0184 (16)	0.0159 (16)	0.0156 (16)	−0.0017 (13)	−0.0031 (13)	−0.0002 (13)
C6	0.0233 (18)	0.0147 (16)	0.0176 (17)	−0.0021 (14)	−0.0022 (14)	0.0005 (13)
C7	0.0181 (16)	0.0132 (16)	0.0163 (16)	−0.0027 (13)	−0.0016 (13)	0.0002 (13)
C8	0.0163 (16)	0.0123 (16)	0.0210 (17)	−0.0001 (13)	−0.0007 (13)	−0.0003 (13)
C9	0.0200 (18)	0.0177 (17)	0.0204 (18)	0.0012 (14)	0.0038 (14)	−0.0018 (14)
C10	0.0190 (17)	0.0178 (17)	0.0149 (16)	−0.0024 (13)	0.0004 (13)	−0.0001 (13)
C11	0.0198 (17)	0.0142 (16)	0.0181 (17)	0.0015 (13)	−0.0030 (13)	0.0008 (13)
C12	0.0189 (17)	0.0144 (17)	0.0188 (17)	0.0014 (13)	−0.0004 (13)	−0.0022 (13)

Geometric parameters (Å, º) top

Cl1—C10	1.741 (4)	C5—C6	1.506 (5)
O1—C6	1.224 (5)	C6—C7	1.506 (5)
N1—C1	1.337 (5)	C7—C12	1.394 (5)
N1—C5	1.345 (5)	C7—C8	1.403 (5)
C1—C2	1.394 (6)	C8—C9	1.387 (5)
C1—H1B	0.95	C8—H8A	0.95
C2—C3	1.385 (6)	C9—C10	1.392 (6)
C2—H2A	0.95	C9—H9A	0.95
C3—C4	1.386 (6)	C10—C11	1.395 (5)
C3—H3A	0.95	C11—C12	1.392 (5)
C4—C5	1.400 (5)	C11—H11A	0.95
C4—H4A	0.95	C12—H12A	0.95

C1—N1—C5	117.0 (3)	C12—C7—C8	119.9 (3)
N1—C1—C2	123.5 (4)	C12—C7—C6	123.3 (3)
N1—C1—H1B	118.3	C8—C7—C6	116.7 (3)
C2—C1—H1B	118.3	C9—C8—C7	120.7 (4)
C3—C2—C1	118.9 (4)	C9—C8—H8A	119.7
C3—C2—H2A	120.6	C7—C8—H8A	119.7
C1—C2—H2A	120.6	C8—C9—C10	118.5 (4)
C2—C3—C4	118.8 (4)	C8—C9—H9A	120.8
C2—C3—H3A	120.6	C10—C9—H9A	120.8
C4—C3—H3A	120.6	C9—C10—C11	121.8 (4)
C3—C4—C5	118.3 (4)	C9—C10—Cl1	120.0 (3)
C3—C4—H4A	120.8	C11—C10—Cl1	118.2 (3)
C5—C4—H4A	120.8	C12—C11—C10	119.0 (4)
N1—C5—C4	123.5 (4)	C12—C11—H11A	120.5
N1—C5—C6	118.5 (3)	C10—C11—H11A	120.5
C4—C5—C6	117.9 (4)	C11—C12—C7	120.0 (4)
O1—C6—C7	120.0 (4)	C11—C12—H12A	120.0
O1—C6—C5	118.0 (4)	C7—C12—H12A	120.0
C7—C6—C5	121.9 (3)

C5—N1—C1—C2	0.7 (6)	C5—C6—C7—C12	16.5 (6)
N1—C1—C2—C3	−1.2 (7)	O1—C6—C7—C8	13.9 (6)
C1—C2—C3—C4	1.6 (7)	C5—C6—C7—C8	−166.2 (4)
C2—C3—C4—C5	−1.5 (6)	C12—C7—C8—C9	−1.0 (6)
C1—N1—C5—C4	−0.7 (6)	C6—C7—C8—C9	−178.4 (4)
C1—N1—C5—C6	176.4 (4)	C7—C8—C9—C10	−0.9 (6)
C3—C4—C5—N1	1.1 (6)	C8—C9—C10—C11	3.1 (6)
C3—C4—C5—C6	−176.0 (4)	C8—C9—C10—Cl1	−177.5 (3)
N1—C5—C6—O1	−152.6 (4)	C9—C10—C11—C12	−3.4 (6)
C4—C5—C6—O1	24.6 (6)	Cl1—C10—C11—C12	177.1 (3)
N1—C5—C6—C7	27.5 (6)	C10—C11—C12—C7	1.5 (6)
C4—C5—C6—C7	−155.3 (4)	C8—C7—C12—C11	0.6 (6)
O1—C6—C7—C12	−163.4 (4)	C6—C7—C12—C11	177.8 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2A···Cl1ⁱ	0.95	2.96	3.633 (4)	129
C11—H11A···O1ⁱⁱ	0.95	2.46	3.406 (5)	173

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

Acknowledgements

This work was supported by Vassar College. X-ray facilities were provided by the US National Science Foundation (grant Nos. 0521237 and 0911324 to JT).

Funding information

Funding for this research was provided by: National Science Foundation, Directorate for Mathematical and Physical Sciences (grant No. 0521237 to Joseph M. Tanski; award No. 0911324 to Joseph M. Tanski).

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