A polymorph of N′-[(4-hy­droxy­phen­yl)methyl­idene]pyridine-4-carbohydrazide

Tom, L.; Jasinski, J.P.; Smolenski, V.A.; Kurup, M.R.P.

doi:10.1107/S2414314626003147

organic compounds

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ISSN: 2414-3146

Volume 11| Part 3| March 2026| x260314

https://doi.org/10.1107/S2414314626003147

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A polymorph of N′-[(4-hydroxyphenyl)methylidene]pyridine-4-carbohydrazide

Lincy Tom,^a ^* Jerry P. Jasinski,^b ‡ Victoria A. Smolenski ^b and M. R. Prathapachandra Kurup ^c

^aDepartment of Chemistry, Nirmala College Muvattupuzha, Ernakulam, 686661, Kerala, India, ^bDepartment of Chemistry, Keene, State College, 229 Main Street, Keene, NH03435-2001, USA, and ^cDepartment of Chemistry, Central University of Kerala, Tejaswini Hills, Periye, Kasaragod 671 320, Kerala, India
^*Correspondence e-mail: [email protected]

Edited by M. Weil, Vienna University of Technology, Austria (Received 11 March 2026; accepted 24 March 2026; online 27 March 2026)

The synthesis and single-crystal X-ray diffraction analysis of a polymorphic form of the isoniazid derivative N′-[(4-hydroxyphenyl)methylidene]pyridine-4-carbohydrazide, C₁₃H₁₁N₃O₂, are reported, revealing that both the molecular conformation and the hydrogen-bonding scheme differ in the two polymorphs. The crystal packing of the title polymorph is primarily consolidated by N—H⋯O and O—H⋯N hydrogen-bonding interactions, leading to the formation of a supramolecular layer parallel to (001). The intermolecular contacts were further quantified and analysed using Hirshfeld surface analysis.

Keywords: isoniazid; crystal structure; hydrogen bonding; packing polymorphism; Hirshfeld.

CCDC reference: 2540578

Structure description

N-containing heterocycles constitute a major class of natural products and possess a wide range of applications (Goetz et al., 2015 ). They are widely used as starting materials for the synthesis of biologically important compounds. Among them, isoniazid-based scaffolds, which contain nitrogen heterocycles, have attracted considerable attention in medicinal chemistry due to their diverse biological activities, including anti-carcinogenic, anti-fungal, anti-mycobacterial, analgesic, antibacterial, and antiviral properties (Tom et al., 2020 ; Rodrigues et al., 2014 ; Mohanram & Meshram, 2014 ; Judge et al., 2013 ; Hu et al., 2017 ; Costa et al., 2024 ). Among these, their anti-tubercular activity is particularly significant. As part of our ongoing research in this field, we report here on the synthesis and crystal structure of a polymorph of N′-[(4-hydroxyphenyl)methylidene]pyridine-4-carbohydrazide, an isoniazid-derived molecule with potential antitubercular activity.

Single-crystal X-ray diffraction analysis of the title compound, C₁₃H₁₁N₃O₂, revealed that it is dimorphic. The title P_A polymorph (Fig. 1) crystallizes in the monoclinic space group P2₁/c. The previously reported polymorph P_B (Deng et al., 2005 ) crystallizes in the same space group type but with different unit-cell parameters. The differences between the P_A and P_B forms can mainly be attributed to crystal-packing effects. An additional monohydrated orthorhombic form has also been reported (Tai et al., 2007 ). The overlay of the two molecules of the polymorphs (Fig. 2) indicates that they possess distinct molecular conformations. P_A adopts a slightly twisted conformation compared to the more planar P_B form. The dihedral angles between the pyridine ring (C2, C3, C4, N3, C5, C6) and hydrazide moiety (N1, N2, C1, O1, C7) are 36.14 (8)° in P_A and 9.59 (8)° in P_B. Similarly, the dihedral angles between the hydrazide moiety and phenol ring are 23.97 (8)° in P_A and 3.96 (7)° in P_B.

Figure 1
Molecular structure of polymorph P_A with displacement ellipsoids drawn at the 30% probability level.

Figure 2
Superimposition of the molecular structures of P_A (gold) and P_B (blue).

The molecular packing and hydrogen-bonding patterns differ significantly in the two extended structures of P_A and P_B. The polymorphs exhibit different combinations of hydrogen-bonding donor and acceptor sites, leading to distinct supramolecular networks. The P_A polymorph reported here exhibits two types of classical hydrogen-bonding interactions (Table 1). The NH group of the N=NH—C=O moiety is hydrogen-bonded to the O atom of the same moiety of a neighbouring molecule into chains extending parallel to [100]. These chains are connected through O—H⋯N hydrogen-bonding interactions involving the phenol OH group and the pyridine N atom, leading to the formation of a supramolecular layer extending parallel to (001) (Fig. 3). In polymorph P_B, the NH group of the N=NH—C=O moiety bonds to the pyridine N atom, and the phenol OH group forms bifurcated hydrogen bonds to the N=NH—C=O moiety and the carbonyl O atom of neighbouring molecules, thus leading to a different supramolecular arrangement.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1ⁱ	0.86	2.34	3.1452 (15)	156
O2—H2⋯N3ⁱⁱ	0.82	1.96	2.7356 (16)	159
Symmetry codes: (i) ; (ii) .

Figure 3
Formation of supramolecular (001) layers in the crystal structure of P_A. Hydrogen bonds are shown as dotted lines.

To visualize and quantify the contributions of intermolecular interactions in the supramolecular assembly of the title compound, a Hirshfeld surface (HS) analysis (Spackman & Jayatilaka, 2009 ) was performed using CrystalExplorer (Spackman et al., 2021 ). The Hirshfeld surface mapped over d_norm is shown in Fig. 4, where prominent deep-red spots correspond to significant intermolecular contacts. These spots appear around atoms N3, N1, O1 and O2, indicating that these atoms participate in the intermolecular hydrogen bonds, as discussed above. The associated two-dimensional fingerprint plots provide quantitative insight into the various non-covalent interactions contributing to the crystal packing. The H⋯H, C⋯H, N⋯H and O⋯H, interactions dominate the packing, collectively accounting for approximately 95% of the total Hirshfeld surface area (Fig. 5).

Figure 4
The Hirshfeld surface of P_A mapped over d_norm.

Figure 5
The two-dimensional fingerprint plots for P_A for different contact types.

Synthesis and crystallization

A mixture of p-hydroxybenzaldehyde (1 mmol) and isonicotinic hydrazide (1 mmol) was refluxed in methanol (20 ml) at 343 K for 30 min. After completion of the reaction, the mixture was allowed to cool to room temperature. Colourless crystals suitable for X-ray diffraction were obtained by slow evaporation of the solution at room temperature.

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₁₃H₁₁N₃O₂
M_r	241.25
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	293
a, b, c (Å)	5.36340 (13), 14.4462 (4), 14.6619 (4)
β (°)	91.229 (3)
V (Å³)	1135.75 (5)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	0.81
Crystal size (mm)	0.42 × 0.33 × 0.29

Data collection
Diffractometer	Rigaku Oxford Diffraction Gemini Eos
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2015 )
T_min, T_max	0.858, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	7898, 2185, 1901
R_int	0.027
(sin θ/λ)_max (Å⁻¹)	0.624

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.039, 0.112, 1.05
No. of reflections	2185
No. of parameters	164
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.22, −0.25
Computer programs: CrysAlis PRO (Rigaku OD, 2015), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ), ORTEP-3 for Windows (Farrugia, 2012 ), Mercury (Macrae et al., 2020 ) and publCIF (Westrip, 2010 ).

Structural data

CCDC reference: 2540578

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314626003147/wm4248sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314626003147/wm4248Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314626003147/wm4248Isup3.cml

checkCIF report

Computing details top

N'-[(4-Hydroxyphenyl)methylidene]pyridine-4-carbohydrazide top

Crystal data top

C₁₃H₁₁N₃O₂	F(000) = 504
M_r = 241.25	D_x = 1.411 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
a = 5.36340 (13) Å	Cell parameters from 3210 reflections
b = 14.4462 (4) Å	θ = 4.3–71.3°
c = 14.6619 (4) Å	µ = 0.81 mm⁻¹
β = 91.229 (3)°	T = 293 K
V = 1135.75 (5) Å³	Block, pale yellow
Z = 4	0.42 × 0.33 × 0.29 mm

Data collection top

Rigaku Oxford Diffraction Gemini Eos diffractometer	1901 reflections with I > 2σ(I)
Radiation source: Enhance (Cu) X-ray Source	R_int = 0.027
ω scans	θ_max = 74.3°, θ_min = 4.3°
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2015)	h = −6→5
T_min = 0.858, T_max = 1.000	k = −17→17
7898 measured reflections	l = −17→18
2185 independent reflections

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.039	H-atom parameters constrained
wR(F²) = 0.112	w = 1/[σ²(F_o²) + (0.0635P)² + 0.3435P] where P = (F_o² + 2F_c²)/3
S = 1.05	(Δ/σ)_max = 0.001
2185 reflections	Δρ_max = 0.22 e Å⁻³
164 parameters	Δρ_min = −0.25 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
C1	0.4746 (3)	0.44240 (9)	0.39335 (9)	0.0229 (3)
C2	0.5399 (2)	0.34115 (9)	0.39757 (9)	0.0211 (3)
C3	0.7526 (2)	0.30837 (9)	0.43964 (9)	0.0235 (3)
H3	0.863180	0.348585	0.469094	0.028*
C4	0.7997 (3)	0.21405 (10)	0.43747 (10)	0.0252 (3)
H4	0.943707	0.192648	0.466990	0.030*
C5	0.4466 (3)	0.18484 (10)	0.35751 (10)	0.0269 (3)
H5	0.337940	0.143061	0.329277	0.032*
C6	0.3834 (2)	0.27780 (10)	0.35686 (9)	0.0246 (3)
H6	0.235113	0.297153	0.328877	0.029*
C7	0.8580 (3)	0.63450 (9)	0.36248 (9)	0.0236 (3)
H7	0.996667	0.598599	0.349456	0.028*
C8	0.8798 (2)	0.73497 (9)	0.35866 (9)	0.0218 (3)
C9	0.6961 (2)	0.79454 (10)	0.39373 (9)	0.0237 (3)
H9	0.554751	0.769727	0.420074	0.028*
C10	0.7254 (3)	0.88975 (10)	0.38910 (10)	0.0262 (3)
H10	0.605271	0.928803	0.412908	0.031*
C11	0.9400 (3)	0.92725 (10)	0.34775 (10)	0.0252 (3)
C12	1.1243 (3)	0.86858 (10)	0.31337 (10)	0.0250 (3)
H12	1.265131	0.893409	0.286667	0.030*
C13	1.0954 (3)	0.77356 (10)	0.31942 (10)	0.0240 (3)
H13	1.218714	0.734688	0.297531	0.029*
N1	0.6758 (2)	0.49791 (8)	0.38618 (8)	0.0244 (3)
H1	0.821556	0.473419	0.383314	0.029*
N2	0.6528 (2)	0.59354 (8)	0.38331 (8)	0.0252 (3)
N3	0.6540 (2)	0.15252 (8)	0.39630 (8)	0.0265 (3)
O1	0.25700 (19)	0.46875 (7)	0.39380 (8)	0.0327 (3)
O2	0.9794 (2)	1.01946 (7)	0.34003 (9)	0.0354 (3)
H2	0.858366	1.047600	0.359096	0.053*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0241 (7)	0.0206 (7)	0.0240 (7)	0.0022 (5)	−0.0011 (5)	−0.0009 (5)
C2	0.0210 (7)	0.0194 (7)	0.0230 (7)	0.0008 (5)	0.0024 (5)	0.0005 (5)
C3	0.0216 (7)	0.0219 (7)	0.0268 (7)	−0.0018 (5)	−0.0013 (5)	0.0003 (5)
C4	0.0217 (7)	0.0237 (7)	0.0301 (7)	0.0009 (5)	−0.0008 (6)	0.0024 (6)
C5	0.0259 (7)	0.0232 (7)	0.0315 (8)	−0.0046 (6)	−0.0012 (6)	−0.0026 (6)
C6	0.0198 (7)	0.0258 (7)	0.0280 (7)	−0.0008 (5)	−0.0018 (5)	0.0008 (5)
C7	0.0246 (7)	0.0200 (7)	0.0259 (7)	0.0038 (5)	−0.0027 (5)	−0.0017 (5)
C8	0.0230 (7)	0.0188 (7)	0.0233 (7)	0.0017 (5)	−0.0049 (5)	−0.0001 (5)
C9	0.0203 (6)	0.0212 (7)	0.0295 (7)	−0.0009 (5)	0.0006 (5)	0.0004 (5)
C10	0.0215 (7)	0.0238 (7)	0.0334 (7)	0.0039 (5)	0.0011 (6)	−0.0028 (6)
C11	0.0261 (7)	0.0186 (7)	0.0308 (7)	0.0002 (5)	−0.0040 (6)	0.0008 (5)
C12	0.0207 (6)	0.0254 (7)	0.0290 (7)	−0.0022 (5)	0.0018 (5)	0.0017 (6)
C13	0.0211 (7)	0.0237 (7)	0.0273 (7)	0.0049 (5)	−0.0008 (5)	−0.0027 (5)
N1	0.0238 (6)	0.0153 (6)	0.0340 (7)	0.0029 (4)	−0.0011 (5)	−0.0004 (5)
N2	0.0285 (6)	0.0166 (6)	0.0306 (6)	0.0017 (5)	−0.0021 (5)	−0.0013 (5)
N3	0.0269 (6)	0.0195 (6)	0.0332 (7)	0.0003 (5)	0.0028 (5)	0.0004 (5)
O1	0.0240 (5)	0.0257 (5)	0.0484 (7)	0.0053 (4)	−0.0031 (4)	0.0013 (5)
O2	0.0307 (6)	0.0174 (5)	0.0583 (8)	−0.0003 (4)	0.0063 (5)	0.0003 (5)

Geometric parameters (Å, º) top

C1—O1	1.2279 (18)	C7—H7	0.9300
C1—N1	1.3501 (18)	C8—C9	1.4132 (19)
C1—C2	1.5049 (18)	C8—C13	1.417 (2)
C2—C3	1.3696 (19)	C9—C10	1.3862 (19)
C2—C6	1.3701 (19)	C9—H9	0.9300
C3—C4	1.3862 (19)	C10—C11	1.420 (2)
C3—H3	0.9300	C10—H10	0.9300
C4—N3	1.3212 (18)	C11—O2	1.3538 (17)
C4—H4	0.9300	C11—C12	1.404 (2)
C5—N3	1.3234 (18)	C12—C13	1.3844 (19)
C5—C6	1.385 (2)	C12—H12	0.9300
C5—H5	0.9300	C13—H13	0.9300
C6—H6	0.9300	N1—N2	1.3875 (16)
C7—N2	1.2916 (19)	N1—H1	0.8600
C7—C8	1.4573 (18)	O2—H2	0.8200

O1—C1—N1	125.28 (12)	C13—C8—C7	118.31 (12)
O1—C1—C2	121.43 (12)	C10—C9—C8	120.38 (13)
N1—C1—C2	113.26 (12)	C10—C9—H9	119.8
C3—C2—C6	117.50 (13)	C8—C9—H9	119.8
C3—C2—C1	123.05 (12)	C9—C10—C11	119.56 (13)
C6—C2—C1	119.44 (12)	C9—C10—H10	120.2
C2—C3—C4	118.69 (13)	C11—C10—H10	120.2
C2—C3—H3	120.7	O2—C11—C12	116.86 (13)
C4—C3—H3	120.7	O2—C11—C10	122.71 (13)
N3—C4—C3	124.43 (13)	C12—C11—C10	120.43 (13)
N3—C4—H4	117.8	C13—C12—C11	119.66 (13)
C3—C4—H4	117.8	C13—C12—H12	120.2
N3—C5—C6	123.26 (13)	C11—C12—H12	120.2
N3—C5—H5	118.4	C12—C13—C8	120.64 (13)
C6—C5—H5	118.4	C12—C13—H13	119.7
C2—C6—C5	119.81 (13)	C8—C13—H13	119.7
C2—C6—H6	120.1	C1—N1—N2	121.55 (11)
C5—C6—H6	120.1	C1—N1—H1	119.2
N2—C7—C8	122.33 (12)	N2—N1—H1	119.2
N2—C7—H7	118.8	C7—N2—N1	112.82 (11)
C8—C7—H7	118.8	C4—N3—C5	116.27 (12)
C9—C8—C13	119.31 (13)	C11—O2—H2	109.5
C9—C8—C7	122.37 (13)

O1—C1—C2—C3	−147.48 (14)	C8—C9—C10—C11	0.8 (2)
N1—C1—C2—C3	34.59 (18)	C9—C10—C11—O2	179.30 (13)
O1—C1—C2—C6	33.4 (2)	C9—C10—C11—C12	−1.3 (2)
N1—C1—C2—C6	−144.56 (13)	O2—C11—C12—C13	179.82 (13)
C6—C2—C3—C4	1.1 (2)	C10—C11—C12—C13	0.4 (2)
C1—C2—C3—C4	−178.08 (13)	C11—C12—C13—C8	1.0 (2)
C2—C3—C4—N3	0.8 (2)	C9—C8—C13—C12	−1.50 (19)
C3—C2—C6—C5	−1.6 (2)	C7—C8—C13—C12	179.42 (12)
C1—C2—C6—C5	177.62 (13)	O1—C1—N1—N2	3.5 (2)
N3—C5—C6—C2	0.2 (2)	C2—C1—N1—N2	−178.65 (11)
N2—C7—C8—C9	12.3 (2)	C8—C7—N2—N1	−177.78 (11)
N2—C7—C8—C13	−168.67 (13)	C1—N1—N2—C7	−170.07 (12)
C13—C8—C9—C10	0.57 (19)	C3—C4—N3—C5	−2.1 (2)
C7—C8—C9—C10	179.61 (12)	C6—C5—N3—C4	1.6 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1ⁱ	0.86	2.34	3.1452 (15)	156
O2—H2···N3ⁱⁱ	0.82	1.96	2.7356 (16)	159

Symmetry codes: (i) x+1, y, z; (ii) x, y+1, z.

Footnotes

‡Deceased.

Acknowledgements

The NSF–MRI program (grant No. CHE-1039027) is acknowledged for funds to purchase the Rigaku X-ray diffractometer.

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