Comparative Analysis of the Substituent Effects on the Supramolecular Structure of N′-(4-Methyl-2-nitrophenyl)benzohydrazide and N′-(2-Nitro-(4-trifluoromethyl)phenyl)benzohydrazide)

Abstract

N′-Phenylbenzohydrazides are valuable precursors for air- and moisture-stable Blatter radicals, with applications in magnetism and spintronics. This study presents the single-crystal X-ray structures of N′-(4-methyl-2-nitrophenyl)benzohydrazide (I) and N′-(2-nitro-(4-trifluoromethyl)phenyl)benzohydrazide (II), highlighting the influence of substituents on supramolecular arrangement. Compounds I and II are found to crystallize within the monoclinic crystal system, with the space groups I2/a and P2₁/n, respectively, with centrosymmetric, one-dimensional columnar packing driven by π-π stacking. In I, π-π dimers form between benzoyl rings (3.018 Å), with additional stacking between aryls (3.408 Å) of neighboring dimers. In II, alternating benzoyl and aryl rings stack with interplanar distances of 2.681 and 2.713 Å. Bifurcated intra- and intermolecular hydrogen bonds (1.938–2.478 Å) further stabilize the packing. Compound II exhibits inter-stack F···F contacts (2.924 Å), attributed to steric effects. The trifluoromethyl group enhances N′NCO-NO₂ conjugation, resulting in a near-parallel arrangement of aromatic rings and planar geometry at the N′ nitrogen. In contrast, compound I shows reduced conjugation, leading to pyramidalization at the N′ nitrogen and increased hydrazide bond flexibility, as seen in the 56° angle between aromatic rings.

1. Introduction

Acyl hydrazides, first introduced by Kurzius in 1895 [1], have continued to attract scientific interest because of their relevance in drug development, agriculture, and material sciences, including polymer research [2]. A broad spectrum of biological effects has been reported among different structures with hydrazide core [3]. Various hydrazide analogs have been found to exhibit a wide range of biological activities [3]. For instance, the hydrazide scaffold has been incorporated in compounds with anticonvulsant [4], anti-inflammatory [5], antimicrobial [6], antimalaria [7] antidepression [8], and anticancer [9] properties. Hydrazide derivatives have been used as antifungal agents in agriculture [10] due to their superior activity compared to amides. From a synthetic perspective, acyl hydrazide allow access to heterocycles that are often moieties of active compounds in drug design. Moreover, in recent years hydrazides have been used as precursors for Blatter radicals, well known for their stability and applications in magnetism and spintronics [11,12].

The stability of Blatter radicals is controlled by delocalization of spin density involving the N atoms and the aromatic moieties in their close proximity. At the same time π-π interactions among phenyl and triazine rings contribute to the unpaired electron delocalization and implicitly to the magnetic properties [13,14]. Benzohydrazides offer a molecular scaffold where the effect and scope of structural and electronic changes on crystal structure and electronic properties could be studied and the knowledge applied in the synthetic methodology for Blatter radicals with tunable properties.

A literature search led to 78 single-crystal structures with phenylbenzohydrazide moieties reported in Cambridge Structural Database (CSD) [15]. Based on the following criteria: one phenylbenzohydrazide moiety, substituents at the aromatic rings; substituents at the N′ atom, no substituents at the acyl N, and no cyclic structures involving the N atoms, we selected 16 neutral compounds included in

Table 1. Phenylbenzohydrazide derivatives reported in CSD.

Entry	Compound Name	Reference
1	1-Phenyl-2-benzoylhydrazine	[16]
2	2-Amino-N′-phenylbenzohydrazide	[17]
3	N -(4-Nitrobenzoyl)-N′-phenyl hydrazine	[18]
4	N-(3,5-Dinitrobenzoyl)-N′-phenylhydrazine	[19]
5	N′-(2,4-Dinitrophenyl)benzohydrazide	[20]
6	1-Anilidocarbamoyl-2,4-dimethoxybenzene	[21]
7	Methyl-5-(N-benzoylhydrazino)-2-methoxybenzoate	[21]
8	Methyl-3-(N-benzoylhydrazino)-4-methoxybenzoate	[21]
9	N′-(2,4-Dinitrophenyl)-2-fluorobenzohydrazide	[22]
10	4-{[4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl]methyl}-N′-[2-(trifluoromethyl)phenyl]benzohydrazide	[23]
11	Methyl-4-(2-(4-chlorobenzoyl)hydrazino)-3-nitrobenzoate	[24]
12	4-Chloro-N′-((4-chlorophenyl)(imino)methyl)-N′-phenylbenzohydrazide	[25]
13	N′-(3-Methylbut-2-en-yl)-N′-phenylbenzohydrazide	[26]
14	Methyl-3-[2-(4-methylbenzene-1-carbonyl)-1-phenylhydrazinyl]propanoate	[27]
15	N′-(4-benzyl-5-oxo-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl)-N′-(4-fluorophenyl)-2-methoxybenzohydrazide	[28]
16	N′-(4-bromophenyl)-N′-methylbenzohydrazide	[29]

.

The reference compound, 1-phenyl-2-benzoylhydrazine, Table 1 entry 1, displays a planar geometry for the acyl N, evidence of conjugation with the carbonyl group, while N′ has a pyramidalized geometry with the sum of the angles 338° suggesting a reduced conjugation with the neighboring phenyl ring [16]. The angle between the two aromatic ring is almost orthogonal, 88.74°. The packing is characterized by a network of N-H…O hydrogen bonds [d = 2.11(1) and 2.02(2) Å] and edge-to-face π-π stacking (d = 3.267 Å).

Functionalization of the aromatic rings, entries 2–11 [17,18,19,20,21,22,23,24], has little impact on the acyl N geometry which maintains its planarity with one exception, when p-Cl on the benzoyl ring leads to deviation from planarity by 12° [24]. On the other hand, the N′ atom is significantly more sensitive to the electronic effects of the substituents: nitro groups on benzoyl ring do not alter its pyramidalization [18,19], but electron donating groups such amino [17] or methoxy [21] lead to a trigonal planar geometry of N′. NO₂ groups in ortho and para to the N′ have a similar effect due to increased conjugation and electron delocalization [20]. If groups with opposite electronic effects are present on the phenyl ring the ability of the electronic withdrawing group to participate in an extended conjugation with N′ is reflected in its geometry [21,22,23]. For most part the dihedral angle between the two aromatic rings is close to orthogonality in the range 52.8–88.7°, except for entry 11 where the corresponding value is 10.51°. The packing is governed primarily by intermolecular N-H…O hydrogen bonds in the range 1.96–2.30 Å. Additionally close contacts (3.32–3.67 Å) between aromatic rings suggest edge-to-face [18] and parallel [19] π-π stacking interactions. In fluorinated compounds N-H…F hydrogen bonds, 2.10 Å, are observed [22].

Entry 12 has an aromatic moiety at the amino N′ atom in addition to the attached aryl group [25]. The N′ atom has a pyramidal geometry, with the angle sum at 348.4°, suggesting limited conjugation with the aromatic rings. The angles between the benzoyl and aryl rings and the aryl ring and the aromatic moiety that constitutes the second substituent at N′ atom are 60.09° and 60.31°, respectively, presumably due to steric constraints. Intermolecular N-H…O hydrogen bonds, in the range 1.927–2.108 Å, contribute to the molecule’s arrangement.

Entries 13–16 have as the second substituent at the N′ atom, in addition to the aryl ring, a non-aromatic moiety [26,27,28,29]. N′ is pyramidal in almost all compounds in this group with a significant deviation from planarity in the range 12–20°. The exception is with the last entry where the N′ atom is planar suggesting that the combination of p-Br and a small aliphatic substituent, CH3, facilitates conjugation. The dihedral angle between the phenyl and benzyl ring are in the range 54.8–74.8° and the main noncovalent interactions in the crystal packing are the N-H…O hydrogen bonds (d = 1.869–2.054 Å) and close C-H…F (d = 2.598 Å) [28], and C-H…Br (d = 3.024 Å) [29] contacts in the structures that contain halogens.

To summarize, among the reported crystal structures of compounds with a benzohydrazide core, pyramidalization of N atoms, indicative of lack of conjugation, is impacted by substituents that can engage in electron delocalization, specifically aromatic rings. Moreover, even when conjugation is present, the relative disposition of the aromatic moieties is neither coplanar nor orthogonal, resulting in a supramolecular arrangement governed primarily by hydrogen bonding with scarce π-π stacking interactions.

In our study, we selected two acyl hydrazides: N′-(4-methyl-2-nitrophenyl)benzohydrazide (I) and N′-(2-nitrophenyl-(4-trifluoromethyl))benzohydrazide (II) that offer an instance where the effect of an electron withdrawing group, trifluoromethyl, on the electron delocalization and π-π stacking interactions in the crystal structure can be investigated. For clarity, our comparative discussion of the two compounds will use crystallographic numbering.

2. Materials and Methods

All reagents, chemicals, and solvents were sourced from Sigma-Aldrich St. Louis, Missouri, USA and used directly without any further purification. NMR spectra for both ¹H and ¹³Cwere recorded on a Bruker Avance 400 MHz spectrometer Bruker BioSpin GmbH, Rheinstetten, Germany. Residual solvent signals were used as internal references, and all chemical shifts are expressed in parts per million (ppm). High-resolution mass spectrometry (HRMS) and associated fragmentation data were collected using a Waters Xevo G2–XS QTof mass spectrometer Waters Corporation, Wilmslow, Cheshire, United Kingdom operating in positive electrospray ionization (ESI⁺) mode. The measurements were performed by direct flow injection at a flow rate of 0.2 mL/min, using a 95:5 (v/v) methanol–water solvent system as the mobile phase. Single-crystal X-ray diffraction data were obtained using a Rigaku MicroMax-007HF diffractometer Rigaku Corporation, Tokyo, Japan. Melting points were determined with a Mel-Temp melting point apparatus Stanford Research Systems (SRS), Sunnyvale, California, USA.

Synthesis of N′-(4-Methyl-2-nitrophenyl)benzohydrazide (I)

A dry DMSO solution (10 mL) containing 1-fluoro-4-methyl-2-nitrobenzene (3.10 g, 20.0 mmol) and benzohydrazide (2.72 g, 20.0 mmol was stirred at 80 °C for 48 h. After allowing the reaction to cool to room temperature, ethyl acetate (100 mL) was added, followed by water (150 mL). The resulting biphasic system was separated, and the aqueous portion was subjected to two additional extractions using small volumes of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude solid product was recrystallized from ethanol, yielding 3.34 g (62%) of a yellow crystalline compound.

Melting point: 163–164 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.03 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.89 (d, 2H, J = 7.4 Hz), 7.62 (t, 1H, J = 7.7 Hz), 7.52 (t, 2H, J = 7.3 Hz), 7.32 (d, 1H, J = 6.7 Hz), 7.10 (d, 1H, J = 8.6 Hz), 2.33 (s, 3H); ¹³C NMR (400 MHz, CDCl₃): δ 167, 143, 137, 133, 132, 129, 127, 126, 115, 20; HRMS (ES⁺): m/z [M + H]⁺ calculated for C₁₄H₁₃N₃O₃: 272.1035, found 272.1039; EI-MS (70 eV): m/z = 105, 77 (100%).

Synthesis of N′-[2-nitro-4-(trifluoromethyl)phenyl]benzohydrazide (II) [28]

A reaction mixture comprising 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (4.18 g, 20.0 mmol) and benzohydrazide (2.72 g, 20.0 mmol) in dry DMSO (10 mL) was stirred at 80 °C for 48 h. Upon cooling, ethyl acetate (100 mL) and then water (150 mL) were added. The organic layer was collected, and the aqueous phase was re-extracted twice with ethyl acetate. After combining the organic portions, drying them over Na₂SO₄, and concentrating the mixture, the residue was recrystallized (ethanol) to afford 4.55 g (70%) of an orange crystalline product.

Melting point: 165–166 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (s, 1H), 9.91 (s, 1H), 8.40 (s, 1H), 7.98 (m, 2H), 7.87 (dd, 1H, J = 9.0, 1.6 Hz), 7.65 (tt, 1H, J = 7.3, 1.5 Hz), 7.57 (t, 2H, J = 7.5 Hz), 7.34 (d, 1H, J = 9.0 Hz); ¹³C NMR (400 MHz, DMSO-d₆): δ 167, 148, 133, 131, 129, 128, 118, 116; HRMS (ES⁺): m/z [M + H]⁺ calculated for C₁₄H₁₀F₃N₃O₃: 326.0753, found: 326.0755; EI-MS (70 eV): m/z = 105 (base peak), 77.

Crystal Structure Determination.

Unit cell parameters were refined using CrysAlis PRO version 1.171.43.130a [30]. Indexing and image collection were performed based on strategy calculations from DTREK 9.9.9.4 W9RSSI [31]. Absorption correction was carried out using spherical harmonics via the SCALE3 ABSPACK algorithm from CrysAlis PRO. The structure was solved with the ShelXT 2018/2 [32] solution program using dual methods and Olex2 1.5-alpha [33] as the graphical interface. Final structure refinement was achieved using full matrix least-squares minimization within SHELXL 2019/3 [34]. All non-hydrogen atoms were refined anisotropically, while hydrogen atoms were positioned geometrically and refined under the riding model.

CCDC 2474027 and 2474028 contain the supplementary crystallographic data for N′-(4-methyl-2-nitrophenyl)benzohydrazide I and N′-(2-nitrophenyl-(4-trifluoromethyl))benzohydrazide II, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/structures (accessed on 14 August 2025) (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk.

3. Results and Discussion

The N′-(-2-nitrophenyl)benzohydrazides were synthesized in good yields from either 1-fluoro-4-methyl-2-nitrobenzene or 1-fluoro-2-nitro-4-trifluoromethylbenzene and benzohydrazide reacted in dry DMSO for two days (Scheme 1).

Crystal Data for C₁₄H₁₃N₃O₃ (M = 271.27 g/mol): monoclinic, space group I2/a (no. 15), a = 16.3097(4) Å, b = 4.89340(10) Å, c = 32.4384(6) Å, β = 99.862(2)^°, α = γ = 90°, V = 2550.65(10) ų, Z = 8, Z’ = 1, T = 85 K, μ(Cu K_a) = 0.846 mm⁻¹, Dcalc = 1.413 g/cm³, 18,640 reflections measured, 2353 unique (R_int = 0.0682) which were used in all calculations. The final R₁ was 0.0390 (I ≥ 2 σ(I)) and wR₂ was 0.1066 (all data).

Crystal Data for C₁₄H₁₀F₃N₃O₃ (M = 325.25 g/mol): monoclinic, space group P2₁/n (no. 14), a = 6.81970(10) Å, b = 27.7444(4) Å, c = 7.61970(10) Å, β = 106.351(2)^°, α = γ = 90°, V = 1383.40(4) ų, Z = 4, Z’ = 1, T = 85 K, μ(Cu K_a) = 1.212 mm⁻¹, Dcalc = 1.562 g/cm³, 20,974 reflections measured, 2543 unique (R_int = 0.0544) which were used in all calculations. The final R₁ was 0.0411 (I ≥ 2 σ(I)) and wR₂ was 0.1031 (all data).

3.1. Geometry Characteristics of the Molecular Structure

The synthesized hydrazides I and II (Figure 1) crystallize in the monoclinic space groups I2/a and P2₁/n with one molecule in the asymmetric unit and 8 and 4 molecules in the symmetric unit cell, respectively. The molecular structures of I and II are characterized by two aromatic rings with typical aromatic C-C bonds around 1.389 Å (

Table 2. Crystallographic bond lengths (Å) and angles (°) for compounds I and II.

Bond	Compound I	Compound II	Angle	Compound I	Compound II
C1-C2	1.387(2)	1.387(2)	C1-C2-C3	120.1(1)	120.1(1)
C2-C3	1.389(2)	1.388(2)	C2-C3-C4	120.2(1)	119.9(1)
C3-C4	1.382(2)	1.389(2)	C3-C4-C5	120.1(1)	120.6(1)
C4-C5	1.386(2)	1.389(2)	C4-C5-C6	119.5(1)	119.8(1)
C5-C6	1.397(2)	1.387(2)	C5-C6-C1	119.9(1)	119.8(1)
C6-C1	1.393(2)	1.395(2)	C6-C1-C2	120.1(1)	120.0(1)
C8-C9	1.408(2)	1.418(2)	C8-C9-C10	121.6(1)	121.6(1)
C9-C10	1.398(2)	1.392(2)	C9-C10-C11	121.2(1)	120.1(1)
C10-C11	1.380(2)	1.375(2)	C10-C11-C12	117.4(2)	119.5(1)
C11-C12	1.402(2)	1.403(2)	C11-C12-C13	121.7(1)	120.8(1)
C12-C13	1.375(2)	1.367(2)	C8-C12-C13	121.8(1)	121.5(1)
C8-C13	1.401(2)	1.415(2)	C8-C9-C13	116.2(1)	116.5(1)
C7-N1	1.355(2)	1.350(2)	N1-N2-H2	111.0(1)	115.0(1)
C8-N2	1.397(2)	1.352(2)	H2-N2-C8	113.0(1)	121.0(1)
C9-N3	1.458(2)	1.444(2)	C8-N2-N1	114.5(1)	121.6(1)
N1-N2	1.410(1)	1.391(2)

).

The impact of the electron withdrawing groups present in compound I is illustrated by the elongation of the C-C bonds in their vicinity: C1-C6 = 1.393(2) Å, C5-C6 = 1.397(2) Å, due to C=O; C8-C9 = 1.408(2) Å, C8-C13 = 1.401(2) Å, due to NO₂. The stronger electron withdrawing effect of the latter group is supported by the alternating bond lengths in the aryl ring. The angles in the aryl and benzoyl rings are very similar around 120°, while in the aryl ring there are two compressed angles, C9-C8-C13 and C10-C11-C12 at 116.2(1)° and 117.4(2)° at the substituted positions balanced by larger angles at the vicinal positions. The angle between the two rings is 56.1° indicating the absence of extended conjugation between them and the flexibility of the hydrazide connection. By contrast, in compound II, the CF₃ substituent disrupts bond uniformity in the aryl ring, causing significant elongation of the C8-C9 [1.418(2) Å] and C8-C13 [1.415(2) Å] bonds and concomitant shortening of the C9-C10 [1.392(2) Å], C10-C11[1.375(2) Å], and C12-C13 [1.367(2) Å] bonds relative to the corresponding bond lengths in compound I (Table 2).

The conjugation between the N1 and the carbonyl in compound I leads to a shorter C7-N1 bond, 1.355(2) Å, than C8-N2 bond 1.397(2) Å, suggesting a planar geometry around N1, consistent with a sp² hybridization. At the same time, N2 experiences a significant pyramidalization being situated at 0.326 Å from the C8-H2-N1 plane and a sum of the surrounding angles of 338.5°, intermediate between the values corresponding to sp² and sp³, 360° and 328.5°, respectively. The absence of pyramidalization at N2 in compound II, together with its unusually short C8–N2 distance [1.352(2) Å], elongated C8-C9 [1.418(2) Å] and shortened C9–N3 distance [1.444(2) Å] indicates conjugation between N2 and the NO₂ group. This imparts partial double-bond character to the N2–C8 bond and forces the two rings to lie almost parallel, with an interplanar angle of 4.26°.

Compound I displays two intramolecular close contacts are observed N2-H2^…O1 = 2.478 Å and N2-H2^…O2 = 1.971 Å with corresponding angles of N2-H2-O1 = 91.2° and N2-H2-O2 = 131.1° pointing to a bifurcated hydrogen bond with a stronger participation from NO₂ unit due to proximity and almost linear atom arrangement. Moreover, by comparison to the N1-H1 bond, which is not involved in any intramolecular interaction, a minor elongation of the N2-H2 bond is present. A similar bifurcated hydrogen bond is observed in hydrazide II, but the rigidity of the system in that area allows for more balanced interactions with distances of 2.261 and 1.980 Å, and angles of 104.8° and 128.3°.

3.2. Supramolecular Arrangement

The crystal packing of hydrazide I is controlled by π-π stacking interactions involving both aromatic rings and leading to formation of unidimensional (1D) centrosymmetric columns of dimers (Figure 2, Figure 3 and Figure 4). There are two sets of close contacts in the dimer: C2^…N2 [3.247(2) Å] and C2^…H2 [2.78(2) Å], with the aryl rings opposing each other due to the inversion center, and a π-π stacking interaction between the benzoyl rings (Figure 2). Two additional stacking interactions are observed on each side of the column between the aryl rings of neighboring dimers. The benzoyl rings are 3.018 Å apart and their stacking interaction has a translation along b axis with an offset of 3.851 Å and longitudinal and latitudinal slippages: 14.2° and 51.4° (Figure 3). The stacking interaction of the aryl rings which are placed at 3.408 Å distance, is also translational along b axis with a smaller offset, 3.510 Å, and predominantly latitudinal slippage, 42.2°; by comparison longitudinal slippage is minimal at 3.9° (Figure 4). Between each neighboring dimer two symmetrical N-H^…O hydrogen bonds are observed [d = 1.92(2) Å and angle = 168.0(2)°].

A similar centrosymmetric unidimensional columnar crystal packing along a axis is observed for hydrazide II (Figure 5, Figure 6 and Figure 7). The column contains alternating dimers in which the benzoyl and aryl rings are placed opposite each other through an inversion center. A π-π stacking interaction occurs in each dimer between the benzoyl and aryl rings of the two molecules with distances of 2.681 Å (dimer 1) and 2.713 Å (dimer 2). The interaction’s translation is along the ab diagonal with very similar offset values, 2.391 Å and 2.354 Å, and slippage, longitudinal 20.0° and latitudinal 16.4°.

A network of intrastack interactions comprising hydrogen bonds N-H^…O (d = 1.937 Å and angle = 170.8°) via the O=C-NH hydrazide moieties, with each molecule participating in two interactions, contributes to efficient packing. Intermolecular interactions involving covalently bound fluorine, such as hydrogen bonding or F^…F, are considered generally weak and to have little impact on the crystal structure [34,35,36]. In the structure of hydrazide II, along the b axis the molecules are linked in a head-to-tail pattern by intercolumnar interactions C-H^…F (d = 2.523 Å and angle = 147.0°), leading to a 2D ribbon pattern. Additional close contacts between parallel ribbons, C^…F = 2.593 Å and F^…F = 2.924 Å, are presumably more a result of the geometry constraints rather than nonbonding interactions.

4. Conclusions

The crystal structures of the two reported benzohydrazides display conjugation of both N atoms with the carbonyl and nitro groups. The presence of trifluoromethyl increases the N-NO₂ conjugation through a minimal disruption of the aromatic delocalization, which has a large impact leading to a planar N and an almost parallel orientation of the two aromatic rings. At the supramolecular level, in addition to hydrogen bonding, π-π stacking interactions contribute to efficient packing with closer contacts for the trifluorobenzoahydrazine. The identified F^…F contacts are close to the sum of Van der Waals radii and presumably the result of steric constraints.