Structural Characterization of 7-Chloro-4-(4-methyl-1-piperazinyl)quinoline Monohydrate

Abstract

The crystal structure of the hydrated form of 7-chloro-4-(4-methyl-1-piperazinyl)quinoline (BPIP) was determined by single-crystal X-ray diffraction analysis. This study revealed a one-dimensional supramolecular network stabilized by hydrogen bonding interactions between BPIP and water molecules. This compound represents one-half of a piperaquine molecule, a member of the 4-aminoquinoline class of antimalarial treatments, currently employed as a partner agent in modern combination therapies. As a simplified structural analog, BPIP can serve as a critical model system for probing the intermolecular interactions, physicochemical properties, and structural behavior of the parent compound. As a result, conducting a thorough solid-state characterization of BPIP is critical for gaining insight into its physical properties and verifying the material’s identity and purity.

1. Introduction

Many derivatives of 4-aminoquinoline are well-known antiparasitic medicines used in the treatment and prophylaxis of malaria. The same structural fragment has also been employed as building block in the design and synthesis of drugs that are highly effective against various diseases including viral infections and different types of cancer [1].

Pharmaceutical drugs can typically exist in different crystal or solid-state forms such as polymorphs, solvates/hydrates, and amorphous phases that can differ widely in their physical properties, including their solubility, dissolution rate, melting point, and tablet-forming ability. Such differences can significantly impact the performance and bioavailability of pharmaceutical products [2]. A thorough structural characterization is essential for assessing the relative stability of polymorphic and solvate forms. This plays a critical role in the development of new drugs as well as in optimizing crystallization processes and formulation strategies to ensure consistent, high-quality product performance [3].

Similarly, to ensure the reliability of activity studies for a drug or its analogous derivatives used for comparison, it is crucial to confirm the nature of the products in their solid state, also using straightforward analytical methods [4]. However, this is only possible when the necessary experimental data are readily available. In industrial drug production, structural identification is an essential part of rigorous quality control, ensuring that products meet expected specifications and maintain high standards of efficacy and consistency across batches.

In this article, the crystal structure of a monohydrate adduct of 7-chloro-4-(4-methyl-1-piperazinyl)quinoline (BPIP∙H₂O), a truncated analog of the piperazinyl-quinoline class of active antimalarial compounds, is reported. BPIP corresponds to half a molecule of piperaquine (PQ), a drug previously used extensively to treat chloroquine-resistant falciparum malaria and recently rediscovered to be a promising partner in combination therapies, including artemisinin-based strategies [5]. Therefore, the title compound can serve as a simplified molecular entity of certain antimalarials, making it an effective model system for investigating drug mechanisms [6,7] and interactions with biologically relevant metal ions. Consequently, its solid-state characterization is crucial, complementing existing crystal structures of other antimalarial compounds [8,9,10,11].

2. Results

2.1. Solid-State Structure

Single-crystal data revealed that the BPIP∙H₂O structure crystallizes in the monoclinic system with the space group P2₁/c. The asymmetric unit comprises one independent quinoline derivative and one water molecule (Figure 1).

The quinoline double-ring shows a distortion from the planarity (rms deviation from the best fit plane 0.0567 Å), with the benzene and pyridine inclined at a dihedral angle of 5.83(3)° with respect to each other. The piperazinyl ring adopts a chair conformation with puckering parameters of Q = 0.5886(16) Å and θ = 178.43(16)° [12] and is oriented at a dihedral angle of about 39.1° with respect to the quinoline moiety.

In the crystal structure, BPIP and water molecules are alternatively linked via hydrogen bonding interactions into chains running in the $[20\overline{1}]$ direction generated by the glide plane c (Figure 2). The water molecule acts as a double donor to the pyridinic nitrogen and the terminal N atom of the piperazinyl group, generating quasi-linear hydrogen bonds (O⋯N distance (Å), O—H⋯N angle (°): 2.9194(19), 175(3); 2.9417(19), 166(2)) (Table S1).

Volumetric analysis indicates that water molecules occupy 3.2% of the unit cell volume (probe radius of 1.0 Å) and reside within discrete, isolated pockets of the crystal framework without having discernible pathways to egress.

2.2. Intermolecular Interaction Analysis

The “Aromatics Analyser” functionality in the CSD-Materials [13] was employed to identify and quantify aromatic interactions within the crystal lattice. The analysis shows that the crystal structure is stabilized by a strong π–π interaction involving the chloro-benzene rings of the quinoline unit (score 9.5). Aromatic stacking dimers are formed in which the molecules are related by inversion symmetry. These dimers exhibit a parallel displaced arrangement with a centroid–centroid distance of 3.96 Å and a relative orientation angle of 0° (Table S2).

Hirshfeld surface (HS) and 2D fingerprint (FP) analysis were further performed by using CrystalExplorer [14] to investigate, visualize, and quantitatively evaluate the intermolecular interactions within the crystal packing of the title compound (Figure 3, Figures S1 and S2). The greatest contribution to the HS comes from the H⋯H contacts (51.3%) due to the large hydrogen content of the molecule. These contacts are responsible for the widespread, high-density blue point distribution in the FP with two beak-shaped tips at d_e + d_i ≈ 2.5 Å (c₁ in Figure 3). The light blue stripe roughly along the diagonal reflects the fraction of points on the Hirshfeld surfaces that involve nearly head-to-head H∙∙∙H contacts with an almost linear orientation between two pairs of axial hydrogens of a neighboring piperazinyl ring (c₂ in Figure 3).

The characteristic pair of long outer spikes with their tips at d_e + d_i ∼1.8 Å (a in Figure 3) are due to the presence of the O_water—H⋯N_pyridinic hydrogen bond, which covers 9.6% of the overall crystal packing. The O⋯H contacts make a 5.9% contribution to the HS and are represented by a second shorter pair of spikes in the region d_e + d_i ≃ 2.2 Å (b in Figure 3). This feature underscores the role of the water oxygen atom as an acceptor in a weak intermolecular C—H⋯O hydrogen bond, with the terminal methyl group of the piperazinyl ring (2.567 Å). The short interatomic C···H/H···C and Cl⋯H/H⋯Cl contacts are overlapped in the FP and appear as a forceps-like distribution with parabolic tips at d_e + d_i ∼2.8 Å (C⋯H) and 3.0 Å (Cl⋯H), respectively (d in Figure 3). Their overall contributions are 14.4% for C···H/H···C and 10.7% for Cl⋯H/H⋯Cl. The contribution of C···H/H···C contacts largely corresponds to the aromatic interactions described above. The decomposition of fingerprint plots into individual atom–atom interactions is depicted in Figures S1 and S2.

A comparison of these results with the Hirshfeld surface analyses conducted separately on BPIP and the water molecule reveals that hydrogen bonding dominates the water–BPIP interactions, while the supramolecular assembly primarily arises from other intermolecular contacts, predominantly involving the primary molecule.

3. Discussion

Knowledge of the solid-state structure of a molecule is crucial for evaluating its properties and reactivity using both experimental and computational methods. However, until now, crystallographic data have been available for some compounds analogous to BPIP such as 7-chloro-4-(piperazin-1-yl)quinoline [15] but not for the BPIP system. Thus, to determine the crystal structure and the packing architecture of the title compound, a single-crystal X-ray diffraction study was performed. The structure determination revealed that the solid phase is the monohydrate form of the substance showing an extended hydrogen bonding network involving water–BPIP interactions.

To understand if the hydration water was already present in the source material or was incorporated during the crystallization process, a powder diffraction experiment was carried out on the starting bulk material. The nature of the reactive was assessed by taking and testing the whole content of a freshly opened 100 mg vial of the reactive as supplied by the manufacturer.

The experimentally observed PXRD pattern shown in Figure 4 was found to be in agreement with the simulated pattern obtained from the single-crystal data, confirming the hydration state of the commercial product and the bulk homogeneity of the samples. The melting point of the compound was measured and compared with the literature data to establish a reliable, easily obtainable, and cost-effective reference value for assessing the substance’s identity and purity. The measurement, conducted using a standard melting point apparatus, yielded a range of 82.8–83.5 °C. This result shows reasonable consistency with the findings reported in [16] (86 °C), where isopropanol was used as recrystallization solvent. Other available melting point data report somewhat different values, i.e., 80 °C [17] for a pale-brown solid precipitated from an aqueous solution and subsequently dried and 88–89 °C [6] for white crystals obtained from methanol, with a mass corresponding to the anhydrous form as determined by high-resolution mass spectrometry (HRMS).

The identification of anhydrous and hydrated forms of a drug substance is of great importance for ensuring that products meet expected specifications in terms of bioavailability [18]. The hydrate form with a well-defined stoichiometric water content exhibits a unique molecular arrangement in the solid state generated by a complex and extended hydrogen bond network, which is responsible for the characteristic physical and chemical properties of the compound.

4. Materials and Methods

4.1. Materials

The 7-chloro-4-(4-methylpiperazin-1-yl)quinoline (BPIP) (CAS number: 84594-63-8) was purchased from Merk Life Science S.r.l., Milano, Italy. The reactive is a Sigma-Aldrich product sold without any assurance as to the identity and purity of the product. 2-propanol was supplied by Sigma-Aldrich (Merck SpA), Milano, Italy and was of ACS reagent grade. The materials were used as received, without any further purification.

4.2. Single-Crystal X-Ray Diffraction

Materials X-ray-quality crystals were obtained by the slow evaporation of an isopropanol solution of BPIP at room temperature.

The single-crystal X-ray data collection for BPIP-H₂O was performed on an air-stable single crystal mounted on a glass fiber at a random orientation on a Bruker SMART-APEX II diffractometer [19] equipped with graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). The data were collected by the ω-scan method (width of 0.5° frame⁻¹, exposure time of 20 s per frame) within the limits 2.2°< θ < 31.7°.

Cell parameters were retrieved and refined using SAINT software v8.34A [20] on 1624 reflections (19% of the observed reflections). Data processing and space group determination were performed with the SAINT and XPREP (2013) programs [20]. The structures were solved by direct methods (SIR2019) and refined by full-matrix least squares on F² (SHELX 2018) [21] with the WINGX (2023.1) interface [22]. The collected intensities were corrected for Lorentz and polarization effects and for absorption effects by applying a multi-scan method by using the SADABS (2013) program [20]. The structure pictures were generated using the ORTEPIII (v1.0.3) [22] and VESTA(v3.5.8) programs [23].

All non-H atoms were refined with full occupancies and anisotropic displacement parameters. No disorder was observed. All hydrogen atoms were located from the difference-Fourier map and were refined using a riding model of U_iso = 1.5 Ueq (parent atom) for -CH₃ and -OH and U_iso = 1.2 U_eq (parent atom) for -CH- and -CH₂-. Bond lengths and angles are summarized in Table S3.

Crystal data and refinement details for BPIP∙H₂O: C₁₄H₁₆ClN₃·H₂O—M_r = 279.76, T = 296(2) K, λ = 0.71073 Å, monoclinic, space group P2₁/c, a = 9.4737 (11), b = 17.650 (2), c = 8.5451 (10) Å, β = 90.156 (2)°, V = 1428.9 (3) ų, Z = 4, ρ_calc = 1.300 g cm⁻³, µ_calc = 0.264 mm⁻¹, F(000) = 592, crystal size 0.42 × 0.30 × 0.04 mm, θ range = 2.2–31.7°, 22429 reflections collected, 4534 reflections unique, R_int = 0.0287, observed reflections [I > 2σ(I)] 2831, 0 restraints, 226 parameters, R1 (all data) = 0.0857, wR2 (all data) = 0.1247, R1 (observed) = 0.0434, wR2 (observed) = 0.1052, ∆ρ_max = 0.25 eÅ⁻³, and ∆ρ_min = −0.21 eÅ⁻³.

4.3. X-Ray Powder Diffraction

Ambient X-ray Powder Diffraction measurements were performed using a Miniflex-600 diffractometer (Rigaku, Japan) with Cu Kα (λ = 1.540598 Å) radiation over an angular range of 5°–60° (2θ), with an incremental step size of 0.02° (2θ) and a counting time of 2 s∙step⁻¹. Phase identification was performed by comparing the experimental powder pattern with that simulated from single-crystal data. The analysis of PXRD data was carried out by using FullProf suite software [24].

4.4. Melting Point Measurements

Melting point measurements were conducted using thin glass capillary tubes with internal diameters of 1 mm and wall thicknesses of 0.1–0.2 mm, employing a standard melting point apparatus (FALC Instruments, vs. 1.11). The specimens were initially heated at a rapid rate (20 °C·min⁻¹) up to 75 °C, after which the heating rate was reduced to 1 °C·min⁻¹ until the melting point was reached.