THEORETICAL CHEMICAL TECHNOLOGY Structural characterization of hydrogen bonding for antipyrine derivatives: Single-crystal X-ray diffraction and theoretical studies

Objectives. The paper is devoted to the crystal structure characterization of 5-methyl-2-phenyl-4H-pyrazol-3-one (compound I ) and 2-(4-chlorophenyl)-5-methyl-4H-pyrazol-3-one (compound II ). Methods. Single-crystal X-ray diffraction studies and theoretical calculations: Density functional theory and quantum theory of atoms in molecules. Results. In the solid state, the crystal structure of compound I is characterized by the alternation of OH and NH tautomers connected via O–H---O and N–H---N hydrogen bonds. For compound II , the existence of chains built from the NH monomers via hydrogen bonding can be explained by the peculiarities of cooperative effects. In the framework of quantum theory of results for compared Conclusions. An important role of intermolecular hydrogen bonding in the crystal packing, molecule association and self-organization via dimer- or more extended species formation has been demonstrated.


INTRODUCTION
Antipyrine (1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one; compound III) and related compounds are known to possess a number of bioactive properties, such as analgesic and antipyretic ones. They form a large number of complexes with alkaline-, transition-, and rare-earth metals [1][2][3][4][5][6][7][8]. From this point of view, searching for new ligands (including representatives of antipyrine-based ones) is very important [4,9]. Using the method of computer prognosis based on the Prediction of Activity Spectra for Substances (PASS) system [10], it has been demonstrated that some pyrazolone derivatives, such as 5-methyl-2-phenyl-4H-pyrazol-3-one (compound I) and 2-(4-chlorophenyl)-5-methyl-4H-pyrazol-3-one (compound II), possess a relatively high probability of antimetastatic activity. It should be underlined that the compound properties are determined mainly by the specific features of chemical bonding, including hydrogen bonding and intermolecular interactions, between structural units. These distinguishing features are responsible for the self-organization of ions and molecules in crystal packing with the formation of channels opened to the intercalation of small species, for example, complexes with neridronic acid (6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid) showing promise for treating osteogenesis and the Paget's disease [11]. In the case of solvation (e.g., styryl dyes of the benzoselenazole series), the system of hydrogen bonding makes the structure more rigid compared with the non-solvation one owing to the solvate molecules participation in the hydrogen bond formation [12]. This results in different photocycloaddition reactivity of the solvated and nonsolvated compounds and thus a decreased reaction rate for the solvated species. The same has been demonstrated [13] for water molecules and imidazolium salts with respect to the interaction and formation of guest(H 2 O)@host (ionic liquid [IL]) complexes through strong H-bonds involving the hydrogen atoms of water molecules and nitrogen atoms of IL anions to produce a quest@host supramolecular structure. Many biologically active molecules contain multiple hydrogen-bonding sites; e.g., barbiturates, a class of compounds widely used for their physiological action as sedatives and anticonvulsants, contain both donor and acceptor atoms for multiple hydrogen-bonding formation. It should be underlined that crystal engineering and design allow obtaining different solid state structures in cocrystals of barbiturate and melamine molecules (linear tape, crinkled tape, or cyclic hexamer) [14]. The hydrogenbonding importance and its impact on drug efficacy have been demonstrated [15]. In this connection the aim of this paper is to explain structural particularities and their comparison with results of theoretical studies for compounds I, II, and III.

EXPERIMENTAL
Compounds I, II ( Sigma-Aldrich, St. Louis, Missouri, USA), and III (All-Russian Product Classifier 931335, chem. pure) were first recrystallized from ethanol. Single crystals were grown from saturated aqueous solutions by isothermal evaporation of the solvent at ambient temperature (ca. 20 °C). Thermogravimetric and differential scanning calorimetric (STA-409 Differential Scanning Calorimeter, Netzsch, Germany) measurements were carried out over the temperature range 293-573 K with a heating rate of 10 K/min under a helium atmosphere. Aluminum oxide was used as a reference material.
Computational methods The tautomers of compounds I and II (Scheme 1) were examined by density functional theory using the Priroda package [16]. Calculations were made using the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional [17] and TZ2P Gaussian-type basis sets. The solvation effects were estimated in Gaussian 09 [18] using the polarizable continuum model and solvation model based on density (PCM-SMD; water used as solvent, ε = 78.3553). Vibrational harmonic frequency analysis was conducted for the optimized geometries to ensure that a true local minimum was present with no imaginary frequencies. The starting atomic coordinates of compounds were taken from the X-ray refinement results. Convergence criteria for self-consistent field Tonkie Khimicheskie Tekhnologii = Fine Chemical Technologies. 2021;16 (2):113-124 cycles and geometry optimization were 1 × 10 −6 and 1 × 10 −5 a.u., respectively. The quantum-topological characteristics of electron density in the critical points of the intermolecular hydrogen bond were calculated in the framework of the quantum theory of atoms in molecules (QTAIM) using the Multiwfn 3.6 program [19].
Single-crystal X-ray crystallography Crystallographic data were collected and refined on CAD-4 EXPRESS diffractometer 1 . Data reduction was carried out using XCAD4 2 . The following programs were used for theoretical modeling: SHELXS97 for structure solving [20], SHELXL97 for structure refining [20], and Mercury for molecular graphics [21]. The results are given in Table A1 (see Appendix A, pages 125-126).
CCDC 1891632-1891634 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.

RESULTS AND DISCUSSION
There are three possible tautomers for compounds I and II (CH: Ia, IIa; NH: Ib, IIb; OH: Ic, IIc; Scheme 1, Table 1) [22]. Here we compare theoretical and single-crystal X-ray diffraction data to examine the crystal packing particularities of compounds I-III. The following order of stability for compound-I tautomers in the gas phase was derived from Table 1: [22]. The same order of relative stability was theoretically obtained, the results of which are shown in Table 2. Calculation results of Gibbs free energy (ΔG 298 ) values considering solvation effects demonstrate a slightly lower energy gap between Ia and Ib and a slightly higher energy gap between Ib and Ic (0.0, 24.4, and 31.2 vs. 0.0, 9.1, and 28.4 kJ·mol −1 , respectively, Table 2). The same tendency can be observed for compound II (Table 2). Scheme 1. Different possible tautomers for compounds I and II: R = H for the former and R = Cl for the latter.  We calculated the parameters of dimer formation from the monomers of compounds I and II, and compared the experimental and theoretical results ( Table 3). The crystal structure of compound I is characterized by the alternation of Ib and Ic tautomers ( Fig. 1a Table 3, entries 1 and 2). Extended infinite chains can be observed (Fig. 1b), as confirmed by the calculation results ( Table 3, (Table 3, entries 3, 4, 7 and 5, 6), as confirmed by the ΔG 298 values for the tautomer dimerization (Table 3, entries 1-7, column 6). Compound II exists as the NH tautomer ( Fig. 2), the molecules of which are linked by N-H---O-type H-bonds (r N-H---O = 2.729 Å; Fig. 2a and Table 3, entry 10). This results in the formation of noninteracting extended chains with mutual antiorientation (Fig. 2b). In the crystalline state, compound II consists of IIb tautomers, not IIa tautomers. The calculated ΔG 298 values for IIb and IIc dimerization (IIa unable to form dimers with strong hydrogen bonding) demonstrate that the IIb- Table 3, entries 8 and 10). It is easy to imagine that the elongation of the chain built from the IIb monomers due to H-bonding ( Fig. 2) results in energy gain growth with the number of monomers due to the predominance of the enthalpy contribution (ΔH 298 = −39.2 kJ·mol −1 ) over the entropy one (−TΔS 298 = 35.5 kJ·mol −1 ; Table 3, entry 10). The formation of chains built from the Ib tautomers is possible, but, in this case, the enthalpy contribution is approximately equal to the entropy contribution (Table 3, entry 3), which can explain the differing mode of monomer alteration for compound For all dimers 1-11, the following topology characteristics were calculated using QTAIM theory: electron density (ρ), Laplacian of electron density ( 2 ρ), density of kinetic (G), potential (V), and total energy (H) in the critical point of the intermolecular hydrogen bond (Table 4). On the basis of the 2 ρ and H signs as well as the V/G (1 < |V|/G < 2) ratio, it can be concluded that hydrogen bond in dimers 1-4 and 7-11 can be assigned to the intermediate (between covalent and dispersion types) interaction, whereas the H-bond in dimers 5 and 6 can be assigned to the dispersion interaction, i.e., the weak interaction. Analysis of ρ and H values demonstrates that the strongest intermolecular H-bonds take place The same dimers are characterized by the shortest X-H---Y distances and by a non-significant increase in the electron localization function (η). By comparing these results with the Gibbs free energy values for dimerization, it can be concluded that the dimer interaction energy is not sufficiently strong to overcome entropy loss during their formation. However, in spite of the H-bond-favorable topology characteristics, the formation of dimers 9 and 11 is unlikely due to the positive ΔG 298 value.
Packing for compound III is characterized by the absence of H-bonding and is based on the presumably steric requirements (Fig. 3, Tables A1, A8-A10), the crystallographic parameters of which are consistent with the existing literature [23][24][25]. The experimental and theoretical results are confirmed by the thermal analysis data. The melting points for the compounds in question are as follows: 397.6-398.4 (I), 431. , and 381.5-381.9 K (III), the melting enthalpy being equal to 18. 5, 12.3, and ca. 16