INTRODUCTION

2-Thiobarbituric acid (H2tba) is an ancestor of an important class of drugs referred to as thiobarbiturates [1]. The ability of H2tba and its anion Htba− to participate in numerous hydrogen bonds (HBs) and π–π interactions enriches the supramolecular chemistry of their derivatives [2]. It is of theoretical interest to compare the structure of thiobarbituric salts containing organic base cations with 6-membered rings, in particular, norfloxacin (NfH) and 2,2′-bipyridyl (Bipy). These cations may also act as donors and acceptors in HBs and participate in π–π interactions both with the Htba− anion and with each other to form unusual supramolecular structures. Note that NfH belongs to one of the most successful classes of synthetic antibiotics referred to as quinolones (FQH) [3]. It is particularly effective against gram-negative bacteria and is used for disease prevention and treatment of various infectious diseases. One main disadvantage of NfH is its low solubility in water [4]. An effective way to improve the bioavailability of norfloxacin implies the used of its organic salts that are highly soluble in water [5]. The main goal of the present work is to prepare and establish the supramolecular structure of \(\text{NfH}_{2}^{+}\) and BipyH+ containing thiobarbituric salts. The synthesis, structure, and thermal stability of two novel salts with the composition NfH2(Htba)·6H2O (I) and BipyH(Htba)·2H2O (II) are described.

EXPERIMENTAL

Norfloxacin C16H18FN3O3 (Zhejiang Kangyu Pharmaceutical Co., Ltd, China), H2tba (puriss.), Bipy (Sigma-Aldrich), and acetone (puriss.) were used without further purification.

Synthesis of NfH2(Htba)·6H2O (I). A mixture of H2tba (0.10 g, 0.69 mmol) and NfH (0.22 g, 0.69 mmol) was dissolved in 300 mL of water at 90 °С. The solution with рН 4-5 was cooled to room temperature and maintained for a week at 4 °С in a fridge. Here and below, the approximate рН values were determined using universal pH paper (0-12 рН range). As a result, several orange crystals in the form of rectangular blocks were obtained. The crystals were filtered, washed in 1 mL of acetone, and dried in air. One of them was selected for XRD analysis. For better yield, the filtrate was maintained in a fridge for 3 months at 4 °С until the mixture volume of about 10 mL. Then substance I was filtered, washed in 3-5 mL of acetone, and dried to constant weight in air. Yield: 58% (0.23 g). Note that both the evaporation of the solvent at room temperature and the evaporation of the solution lead to the formation of poorly crystallized precipitates containing unidentified products, apparently, resulting from partial reactant decomposition.

Synthesis of BipyH(Htba)·2H2O (II). A mixture of H2tba (0.10 g, 0.69 mmol) and Bipy (0.11 g, 0.69 mmol) was dissolved in 2 mL of water at 90 °С. The resulting yellow-orange solution (рН ≈ 4) was slowly cooled and maintained in air at room temperature. After 24 hours, yellow-orange rhombic crystals were filtered off, washed with a little amount of water, and dried to constant weight in air. Yield: 61% (0.14 g). A single crystal for XRD was selected from the total precipitate substance.

The powder XRD patterns of I and II obtained at room temperature (Bruker D8 ADVANCE diffractometer, Common Use Center of the Institute of Physics SB RAS; VANTEC linear detector; CuKα radiation) coincided with those calculated from single crystal XRD data to confirm that the phase of polycrystalline samples is identical to that of studied single crystals.

XRD. Crystal I with a size of 0.4×0.35×0.25 mm and crystal II with a size of 0.32×0.07×0.05 mm were studied at 100 K. The reflection intensities were measured on a D8 Venture single-crystal diffractometer (Baikal Analytical Center SB RAS) with a CCD detector (Bruker AXS, MoKα radiation). The experimental absorption corrections were introduced with the SADABS software [6] using the multiscanning method. The structures were solved by direct methods and refined using the SHELXTL program package [7]. Hydrogen positions were determined from difference electron density syntheses and then idealized and refined in the form related to the main atoms. Table 1 lists the experimental parameters and the results of structure refinements.

Structures I and II were deposited with the Cambridge Crystallographic Data Centre (No. 1967494-1967495; deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk/data_request/cif).

The thermal analysis of I and II was performed on a SDT-Q600 analyzer (TA Instruments, USA) under air flow (50 mL/min) in the region of 22-350 °C with a heating rate of 10 °C/min. The composition of gaseous products was determined using a Nicolet380 IR Spectrometer (Thermo Scientific, USA) combined with the thermal analyzer.

RESULTS AND DISCUSSION

The asymmetric part of the unit cell I contains one \(\text{NfH}_{2}^{+}\), one Htba–, and six H2O molecules (Fig. 1a). The geometric structure of the \(\text{NfH}_{2}^{+}\) ion is typical of fluoroquinolones [8-12]; it consists of a flat bicyclic fragment composed of aromatic rings and a piperazine ring having the chair conformation. Neutral norfloxacin molecules have a bipolar structure containing a deprotonated carboxyl group (O2B–С12B–O3B)−, and the N1B atom of the piperazine ring connects simultaneously two protons to form a \(>\text{NH}_{2}^{+}\) group. As a result of the interaction of the NfH± zwitterion with a H2tba molecule in water, the proton is transferred from atom C5A of thiobarbituric acid to atom О of the deprotonated carboxyl group of the zwitterion to form a Htba− anion and a \(\text{NfH}_{2}^{+}\) cation, which are then included in the solid salt composition. After the protonation, the geometric parameters of NfH± remain virtually unchanged and coincide with those determined earlier for the \(\text{NfH}_{2}^{+}\) ion [13, 14]. The geometric parameters of the Htba− ion are also virtually identical to those deposited with the CSD database [15], e.g., with the data reported in [16, 17]. These data testify electron density delocalization (characteristic of fluoroquinolones) in the О=С–СН–С=О group [10–12, 16, 17], as is indicated by O1A–C4A (1.259(2) Å), O2A–C6A (1.263(2) Å) bond lengths and the C6A–C5A–C4A (120.45(15)°) angle.

Table 1 Crystal Data and Structure Refinement Details
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The structure analysis revealed 18 hydrogen bonds (Table 2) N–H⋯O, O–H⋯O, and C–H⋯F involving Htba−, \(\text{NfH}_{2}^{+}\) ions and all water molecules. The HBs form a three-dimensional framework containing a layer perpendicular to axis b and supramolecular motifs \(\text{R}_{2}^{2}(8)\), S(6), \(\text{R}_{5}^{3}(10)\), \(\text{R}_{4}^{4}(14)\), and \(\text{R}_{8}^{6}(18)\) (Fig. 2a). Two hydrogen bonds N–H⋯ O combine each Htba− and two similar neighboring ions to form an infinite zigzag chain based on the \(\text{R}_{2}^{2}(8)\) supramolecular motif. Each Htba− ion is connected simultaneously with two \(\text{NfH}_{2}^{+}\) ions via similar atomic chains formed by OW–H⋯OHtba, OW–H⋯OW, and NHNfH2–H⋯OW hydrogen bonds. The sulfur atoms in Htba− are not involved in hydrogen bonding. The \(\text{NfH}_{2}^{+}\) ion (Fig. 1a) contains only two potential HB donors (the О3 atom of the carboxyl group and the N1B atom of the \(\text{NH}_{2}^{+}\) group) and seven HB acceptors (three N atoms, three O atoms, and one F atom). Similarly, the Htba− ion has two HB donors (atoms N1A and N3A) and five HB acceptors (two O atoms, two N atoms, and one S atom). The imbalance between the numbers of HB donors and acceptors in I is counteracted by the participation of water molecules in numerous HBs and by the self-association of Htba− ions via N–H⋯O bonds. Similarly to other fluoroquinolones [8-14], two intramolecular hydrogen bonds О3В–H⋯O1В and C1B–H1A⋯F in the \(\text{NfH}_{2}^{+}\) cation form typical supramolecular motifs S(6), and the Н atom of the СООН group forms a strong intramolecular hydrogen bond O2carboxyl–H⋯О1ketone (Fig. 2a) which reduces its ability to participate in intermolecular interactions. The \(\text{NfH}_{2}^{+}\) ions are connected by water molecules. The topological analysis of hydrogen bonds carried out in the ToposPro program [18] revealed a new eight-sited three-dimensional network with a topological point symbol (4.52.62.8)(4.52)(5.62.72.9)(5.72.82.9)(5.72)(52.62.7.8)(62.73.8)(63.72.8).

Fig. 1
figure 1

Asymmetric part of the unit cell: NfH2(Htba)·6H2O (I) (a); BipyH(Htba)·2H2O (II) (b). Hydrogen bonds are shown by dashed lines.

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Earlier, we determined the structures of thiobarbituric salts of fluoroquinolones with the composition PefH2(Htba) (III), PefH2(Htba)·3H2O (IV) [10] (PefH is pefloxacin), CfH2(Htba)·3H2O (V) [12] (CfH is ciprofloxacin), and LevoH2(Htba)·3H2O (VI) [11] (LevoH is levofloxacin). In PefH2(Htba)·3H2O, the Нtba− ions are not directly connected to each other but are involved in common chains with water molecules via HBs. In anhydrous PefH2(Htba), the imbalance between the number of HB donors and acceptors is counteracted by the self-association of Нtba− ions forming infinite chains. In CfH2(Htba)·3H2O, two hydrogen bonds N–H⋯O form pairs of Нtba− ions (\(\text{R}_{2}^{2}(8)\) motif) connected by water molecules. In III–IV, \(\text{PefH}_{2}^{+}\) and Нtba− are bound by N–HHtba⋯OPefH2 bonds. In LevoH2(Htba)·3H2O, \(\text{LevoH}_{2}^{+}\) and Нtba− are connected by N–HHtba⋯OLevoH2 and О–HLevoH2⋯OHtba bonds, and Нtba− are not connected to each other. In CfH2(Htba)·3H2O (V), similarly to I and IV, \(\text{CfH}_{2}^{+}\) and Нtba− are connected by water molecules. Thus, the system of hydrogen bonds in the salts formed by the singly-charged fluoroquinoline cation \(\text{FQH}_{2}^{+}\) and the Нtba− thiobarbiturate ion depends both on water content and on the fluoroquinolone nature. The \(\text{NfH}_{2}^{+}\) ions in I are connected pairwise by head-to-tail π–π interactions (Table 3) [19] (Fig. 3а), and each of them also participates in a stacking interaction with one of Нtba− ions. In III–VI, \(\text{FQH}_{2}^{+}\) ions also form pairs as a result of head-to-tail π–π interactions. In III and V–VI, similarly to I, \(\text{FQH}_{2}^{+}\) and Нtba− ions are also connected by π–π interactions. These data show that the crystal packing in thiobarbituric salts of fluoroquinolones favors π–π interactions.

Table 2 Geometric Parameters of Hydrogen Bonds in Structures I, II
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The asymmetric part of the BipyH(Htba)·2H2O (II) unit cell contains one BipyН+, one Htba–, and two H2O molecules (Fig. 1b). The formation of salts upon the interaction of H2tba both with Bipy and with NfH is due to quite a large difference between pKa values of organic bases [20, 21] and H2tba [22], in accordance with the “ΔpKa rule” that was proposed earlier for bicomponent crystals [23] and states that a salt rather than a cocrystal is formed if ΔpKa = pKa(base) – pKa(acid) > 2 or 3. The geometric parameters of Htba− and BipyH+ ions are virtually identical to those deposited with the CSD database [15]. BipyH+ is planar, the standard deviation of atoms from this plane does not exceed 0.34 Å. Positions of nitrogen atoms corresponds to the usual cis conformation of the BipyH+ cation [24-26] with the N–C–C–N torsion angle equal to –23.0(2)°. As a result of the protonation of atom N1B, the C8B–N1B–C12B angle increased (124.4(2)°) compared to the C3B–N2B–C7B angle (116.61(17)°). Like in I, the values of geometric parameters in the Htba– ion indicate electron density delocalization in О=С–СН–С=О groups, e.g., d(O1A–C4A) = 1.2638(19) Å, d(O2A–C6A) = 1.2624(19) Å, and ∠C6A–C5A–C4A (120.55 (15)°).

Fig. 2
figure 2

Hydrogen bonds in NfH2(Htba)·6H2O (a); layer in the plane perpendicular to axis b; hydrogen bonds in BipyH(Htba)·2H2O (b). The supramolecular motifs (outlined by closed curves) are designated.

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The structure analysis showed a presence of eight HBs (Table 2) (N–H⋯O, O–H⋯O, and C–H⋯S) involving Htba−, BipyН+ ions and all water molecules. The HBs form a three-dimensional framework containing a layer in the plane of vectors a+c and b. The layer contains supramolecular motifs \(\text{R}_{2}^{2}(8)\), \(\text{R}_{6}^{6}(20)\), \(\text{R}_{10}^{6}(24)\) (Fig. 2b). Like in I, N–H⋯O bonds combine Htba− into infinite zigzag chains due to the formation of the \(\text{R}_{2}^{2}(8)\) supramolecular motif. Each of these chains is H-bonded to two similar chains due to the participation of water molecules combined pairwise by ОW–H⋯OW interactions. In contrast to I, atom S of the thiobarbiturate ion is involved in the formation of a weak C9B–H9B⋯S hydrogen bond (Table 2). Also, the BipyН+ ion is connected with a water molecule by the N1B–H1B⋯O1W hydrogen bond. Of all BipyH+ containing compounds of 2-thiobarbituric acids, only the structure of the salt cocrystal [27] BipyH(Detba)·HDetba (HDetba is 1,3-diethyl-2-thiobarbituric acid) was described [28]. In contrast to Htba− in II, the Detba− ion in this anhydrous substance is directly connected with one BipyH+ ion by two С–H⋯O hydrogen bonds and with the other ion by one C–H⋯S hydrogen bond. Naturally, in the absence of water and insufficient number of HB donors, the structure of this compound is stabilized by weak C–H⋯X hydrogen bonds (X = O, S). The topological analysis of hydrogen bonds performed with the ToposPro program [18] revealed a three-sited three-dimensional network with a topological point symbol (4.6.8)2(6.84.10) referred to as moa in topological bases. Currently, there is only one known Bipy containing compound, [Pt(Bipy)(N,S-aminoethanethiolate)]Cl [29], that has a similar topological network of hydrogen bonding.

Table 3 Parameters of π–π Interactions in Crystals
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Fig. 3
figure 3

π–π-Interaction between Htba— ions in NfH2(Htba)·6H2O (I) (а) and BipyH(Htba)·2H2O (II) (b).

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Fig. 4
figure 4

TG and DSC decomposition curves for NfH2(Htba)·6H2O (a) and BipyH(Htba)·2H2O (b).

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The parameters of π–π interactions in II (Table 3) forming chains of alternating Htba− and BipyН+ ions were determined. In turn, these chains are connected by π–π interactions between two BipyН+ ions from the neighboring chains (Fig. 3b) with the participation of the rings with protonated nitrogens which are directly not included in the chains. This interaction binds the ions into infinite ladder-shaped …BipyН+…BipyН+…Htba−…BipyН+…BipyН+… chains. As a result, a two-dimensional network is formed in the plane of vectors a+c and b. In BipyH(Detba)·HDetba [28], the structure is also stabilized by π–π interactions BipyН+…BipyН+, BipyН+…Htba−, and Htba−…Htba−…. . The strategy of using relatively weak but numerous π–π interactions in crystal engineering is still poorly elaborated in scientific literature [30] and deserves more attention. Despite the fact that the energy of these interactions is only about 10 kcal/mol, they can significantly contribute to the stabilization of structures [31], like it is the case of salts I and II. Also, the structural stability of these compounds is greatly facilitated by the formation of numerous HBs involving water molecules.

The decomposition of compounds I and II begins with dehydration at ~50 °C and 60 °C (Fig. 4) accompanied by endo-effects at 73 °C and 80 °C. The weight losses (Δm) at this stage are in good agreement with theoretical calculations in the assumption of complete dehydration (for I: Δmexp = 18.2%, Δmcalc = 18.9% (–6Н2О); for II: Δmexp = 11.0%, Δmcalc = 10.7% (–2Н2О)).

The oxidative degradation of I and II begins at ~270 °C and 100 °C, respectively, and proceeds in several steps. The solid residue disappears (Δmexp ≈ 100%) at 650 °C and 670 °C, respectively. The products of I and II dehydration are thermally more stable than initial reagents (Tm/dec = 250.6 °C for H2tba [32], Tm/dec = 216.7 °C for NfH [33], and Tm = 69.5 °C for Bipy). The thermal degradation of I is accompanied by a weak endo-effect at 278 °C and a strong exo-effect at 598 °C (Fig. 4а). The decomposition of II is accompanied by endo-effects at 175 °C, 319 °C and a strong exo-effect at 610 °C (Fig. 4b). The revealed products of I and II thermolysis include SO2, CO2, CS2, and pyridine.