Synthesis and Crystal Structure of A Pyrithione Derivative: Bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-)

Abstract

The pyrithione derivative, bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-) (1a) has been obtained by the reaction of one equivalent of 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride with one and a half equivalents of copper (II) chloride dihydrate in methanol in a very good yield. The structure of this product was confirmed by X-ray crystallography, infrared spectroscopy, and elemental analysis.

1. Introduction

Coordination chemistry of pyrithione (N-hydroxypyridine-2(1H)-thione (Hmpo)), its heavy metal salts, and complexes have been widely investigated. Hmpo constitutes a universal O, S-donor ligand [1,2,3,4]. The infrared spectra of Hmpo indicates that the compound exists predominantly in its tautomeric thione form [5,6]. Recent UV spectra of pyrithione have shown that tautomeric equilibrium depends on the solvent used. Thione form dominates in polar and protic solvents, whereas 2-mercaptopyridine N-oxide exists in non-polar solvents [7]. Strong bactericidal and fungicidal properties of pyrithione have been well demonstrated [8]. Pyrithione acts as a proton conductor and inhibits the membrane transport processes in fungi. However, it was found that fungi can detoxify this agent at low concentration [9]. A zinc complex of N-hydroxypyridine-2(1H)-thione (zinc pyrithione) is widely used in dandruff shampoos for treating dandruff and seborrhoeic dermatitis [10]. Moreover, it was demonstrated that zinc pyrithione exhibits also antibacterial properties. Zinc pyrithione is a good example of an antibiofilm agent, which improves the antibacterial activity of silver sulfadiazine ointment [11]. Copper pyrithione has been recently considered in supplanting zinc pyrithione in view of its low toxicity [12]. Pyrithione derivative, 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide, as a free base [CAS Registry Number 90764-93-5] [13,14,15] and its water-soluble acid addition salts, hydrobromide [CAS Registry Number 6937-05-9] [13,14,15,16] and hydrochloride [CAS Registry Number 62377-10-0] [17], are regarded as useful chemical agents that control microbial growth. They possess both fungistatic and bacteriostatic effects and may serve as preservatives.

2. Results and Discussion

The title compound: bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-) (1a) was synthesized by slow evaporation of methanolic solution of the 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride (1) with excess of copper (II) chloride dihydrate.

For the preparation of 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide (as free base or acid addition salt), 2-bromopyridine 1-oxide was reacted with an imidazolidine-2-thione in a halogenated hydrocarbon solvent (chloroform) or in ethanol. According to the literature’s data, the mixture required heating for 12 h to give acid addition salt (hydrobromide). The free base may be obtained in dioxane by treatment with an equivalent of dimethylaniline [13,14].

Generally, 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride (1) [CAS Registry Number 62377-10-0] can be synthesized as a result of the nucleophilic attack of the sulfur atom of 2-mercaptopyridine 1-oxide on C2 carbon of 2-chloro-4,5-dihydro-1H-imidazole (2-chloroimidazoline). The reaction was carried out in dichloromethane at room temperature in high yield and the product 1 precipitated after mixing the reactants. This method provides a certain advantage over traditional thermal heating. The reaction completes within a significantly shorter time. In the next step, brown single crystals of the bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-) (1a) suitable for X-ray diffraction analysis were obtained by slow evaporation of methanolic solution, containing the 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride (1) and copper (II) chloride dihydrate at room temperature (Scheme 1).

The crystal structure of the bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-) (1a) is shown in Figure 1a (see also supplementary crystallographic data). The asymmetric unit of 1a consists of the organic cation and one half of the C₂ symmetric [CuCl₄]²⁻ anion. In the 2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium cation, the two rings attached to the S atom are nearly perpendicular with the dihedral angles between the imidazoline and pyridine best planes of 87.1° and the pyridine N-oxide group is oriented anti-relative to the imidazolinium ring. The conformation adopted by the cation results in a large deviation from 120° of the endocyclic bond angles at the pyridine C2 atom, [N1-C2-S7 111.01(11)° and C3-C2-S7 129.23(11)°], and in short intramolecular contact H3···C8 of 2.51 Å. The most probable reason for these angular deviations is repulsive interactions between H3 and C8. The cations are connected by a pair of N-H···O hydrogen bonds [N9···O1ⁱ 2.7714(16) Å, H9···O1ⁱ 1.91 Å, <N9-H9···O1ⁱ 166°; symmetry code i: −x+1/2, −y+3/2, −z] into centrosymmetric dimers that, in turn, interact with [CuCl₄]^2- anions via N-H⁺···Cl⁻ bonds [N12···Cl1ⁱ 3.2622(12) Å, <N12-H12··· Cl1ⁱ 156°; symmetry code i: x, y+1, z], forming chains extended along [1 0 1] (Figure 1b). In addition, there is a short contact C2-S7··· Cl2i [S2··· Cl2i 3. 3279(5) Å, < C2-S7··· Cl2i 169.60(5)° symmetry code i: −x, −y+1, −z] pointing to a weak chalcogen bonding between cations and anions from adjacent chains.

3. Materials and Methods

3.1. General Methods and Physical Measurements

All reagents and solvents were purchased from commercial sources and used without further purification. The IR spectra were recorded on a Nicolet 380FT-IR spectrophotometer. The ¹H NMR spectrum of compound 1 was registered at 20–22 °C on Varian Gemini 200 (¹H = 200 MHz), using the signal of DMSO-d₆ as an internal standard. The values of chemical shifts are given in ppm and coupling constants (J) are expressed in hertz (Hz). Measured C, H, N elemental analyzes were within 0.40% of calculated values. The diffraction data for single crystals of 1a were collected with an Oxford Diffraction XcaliburE diffractometer using Mo Kα radiation. The intensity data were collected and processed using CrysAlisPro Software [19]. The structure was solved by direct methods with the program SHELXS-97 [20] and refined by the full-matrix least-squares method on F² with SHELXL-2018 [21]. All H atoms were refined as riding on their carriers.

3.2. Synthesis of 2-[(4,5-Dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride (1)

2-Chloro-4,5-dihydro-1H-imidazole sulfate [22] (5.1 g, 25 mmol) was added gradually to a 5% solution of sodium hydroxide at a temperature of 5 °C and extracted with dichloromethane (4 × 20 mL). The combined organic phases were dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to a volume of 30 mL. 2-Mercaptopyridine 1-oxide (3.18 g, 25 mmol) was added to the resulting solution of 2-chloro-4,5-dihydro-1H-imidazole in dichloromethane. When the exothermic reaction had subsided, the white precipitate was filtered, washed with dichloromethane, and dried. The product was obtained as a white solid and yield was 5 g (86%); mp. 172–175 °C; IR (KBr) ν (cm⁻¹): 3000, 2891, 2835, 2634, 1595, 1561, 1466, 1417, 1289, 1249, 1213, 1201, 1084, 1025, 840, 762; ¹H NMR (200 MHz, DMSO-d₆) δ (ppm): 3.93 (s, 4H, 2×CH₂); 7.42–7.60 (m, 2H, arom.); 7.93 (dd, J₁ = 1.8 Hz, J₂ = 8.0 Hz, 1H, arom.); 8.49 (d, J = 5.5 Hz, 1H, arom.); 10.87 (br.s, 2H, 2×NH⁺). Anal. calculated for C₈H₁₀ClN₃OS (231.70): C, 41.47; H, 4.35; N, 18.14. Found: C: 41.41; H, 4.32; N, 17.87.

3.3. Synthesis of Bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-) (1a)

Copper(II) chloride dihydrate (0.553 g, 3.24 mmol) was dissolved in 1 mL of anhydrous methanol and the solution was gradually added (dropwise) to a solution of 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride (0.5 g, 2.16 mmol) (1) in anhydrous methanol (10 mL) at a temperature of 40 °C. Upon slow evaporation of the solvent over 24 h at room temperature (20–22 °C), brown crystals were formed. Precipitate was filtered off, washed with methanol (2 × 0.5 mL), and dried in a desiccator. The product was obtained as a brown crystals and yield was 0.46 g (71%); mp. 143–148 °C; IR (KBr) ν (cm⁻¹): 3175, 3068, 3033, 2869, 2596, 1591, 1553, 1471, 1421, 1278, 1211, 1154, 1093, 1019, 834, 772; ¹H NMR (200 MHz, DMSO-d₆) δ (ppm): 3.95 (s, 4H, 2×CH₂); 7.46–7.57 (m, 2H, arom.); 7.92 (d, J = 7.0 Hz, 1H, arom.); 8.49 (d, J = 5.7 Hz, 1H, arom.); 10.69 (br.s, 2H, 2×NH⁺). Anal. calculated for C₁₆H₁₈Cl₄CuN₆O₂S₂ (595.84): C, 32.25; H, 3.04; N, 14.10. Found: C, 32.18; H, 2.99; N, 14.12.

Crystal data for 1a: 2(C₈H₁₀N₃OS)·CuCl₄, monoclinic, space group C2/c, a = 20.9638(10), b = 6.8597(3), c = 15.9721(7) Å, β = 106.708(5)°, V = 2199.90(17) ų, Z = 4, T = 130 K, d_x = 1.805 g·cm⁻³, µ(Mo Kα) = 1.697 mm⁻¹, 8519 were collected up to θ_max = 27.0° (R_int = 0.0159, R_σ = 0.0164). Final R indices for 2364 reflections with I > 2σ(I) and 141 refined parameters were: R₁ = 0.0191, wR₂ = 0.0505 (R₁ = 0.0222, wR₂ = 0.0512 for all 2629 data). Crystallographic data for compound 1a have been deposited with the Cambridge Crystallographic Data Centre, with the deposition No. CCDC 1914490.

Supplementary Materials

Supplementary files are available online. CCDC 1914490 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via the Cambridge Crystallographic Data Centre http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: [phone]; E-mail: [email protected]).

Author Contributions

F.S. and L.B. conceived and designed the experiments; L.B. performed the experiments; M.G. analyzed the data; L.B. and M.G. wrote the paper.

Funding

The publication of this article was supported by the Funds for Statutory Activity of the Medical University of Gdańsk (ST-020038/07).

Acknowledgments

The NMR spectra were carried out at The Nuclear Magnetic Resonance Laboratory, Gdańsk University of Technology, Poland.

Conflicts of Interest

The authors declare no conflict of interest.

Figure and Scheme

Scheme 1. Synthesis of the 2-[(4,5-dihydro-1H-imidazol-2-yl)thio]pyridine 1-oxide hydrochloride (1) and bis{2-[(1-oxidopyridin-2-yl)sulfanyl]-4,5-dihydro-1H-imidazol-3-ium} tetrachlorocuprate(2-) (1a).

Figure 1. (a) ORTEP [18] representation of the molecular structure of 1a. Displacement ellipsoids are shown at the 50% probability level; ‘i’ relates to symmetry generated atoms. (b) Crystal packing viewed along the b axis with hydrogen bonds shown as dashed lines. Chains of hydrogen-bonded ionic species are extended along [1 0 1].