(4Z,4′Z)-2,2′-(Ethane-1,2-diylbis(sulfanediyl))bis(1-phenyl)-4-(pyridin-2-ylmethylene)-1H-imidazol-5(4H)-one)dicopper(II) Tetrabromide

Abstract

The title compound was characterized for the first time by a full range of physical methods including UV, FTIR, mass spectrometry and X-ray structure determination. The copper atoms have a distorted tetrahedral structure close to a trigonal pyramid.

1. Introduction

Efficient and cost-effective approaches to obtaining biologically active coordinated metal derivatives from available materials have attracted widespread attention [1]. In particular, the copper (II) complexes exhibit broad cytotoxicity against tumor cells [2]. The mechanism of this effect is attributed to the spatial structure of the central atom of the complex. These structures vary from the most frequent plano-square in bidentate ligands to trigonal-bipyramidal through tetrahedral, octahedral, and square-bipyramidal forms [3,4]. A number of coordination compounds are in various stages of clinical trials as antitumor drug candidates [5,6].

Modifications of copper–organic complexes presume changes in the coordination structure of the metal ion by varying the donor–acceptor properties and ligand dentation. Alternatively, the substituents in the organic ligand can distort the structure of the central ion due to electrostatic or steric interactions. For instance, the introduction of a thiol fragment at the α position to one of the ligand’s nitrogen atoms was beneficial for antitumor efficacy [7,8].

The electronic characteristics of the organic ligand (such as donor/acceptor substituents) determine its oxidation potential and complexation with copper ions. In previous work, we synthesized a series of 3-aryl-substituted 2-thioxoimidazole-4-ones and binuclear coordination compounds based on Cu (II) dichloride [9,10]. We were interested in the molecular structure of this chemical class. In the present study, the structure of the complex was resolved for the first time (Scheme 1).

2. Results

In tetradentate derivatives with a 1,2-dithioethylene 2,2′-ethane-1,2-diylbis(sulfanediyl) bridge, the ligand undergoes a transition from an unfolded structure to a tense pincer carcass even in a solution (Scheme 1). We attempted to change the structure of the complex from pincer to linear by increasing the steric component. In doing so, the chlorine atoms were replaced with bromine. This replacement did not affect the structure, i.e., the pincer shape was preserved.

Nevertheless, some aspects deserve discussion. UV spectra showed absorption at 366 nm (0.203 A) and 368 nm (0.188 A) for ligand 1 and complex 2 (Figure S1, Supplementary Materials). IR spectra demonstrated a shift of C=O maximum at 1720 cm⁻¹ for 1 and 1738 cm⁻¹ for 2 to the short wavelength region (Figure S2). This non-trivial finding indicates the coordination of the copper ion with nitrogen atoms. The MALDI experiment showed a result with an m/z distribution of 651.40 [L + Cu]⁺, which is typical for such complex compounds (Figure S3). The prepared crystals of compound 2 (CCDC 2221326) were directly suitable for X-ray diffraction analysis (Figure 1 and Figure S4). Crystal data and clarification of the structure of tetrabromide 2 are given in Tables S1–S4; see the Supplementary Materials. The tetrahedral structure of the copper ion was significantly distorted while the intramolecular N-Cu-N angle of 93–94° was retained. We believe that such a distortion is the biggest among the structures of this type. Thus, a comparison of copper complexes obtained in similar reactions of the bis-pyridylmetnhylene-imidazolone ligand with CuCl₂ or CuBr₂ shows that the halide anion nature in the initial copper salt determines the structure of the complex.

3. Experimental Section

Melting points were determined using an OptiMelt MPA100 automated melting point system, 1 °C/min, 0.1 °C resolution (Stanford Research Systems, Sunnyvale, CA, USA). Infrared spectra were recorded on a Thermo Nicolet iS5 FTIR, the number of scans was 32, the resolution was 4 cm⁻¹, and sampling was conducted via ATR (Thermo Fisher Scientific, Waltham, MA, USA). Electronic spectra in the UV and visible regions were recorded on a GENESYS 50 UV-Vis (Thermo Fisher Scientific, Madison, WI, USA) instrument with an operating wavelength range of 190–1100 nm and spectral bandwidth of 2 nm in a quartz cuvette manufactured by Agilent Technologies with an optical path of 10 mm. The data of X-ray diffraction analysis were collected by using an STOE diffractometer, a Pilatus100K detector (Baden, Switzerland), the focusing mirror collimation Cu Kα (1.54186 Å) radiation, and the rotation method mode. Data collection and image processing were performed with X-Area 1.67 (STOE & Cie GmbH, Darmstadt, Germany). Intensity data were scaled with LANA (part of X-Area) to minimize differences in intensities of symmetry-equivalent reflections (a multiscan method). The structures were resolved and refined with the SHELX program [11]. Non-hydrogen atoms were refined using the anisotropic full matrix least square procedure. Hydrogen atoms were placed in the calculated positions and allowed to ride on their parent atoms. The molecular graphics were prepared using DIAMOND software [12]. Mass spectra of matrix-activated laser desorption/ionization (MALDI) were recorded on a Bruker Autoflex II instrument (resolution FWHM 18000, Bremen, Germany) equipped with a nitrogen laser with a working wavelength of 337 nm and a time-of-flight mass analyzer operating in the reflectron mode. The accelerating voltage was 20 kV. The samples were applied to a polished steel substrate. The spectra were recorded in the positive ion mode. The resulting spectrum was the sum of 50 spectra obtained at different points in the sample. trans-2-[3-(4-tert-Butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB) and 9-nitroanthracene (Ant) (Acros, 99%) were used as matrices where needed to facilitate ionization.

(4Z,4′Z)-2,2′-(Ethane-1,2-diylbis(sulfanediyl))bis(1-phenyl)-4-(pyridin-2-ylmethylene)-1H-imidazol-5(4H)-one)dicopper(II) Tetrabromide (2)

In total, 0.1 mL of n-BuOH was carefully added to a solution of 15 mg of the ligand (1) in 1 mL of DCM to achieve separable layers. A solution of 2 eq. of CuBr₂ × 2H₂O in 1 mL of n-BuOH was then carefully added, keeping the separation in a two-phase system. The tightly closed reaction mixture was left for 1–2 days in the dark until a homogenous solution was formed. The precipitate was separated by decanting and washed with a small amount of ice-cold DCM and then with Et₂O until the washing solvent became colorless. The final product (2) was obtained as a black crystalline powder after air drying. Yield—41%; M.p—214–215 °C; FTIR (KBr, ν/cm⁻¹)—543, 593, 653, 690, 733, 781, 862, 920, 977, 1014, 1080, 1160, 1223, 1262, 1307, 1358, 1440, 1463, 1499, 1591, 1637, 1738, 3059, 3452; UV–Vis (λ, nm, (ε, l·mol⁻¹·cm⁻¹))—368 (37600); MALDI m/z—651.40 [L + Cu]⁺.

Crystal data for C₃₃H₂₄Br₄Cu₂N₆O₂S₂ (M = 1035.41 g/mol): triclinic, space group P-1, a = 11.2798(8) Å, b = 12.8610(10) Å, c = 14.4480(10) Å, α = 99.265(6)°, β = 105.814(6)°, γ = 95.406(6)°, V = 1969.2(3) ų, Z = 2, T = 295(2) K, μ(CuKα) = 8.652 mm⁻¹, D_calc = 1.889 Mg/m³, F(000) = 1092. The CCDC deposition number is 2221326.

Author Contributions

Conceptualization, A.V.B. and A.S.H.A.-K.; Writing—original draft preparation, X.B.; Writing—review and editing, A.V.F. and A.A.S.; Visualization, V.A.T. and R.S.B.; Methodology, A.S.H.A.-K. and E.N.O.; Formal analysis, J.B. and A.A.S.; Supervision, A.V.F. and A.A.S.; Funding, A.V.F. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

X-ray data are deposited at CCDC 2221326 (Supplementary Materials).

Acknowledgments

FTIR, UV, Mass and X-ray studies were supported by MSU and TIPS RAS Program of Development.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figure and Scheme

Scheme 1. Construction of complexes A and 2.

Figure 1. The molecule of 2 in the crystal structure (CCDC 2221326, thermal ellipsoids at 50% level).

Supplementary Materials

The following supporting information can be downloaded online. Figure S1: UV–vis spectra of ligand 1 and complexes 2 (5∙10⁻⁸ M, DMF); Figure S2: IR spectra of ligand 1 and complexes 2 (KBr, cm⁻¹).; Figure S3: MALDI spectra of ligand 1 and complexes 2.; Figure S4. Crystal structure of tetrabromide 2. Table S1. Crystal data and structure refinement for tetrabromide 2. Table S2. Bond lengths [Å] and angles [°] for tetrabromide 2. Table S3. Torsion angles [°] for tetrabromide 2. Table S4. Hydrogen bonds for tetrabromide 2 [Å and °].

References

1. Guk, D.A.; Krasnovskaya, O.O.; Beloglazkina, E.K. Coordination compounds of biogenic metals as cytotoxic agents in cancer therapy. Russ. Chem. Rev.; 2021; 90, pp. 1566-1623. [DOI: https://dx.doi.org/10.1070/RCR5016]

2. Ndagi, U.; Mhlongo, N.; Soliman, M. Metal complexes in cancer therapy—An update from drug design perspective. Drug Des. Dev. Ther.; 2017; 11, pp. 599-616. [DOI: https://dx.doi.org/10.2147/DDDT.S119488] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28424538]

3. Prosser, K.E.; Chang, S.W.; Saraci, F.; Le, P.H.; Walsby, C.J. Anticancer copper pyridine benzimidazole complexes: ROS generation, biomolecule interactions, and cytotoxicity. J. Inorg. Biochem.; 2017; 167, pp. 89-99. [DOI: https://dx.doi.org/10.1016/j.jinorgbio.2016.11.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27915178]

4. Acilan, C.; Cevatemre, B.; Adiguzel, Z.; Karakas, D.; Ulukaya, E.; Ribeiro, N.; Correi, I.; Pessoa, J.C. Synthesis, biological characterization and evaluation of molecular mechanisms of novel copper complexes as anticancer agents. Biochim. Biophys. Acta (BBA) Gen. Subj.; 2017; 1861, pp. 218-234. [DOI: https://dx.doi.org/10.1016/j.bbagen.2016.10.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27773706]

5. Reina, M.; Hernández-Ayala, L.F.; Bravo-Gómez, M.E.; Gómez, V.; Ruiz-Azuara, L. Second generation of Casiopeinas: A joint experimental and theoretical study. Inorg. Chim. Acta; 2021; 517, 120201. [DOI: https://dx.doi.org/10.1016/j.ica.2020.120201]

6. Alem, M.B.; Damena, T.; Desalegn, T.; Koobotse, M.; Eswaramoorthy, R.; Ngwira, K.J.; Ombito, J.O.; Zachariah, M.; Demissie, T.B. Cytotoxic mixedligand complexes of Cu(II): A combined experimental and computational study. Front. Chem.; 2022; 10, 1028957. [DOI: https://dx.doi.org/10.3389/fchem.2022.1028957] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36247670]

7. Drzewiecka-Antonik, A.; Rejmak, P.; Klepka, M.; Wolska, A.; Chrzanowska, A.; Struga, M. Structure and anticancer activity of Cu(II) complexes with (bromophenyl)thiourea moiety attached to the polycyclic imide. J. Inorg. Biochem.; 2020; 212, 111234. [DOI: https://dx.doi.org/10.1016/j.jinorgbio.2020.111234] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32927369]

8. Krasnovskaya, O.O.; Guk, D.A.; Naumov, A.E.; Nikitina, V.N.; Semkina, A.S.; Vlasova, K.Y.; Pokrovsky, V.; Ryabaya, O.O.; Karshieva, S.S.; Skvortsov, D.A. et al. Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones. J. Med. Chem.; 2020; 63, pp. 13031-13063. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.0c01196] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32985193]

9. Finko, A.V.; Guk, D.A.; Saakian, A.S.; Moiseeva, A.A.; Tafeenko, V.A.; Shiryaeva, E.S.; Pergushov, V.I.; Melnikov, M.Y.; Komlev, A.S.; Beloglazkin, A.A. et al. Structurally similar mixed-valent coordination compounds formed during the interaction of bis-5-pyridylmethylene-2-thioimidazolone with CuBr₂ и CuCl₂. Polyhedron; 2022; 225, 115998. [DOI: https://dx.doi.org/10.1016/j.poly.2022.115998]

10. Finko, A.V.; Sokolov, A.I.; Guk, D.A.; Tafeenko, V.A.; Moiseeva, A.A.; Skvortsov, D.A.; Stomakhin, A.A.; Beloglazkin, A.A.; Borisov, R.S.; Pergushov, V.I. et al. Copper coordination compounds with (5Z,5Z′)-2,2′-(alkane-α,ω-diyldiselenyl)-bis-5-(2-pyridylmethylene)-3,5-dihydro-4H-imidazol-4-ones. Comparison with sulfur analogue. RSC Adv.; 2022; 12, pp. 7133-7148. [DOI: https://dx.doi.org/10.1039/D1RA08995A] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35424664]

11. Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. A; 2008; A64, pp. 112-122. [DOI: https://dx.doi.org/10.1107/S0108767307043930] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18156677]

12. Brandenburg, K.; Brendt, M. DIAMOND, Release 2.1 d; Crystal Impact GbR: Bonn, Germany, 2000; pp. 302-303.