Copper and palladium complexes with substituted pyrimidine-2-thiones and 2-thiouracils: syntheses, spectral characterization, and X-ray crystallographic study

Abstract Copper(I) and palladium(II) complexes containing 5-acetyl-6-methyl-1,2,3,4-tetrahydropyrimidine-2-thione (L1), ethyl 4,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (L2), cis-5-acetyl-6-ethyl-5,6-dihydro-2-thiouracil (L3), and 5,6-dihydro-2-thiouracil (L4) have been synthesized. All complexes were characterized by elemental analysis, IR, 1H, and 13C NMR spectroscopy. To assign bands in the IR spectra of L1 and L2 and complexes with Cu(I) and Pd(II), deuterium substitution of movable protons at N-atoms was used. The crystal structures of two compounds, [Cu(L2)2Cl] and [Pd(L4)2Cl2], were determined by X-ray single-crystal and powder diffraction, respectively. In [Cu(L2)2Cl], copper has a rare coordination number of three and triangular surrounding of two neutral L2 molecules, coordinated through sulfurs, and chloride. In [Pd(L4)2Cl2], palladium has a standard square-planar geometry, formed by two uracil molecules and two chlorides. A new method for the synthesis of 5,6-dihydro-2-thiouracil, starting from β-aminopropionic acid, was suggested.


Introduction
Investigations of chemical behavior of functionalized pyridine-thiones(ones), especially thiouracils(uracils), are of interest owing to roles in various biological systems. For instance, they demonstrate intriguing antiviral activity [1,2]. Research  complexes, of those organic compounds is also important. Copper plays a significant role in thyroid hormone metabolism [3,4]. Removal of copper ions by complexation with this type of ligand can serve as an effective way to find new antithyroid drugs [5]. Kamalakannan and Venkappayya observed good antimicrobial and antifungal activities of copper, zinc, cadmium, and mercury complexes of 5-dimethylaminomethyl-2-thiouracil [6]. Palladium complexes of 2-thiouracil have perspectives to be used as antitumor reagents because of their promising in vitro cytotoxicity [7]. Palladium complexes, in contrast to platinum analogs, show no mutagenic activity [8] and, therefore, are promising compounds for the replacement of platinum-containing drugs. Pyrimidine-2-thione and its derivatives (including different 2-thiouracil species) are very interesting ligands since they adopt many coordination modes through S or N, involving one, two, or even three metal ions [9]. In the anionic forms, these ligands can be coordinated through one sulfur [10,11], through one nitrogen and one sulfur [9,12,13], or through all nitrogen and sulfurs [14]. For neutral substituted pyrimidine-2-thiones and 2-thiouracils, coordination through the sulfur was found [15][16][17][18][19][20]. In some cases, heteroatoms of substituents are involved in coordination [9,17].

Complexes of copper(I)
All target complexes were prepared from chlorobis(acetonitrile)copper(I), which was obtained by dissolution of CuCl at room temperature in absolute acetonitrile:

Complexes of palladium(II)
All the complexes were obtained by the reactions of L 1 -L 4 with dichlorobis(acetonitrile)-palladium(II), which was prepared by refluxing of PdCl 2 in dry acetonitrile under vigorous stirring for 1 h till the formation of a transparent brown solution (without dark brown residue of PdCl 2 ):

Analysis methods
Microanalytical results were obtained with an EA1112 Thermo Finnigan analyzer. Melting points were determined by an automatic PTP(M) instrument in a capillary with 1.5 mm diameter; thickness of a layer of the compounds was about 2 mm. Infrared spectra were obtained using a BRuKER VECToR 22 spectrometer (400-4000 cm −1 , in Nujol, . NMR spectra were recorded using a Bruker Avance III 600 spectrometer (600.13 or 150.90 MHz for 1 H and 13 C, respectively, in dMSo-d 6 (99%) or Cd 3 CN-d 3 (99%), deutero GmbH). All measurements were carried out at 298 K.
X-ray diffraction analysis of 2 was carried out on a Bruker KAPPA APEX II diffractometer (MoK α radiation, graphite monochromator) at room temperature. Absorption was corrected with the use of SAdABS. The structures were solved by direct methods (SHELXS97) and refined by full-matrix least-squares method in the anisotropic approximation for all non-hydrogen atoms (SHELXL97) using all reflections [21]. Hydrogens were positioned geometrically and refined as riding, with U iso (H) = 1.2-1.5 U eq of the parent carbon. The crystal data, data collection, and refinement parameters for [Cu(L 2 ) 2 Cl] are given in Table 1.
X-ray powder diffraction data for [Pd(L 4 ) 2 Cl 2 ] (8) were collected at room temperature using a Panalytical EMPyREAN instrument with a linear X'celerator detector using nonmonochromated CuK α radiation. The unit-cell dimensions were determined using three indexing programs: TREoR90 [22], ITo [23], and AuToX [24,25]. Based on systematic extinctions, the space group was determined as P2 1 /c. The unit-cell parameters and space groups were further tested using a Pawley fit [26] and confirmed by the successful crystal structure solution and refinement. The crystal data, data collection, and refinement parameters for 8 are given in Table 2. The crystal structure was solved with the use of simulated annealing technique [27], taking into account an empirical formula, unit-cell volume, and space group symmetry, which led to a conclusion that the Pd(II) ions have to reside on inversion centers. In simulated annealing runs, the total number of varied degrees of freedom was 9, with three positional parameters for one independent Cl anion and three translational and three orientational for the rigid ligand molecule. The solution found was fitted with the program MRIA [28] in the bond-restrained Rietveld refinement using a split-type pseudo-Voigt peak profile function [29]. Anisotropic line broadening was taken into account with the use of nine variables [30], and symmetrized harmonics expansion up to the fourth order [31,32] was used for correction of the texture effect (the minimum and maximum texture multipliers for the calculated intensities were 0.79 and 1.51, respectively). Restraints were applied to the intramolecular bond lengths and contacts in the ligand molecule; the strength of the restraints was a function of interatomic separation and, for intramolecular bond lengths, corresponded to r.m.s. deviation 0.01 Å. All non-H atoms were refined isotropically. Hydrogens were positioned geometrically (C-H 0.97 Å; N-H 0.86 Å) and not refined. The diffraction profile after the final bond-restrained Rietveld refinement is shown in Figure 1.

Spectral characterization
To assign bands in the IR spectra of L 1 and L 2 , we used deuterium substitution of movable protons at nitrogen by double refluxing of corresponding compounds in CH 3 CN-d 2 o (1:1) mixture for 4 h. Comparison of IR spectra for L 1 , L 2 , and their deuterium-substituted derivatives (L 1d and L 2d , respectively) distinguish vibrations involving NH groups. Substitution of protons at N-atoms of L 1 by deuterium cations are reflected in the decrease of frequencies of the bands corresponding to the stretching vibrations of the NH groups (Table 3) from 3275, 3187, and 3136 cm −1 to 2440, 2360, and 2345 cm −1 (by ~1.37 times), in agreement with theoretical values. The band at 1612 cm −1 remains at the same place (that band does not include an NH component) and, therefore, should be assigned to the mixed vibrations ν(C=o) and ν(C=C). After isotope exchange, the band at 1592 cm −1 shifts to 1278 cm −1 and, hence, it is assigned to the mixed vibrations δ(NH) and ν(CN) (thioamide II). Changes are not so significant in comparison with ν(NH), because δ(NH) is only one of the two components in the thioamide II vibrations. The bands at 1187 and 780 cm −1 disappear after deuteration; they can be assigned to δ(NH) (thioamide III) and δ(NH) (thioamide V), respectively.
IR spectra of the complexes reflect bonding features of the ligands. Thus, the band at 1660 cm −1 in the IR spectrum of L 2 , which is assigned to ν(C=C) + ν(C=o), splits into three bands and shifts to 1654 cm −1 (assigned to ν(C=C), because the shift is insignificant), 1691, and 1710 cm −1 (two bands for different ν(C=o) vibrations) in the spectrum of 2 ( Table 3). Appearance of the additional bands can be caused by the formation of different N-H⋯o hydrogen bonds due to the following probable reasons. The first reason is the occurrence of two diastereomers of the complex, one of which is characterized by X-ray single-crystal diffraction. The second reason is the presence of another isomer of the complex, which can have opposite orientation of L 2 about Cl (rotated by the NH group), with another set of H-bonds. The band at 1584 cm -1 in the spectrum of L 2 assigned to δ(NH) + ν(CN) is widened and shifted down to 1576 cm −1 in the spectrum of 2; probably, this is a result of overlapping of the bands of two isomers. Similar changes, caused by formation of H-bonds, are found in the spectra of other copper complexes. Table 3. selected bands (cm −1 ) in the ir spectra of l 1 , l 1d , l 2 , l 2d , and 2. The changes in the IR spectra of the palladium spectra are identical to the changes of the corresponding copper complexes, indicating similar coordination modes of the ligands. NMR spectra also confirm the formation of the complexes. The signals of protons in the 1 H NMR spectra of the complexes are shifted to weak field as compared to the spectra of uncoordinated L 1 -L 4 due to their lower screening caused by metal coordination ( Table 4). Splitting of the 1 H-signals at nitrogen of the ligands in 1 H-spectra of all palladium complexes can be caused by coordination of palladium by dMSo, serving as the solvent for recording NMR spectra. Solvated complexes could form additional intermolecular interactions resulting in nonequivalence of protons at N-atoms. only signals of two isomers were observed in the NMR spectra of both copper and palladium complexes of thiouracil L 3 , although signals of three isomers were found in the NMR spectra of the initial uncoordinated L 3 . The observation means that complexation changes the equilibrium between the three forms, favoring the formation of keto and (z)-enol forms of thiouracil L 3 .

Assignment
Maximal shift of the signals in the 13 C NMR spectra (up to 5 ppm) was found for carbons of the C=S groups (Table 5), indicating coordination of the ligands through sulfur. Smaller, but still significant, shifts were observed for the sp 2 -hybridized carbons, participating in conjugation. The signals of the sp 3 -hybridized carbons were slightly shifted. The changes in the 13 C NMR spectra of the palladium complexes are identical to the changes for the corresponding copper complexes. Shifts of all signals are greater than for the copper complexes, indicating higher polarity of the Pd-S bond as compared to the Cu-S bond.
Crystals of [Cu(L 2 ) 2 Cl] suitable for analysis were grown from ethanol by slow evaporation of the solvent for 3 days. The structure of [Cu(L 2 ) 2 Cl] is shown in Figure 2. In [Cu(L 2 ) 2 Cl], copper(I) has a rare coordination number three and trigonal two neutral L 2 molecules, coordinated through sulfur, and chloride. The copper is out of the Cu-Cl-S-S plane by 0.038 Å. The Cu-S and Cu-Cl bond lengths in 3 are 2.2142(11), 2.2280 (12), and 2.2565(12) Å. Similar almost trigonal planar coordination for Cu(I) bound to S and Cl − was found in chlorobis-(2-thiouracil)copper(I) dimethylformamide solvate, where 2-thiouracil ligand also coordinates Cu(I) through sulfur [18]. The structure of the CuBr complex with 2,4-dithiouracil and 1,2-bis(diphenylphosphanyl)benzene differs significantly; it corresponds to a four-coordinate Cu(I) in a tetrahedral coordination environment with the heterocyclic dithione ligand being monodentate to the metal center through its exocyclic sulfur donor [19]. The distorted tetrahedral coordination around each copper is also found in dimeric [CuI(eitotH 2 ) 2 ] 2 and monomeric [CuX(PPh 3 ) 2 (eitotH 2 )] (eitotH 2 = 5-carbethoxy-2-thiouracil; X = Cl, Br); the thione ligand is S-bonded [20]. The heterocycle in the complex has a distorted boat conformation similar to free L 2 [40]. The C2, N3, C5, and C6 of the ring are arranged in the same plane, while the N1 and C4 deviate from the C2-N3-C5-C6 plane by 0.148 and 0.375 Å, respectively. The methyl at C4 has almost axial orientation; the C2-N3-C4-C(Me) angles are 88.73° and −89.18° for two ligand molecules. C4 is a chiral center. Every Table 5. 13 C-nmr spectra of l 1 -l 4 and corresponding Cu(i), Pd(ii) complexes. molecule of the complex contains both L 2 enantiomers. Another kind of isomerism can be caused by different orientation of methyl groups at C4 about the coordination plane. However, only one diastereomer (from four possible) with one-side orientation of methyl groups (one ligand with R-and one with S-absolute configuration) is found in the crystal structure of [Cu(L 2 ) 2 Cl]. The structure is stabilized by intramolecular N-H⋯Cl hydrogen bonds, and similar stabilization was found [19]. Complex molecules are combined in layers by N-H⋯o hydrogen bonds. Layers are linked by C-H⋯S and C-H⋯o contacts.
The 5,6-dihydro-2-thiouracil ligands exhibit a half-chair conformation, similar to free 5,6-dihydro-2-thiouracil molecules [41], with C3 and C4 displaced by 0.176 and −0.211 Å on either side of the base plane. The S-C and C-o bond lengths do not change on coordination; they are 1.675(11) and 1.220(13) Å for 8 and 1.676(3) and 1.216(4) for dihydro-2-thiouracil, respectively. The complex molecules are combined in a 3-d framework by one N-H⋯o and two C-H⋯Cl contacts for every ligand molecule.

Conclusion
Eight complexes of Cu(I) and Pd(II) with two pyrimidine-2-thione and two 2-thiouracil ligands were synthesized and characterized by various physical methods. A new method for the synthesis of 5,6-dihydro-2-thiouracil, based on the key-step reaction of β-aminopropionic acid with benzoylisothiocyanate, was suggested. To assign bands in IR spectra of organic molecules and corresponding complexes, deuterium substitution of movable protons on nitrogens was made. That [Cu(L 2 ) 2 Cl] exists as two diastereomers was supported by IR spectroscopy. The NMR method was applied for establishing coordination sites in the complex molecules. The crystal structures of [Cu(L 2 ) 2 Cl] and [Pd(L 4 ) 2 Cl 2 ] were determined by X-ray diffraction. Coordination occurs through the sulfurs of the ligand molecules, causing significant shift of the thiomide II band in the IR spectra and noticeable change of the chemical shift for the carbons of the C=S groups in the 13 C NMR spectra. only one donor of each ligand is involved in coordination with copper(I) or palladium(II), although substituted pyrimidine-2-thione and 2-thiouracil ligands have various potential donor sites. This fact can be explained by softness of the copper(I) and palladium(II) ions; they tend to form bonds with soft sulfurs of the ligands, while harder nitrogens and oxygens do not participate in the coordination.

Disclosure statement
No potential conflict of interest was reported by the authors.