Reactions of Pd(II) and Pt(II) Complexes With Tetraethylthiouram Disulfide

The reactions of tetraethylthiouram disulfide (DTS), an inhibitor of the nephrotoxicity of Pt(II) drugs, an efficient agent in the treatment of chronic alcoholism, in the treatment of HIV infections, AIDS and heavy metal toxicity, and a fungicide and herbicide, with K2[PtCl4], in ratio 1:1 and 1:2, gave the compounds [PtCl2DTS] and [Pt(S2CNEt2)2] respectively. The reaction of the complexes K2[PdCl4], Pd(AcO)2 and [PdCl2(PhCN)2], where PhCN = Benzonitrile, with tetraethylthiouram disulfide in ratio 1:1 or 1:2, yielded orange crystals identified as [Pd(S2CNEt2)2]. The crystals were suitable for study by X-ray diffraction. The -S-S- bridge in the tetraethylthiouram disulfude molecule was broken and the two molecules of the thiocarbamate derivative were bound to the Pd(II) by the equivalents sulfur atoms. All the compounds were characterized by IR, 1H and 13C NMR spectroscopies.


Introduction
Cisplatin and other Pt(ll) complexes are nephrotoxic. A number of nucleophilic agents, mainly sulfur compounds, inhibit these toxic effects1-3. The interaction of cisplatin with several of these compounds such as methionine, penicillamine and glutathione, has been studied in recent years4-13.
To elucidate the mechanisms involved in the inhibition of toxicity, we have studied the behavior of Pt(ll) complexes containing ligands with -S-Sbonds such as tetraethylthiouram disulfide [DTS,bis(diethylthiocarbamoyl) disulfide, 1,1'-dithiobis(N,N'-diethylthioformamide), dithiosulfiram, Antabuse(R), Noxal(R), Abstensil(R), BAN] (1). This compound is used in the treatment of the chronic alcoholism, as a fungicide and herbicide, and. also to inhibit the secondary effects of the cisplatin, in the treatment of HIV infections, AIDS and heavy metal toxicity14-5. The study was also extended to the interaction of the tetraethylthiouram disulfide molecule with Pd(ll) complexes. On the other hand, the diethyldithiocarbamate molecule (DEDTC, Imuthiol(R)) (2), related with tetraethylthiouram disulfide is present in rubbers and plastics16 and it has also been used as inhibitor of cisplatin toxicity without inhibition of the antitumor activity17,8. This may be due to its high affinity for Pt, which causes the breaking of Pt-protein adductsl'9 without capture of the Pt bound to DNA20. Pt(ll)-diethyldithiocarbamate complexes have been found in plasma of patients treated with this inhibitor21.
Both subtances, tetraethylthiouram disulfide (DTS) and its derivative diethyldithiocarbamate (DEDTC) have similar applications as fungicides, pesticides, antioxidants, lubricants, flotation agents, and vulcanization accelerators22 and they are active against some typus of leukemia, probably due to their immunomodulation properties23. The mutual interconversion is easily produced, especially in the biological medium20 and inside lubricants DTS is also converted into DEDTC16.
The crystal structure of tetraethylthiouram disulfide was studied previously24. The most important feature of this molecule is that, although there is no C2 symmetry, the two halves are chemically equivalent. Wang et al. had shown interest in deformation density studies25 due to the short distances and forced angles found at room temperature. However, these studies showed a low electronic density in the zone between the two bound S atoms. This feature facilitates the breaking of the molecule at this point, and two dithiocarbamate ions are produced. Studies on the thermal dissociation of DTS showed that the radical free process is reversible and that the solvent has no influence on it26. At 120-C DTS dissociates to DEDTC. The process can be reversed by the action of cytochrom c or hydrogen peroxide, among others20. Due to the proclivity of DTS to dissociate to DEDTC, only a few compounds of DTS have been described. Brinkhoff et al. 27 synthesized derivatives of Hg, Cuadrado et al. 28  Elemental analyses were carried out on a Carlo Erba 1500 microanalyzer at the Serveis Cientffico-Tcnics at the University of Barcelona. The infrared spectra were recorded in solid state (KBr pellets) on a FT-IR Nicolet 5DZ spectrometer in the 4000-400 cmrange and on a FT-IR Bomem DA-3 spectrometer in the 400-150 cm -1 range. 1H{13C} and 13C{1H} NMR spectra were obtained on a Varian Gemini 300 spectrometer using CDCI 3 as solvent. Chemical shifts were measured relative to TMS.
Suitable crystals for X-ray diffraction experiments were mounted on an Enraf-Nonius CAD4 fourcircle diffractometer. Unit cell parameters were determined from 25 reflections and refined by the least-squares method. Intensity data were collected using graphite monochromated MoKo radiation. Lorentz and polarization corrections were applied but not corrections for absorption due to the small volume of the crystal selected. The structure was solved locating the Pd atom by direct methods using the MULTAN 11/84 program37. The positions of the remaining non-hydrogen atoms were determined by weighted Fourier synthesis. Refinement was carried out using the SHELX-76 program38. Hydrogen atoms were located by difference Fourier synthesis and introduced in the refinement with a global isotropic temperature factor after the convergence of the anisotropic thermal parameters for non-H atoms. Methyl groups were allowed to rotate axially in the last stages of refinement. When the compound (3) was recrystallized in THF or in chloroform, bright orange crystals were formed. These crystals were suitable for study by X-ray. Found: C, 29.80; N, 6.78; S, 32.13. PdCloH2oN2S4 requires: C, 29 19.71; CI, 10.90. All efforts to obtain crystals suitable for study by X-ray were unsuccessful.

Syntheses of the Complexes
Only macled needles could be isolated.
(c) [Pt(S2CNEt2)2] (5) mmol of K2[PdCI4] and 2 mmol of finely powdered tetraethylthiouram disulfide were mixed and 20 mL of ethanol was added. The solution was stirred for h at 40 C and a pale pink precipitate formed, which evolved to dark brown. After 36 h stirring at room temperature the solid was filtered but it could not be identified. Brown needles suitable for X-ray diffraction were obtained from the solution. Found: C, 24 Table I. The spectra of tetraethylthiouram disulfide and diethyldithiocarbamate molecules are very similar. The main difference is the presence of a band at 434 cm-1 in the spectrum of the DTS. This band is assigned to the stretching mode v(S-S)39,40. In the spectrum of (4) this band appears but it is absent in the spectra of (3) and (5), confirming the breaking of the S-S bond. The band assigned to VCN and vs(CNC) coupled with the inner modes from alkyl groups41, also called thioureid band42,43 appears at 1497 cm-1 in DTS and at lower frequency in free DEDTC. This band moves to higher frequencies (30-40 cm-1 for DTS and 40-50 cm-1 for DEDTC) in the new complexes. This is due to the ability of the amines to transfer density of charge towards the S atoms through the system, thus reforcing the C-N bond44. In the case of dithiocarbamates, the resonant form IV (Scheme 3) explains the shift of the band towards higher frequencies42.
The resonant forms which contribute to the electronic structure for the DTS complexes are shown in Scheme 4. The lesser contribution is that of the form IV because the band v(CN) is absent in the complexes of DTS.
The band at 1296 cm-1 assigned to v(CN) appears in the spectra of (3) and (5) but not in the spectrum of (4), confirming the formation of DEDTC complexes in the former and of DTS complex in the latter39. The stretching frequency v(C-S)asvm41, 44 appears at 1000 cmfor DTS and at 987 cmfor DEDTC. In the Pd(ll) and Pt(ll) complexeg of DEDTC only one band appears in this zone, as corresponds to bidentate dithiocarbamates42o In the spectrum of (4) only one band is observed which also indicates bidentate coordination for DTS28, 45. This band shifts to lower frequencies as a consequence of the lengthening of the end C-S bond when it is coordinated to the metal ion The vibration v(C-S)svm appears as a single band at 555 cm-1 in the DTS spectrum and at 566 cmin the DEDTC spectrtm. The band appears split in the spectrum of (4), but not in the spectrum of (3) or (5). In all cases this band is shifted towards higher frequencies in the complexes. The new bands that appear at low frequencies are assigned to v(M-S) and v(M-Cl), (Table 1) X-Ray Study Crystal parameters and a summary of the data collection and refinement process corresponding to compound (3) are given in Table 2. Although the cell parameters suggest a tetragonal cell, the analysis of the equivalence between symmetry related reflections shows that the cell is monoclinic. A perspective view of the molecule, including the atom labeling, is shown in Figure 1. Fractional atomic coordinates with the equivalent temperature factors are listed in Table 3. Table 4 contains the corresponding bond distances and angles with their esd. Anisotropic thermal parameters and the listing of observed and calculated structural factors may be obtained on request from the authors. Crystal packing is depicted in Figure 2. The Pd atoms are situated in the crystallographic center of the cell.
The palladium atom is in planar coordination, the Pd-S distances being equivalent. The angles do not correspond exactly to a square distribution but a rhombus. For example, for the Pdl atom one, the angles S12-Pd1-S11 and S'12-Pdl-S'11 are equal to 75. 6  indicating bond order greater than one. This fact is consistent with the IR data commented above. The dithiocarbamate C-S distances are also equivalent in all cases, indicating the delocalization of the anion charge produced when the initial molecule of dithiosulfiram breaks in the presence of the Pd(ll) ion. The bond order is smaller in this case than in the whole ligand.
The crystal data of this Pd(ll) complex was compared with that from the crystal structure of the tetraethylthiouram disulfide24,25 and with Ni(ll), Cu(ll), Zn(ll), and Mo(V) diethyldithiocarbamates complexes reported in the literature32-34,36. The C-S distances found for the Pd(ll) compound range from 1.735 A to 1.715 A, which is very similar to the valueos for the Ni(!l), Cu(ll) and Zn(ll) diethyldithocarbamate complexes, which are between 1.700 A and 1.725 A. However, the C-N distance in the Pd(ll) complex, 1.294 ,&,, is shorter than that corresponding to the Ni(ll), Cu(ll) and Zn(ll) derivatives, which are between 1.35 ,/k and 1.33 A, and shorter than the C-Nodistances in each perpendicular half of the tetraethylthiouram disulfide molecule, 1.33./x, and 1.36 A. Thus, the bond order for C-N is higher in the Pd(ll) compound than in tetraethylthiouram disulfide and the other complexes. The other lengths are similar and as expected in this type of compound.
The data corresponding to [Pd(S2CNEt2)2] (3), can be also compared with [Pt(S2CNEt2)2], (.5). In the reaction of K2[PdCI4] tetraethylthiouram disulfide in ethanol (1:2), brown needles suitable for Xray study were isolated and identified as the compound of platinum and diethyldithiocarbamate described by Baker46. The resolution of the structure confirmed the breoaking of the S-S atom in DTS, which gave compouond (5). The C-N length in [Pt(S2CNEt2)2] is 1.32 A, while the C-N length in [Pd(S2CNEt2)2] is 1.29 A; therefore, the bond order is lower than that of the Pd compound, but slightly higher than that corresponding to the DTS molecule.  16.430 (2) b(oA) 6.237 (1) c(A) 16.430 (2)  Lone-pair electron density is apparent around all the S atoms. The degree of the density accumulation at the midpoint of bonded atoms follows the order: shorter C-N > C-C > longer C-N, C=S > C-S > S-S. The soft metal ion Pd(ll) can easily coordinates to the S atoms to produce the stable neutral dithiocarbamate complex.
The non equivalence of the protons of -CH2and -CH3 can be observed in the spectrum of DTS. In the case of CH2, instead of the expected quadruplet, a multiple appears. Likewise, two triplets can be observed for the CH3 groups. This means that the two ethyl groups from SC(S)N(Et)2 are not equivalent as a consequence of the hindrance of free rotation due to the high order of the (S2C)-(NEt2) bond25,47, as observed for DMF27. On the other hand, in the spectrum of DEDTC only one signal is observed for both CH2 and CH 3, indicating the equivalence of the protons. When DTS is broken, the two fragments are equivalent (DEDTC anion) and the resonant form III, which allows the free rotation of (S2C)-(NEt2) bond, predominates. Therefore, in the spectra of [Pd(S2CNEt2)2] (3) and [Pt(S2CNEt2)2] (5) the quadruplets and triplets observed were assigned to CH2 and to CH3 respectively. Both groups are equivalent, as confirmed by the X-ray results. The upfield shifts observed for all the protons in comparison with those corresponding to DEDTC are also present in other DEDTC complexes27. In contrast, in the spectrum of [PtCI2(DTS)]2 (4), the non-equivalence of the protons in CH2 and CH3 is evident, which confirms the presence of DTS in the complex. The resonances appear as upfield-shifted, broad multiple signals in comparison to those of DTS. The double bond character for C-N in the complex is greater than the corresponding to DTS27 and as a consequence the hindrance to rotation increases. This observation is consistent with the IR results. atoms fixed at special positions The most spectacular difference in the 13C NMR spectra can be found in the chemical d corresponding to C=S. In tetraethylthiouram disulfide this signal appears at 192.67 ppm and the coordination to the platinum (4) produces a shift to upper fields. In the DEDTC the signal appears at 207.29 ppm but in the complexes (3) and (5)it shifts down-field. In the spectrum of [PtCI2(DTS)]2 (4), all the signals are split due to the non-equivalence of the two halves of the DTS molecule27 or to the presence of two structurally non-equivalent molecules of DTS. Both CH2 and CH3 carbon atoms in (3) and (,5) are equivalent as expected for DEDTC complexes. In the platinum complex the shifts are slightly higher than in the palladium complex which is consistent with the higher acceptance ability of the platinum.   (3), (4) and (,5) are given in Table 5.
The 195Pt NMR spectrum of [PtCI2(DTS)]2 gave only one signal at -1763 ppm (K2PtCI6 as reference).This resonance appears slightly shifted as expected for a PtCI2S2 environment, which could be attributed to the anomalous charge density arrangement on the sulfur atom in DTS before described. The appearance of only one signal indicates that the arrangement of the two platinum atoms in the dimer is equivalent and that only one specie is present in solution48.   ERBCHRXCT 920016 and to Johnson Matthey for K2PdCl4 and K2PtCl4 supplied.