Diaminehalogenoplatinum(II) complex reactions with DMSO

order to shed light upon the apparent kinetic difference from aqueous solution a quantitative study of DMSO reaction rates was undertaken in some (diamine)dihalogenoplatinum(II) systems varying only the halogenides as the leaving group.


Introduction
DMSO (dimethylsulphoxide) as a solvent has been used in studies of biological effects of several cis-bis(amine)dihalogenoplatinum(II) complexes [1] in cases where the solubility in water was too low. DMSO is a good solvent for many of these complexes and is also known to act as a ligand and to form well defined coordination compounds with metal ions including platinum(II) [2].
The solvolysis in DMSO of cis-diammindichloroplatinum(II) (cis-DDP) has been shown to be extensive [3]. Such reactions complicate the interpretation of kinetic data in biological assays when DMSO is used as a solvent. The same is true for aqueous solutions in which a cis-trans equilibration also takes place. Indeed, it has been shown that the cytotoxicity is inhibited of currently used platinum drugs dissolved in DMSO [4,5].
In our earlier kinetic studies of biological effects of platinum(II) complexes we have used the diaqua-derivatives of dichloro-1,2-ethanediaminplatinum(II) (PtenCl 2 ), thus avoiding problems with low solubility and complex kinetics due to cis-trans equili-bration and the simultaneous hydrolysis in aqueous solution of these complexes [4].
A kinetic study of solvolysis in DMSO of PtenCl 2 (and a number of N-and C-substituted analogues) [6] has shown that only one chloride is substituted by DMSO in the coordination sphere. Qualitative studies of the fate of halogenides in some cis-diaminedihalogenoplatinum(II) analogues in DMSO [3,7] demonstrated that iodide behaved as a faster leaving group than bromide and chloride. This is the opposite order of that found in classical kinetic studies [8] of the reaction of bis-(2-aminoethyl)aminehalogenoplatinum(II) (PtdienX + ) with pyridine in aqueous solution. Further studies with other entering groups showed that there is little or no difference between the three halogenides as leaving groups in DMSO [9]. In order to shed light upon the apparent kinetic difference from aqueous solution a quantitative study of DMSO reaction rates was undertaken in some (diamine)dihalogenoplatinum(II) systems varying only the halogenides as the leaving group.

* Iodo(dimethylsulphoxide)-1,2-ethanediamineplatinum(II) iodide [PtIen(DMSO)]I
PtenI 2 (0.5 g, 1 mmol) was dissolved in 2 ml of DMSO and left for 4 h in the dark, after which 8 ml of ethanol was added. The drop wise addition under stirring of 30 ml of toluene resulted in a yellow precipitate (0.5 g, 80%), which was washed with

Instrumentation and 1 H NMR data
1 H NMR-spectra (DMSO-d 6 ) were recorded at 27 °C using an AC250 MHz or an Avance III HD (400 MHz) both from Bruker. 195 Pt NMR-spectra (DMSO-d 6 ) were recorded using a Varian Inova (600 MHz) at different temperatures. 1 H NMR data are given in Table 1.

1 H NMR data
See Table 1 (As indicated in my respose to Q3 Table 1 lay out could be improved: Shading of row 10 plus a special marking of some of the data obtained at 250 MHz. Either the numbers should be in italics while the word "shaded" in brackets is replaced by "in italics" or by ¤ followed by appropriate marking of the relevant data as entered. The last option has been introduced as corrections.) Table 1 Data obtained at 400 MHz or 250 MHz¤ (shaded) both at 300 K. * exact chemical shifts are dependent on concentration; c: coordinated DMSO; l liberated, non-deuterated DMSO; # these signals happen to coincide with that of the sharp non-deuterated DMSO-signal. The combined signal in these cases is significantly broader at the base than pure DMSO in DMSO-d 6 but not separated as for [

Results
The syntheses of [Pt(N-N)X 2 ] were performed around room temperature with an excess of halide present, and were found to work well without by-products, since their solubility in aqueous media is low.

Kinetics of solvolysis
Kinetics of the reactions in DMSO of all the compounds were studied by recording the intensities of the 1 H NMR signals of the amine-protons, considered proportional to the concentrations. The initial spectrum showed in each case one not too broad signal around 5 ppm. In the subsequent spectra (cf. Fig. 1), this signal gradually vanished, while two different signals gradually appeared (approximately at 0.8 ppm downfield). The kinetics was clearly pseudo first-order, and the rate constants given in Table 2 indicate that the lability of X − in the tn-series is a little higher than in the analogous [PtenX 2 ] complexes. In both series the rate constants were found to increase in the order X = Cl < I. Inspection of the gradually appearing non-equivalent amine proton signals (cf. Fig. 1  illustrated in Fig. 2, where the amine proton signals have been recorded in a kinetic run.

Ion pair formation
The observed small changes in chemical shifts, δ obs , for the amine protons as the solvolysis proceeds, cf. Fig. 2, has been taken as evidence of the ion pair [Pt(N-N)X(DMSO)] + , X − being in fast equilibrium with its solvated ions in DMSO, assuming δ pair to be different from δ ion . δ obs is thus interpreted as δ pair α pair + δ ion α ion , and since α ion = 1-α pair , each of the two α's can be expressed in terms of δ obs , δ pair and δ ion . Among these δ obs is an observable in the single experiment, δ pair is unknown, but a constant parameter, and δ ion is known from the spectrum of a salt of [Pt(N-N)X(DMSO)] + with negligible ion pair formation.
Substituting α's with the combination of the three chemical shifts in the equilibrium expression, , gives with the two unknown constants K pair and δ pair . From two experiments with two different stoichiometric concentrations, C Pt , of [Pt(N-N)X 2 ] both of these constants can be estimated.
[PtenCl 2 ] exhibited the largest changes in signal positions of all cases studied, which made an extrapolation back to reaction start less accurate. To get a reliable δ ion the product was isolated as its nitrate and as its perchlorate anticipating that ion pair formation in DMSO would be insignificant in both solutions. The low field signal of the nitrate and the perchlorate were, however observed at 6.20 and 6.09 ppm resp. (65 mM, 27 °C in both cases) and decreased 0.03 ppm for the nitrate but remained unchanged for the perchlorate when the concentration was reduced by a factor of 3 in both cases. In one experiment the two different concentrations were C Pt = 43 mM and 201 mM and the corresponding δ obs were found at 6.35 ppm and 6.50 ppm, resp. With δ ion = 6.09 ppm (from the spectrum of [PtenCl(DMSO)]ClO 4 ), δ pair was found to be 6.70 ppm leading to the value K pair = 29.2 ± 1.1 M −1 at 300 K, which is sufficient to cause a displacement of the appearing chemical shifts further as observed. Small changes in chemical shifts of other signals were also observed, but K pair 's derived in the same way as outlined above were less accurate. Also, for the other 5 [Pt(N-N)X 2 ] complexes, chemical shifts of appearing signals only changed little or very little during a kinetic run. These small changes in chemical shifts either did not allow an estimate or gave less accurate estimates of K pair being smaller than 3·10 1 M −1 in all cases.
The ion pair formation interpretation was further consistent with the following small experiment: To a solution of [PtenClDMSO]ClO 4 (23 mM) was added solid LiCl to give 40 mM of non-coordinated chloride; the low field signal changed to lower fields at a position which agreed within 0.02 ppm with that calculated using K pair = 30 M −1 at 300 K.

Temperature variation
The rate of solvolysis of [PtenCl 2 ] was also studied using 195 Pt NMR at different temperatures. 15 Table 3. An Arrhenius plot gave an activation energy 82 ± 3 kJ mol −1 . From an Eyring plot activation parameters ΔH * and ΔS * were found to be 79 ± 2 kJ mol −1 and −56 ± 3 J mol −1 K −1 , respectively. The negative entropy of activation found confirms that the substitution mechanism is associative.  Small changes of chemical shifts were also observed during these experiment and rough estimates of K pair obtained from the 195 Pt NMR data at different temperatures were of the same order of magnitude (10 1 M −1 ) but less accurate.

DMSO exchange rates
While the solvolysis reactions studied apparently stopped at [Pt(N-N)X(DMSO)] + , DMSO was found to be labile:  Table   2, and confirmed that iodide had a greater cis-labilising effect than chloride

Discussion
In agreement with qualitative observations [3,6] the rate of solvolysis in DMSO of di(amine)dihalogenoplatinum(II) (1,2-ethanediamine and 1,3-propanediamine) was found to decrease in the order of decreasing size of halogenide. The rates were invariably larger in the tn-systems than the analogous en-systems, most so with iodide as the leaving group.
In their early studies of [PtdienX] + + py → [Ptdienpy] + + X in aqueous solution, Basolo, Gray and Pearson [8] demonstrated a large variation in reaction rates for different leaving groups X. Variations were relatively small for X being a halogenide (only a factor of 3.5, X being Cl and I); still a decrease in the order X = Cl > Br > I was observed. This trend in reaction rates was rationalised in terms of an associative bimolecular reaction mechanism with the bond rupture being the determining factor and being in accord with the observation, that the order of lability was opposite to the order of stability in the larger series of leaving groups including as different ligands X as nitrate and cyanide in [PtdienX] + .
We found the opposite order of reaction rates of DMSO with [PtenX 2 ] through the halogenides, (the reaction rate being 40 times faster when X = I than when X = Cl). The exchange of DMSO in [PtenI(DMSO)] + was also found to be significantly faster than in its chloride-analogue (ratio of exchange rate constants ∼ 80). Numbers are comparable with DMSO exchange in [PtenCH 3 (DMSO)] + [12] for which a first-order rate constant 1.2 × 10 −4 s −1 at 25 °C can be estimated by extrapolating the concentration of DMSO to that in pure DMSO.
The opposite order of rates is not due to different solvation in DMSO and in water of the leaving halogenide, since chloride has the largest solvation energy in both media [13]. Also, reaction rates for the hydrolysis of [Pt(H 2 O) 3 X] + were found to increase through the series X = Cl < Br < I [14] in aqueous solution. In this case, the rate was at least two orders of magnitude higher with iodide than with chloride. Likewise, the reaction in aqueous ethanol of [PtdienX] + [15] with dimethyl sulphide followed the same rate pattern (ratio ∼4) as reactions with DMSO in DMSO [16], so other unspecified solvent effects are not dominating either.
Iodide was also a faster leaving group than chloride when azide and other stronger nucleophiles as thiourea was used instead of pyridine in the reactions with [PtdienX] + (30 °C, aqueous solution, [9]). The differences were, however, small (a factor of ∼2 between the rates with iodide and chloride as the leaving group). It was suggested that among a larger series of leaving ligands, the three halogenides behave almost at equal rates [17], embracing the earlier findings with only small differences in rates; this should indicate, that bond breaking is not rate determining.

Conclusion
Our findings clearly support the view that iodide is generally the fastest leaving group of the three halogenides in most square planar platinum(II) systems mentioned here.
However, variations due to entering nucleophile and/or solvent may in the case of the three halogenides as leaving groups cause a reduction of or even efface [17] the difference in reaction rates in the few cases reported [8].