Substitution Reactions of Platinum(II)−Nucleobase Complexes by Associative Mechanism Involving Pseudorotation of the Five-Coordinate Intermediate

Abstract

Substitution reactions of N7-platinated guanosine and adenosine complexes {[Pt(dien)(Guo-N7)](2+) (1), [Pt(dien)(Ado-N7)](2+) (2), dien = diethylenetriamine} by thiourea (tu) and I(-) have been studied in aqueous solution in the pH range 1.4-8.3 at different temperatures. Reactions of both complexes with I(-) follow the usual associative two-path mechanism throughout the pH range studied, as do reactions with thiourea under neutral conditions (pH 6.5). With both nucleophiles (Y), the observed rate constant linearly increases with increasing [Y] up to 1000-fold excess of Y. Plots of k(1,obs) vs [Y] were employed to calculate the rate parameters k(S) for the solvent path and k(Y) for the nucleophile-dependent path by the equation k(1,obs) = k(S) + k(Y)[Y] at different temperatures. The following activation parameters were obtained at 298.2 K for the reaction of thiourea with 1, DeltaH() = (72 +/- 1) kJ mol(-)(1) and DeltaS() = (-79 +/- 4) J K(-)(1) mol(-)(1), and with 2, DeltaH() = (72.8 +/- 0.3) kJ mol(-)(1) and DeltaS() = (-86 +/- 1) J K(-)(1) mol(-)(1). The corresponding data for I(-) with 1 are DeltaH() = (83 +/- 3) kJ mol(-)(1) and DeltaS() = (-49 +/- 8) J K(-)(1) mol(-)(1), and with 2, DeltaH() = (78 +/- 3) kJ mol(-)(1) and DeltaS() = (-67 +/- 10) J K(-)(1) mol(-)(1). Activation parameters for the solvent path are DeltaH() = (85 +/- 1) kJ mol(-)(1) and DeltaS() = (-105 +/- 2) J K(-)(1) mol(-)(1) for 1, and DeltaH() = (87 +/- 7) kJ mol(-)(1) and DeltaS() = (-98 +/- 22) J K(-)(1) mol(-)(1) for 2, on the basis of the data found for reactions with thiourea. Rate parameters for the formation and solvolytic decomposition gave log K values of 7.5 +/- 0.1 and 6.1 +/- 0.2 for the equilibrium constants of 1 and 2, respectively, in aqueous 0.1 M NaClO(4) solution at 298.2 K. Ring opening of the tridentate dien group in acidic solution provides a competing route for the overall substitution by thiourea. All experimental data found are consistent with an associative mechanism involving pseudorotation of the five-coordinate intermediate formed by the attack of thiourea, including activation parameters (298.2 K) DeltaH() = (69.2 +/- 0.3) kJ mol(-)(1) and DeltaS() = (-81 +/- 1) J K(-)(1) mol(-)(1) for 1, and DeltaH() = (70.9 +/- 0.7) kJ mol(-)(1) and DeltaS() = (-79 +/- 2) J K(-)(1) mol(-)(1) for 2. According to kinetic analysis, about 60% of 1 and 70% of 2 yield free nucleoside via the ring-opening step, whereas the remainder give free nucleoside by direct replacement with thiourea. The ratio of these routes is practically independent of thiourea concentration and temperature. The (1)H, (13)C, and (195)Pt NMR spectroscopic data for the isolated ring-opened species 3(1) and 3(2) (from 1 and 2, respectively) are consistent with a four-coordinate species [Pt(dienH)(L-N7)(tu)](3+), in which the dien group acts a bidentate ligand and one of the dien amino groups is trapped by protonation. Although both 3(1) and 3(2) are stable in cold acidic solution, they decompose predominantly back to the starting material when the pH of the solution is increased. According to HPLC analysis, the former gives 1 and guanosine in a 12:1 ratio, and the latter yields 2 and adenosine in a 10:1 ratio. The ability of the dien-NH(2) group to displace coordinated thiourea from Pt(II) contradicts the trans effect S > N and exemplifies the nucleophilic power of the NH(2) group of a partially chelated amine.