Equilibrium and kinetic studies of the aquation of the dinuclear platinum complex [{trans-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+:: pKa determinations of aqua ligands via [1H,15N] NMR spectroscopy

By the use of [H-1,N-15] heteronuclear single quantum coherence (HSQC) 2D NMR spectroscopy and electrochemical methods we have determined the hydrolysis profile of the bifunctional dinuclear platinum complex [{trans-PtCl-((NH3)-N-15)(2)}(2)(mu-(NH2)-N-15(CH2)(6)(NH2)-N-15)](2+) (1,1/t,t (n = 6), N-15-1), the prototype of a novel class of potential antitumor complexes. Reported are estimates for the rate and equilibrium constants for the first and second aquation steps, together with the acid dissociation constant (pK(a1) approximate to pK(a2) approximate to pK(a3)). The equilibrium constants determined by NMR at 25 and 37 degrees C (I = 0.1 M) were similar, pK(1) approximate to pK(2) = 3.9 +/- 0.2, and from a chloride release experiment at 37 degrees C the values were found to be pK(1) = 4.11 +/- 0.05 and pK(2) = 4.2 +/- 0.5. The forward and reverse rate constants for aquation determined from this chloride release experiment were k(1) = (8.5 +/- 0.3) x 10(-5) s(-1) and k(-1) = 0.91 +/- 0.06 M-1 s(-1), where the model assumed that all the liberated chloride came from 1. When the second aquation step was also taken into account, the rate constants were k(1) = (7.9 +/- 0.2) x 10(-5) s(-1), k(-1) = 1.18 +/- 0.06 M-1 s(-1), k(2) = (10.6 +/- 3.0) x 10(-4) s(-1), k(-2) = 1.5 +/- 0.6 M-1 s(-1). The rate constants compare favorably with other complexes with the [PtCl(am(m)ine)(3)](+) moiety and indicate that the equilibrium of all these species favors the chloro form. A pK(a) value of 5.62 was determined for the diaquated species [{trans-Pt((NH3)-N-15)(2)-(H2O)}(2)(mu-(NH2)-N-15(CH2)(6)(NH2)-N-15)](4+) (3) using [H-1,N-15] HSQC NMR spectroscopy. The speciation profile of 1 and its hydrolysis products under physiological conditions is explored.