Hydrolysis Chemistry of the Metallocene Dichlorides M(η⁵-C₅H₅)₂C1₂, M = Ti, V, Zr. Aqueous Kinetics, Equilibria, and Mechanistic Implications for a New Class of Antitumor Agents

This paper reports an integrated chemical/physicochemical investigation of the aqueous chemistry of Cp₂TiCl₂, Cp₂VCl₂, and Cp₂ZrCl₂, employing high-field FT NMR, chloride potentiometry, pH titrimetry, and electrical conductivity. Experimental conditions include those employed previously to study the hydrolysis of cis-dichlorodiammineplatinum(II) (“cisplatin”) and those approximating physiological. In unbuffered aqueous 0.32 M KNO₃ solution at 37 °C, the order of decreasing hydrolytic stability of the M-(η⁵-C₅H₅) bond in the Cp₂MCl₂ complexes (monitored by high-field FT NMR) was found to be V (k_initiai≤ 3.0 × 10^-3 h^-1) > Ti (k_initia| = 6.4 (1) × 10^-3 h^-1) ≫ Zr (k_nitial = 3.8 (1) × 10^-2h^-1). Of the three complexes studied, only Cp₂VCl₂ was found to possess a stable M-(η⁵-C₅H₅) bond at physiological pH. Addition of any of the Cp₂MCl₂ complexes to water (pure or 0.32 M KNO₃) results in rapid chloride ion dissociation with approximate half-lives for the loss of the second chloride (the first is too rapid to measure) of 50 min (M = Ti), 30 min (M = Zr), and 24 min (M = V) in contrast to the relatively slow chloride hydrolysis observed with cisplatin. Chloride dissociation is also more extensive than that in cisplatin. Equilibrium chloride ion concentration measurements indicate that the equilibrium constant (K₁) for the first Cp₂MCl₂ chloride dissociation is too large to measure, while K₂ = 4.2 (2.7) × 10^-2M (M = Ti) and 2.7 (1.2) × 10^-3 M (M = V). Titrimetric studies indicate that the acidity of the Cp₂M²⁺-bound water molecules is uniformly more acidic than the metal-bound water molecules of cis-[Pt(NH₃)₂(H₂O)₂]²⁺ (Ti, pK_a= 3.5 (5) and 4.35 (9); V, pK_a = 4.73 (3) and 5.15 (13)). Implications of these results for the observed biological activity of the Cp₂MCl₂ complexes are briefly discussed.