Donald A. House

The hydrolysis products of cis-dichlorodiammineplatinum(II) 2. The kinetics of formation and anation of the cis-diamminedi(aqua)platinum(II) cation

Abstract In basic solution ([OH−] ⩾ 0.01 M), cis-PtCl2(NH3)2 undergoes hydrolysis of both chloro ligands to give cis-Pt(OH)2(NH3)2 as the stable end product. The rate of this reaction has been studied spectrophotometrically in aqueous NaOH solution (0.01–1.0 M) containing NaClO4 (μ = 0.01–1.0 M) or NaCl (0.1–1.0 M) over a 35 °C temperature range. The reaction rate is almost independent of [OH−], ionic strength and added chloride ion and at 25 °C (μ = 0.1 M, NaClO4), k12OH = 1.90 × 10−5 s−1, ΔH‡ = 84.4 kJ mol−1 and ΔS‡ = −52 J K−1 mol−1. The rate of loss of the chloro ligand from cis-PtCl(OH)(NH3)2 (k2OH, s−1) generated by basification of cis-PtCl(NH3)2(OH2)+ is similar to k12OH, with k2OH = 1.43 × 10−5 s−1, ΔH‡ = 84.3 and ΔS‡ = −55 at 25 °C (μ = 0.1 M). Acidification of cis-Pt(OH)2(NH3)2 (generated from cis-PtCl2(NH3)2 in 0.01 M NaOH) rapidly forms cis-Pt(NH3)2(OH2)2+ and this, in turn is slowly anated by the background chloride ion to give an equilibrium cis-PtCl(NH3)2(OH2)+, cis-Pt(NH3)2(OH2)22+ and Cl− mixture. The equilibrium constant (K2) has been measured spectrophotometrically to give at 25 °C (μ = 0.1 M, NaClO4) K2 = 2.7 × 10−4. Addition of controlled amounts of Cl− to the in situ generated cis-Pt(NH3)2(OH2)22+ allows the spectrophotometric measurement of the rate of the anation reaction (k2). cis-Pt(NH3)2(OH2)22+ + Cl− At 25 °C, k−2 = 9.09 × 10−2 M−1 s−1, ΔH‡ = 72.7 kJ mol−1, ΔS‡ = −29.2 J K−1 mol−1. A knowledge of K2 and k−2 allows the calculation of k2 (K2 = k2/k−2) and at 25 °C k2 = 2.5 × 10−5 s−1. It is difficult to measure k2 directly by spectrophotometry as, at reasonable cis-PtCl(NH3)2(OH2)+ concentrations (> 1 mM), the forward reaction proceeds only to the extent of

The hydrolysis products of cis-dichlorodiammineplatinum(II) 3. Hydrolysis kinetics at physiological pH

The rate of hydrolysis of cis-PtCl2(NH3)2 has been measured in non-buffered aqueous solution (I = 0.2 M NaClO4; T = 45.0 °C) at constant pH over the range pH = 4.0−8.5 using a combined pH-stat/ spectrophotometric technique. The hydrolysis rate at pH = 7.4 (T = 45.0 °C) was also determined with [Cl−] = 0.0−0.1 M (I = 0.2 M; NaCl, NaClO4). At the end of each kinetic run, the resulting solution was made 0.2 M in Cl− by the addition of NaCl and the reverse (anation) reaction was monitored, again under constant pH conditions. A knowledge of the complete pH-rate profile, with and without added chloride ion, allows current models for the hydrolysis of cis-PtCl2(NH3)2 under physiological conditions, to be tested. cis-Pt(NH3)2(OH2)22+ is considered to be the least important of all the potential hydrolysis products available to bind to replicating DNA at pH = 7.4.

The hydrolysis products of cis-diamminedichloroplatinum(II). I. The kinetics of formation and anation of the cis-diammine(aqua)chloroplatinum(II) cation in acidic aqueous solution

Abstract The rate of loss of the first chloro ligand ( k 1 ) from cis -PtCl 2 (NH 3 ) 2 , to give an equilibrium cis -PtCl 2- (NH 3 ) 2 , cis -PtCl(NH 3 ) 2 (OH 2 ) + and Cl − mixture, has been measured spectrophotometrically in 0.1 M HClO 4 , 1.0 MHClO 4 and 0.1 M HClO 4 plus 0.9 M NaClO 4 over a 22 °C temperature range. The absorbance versus time data were analysed in terms of first-order kinetics and the effect of [H + ] and ionic strength (μ) in the above range, is small. At 25 °C (μ=1.0 M, HClO 4 ) kinetic parameters are k 1 = 6.32 × 10 −5 s −1 , E a =84.7±1.9 kJ mol −1 , ΔS # = −49.4 ± 3 J K −1 mol −1 . Removal of the released Cl − from the equilibrium solution (0.1 M HClO 4 ) by anion exchange chromatography with the resin in the ClO 4 − form gives a solution containing about 90% cis -PtCI(NH 3 ) 2 (OH 2 ) + . Addition of known amounts of Cl − (as NaCl in HClO 4 ) to this solution allows a spectrophotometric measurement of the rate of the anation reaction ( k −1 ) to give a new equilibrium solution. At 25 °C (μ=1.0 M; NaCl, HClO 4 ), k −1 = 6.26 × 10 −3 M −1 s −1 , E a =77.2 ± 1.5 kJ mol −1 and δS # = − 36.3 ± 3 J K −1 mol −1 . A knowledge of the forward and reverse rate constants allows calculation of the equilibrium constant ( K 1 ) and from the variation of K 1 with temperature, Δ H ° can be estimated. At 25 °C (μ=1.0 M) K 1 =1.01 × 10 −2 and ΔH° for the endothermic forward reaction is +7.5 kJ mol −1

Chiral heterocyclic ligands. Part IV. Synthesis and metal complexes of 2,6-Bis(pyrazol-1-ylmethyl)pyridine and chiral derivatives

Synthesis of the new tridentate ligand, 2,6-bis(pyrazol-1-ylmethyl)pyridine ( 6 ) and its chiral derivatives ( 11–15 ) are described. The preparations of complexes of these ligands with several divalent transition metal ions (Fe 2+ , Ni 2+ , Cu 2+ , Ru 2+ , Pd 2+ ) are reported. X-ray crystal structures have been determined for the [Ni( 6 ) 2 ](ClO 4 ) 2  16 and [Cu( 13 )(NCS) 2 ] 17 complexes. The salt 16 crystallises in the orthorhombic space group P 2 1 2 1 2 with a = 10.125(1), b = 17.657(4), c = 8.579(2) A and Z = 2. The structure was refined to a conventional R factor of 3.9% and shows the nickel atom to lie on a crystallographic two-fold rotation axis in a ‘symmetrical’ octahedral environment. The complex 17 crystallises in the orthorhombic space group P 2 1 2 1 2 1 with a = 15.795(3), b = 20.433(3), c = 9.618(1) A and Z = 4. The structure was refined to R = 4.7% and shows the bonding geometry at the five-coordinate copper atom to be intermediate between square pyramidal and trigonal bipyramidal. In both structures the six-membered chelate rings exist in boat conformations.

The hydrolysis products of cis-diamminedichloroplatinum(II) 6. A kinetic comparison of the cis- and trans-isomers and other cis-di(amine)di(chloro)platinum(II) compounds

Abstract Di(amine)di(chloro)platinum(II) complexes react in aqueous acid solution to form an equilibrium mixture L 2 PtCI 2 L 2 PtCl(OH 2 ) + + Cl − . Values of k 1 , k −1 and the equilibrium constant K 1 (= k 1 / k −1 ) have been measured for the systems L 2 = cis (NH 3 ) 2 , trans (NH 3 ) 2 , cis (py) 2 , en, RR -chxn, tn and Me 2 tn, with varying temperature and ionic strength ( cis (NH 3 ) 2 only). At 25 °C and I =0.1 M, data for cis -PtCl 2 (NH 3 ) 2 are k 1 =5.18 × 10 −5 s −1 (Δ H # =86.7 kJ mol −1 , Δ S # = −36 J K mol −1 ), k 1 =7.68 × 10 −3 M −1 s −1 (Δ H # =72.7, Δ S # =−41) and K 1 = 6.74 × 10 −3 . Corresponding data for trans -PtCl 2 (NH 3 ) 2 are k j1 =1.90 × 10 −5 s −1 = (Δ H # =92.2, Δ S # =−26), k −1 =3.05 × 10 −2 M −2 s −1 (Δ H # =85.7, Δ S # =+14) and K 1 = 6.22x 10 −4 . These data provide a kinetic explanation for the inactivity of the trans -isomer as an anti-cancer drug.

The hydrolysis products of cis-diamminedichloroplatinum(II) 9. Chloride and bromide anation kinetics for some [PtII(N)2(OH2)2]2+ complexes and the structures of [PtIVBr4(N)2] ((N)2 = en, tn)1

Abstract The rate of the first step in the chloride ion anation of [Pt(N)2(OH2)2]2+ (k−2, M−1s−1) has been measured spectrophotometrically (I = 1.0 M) for (N)2 = cis-(NH3)2, cis-(py)2, en, chxn, tn, Me2tn and trans-(NH3)2. Kinetic parameters at 25°C are: cis-(NH3)2, 102k−2 = 9.27 M−1s−1, ΔH≠ = 66.3 kJ mol−1, ΔS≠ = −42 J K−1mol−1; cis-(py)2, 20.0, 72.0, −17; en, 24.5, 58.8, −59; chxn, 21.4, 66.0, −36; tn, 34.4, 67.2, −28; Me2tn, 33.2, 57.4, −61; trans-(NH3)2, 151, 50.6, −72. Similar data for the bromide ion anation of cis-[Pt(py)2(OH2)2]2+ are: 97, 58.8, −48. Bromide ion anation rates for [PtBr(N)2(OH2)]+ (k−1, M−1s−1) have also been measured giving kinetic parameters (25°C, I = 1.0 M): cis-(NH3)2, 102 k−1 = 1.99 M−1s−1, ΔH≠ = 57.8 kJ mol−1, ΔS≠ = −84 J K−1mol−1; cis-(py)2, 2.10, 57.2, −85; en, 6.40, 63.5, −55; chxn, 9.72, 56.6, −17; tn, 9.25, 52.9, −87; Me2tn, 8.70, 54.8, −62; trans-(NH3)2; 12.6, 69.0, −31. These data also allow an estimation of the rate of bromide release from [PtBr2(N)2] (k1, s−1) with kinetic parameters (25°C, I = 1.0 M): cis-(NH3)2, 104 k1 = 4.25 s−1, ΔH≠ = 87.0 kJ mol−1, ΔS≠ = −17 J K−1mol−1; cis-(py)2, 15.8, 38.5, −93; en, 5.12, 70.0, −73; chxn, 17.4, 53.3, −42; tn, 6.05, 112, +70; Me2tn, 9.88, 109, +141; trans-(NH3)2, 15.2, 45.7, −69. Dilute solutions of [Pt(N)2(OH2)2]2+, in the presence of excess bromide ion and on long (weeks) exposure to air, slowly deposit orange crystals of [Pt(IV)Br4(N)2] on spontaneous evaporation. The structures of ( N ) 2 = en ( monoclinic , C2/c, a = 10.414(3), b = 8.356(2), c = 11.651(9) A , β = 112.77(3)°, V = 934.8(8) A 3 , Z = 4) and ( N ) 2 = tn ( orthorhombic , Pnma, a = 12.666(4), b = 9.789(5), c = 8.352(3) A , V = 1035.5(7) A 3 , Z = 4) have been determined by single crystal X-ray diffraction. The average Pt(IV)-Br and Pt(IV)-N distances are 2.455(5) and 2.04(2) A, respectively.

The hydrolysis products of cis-diamminedichloroplatinum(II) 5. The anation kinetics of cis-Pt(X)(NH3)2(OH2)+ (XCl, OH) with glycine, monohydrogen malonate and chloride

Abstract The spectrophotometrically determined rate constants, k obs (s −1 ), for the anation of cis -PtCl(NH 3 ) 2 (OH 2 ) + with glycine (Nu=gly at pH=7.4), or sodium hydrogen malonate (Nu=Hmal − at pH=4.3) can be represented by the equation k obs = k o + k Nu [Nu], where k o is an hydrolysis rate constant independent of the nucleophile concentration but dependent on pH, and k Nu is a nucleophile dependent path. With Nu=Hmal − , k o ∼0 and the first step is monodentate coordination, followed by a second ( k cy ), nucleophile independent path, due to ring closure. With Nu=gly, the ring closure reaction is sufficiently fast as to appear synchronous with coordination and k o is the base hydrolysis rate constant for cis - PtCl(OH)(NH 3 ) 2 at pH=7.4. Kinetic parameters associated with the anation are k Hmal (25.0 °C, pH=4.3, I =1.0 M)=9.90×10 −4 M −1 s −1 , Δ H ≠ =74.8 kJ mol −1 , Δ S ≠ =−52 J K −1 mol −1 ; k gly (25.0 °C, pH=7.4, I =1.0 M) 2.75×10 −4 M −1 s −1 , Δ H ≠ =62.7 kJ mol −1 , Δ S ≠=−103 J K −1 mol −1 ; k cy (25.0 °C, pH=4.3, I =1.0 M)=1.03×10 −5 s −1 , Δ H ≠ =88.9 kJ mol −1 , Δ S ≠ =−42 J K −1 mol −1 . The rate ( k 3 , s −1 ) of the chloride release from cis -PtCl(OH)(NH 3 ) 2 to give cis -Pt(OH)NH 3 ) 2 (OH 2 ) + and rate of chloride uptake (k −3 , M −1 s −1 ) have been measured at pH=7.4. Kinetic parameters are k 3 =2.39×10 −5 s −1 (25.0 °C, pH=7.4, I =1.0 M) Δ H ≠ =82.4 kJ mol −1 , Δ S ≠ =−57 J K −1 mol −1 and k −3 =9.37×10 −4 M −1 s −1 (25.0 °C, pH=7.4, I =1.0 M), Δ H ≠ =61.7 kJ mol −1 Δ S ≠ =−96 J K −1 mol −1 . From these rate constants, K 3 =( k 3 [ k −3 ] −1 ) is calculated to be 2.55×10 −2 at 25.0 °C. These data have been used to comment on the nucleophilicity of cis -PtCl(NH 3 ) 2 (OH 2 ) + .

Chiral heterocyclic ligands: III. A structural study of the cyclopalladation of (4S, 7R)-7,8,8-trimethyl-1-phenyl-4,5,6,7-tetrahydro-4,7-methano-1H-indazole

Abstract Reaction of the ligand (4 S , 7 R )-7,8,8-trimethyl-1-phenyl-4,5,6,7-tetrahydro-4,7-methano-1 H -indazole, LHV, with lithium tetrachloropalladate gives a trans -Pd(LH) 2 Cl 2 complex, which on further reaction undergoes cyclopalladation to [PdLCl] 2 . These compounds were characterised spectroscopically and their structures confirmed by single crystal X-ray analyses, with refinement to R values of 0.028 and 0.036 respectively.

Kinetics and mechanism for reduction of halo- and haloam(m)ine platinum(IV) complexes by l-ascorbate

Reduction of the model platinum(IV) complexes cis-[PtCl4(NH3)(2)] (1), trans-[PtCl4(NH3)(2)] (2). trans-[PtCl2(en)(2)](2+) (3), trans-[PtBr2(NH3)(4)](2+) (4), [PtCl6](2-) (5), and [PtBr6](2-) (6) with L-ascorbic acid (H(2)Asc) in 1.0 M aqueous medium at 25 degreesC in the region 1.75 less than or equal to pH less than or equal to 7.20 has been investigated using stopped-flow spectrophotometry. The redox reactions follow the rate law: -d[Pt(IV]/dt = k[H(2)Asc](tot)[Pt(IV)] where k is a pH-dependent second-order rate constant and [H(2)Asc](tot), the total concentration of ascorbic acid. The pH-dependence of k is attributed to parallel reduction of Pt(IV) by the protolytic species HAsc(-) and Asc(2-). Analysis of the kinetics data reveals that the ascorbate anion Asc(2-) is up to seven orders of magnitude more reactive than HAsc(-) while H(2)Asc is unreactive. Electron transfer from HAsc(-)/Asc(2-) to the Pt(IV)) compounds is suggested to take place by a mechanism involving a reductive attack on any one of the mutually trans-halide ligands by Asc(2-) and/or HAsc(-) forming a halide-bridged activated complex, The rapid reduction of these complexes supports the assumption that ascorbate Asc(2-) might be an important reductant at physiological conditions for anticancer active Pt(IV) pro-drugs capable of undergoing reductive trans elimination. The parameters DeltaH(not equal) and DeltaS(not equal) for reduction of Pt(IV) with Asc(2) hake been determined from the study of the temperature dependence of k

Hydrolysis products from trichloro-diethylenetriaminechromium(III) and cobalt(III) complexes

Abstract Hydrolysis of green 1,2,3-Cr(dien)Cl 3 in 0·05 F HClO 4 followed byion exchange chromatography, results in the successive isolation of the 1,2,3-Cr(dien)(OH 2 )Cl 2 + (blue) and 1,2,3-Cr(dien)(OH 2 )Cl 2+ (magenta) cations. The 1,2,3-Cr(dien)(OH 2 ) 3 3+ (red) cation is generated in 1 F HClO 4 by addition of excess Hg 2+ ion to 1,2,3-Cr(dien)(Cl 3 . Application of similar ion exchange techniques to the purple 1,2,6-Cr(dien)Cl 3 gives first the purple 1,2,6-Cr(dien)(OH 2 )Cl 2 + cation. Further reaction in solution involves both chloride release and rupture of CrN bonds forming a mixture of products. The brown 1,2,6-Co(dien)Cl 3 hydrolyses similarly to the 1,2,6-Co(dien)(OH 2 ) 2 Cl 2+ cation but the next hydrolysis step also involves isomerisation and the red 1,2,3-Co(dien)(OH 2 )Cl 2+ and 1,2,3-Co(dien)(OH 2 ) 3 3+ cations have been isolated. The 1,2,6-triaquo cations can be obtained from the trichloro complexes without isomerisation by acidification of the trihydroxo complexes generated by base hydrolysis. The orange 1,2,6-Co(dien)(OH 2 ) 3 3+ slowly isomerises to the red 1,2,3-isomer in acid solution but the orange 1,2,6-Cr(dien)(OH 2 ) 3 3+ decomposes with CrN bond rupture to a mixture of unknown products. Maxima and minima of the visible and near u.v. absorption spectra of the new complexes are reported.