Tuning Reactivity of Platinum(II) Complexes

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cis geometry, leading to dramatic changes in the substitution of the aqua ligands. At the same time, the bulky methyl substituents would introduce steric hindrance on the cis- Pt(II) centre. Therefore, the variation of the substituents on the pyrazine-bridge enabled a systematic study of the thermodynamic (pKa, where coordinated water was deprotonated) and kinetic properties of the Pt(II) centres. 4.2 Experimental 4.2.1 Chemicals and Reagents Pyrazine (99%), 2,3-dimethylpyrazine (99%), 2,5-dimethylpyrazine (99%), 2,6- dimethylpyrazine (99%), † NaClO4.H2O (98%), and HClO4 (70%) were obtained from Aldrich and were used without further purification. AgClO4 (99.98%, Aldrich) was stored under nitrogen and used as supplied. Cis-(PtCl2(NH3)2 (99%) was purchased from Strem chemicals. The nucleophiles §thiourea (TU, 99%), N,N-dimethyl-2-thiourea (DMTU, 99%), N,N,N,N-tetramethyl-2-thiourea (TMTU, 98%) used in the kinetic measurements were obtained from Aldrich. Stock solutions of the nucleophiles were prepared, shortly before use, by dissolving known amounts of the nucleophiles in 0.1M NaClO4/HClO4 aqueous solution of constant ionic strength. Since it is well-known that the perchlorate ion, (ClO4 -), does not coordinate to Pt(II), 23 its presence in aqueous solution would not interfere with the kinetic measurements. Ultrapure water (Modulab Systems) was used in all experiments. All other reagents were of analytical grade quality and were used without further purification. Caution! †Perchloric acid and salts are potentially explosive, particularly at high temperatures and must be handled with caution and in small amounts. §Thiourea and its substituted derivatives are suspected carcinogens and the necessary safety measures must be adhered to when handling these reagents. 4
4.2.2 Synthesis of compounds A total of four dinuclear Pt(II) complexes, namely [cis-{PtCl(NH3)2}2-μ-pzn](ClO4)2 (pzn) (pzn = pyrazine), [cis-{PtCl(NH3)2}2-μ-2,3 pzn](ClO4)2 (2,3pzn) (2,3pzn = 2,3- dimethylpyrazine), [cis-{PtCl(NH3)2}2-μ-2,5pzn](ClO4)2 (2,5pzn) (2,5pzn = 2,5- dimethylpyrazine), and [cis-{PtCl(NH3)2}2-μ-2,6pzn]Cl2 (2,6pzn) (2,6pzn = 2,6- dimethylpyrazine) were synthesized starting from the precursor compound [cis- {PtCl(NH3)2(DMF)}]ClO4 using AgClO4 following the procedure reported in literature. 24, 25 4.2.3 Preparation of platinum complexes cis-[{PtCl(NH3)2}2–μ–pzn](ClO4)2(pzn) The cis-[{PtCl(NH3)2}2-μ-pzn](ClO4)2 (pzn) was prepared following a modified procedure to that used previously for similar compounds as illustrated in Scheme 4.1. 26 NH 3 NH 3 NH 3 Cl Pt Cl + Cl NH 3 AgClO 4 N N Pt Pt NH 3 where, NH 3 DMF, 50 o C Cl (ClO 4 ) 2 N N = N N N N [Pt(NH 3 ) 2 (DMF)Cl]ClO 4 C H 3 C H 3 N N N N the dark (78.2 mg, 0.976 mmol) of pyrazine ligand (pzn) at room temperature. The 5 DMF 40-50 o C C H 3 0.5 mol + AgCl (s) CH 3 C H 3 N N pzn 2,6-pzn 2,5-pzn 2,3-pzn Scheme 4.1 Synthetic route for the complexes pzn, 2,3pzn, 2,5pzn and 2,6pzn To 50 ml of stirred solution of (1.039 mmol) [{cis-PtCl (NH3)2(DMF)]ClO4 was added in CH 3
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Tuning Reactivity of Platinum(II) C
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Declaration This thesis report is b
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Abstract Systematic kinetic and the
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Table of contents Acknowledgements
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2.5.5 Effect of Non-participating G
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5.2.1 Chemical and Solutions ......
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7.2 Experimental Section ..........
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procurements, Messers P. Forder and
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Figure 2.2 Potential energy profile
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Figure 4.6 Concentration dependence
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Figure 6.1 Spectrophotometric titra
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List of Tables Table 2.1 A selectio
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Table 6.4 Summary of rate constants
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TU thiourea DMTU 1,3-dimethyl-2-thi
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Table of Contents-1 Chapter 1 .....
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1.0 Introduction 1.1 Cancer Disease
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toxic potential. The most well-know
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1.3.2.2 Cellular Uptake Cisplatin i
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H 3N OH 2 Pt H 3N OH 2 Active Pt(II
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transformational pathways that comp
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the hydrolysis of the complex, wher
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1.3.4 Terpyridine Platinum(II) Comp
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H 3 N Cl Pt NH 3 H 3 N NH 2 (CH 2 )
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1.4 Kinetic Interest The platinum-b
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3. The effect of varying the positi
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17 R. A. Henderson, The Mechanism o
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Altona J. H. van Boom, G. A. van de
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76 (a)J. Kašpárková, J. Zehnulov
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Table of Contents-2 Chapter Two ...
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List of Tables Table 2.1: A selecti
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The mononuclear Pt(II) complexes 1-
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Potential Energy R + X RX 1 transit
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For the associative mechanism (A),
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the concentration of one of the rea
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k obs , s -1 0.00030 0.00025 0.0002
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k = Ae -Ea/RT 2.14 lnk = lnA - E a
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= 23.76 + R Hence, a plot of ln ⎛
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iii. # Δ V ≈ 10 cm3 mol-1 featur
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conventional methods are classical
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Figure 2.6: Schematic diagram of a
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The light transmitted from the samp
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c. Oxidizability: Ligands that are
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Table 2.1: A selection of n o pt va
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eaction with different nucleophiles
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eaction site from direct attack by
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PEt 3 PEt 3 R PEt 3 Pt Pt Y Y Cl R
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direct displacement of the leaving
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therefore, weaken the bond of the l
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σ-Donation According to classical
Page 100 and 101: References 1 (a) J. Reedijk, Chem.
Page 102 and 103: 34 R. B. Jordan, Reaction Mechanism
Page 104 and 105: Table of Contents-3 Chapter 3.The
Page 106 and 107: Chapter 3 The π-Acceptor Effect in
Page 108 and 109: In order to extend our understandin
Page 110 and 111: after which water was added to quen
Page 112 and 113: O CH 3 + I + N O oH - N O O 7 CH 3
Page 114 and 115: 84% (34.7 mg, 0.0618 mmol). 1 H NMR
Page 116 and 117: PhCN PhCN Pt Cl Cl + N N CH 3 N CH
Page 118 and 119: Complex Structure HOMO LUMO PtCl CH
Page 120 and 121: The geometry-optimised structures i
Page 122 and 123: against the concentration of the in
Page 124 and 125: Table 3.2: Summary of the second-or
Page 126 and 127: constants of CH3PhisoqPtCl decrease
Page 128 and 129: with π*-orbitals of the ligand. Th
Page 130 and 131: 3.6 References 1 D. Rosenberg, L. V
Page 132 and 133: 30 Microcal TM Origin TM Version 5.
Page 134 and 135: Figure S3.1: Kinetic trace at 448 n
Page 136 and 137: ln(k 2 /T) -6.0 -7.5 -9.0 -10.5 -12
Page 138 and 139: Table S3.3b: Average observed rate
Page 140 and 141: Table S3.5b: Temperature dependence
Page 142 and 143: Table S3.8: DFT calculated electros
Page 144 and 145: List of Figures Figure 4.1: Structu
Page 146 and 147: Table 4.2: Summary of pKa values fo
Page 148 and 149: 4.1 Introduction Platinum compounds
Page 152 and 153: ligand was added to the [{cis-PtCl(
Page 154 and 155: spectra were measured in and refere
Page 156 and 157: 4.3.1 DFT calculated Optimized Stru
Page 158 and 159: Table 4.1: A summary of the DFT cal
Page 160 and 161: H2O-Pt-L-Pt-OH2 H2O-Pt-L-Pt-OH2 H2O
Page 162 and 163: electrophilicity and acidity of the
Page 164 and 165: (A) 18 Absorbance 0.08 0.07 0.06 0.
Page 166 and 167: k obs(3 rd ) , s -1 -5 6.00x10 TMTU
Page 168 and 169: 4.3.4 Kinetics with NMR The substit
Page 170 and 171: ln([ML] t ) 4.0 3.5 3.0 2.5 2.0 1.5
Page 172 and 173: ln(k 2(1 st ) /T) -3.5 -4.0 -4.5 -5
Page 174 and 175: Comple x Table 4.4: Summary of Acti
Page 176 and 177: The decrease in reactivity of 2,6pz
Page 178 and 179: Table 4.5: DFT calculated (NBO) cha
Page 180 and 181: eaction proceeds via bimolecular pa
Page 182 and 183: References 1 T. Storr, K. H.Thomson
Page 184 and 185: 36 D. Jaganyi, D. Reddy, J.A. Gerte
Page 186 and 187: Appendix 4 THE INFLUENCE OF THE PYR
Page 188 and 189: Absorbance at 368. 0 nm 0. 0 8 0. 0
Page 190 and 191: Table S4.3: Average observed rate c
Page 192 and 193: k nd obs(2 ) , s-1 0.003 TU DMTU TM
Page 198 and 199: k obs2 , s -1 2.40x10 -4 2.20x10 -4
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Table S4.13: Average observed rate
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k obs(1 st ) , s -1 0.06 0.04 0.02
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ln(k 2(3 rd ) /T) -10.0 -10.5 -11.0
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SpinWorks 2.5: 2,6 pznClO4 in D2O N
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Table of Contents-5 Chapter 5 .....
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List of Tables Table 5.1: A summary
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5.1 Introduction Multinuclear plati
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onding. For this reason, pKa titrat
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400-300 cm -1): 3308, 3117, 3071 (N
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5.2.6 Spectrophotometric pKa Titrat
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Table 5.1: A summary of DFT-calcula
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However, because the highest occupi
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Table 5.2: Acid dissociation consta
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Table 5.3: A summary of DFT calcula
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H3N 6 eq TU 0 eq TU Ha NH3 Ha Cl TU
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third step due to the trans-effect
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[H 2 O-Pt-(NN)-Pt-OH 2 ] +4 [NU-Pt-
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k obs(1st) / s -1 0.20 TU DMTU TMTU
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thiourea nucleophile is large enoug
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ln(k st 2(1 ) /T) -3 -4 -5 -6 -7 -8
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is the same as the electron-withdra
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associative mode of substitution me
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16 H. Ertürk, J. Maigut, R. Puchta
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43 (a) D. Jaganyi, A. Hofmann and R
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276 nm Absorbance 0 . 6 5 0 . 6 4 0
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k obs(1 st ) , s -1 0.4 0.3 0.2 0.1
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Table S5.5: Average observed rate c
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ln(k 2(2 nd ) /T) -8.0 TU -8.5 -9.0
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pzn PPM -1750.0 -1850.0 -1950.0 -20
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Figure S5.13: UV/Visible spectra fo
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k obs(1 st ) in s -1 0.030 0.025 0.
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ln(k 2(2 nd ) /T) -10 -11 -12 -13 -
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9.61 ppm Ha PPM 9.8 9.6 9.4 9.2 9.0
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k obs(3rd) / s -1 -5 8 .00 x 10 T U
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ln(k st 2(1 ) /T) -1.5 TU DMTU TMTU
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ln(k rd 2(3 ) /T) -8.5 -9.0 -9.5 -1
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SpinWorks 2.5: znPt(II)-OP4 in D2O
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Figure S5.31: Mass spectrum for com
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ln(k st 2(1 ) /T) -4 -5 -6 -7 -8 -9
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SpinWorks 2.5: phtPt(II)-OP2 in D2O
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Figure S5.41: Mass spectrum for com
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List of Figures Figure 6.1: Spectro
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Chapter 6 Tuning Reactivity of Plat
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Against this background, several re
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6.2.2 Instruments Microanalyses wer
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Metal Complex Pt3 Yield: 52.5 mg (0
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6.3 Results 6.3.1 Synthesis and Cha
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The pKa values obtained are summari
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Table 6.2: DFT-calculated parameter
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that of dinuclear Pt(II) complexes
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It can be concluded that substituti
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ate constants, kobs(1 st /2 nd ), w
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Table 6.3: Summary of rate constant
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6.3.6 Activation Parameters The act
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pKa1 values become smaller. In addi
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of steric influence is felt by the
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6.5 Conclusion The present study ha
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17 O. F. Wendt and L. I. Elding, 19
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51 Y. Iwadata, K. Kawamura, K. Igar
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Table S6.4(b): Average observed rat
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ln(k 2(2 nd ) /T) -4 -6 -8 -10 -12
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45.0 40 35 30 25 20 %T 15 10 5 0 -5
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k st obs(1 ) in s-1 0.30 Br TU 0.25
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-2304.16 ppm H 3N PPM -2200.0 -2220
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Absorbance 1.6 1.4 1.2 1.0 0.8 0.6
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SH N SH + Mechanism Br N + CO 3 2-
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Figure 7.5: 195Pt NMR spectra of mi
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linker remained coordinated to the
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complexes, have a lower charge and
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ange 326-400 cm -1 (weak) for Pt-Cl
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ButPt, HexPt, OctPt and DecPt, were
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7.3 Results 7.3.1 DFT Calculations
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Structure HOMO LUMO EnPt (C2h) Prop
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Absorbance Table 7.2: Summary of pK
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coordination to the soft Pt(II) cen
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observed at -2962.4 and -3024.1 ppm
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H 3N NH 3 Pt NH 2 OH 2 n NH 3 NH 2
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k obs2 , in s -1 -3 TU 1.2x10 DMTU
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7.3.4 Activation Parameters The tem
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density is located on the metal cen
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acetylmethionine, which reported th
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References 1 (a) B. Rosenberg, L. V
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32 N. Summa, J. Maigut, R. Puchta a
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Appendix 7 Table S7.1: Summary of s
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k obs(2 nd ) , in s -1 0.00020 0.00
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ln(k 2(2 nd ) /T) -8.5 -9.0 -9.5 -1
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k obs(1 st ) , in s -1 0.06 TU DMTU
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ln(k 2(1 st ) /T) -3.2 TU DMTU TMTU
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Table S7.11: Summary of kobs(2 nd )
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%T 22.0 20 18 16 14 12 10 8 6 4 2 0
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k st obs(1 ) , in s-1 0.10 0.08 0.0
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ln(k st 2(1 ) /T) -4.0 TU DMTU TMTU
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Figure S7.23: Mass spectra for HexP
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Table S21: Average observed rate co
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Table S7.23: Summary of kobs(2 nd )
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90.0 80 70 60 50 40 30 20 %T 10 0 -
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Figure S7.37: Mass spectrum for Hex
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Chapter 8 Tuning Reactivity of plat
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dinuclear Pt(II) complexes to relea
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finally Pt2. The order of reactivit
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• prolonged survival in the cell
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