Tuning Reactivity of Platinum(II) Complexes

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The decrease in reactivity of 2,6pzn for the first substitution is due to the positive inductive effect of the 2,6-dimethylpyrazine ring that leads to accumulation of electron density at metal centre. This makes the Pt1(II) centre less electrophilic, resulting in lower reactivity towards the nucleophiles. This is well supported by the large HOMO- LUMO energy gap coupled with reduced positive NBO charges (Table 4.1) for 2,6pzn. Smaller values of k1 were observed for the first substitution step of the aqua ligand in the complexes 2,3pzn and 2,5pzn by a factor of 10 than pzn and also smaller than that of 2,6pzn. Previous studies have shown that methyl groups and other electron-donating groups collectively lead to a reduction in the rate of ligand substitution, by reducing the positive charge density on the platinum atom, thereby lowering the electrophilicity of the metal centre. 3,31,32,36,44,45 As a result, the incoming nucleophile is repelled by the increased amount of electron density around the metal centre, leading to a less stable five-coordinate transition state and decreased rate of substitution. The difference between the 2,6pzn and the 2,3pzn and 2,5pzn indicates that the distribution of the methyl groups around the pyrazine linker plays a role in controlling the reactivity. This is because the position of the methyl group influences the electronic as well as the steric effects around the Pt(II) centres. The reactivity of 2,3pzn and 2,5pzn are similar because of having symmetrically equal effects in terms of electronic and steric hindrance. The reactions for the second step are significantly slower, by a factor of 10, than for the first in all cases. This is probably because of the electronic communication between the two platinum atoms and also steric hindrance from the first substitution at the Pt(II) centre. The DFT calculations show a change in NBO charges if TU is substituted to one platinum centre as can be seen in Table 5, suggesting that electronic information is somehow conveyed through the bridging ligand. The order of reactivity for the second step is pzn > 2,3pzn ≈ 2,5pzn > 2,6pzn. In case of 2,6pzn there is additional steric effect which blocks entry of the incoming nucleophile on both sides of the Pt2 centre (Figure 4.14), 3, 39,46-52 accounting for the slowest rate of reactivity. 30
pzn 2,3pzn 2,5pz 2,6pzn Figure 4.14: DFT-calculated electron density distribution plots for the investigated complexes illustrating steric hindrance by the bridging pyrazine ligand and the coordinated thiourea nucleophiles. The blue (arrows indicate the least sterically hindered pathway for the incoming thiourea nucleophiles, while the red arrows indicate pathways that are subject to increased axial steric hindrance by the methyl groups present on the linker and the already attached thiourea ligand. 31
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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
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References 1 (a) J. Reedijk, Chem.
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34 R. B. Jordan, Reaction Mechanism
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Table of Contents-3 Chapter 3.The
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Chapter 3 The π-Acceptor Effect in
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In order to extend our understandin
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after which water was added to quen
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O CH 3 + I + N O oH - N O O 7 CH 3
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84% (34.7 mg, 0.0618 mmol). 1 H NMR
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PhCN PhCN Pt Cl Cl + N N CH 3 N CH
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Complex Structure HOMO LUMO PtCl CH
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The geometry-optimised structures i
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against the concentration of the in
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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 150 and 151: cis geometry, leading to dramatic c
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 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
Page 200 and 201: Table S4.13: Average observed rate
Page 206 and 207: k obs(1 st ) , s -1 0.06 0.04 0.02
Page 210 and 211: ln(k 2(3 rd ) /T) -10.0 -10.5 -11.0
Page 212 and 213: SpinWorks 2.5: 2,6 pznClO4 in D2O N
Page 214 and 215: Table of Contents-5 Chapter 5 .....
Page 216 and 217: List of Tables Table 5.1: A summary
Page 218 and 219: 5.1 Introduction Multinuclear plati
Page 220 and 221: onding. For this reason, pKa titrat
Page 222 and 223: 400-300 cm -1): 3308, 3117, 3071 (N
Page 224 and 225: 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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Table S5.17: Average observed rate
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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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Tuning Reactivity of Platinum(II) Complexes

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