SUBSTITUTION ON OCTAHEDRAL 4d6 METAL ION COMPLEXES: KINETIC AND MECHANISTIC STUDIES WITH BIOACTIVE LIGANDS

THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN SCIENCE (CHEMISTRY)

OF THE UNIVERSITY OF BURDWAN BURDWAN, WEST BENGAL, INDIA

BY SUBALA MONDAL DEPARTMENT OF CHEMISTRY THE UNIVERSITY OF BURDWAN BURDWAN, WEST BENGAL

JUNE, 2014

2

DEDICATED TO MY PARENTS

3

The University of Burdwan Golapbag, Burdwan–713 104, India

Dr. A. K. Ghosh

Tel: (0342) 2558545 Extn. 20 & 21

Associate Professor & Head

Email: [email protected]

Department of Chemistry

Fax: 91-0342-2530452 Mobile : 94343 87256 June 10, 2014

Certified that the work described in the accompanying thesis entitled,

‘SUBSTITUTION

ON

OCTAHEDRAL

4d6

METAL

ION

COMPLEXES: KINETIC AND MECHANISTIC STUDIES WITH BIOACTIVE LIGANDS’ has been carried out entirely by the candidate Subala Mondal, M.Sc. under my supervision and guidance. This thesis has not been submitted previously anywhere for any degree whatsoever by her or by anyone else. Certified further that the candidate has fulfilled all the conditions necessary for Ph.D. degree examination of the University of Burdwan.

A.K.Ghosh (Supervisor)

4

ACKNOWLEDGEMENT

I would like to express my deep sense of gratitude and thanks to my supervisor Dr. Alak Kumar Ghosh, Associate Professor and Head, Department of Chemistry, The University of Burdwan, for his encouragement, scholastic guidance, valuable advice, constructive comments and suggestions through out my research work. I am thankful to Burdwan University authority for giving me necessary permission and infrastructural facilities. I also acknowledge the cooperation received from the teachers, research scholars and non-teaching staff of the Department of Chemistry, The University of Burdwan. My special thanks and appreciation go to my school authority for giving me necessary permission to carry out my research work. I would like to express my thanks for the cooperation received from my labmates, Dr. Subhasis Mallick, Dr. Biplab Kumar Bera, Dr. Parnajyoti Karmakar, Arup Mandal, Debabrata Nandi, Sumon Ray and Animesh Chattopadhyay. I am extremely grateful to my husband Dr. Arup Kumar Basu for his constant encouragement; moral support and friendly advice. The completion of this study would not have been possible without his constant encouragement and help. It is beyond words to express thanks to my parents Lt. Subhas Chandra Mondal & Mrs. Amala Mondal and my father & mother in-law Mr. Monoranjan Basu & Mrs. Smritikana Basu for their unfailing support and care towards me. I wish to convey my deep sense of love and regard to my brothers and

sister in-law. There are a number of persons who have helped me during the course of my research work; however, whose names cannot be mentioned in this small space. I hope that they would accept my sincere thanks and appreciation.

June 12, 2014 Department of Chemistry The University of Burdwan Burdwan, West Bengal, India

Subala Mondal

5

CONTENTS

Sl. No.

Chapters

Title

Page

1

Foreword

6

2

Abbreviations

11

3

Introduction

A brief survey of kinetic studies of substitution

12

6

reaction on 4d systems: [Ru(II) and Rh(III)]. 4

Chapter 1

Kinetics and mechanism of the interaction of bio-

65

active ligands with cis-diaqua-bis(bipyridyl) ruthenium(II) in aqueous medium. 5

Chapter 2

Kinetic and mechanistic studies on the interaction of

azide

with

86

cis-diaqua-bis(bipyridyl)

ruthenium(II) in aqueous medium. 6

Chapter 3

Kinetics and mechanism of the ligand substitution reaction of

106

[(H2O)(tap)2RuORu(tap)2(H2O)]2+

{tap=2-(m-tolylazo)pyridine diethyldithiocarbamate

with

anion

in

aqueous

solution. 7

Chapter 4

Interaction of

thiourea

and

L-cysteine

with

127

[(H2O)(tap)2RuORu(tap)2(H2O)]2+{tap=2-(mtolylazo)pyridine} in aqueous medium: kinetic and mechanistic studies. 8

Chapter 5

Mechanistic aspects of ligand substitution on

149

hydroxopentaaquarhodium(III) ion in aqueous solution by sulphur containing bioactive ligands. 9

Chapter 6

Displacement

of

aqua

ligand

from

the

174

hydroxopenta aquarhodium(III) ion by azide: A kinetic and mechanistic approach. 10

Summary and Conclusion

195

11

List of Publications

231

6

FOREWORD Transition metals exhibit different oxidation states, a wide range of coordination numbers and geometries, accessible redox states, a wide structural diversity and can interact with a number of negatively charged molecules. These activities of transition metals have started the development of metal-based drugs with promising

pharmacological

application

and

may

offer

unique

therapeutic

opportunities. Research has shown significant progress in utilization of transition metal complexes as drugs to treat several human diseases. The advances in inorganic chemistry provide better opportunities to use metal complexes as therapeutic agents. The mode of action of metal complexes on living organism is differing from non metals. These complexes show a great diversity in action. During the last decade it has become clear that platinum amine coordination compounds are very interesting from a biological point of view. It is generally accepted that the antitumor activity of various platinum containing drugs is related to the platination of DNA, most commonly via binding to guanine. The successful development of metal-containing anticancer drugs starts with the discovery of cisdichlorodiammineplatinum(II) or commonly called cisplatin as an anticancer drug, but the drug has considerable adverse side effects, such as nephrotoxicity, ototoxicity, neurotoxicity, nausea, vomiting, and myelosuppression. Consequently, there is much interest in obtaining drugs that have lower toxicity and more favourable therapeutic activity. To overcome these limitations, intensive research efforts have been engaged over the past 40 years. This led to the clinical development of cisplatin analogues such as oxaliplatin and carboplatin, widely used for treating colorectal cancers and ovarian tumours, respectively. However, these compounds still display side effects, such as peripheral neuropathy or myelosuppression. One of the efforts to escape the toxicity is to modify the drug itself by varying the metal ion and the attached ligand and altering the treatment methods. Different research groups are trying to use other transition metal complexes with favourable anti-tumor activity as ruthenium, rhodium and palladium complexes. Work progressed with different platinum(II) amine complexes and their derivatives as well as complexes of other 4d and 5d metal ions with nucleic acid constituents. Work with nucleosides and nucleic acids indicate that coordination

7

of ruthenium(II) to such ligands is similar to that of cisplatin or its analogues. It is also observed that being a 4d congenor of iron and cobalt (the most important biological metals in the periodic table), ruthenium and rhodium complexes are less toxic. In general ruthenium complexes are less toxic than cisplatin. Among the platinum family elements, ruthenium and rhodium have been successfully developed as anti-tumor properties. Studies in this area are mainly limited to structural identification using NMR, ESI-MS and X-ray crystallographic techniques. A negligible amount of work has been done in the reactivity, i.e., kinetic and mechanistic understanding of how metal complexes achieve their activities is crucial in rationalizing the efficiency of the metallo-drugs in biological conditions. The continued progress of ruthenium and rhodium compounds in clinical trials, and the frequent and exciting reports of new ruthenium and rhodium containing drug candidates in the literature point towards a future where medicinal chemists look beyond the classical 'biological' elements of carbon, hydrogen, nitrogen and oxygen, and begin to consider the potential of the less explored regions of the periodic table to generate powerful and effective drugs. Keeping a view on all the above facts we have taken a program to study the interactions of two aquaruthenium(II) and one aquarhodium(III) complexes and their reactions with some biologically important ligands. A comprehensive review on the kinetics and mechanism of substitution in octahedral ruthenium(II/III) and rhodium(III) complexes have been presented in the beginning of this thesis. It covers the outlines of the general mechanistic and kinetic aspects along with the different types of substitution reactions adopted by various metal ions with a special emphasis on ruthenium(II) and rhodium(III). Chapter 1 describes kinetics and mechanism of the interactions of bio-active ligands with cis-diaqua-bis(bipyridyl) ruthenium(II) in aqueous medium at pH 4.5. Here thioglycolic acid and 2-thiouracil used as ligands. At pH 4.5, the reaction has been found to proceed via two distinct consecutive steps where the first step is [ligand] dependent but the second step is [ligand] independent. The rate constants for the processes are: k1~10 -3 s-1 and k2 ~10 -4 s-1. At first an outer sphere association complex is formed; one of the donor centers of the ligands attacks the ruthenium(II) center. In the second step, cyclisation occurs through a fast step. The low H value associated

8

with large negative S value indicates a ligand assisted associative activation for all two ligands. The activation parameters were calculated from Eyring plots. Based on the kinetic and activation parameters an associative interchange mechanism is proposed for the interaction process. The thermodynamic parameters H0, S0 and G0 have also been calculated from the temperature dependence of the KE values of the pre-equilibrium step. The products of the reactions have been characterized by IR and ESI-mass spectroscopic analysis. In Chapter 2, kinetic and mechanistic studies on the interaction of azide with cis-diaqua-bis(bipyridyl) ruthenium(II) in aqueous medium has been presented. The reaction has been monitored at 510 nm where the spectral difference between the reactant and product is a maximum. At pH 4.5, the reaction has been found to proceed via two distinct consecutive steps and both the steps are dependent on ligand concentration. Each step proceeds via an associative interchange mechanism. At the outset of each step an outer sphere complex formed which is stabilised through Hbonding and is followed by an interchange from outer sphere to inner sphere complex. The outer sphere association equilibrium constants (KE1 and KE2), a measure of the extent of H-bonding for each step at different temperatures are evaluated. From the temperature dependence of the KE1 and KE2 values the thermodynamic parameters are calculated. ΔG0 values, calculated for both the steps at all temperatures studied, have a negative magnitude, which is once again in favour of the spontaneous formation of an outer sphere association complex. The product of the reaction has been characterized by IR and ESI-mass spectroscopic analysis. Chapter 3 describes the kinetics and mechanism of the ligand substitution reaction

of

[(H2O)(tap)2RuORu(tap)2(H2O)]2+{tap=2-(m-tolylazo)pyridine}

with

diethyldithiocarbamate anion in aqueous solution at physiological pH (7.4). At this pH the complex exists as [(H2O)(tap)2RuORu(tap)2(H2O)]2+ and the ligand exists as anionic form. The interaction reaction followed two parallel paths: both the paths are dependent on [ligand] and showed a limiting nature at higher concentration of the ligand. Rate constants (k1~10 -3 s-1 and k2~10-5 s-1), activation parameters were calculated. The Job’s method of complexation shows a 2:1 metal-ligand complexation in solution, which indicates a bridged product. A rate law involving the outer sphere association complex formation has been established at pH 7.4 as Rate = k1KE[{(H2O)(tap)2RuORu(tap)2(H2O)}2+][ligand]/(1+KE[ligand])

9

Based on the kinetic and activation parameters an associative interchange mechanism is proposed for the interaction process. From the temperature dependence of the outer sphere association equilibrium constant, the thermodynamic parameters were also calculated, which gives a negative ∆G0 value for both the paths at all temperatures studied, supporting the spontaneous formation of an outer sphere association complex. The product of the reaction has been characterized, as IR and ESI-mass spectroscopic analysis. Chapter 4 describes the interactions of

thiourea and L-cysteine with

2+

[(H2O)(tap)2RuORu(tap)2(H2O)] {tap=2-(m-tolylazo)pyridine} in aqueous medium at pH 7.4. The reactions were studied spectrophotometrically as a function of complex and ligand concentration, pH and temperature at constant ionic strength. The substitution reactions show two consecutive steps: the first is the ligand-assisted anation followed by a chelation step (k1 ~ 10-3 s-1 and k2 ~ 10-5s-1). The activation parameters for both the steps have been evaluated using Eyring equation. The low positive value of ∆H≠ and the large negative value of ∆S≠ indicate an associative mode of activation for both the aqua ligand substitution process. The products of the reaction s have been characterized with the help of infrared and electrospray ionization mass spectroscopic analysis. Chapter 5 includes mechanistic aspects of ligand substitution on hydroxopentaaquarhodium(III) ion in aqueous solution by sulphur containing bioactive ligands, thioglycolic acid, 2-thiouracil and glutathione. The reaction is a two step process in which the first step is ligand dependent but the second step is ligand independent and it is chelation step. The activation parameters for both the steps were evaluated using Eyring’s equation. Based on the kinetics and activation parameters, an associative interchange mechanism is proposed for the interaction process. The products of the reactions have been characterized from IR and ESI mass spectroscopic analysis. From the temperature dependence of the outer sphere association equilibrium constant, the thermodynamic parameters were also calculated, which gives a negative ∆G0 value for all the ligands, supporting the spontaneous formation of an outer sphere association complex. A rate law involving the outer sphere association complex formation has been established as

k(obs) =

k1KEKc(1)Ka [ligand]t Ka Kc(1)(1 +KE [ligand]t)+ [H+](Ka + Kc(1)) + [H+]2

10

In Chapter 6, kinetics and mechanism of displacement of aqua ligand from the hydroxopentaaquarhodium(III) ion by azide has been presented. The reaction has been monitored at 288 nm where the difference in absorbance between the reactant and product is a maximum at pH 4.3. The reaction has been found to proceed via two distinct consecutive steps and both the steps are dependent on ligand concentration. Each step proceeds via an associative interchange mechanism. At the outset of each step an outer sphere complex formed which is stabilised through H-bonding and is followed by an interchange from outer sphere to inner sphere complex. The rate constants for the processes are: k1~10-3 s-1 and k2 ~10 -5 s-1. The activation parameters for both the steps were evaluated using Eyring’s equation. Based on the kinetics and activation parameters, an associative interchange mechanism is proposed for the interaction process. The product of the reaction has been characterized, as IR and ESImass spectroscopic analysis. In the last part i.e. in summary and conclusion section, all the experimental findings have been summarised.

11

ABBREVIATIONS USED ADP

Adenosine 5’- diphosphate

ATP

Adenosine 5 ’- triphosphate

bpy

Bipyridyl

Bu

Butyl Group

BzNC

Benzyl isocyanide

Cyclam

1, 4, 8, 11-tetraazacyclotetradecane

DDP

Dichlorodiammineplatinum(II)

DDTC

Diethyl dithio carbamate

dien

Diethylenetriamine

DMSO

Dimethylsulphoxide

DNA

Deoxyribonucleic acid

en

Ethylenediammine

Et4dien

(N, N, N, N tetraethyl) diethylenetriamine

hedtra

N-hydroxyethylethylenediaminetriacetate

HPLC

High performance liquid chromatography

HPCE

High performance capillary electrophoresis

Hspy

2-mercaptopyridine

im

Imidazole

ind

Indazole

N3 -

Azide ion

Rh

Rhodium

RNA

Ribonucleic acid

Ru

Ruthenium

tap

{2-(m-tolylazo)pyridine}

tpy

2, 2’:6’, 2”-terpyridine

tgaH2

Thioglycollic acid

tuc

2-thiouracil

12

INTRODUCTION

13

A brief survey of kinetic studies of substitution reaction on 4d6 systems [Ru(II) and Rh(III)] Metal-based pharmaceuticals offer unprecedented versatility in medicinal chemistry because of the different building blocks from which they can be constructed, the variety of available interactions (H-bond, p-stacking, coordinative bond, spatial recognition), the combination of rigidity around the metal and flexibility in the ligands, the kinetics of ligand substitution when coordinative bonds with biomolecules are formed and because of their redox properties. Recently, the benefits of these properties in medicinal chemistry have begun to emerge. Cis-diamminedichloroplatinum(II), commonly known as cisplatin [1] was heralded as a completely novel type of antitumour agent, and its discovery enticed a veritable army of inorganic chemists to devise and test other precious metal-based therapies. Among the platinum group metals ruthenium and rhodium chemistry are well studied for its wide applications in medicine, industry, catalysis and synthesis. Ruthenium's properties are well suited towards pharmacological applications. It can access a range of oxidation states (II, III and IV) under physiologically relevant conditions. Also, the energy barriers to interconversion between these oxidation states are relatively low, allowing for ready oxidation state changes when inside the cell. In spite of this flexibility in oxidation state, ruthenium complexes display relatively slow ligand exchange rates in water - its kinetics are on the timescale of cellular reproduction (mitosis), meaning that if a ruthenium ion does bind to something in the cell, it is likely to remain bound for the remainder of that cell's lifetime. Furthermore, ruthenium tends to form octahedral complexes, which gives the chemist two more ligands to exploit compared with platinum(II) complexes, which adopt a square planar geometry. Ruthenium can also form strong chemical bonds with a range of different elements of varying chemical 'hardness' and electronegativities, meaning that ruthenium can bind to a range of biomolecules, not just DNA. Recent structural studies suggest that the anti-tumour activity of dirhodium(II) carboxylates may be by binding to adjacent guanines on DNA, in a similar manner to cisplatin [2]. Anti-tumour rhodium(I) compounds, with in vivo activity, and square planar rhodium(I) cyclo-octadiene complexes, are active against Ehrlich ascites tumours [3]. A number of rhodium(III) analogues of ruthenium(III) complexes have also shown antineoplastic activity. Some rhodium

14

metallointercalators exhibit specific DNA binding, suggesting that these may be a new type of DNA targeting agent. To understand the specific and selective role of metal ions in biological systems, thermodynamic and kinetic investigations are of interest [4, 5]. The interesting nature is also reflected in the fascinating field of kinetics of ligand substitution and diverse types of mechanism proposed thereof and their varied reactions in multiple oxidation states e.g. redox phenomena and photo substitution reactions [6-27]. There are many similarities of the mechanistic inorganic chemistry of iron and cobalt complexes with those of ruthenium and rhodium but there are also many differences. The discussion in this brief literature survey is restricted to three major types of nucleophilic substitution reactions, viz.; aquation, base hydrolysis and anation. Octahedral complexes of cobalt and chromium have been studied extensively through the last three decades, but only a few kinetic studies are reported for rhodium and ruthenium complexes. However, in recent years ruthenium(II)/ ruthenium(III) and rhodium(III) species have been investigated extensively specially in the light of mechanisms. This review focuses on this area, which may also helpful for preparative, biological and analytical procedures of coordination chemistry.

Early history It is about one hundred years since the kinetic studies of inorganic complexes in solution were started by Lamb and Marden [28] in the year 1911 who studied the rate of aquation of acid-pentammine cobalt(III) complex by observing the change in conductance with time. In the year 1952 the first review on ligand substitution dynamics by Taube [29] appeared. But upto this time the kineticist did not pay due attention to this field though the review created widespread interest in this field. During last three decades it has gained considerable momentum. While many of the kinetic problems have been answered, newer questions have been raised by those answers and much work has yet to be done to reconcile all the facts on a sound theoretical basis. Subsequently many authors have enriched the area [30-37]. The nucleophilic substitution processes started first with chromium and cobalt in the early 1950s. The Basolo and Pearson’s book ‘Mechanisms of Inorganic Reactions’ (1958) probably marks the beginning of a systematic mechanistic approach to inorganic reactions but little work was reported for rhodium centers in this period (1950 - 1970).

15

More recently (1970 – onwards) mechanistic studies on rhodium complexes of carboxylate, butyrate, propionate, acetate, methoxyacetate, 2,6-diaminopyridine, polypyridyl, specially aqua complexes of rhodium, its substituted derivatives and analogues have been of great interest because of their biochemical, photosensitizing and redox properties.

Classification of ligand substitution reaction mechanisms The ligand substitution reaction [38-44] is one in which the previous coordinating ligands of the metal ion in the first sphere of attraction are replaced by incoming ligand/s, e.g. L3MX +

Y

L3MY

+ X.

(1)

In this reaction L3MX is called the substrate, Y the entering group and X, the leaving group. The rate of such reactions differs widely.

According to Hughes and Ingold [45] substitution reactions are those, in which a lewis base is the entering group in place of previous coordinating ligand(s) are called nucleophilic substitution reactions and are symbolized as SN reactions. Ligand substitution reactions of coordination complexes can be illustrated by the general equation, MXn +

Y  MXn-1Y +

X

(2)

Where, M is a metal atom or ion and X and Y are any two ligands. For simplicity we have not considered the charge. By following organic terminology, inorganic chemists have found it convenient to divide the inorganic substitution reactions into nucleophilic (SN) and electrophilic (SE) substitutions. 

MXn +

Y

MXn +

M 

’

MXn-1Y ’

M Xn

+

X

SN

(3)

+

M

SE

(4)

Electrophilic substitution mechanisms will not be considered further since our study is related to ligand substitution reaction. For a ligand substitution process, SN mechanisms are relevant and are further subdivided into two paths. (i) SN1 dissociation (substitution, nucleophilic, unimolecular):

16

slow MXn

MXn-1 + Y

MXn-1 fast 

+

X

(5)

MXn-1Y

(6)

Such reactions are clearly insensitive to the nature of the incoming nucleophile, ‘Y’, but sensitive to the leaving group ‘X’ and reach the transition state principally by the internal accumulation of the energy to break the bond of the leaving group. The detection of an intermediate coordination number is the best diagnosis of the SN1 mechanism. (ii) SN2 displacement (substitution, nucleophilic, bimolecular): slow fast MXn + Y Y ----- M ----- X  MXn-1Y + (X)n-1

X

(7)

These reactions are sensitive to the nature of the entering group. Stereospecificity i.e. retention of configuration suggest an SN2 reactions pathway. One of the great complicating factors in assigning mechanism of substitution reactions is the existence of borderline mechanism or intermediate mechanism between SN1 and SN2. Depending upon the nature of participation of entering ligand in the transition state, it has been suggested to classify ligand substitution reactions into four categories. (a) SN1(lim), where the rate determining step involves only bond breaking and definite evidence for intermediate of reduced coordination number exists. (b) SN1, in which no such definite evidence of intermediate can be presented but otherwise, satisfies the requirement of dissociation mechanism. (c) SN2(lim), in which the rate determining step involves only bond making and definite evidence for a detectable intermediate of increased coordination number exists. (d) SN2, in which bond making is important in the rate determining step but no definite evidence can be given for the existence of an intermediate of higher coordination number. The above classification is based on the molecularity of the rate determining step and related to the stoichiometric mechanism and is introduced by Hughes and Ingold [45].

17

The current categorization of substitution mechanism includes cases which seem bimolecular in the strict stoichiometric sense but which are thought to be related to unimolecular cases, because their intimate mechanism seems to behave like that of unimolecular process. An alternative classification has been proposed by C. H. Langford and T. R. Stengle [19]. According to them mechanism is divided in two parts. One is stiochomertric mechanism other is intimate mechanism. Stoichiometric mechanism: The sequence of elementary steps by which the overall reaction takes place. Intimate mechanism: The details of the activation process & the energetic of formation of an activated complex in the rate determining step. A reformulation is possible by the mechanistic designation of Langford and T.R. Stengle, according to them three possible simple pathways are stoichiometrically distinct. They are: (i)

A dissociative path (D) in which the leaving ligand is lost in the first step,

producing an intermediate of reduced coordination number; (ii)

An associative path (A) in which the entering ligand adds to the substrate in the

slow step, producing an intermediate of increased coordination number, and (iii) The concerted path, also called interchange (I), since the leaving group is moving from inner to outer coordination sphere and the entering group is moving from outer to inner coordination sphere. In this category there is partial bond formation in the transition state. These three paths are illustrated as: -X MXn ⇌ +X

+Y MXn-1 ⇌ -Y

+Y MXn ⇌ MXnY -Y

-X ⇌ +X

MXn-1Y

MXn-1Y

(D- path)

(A- path)

(8)

(9)

18

MXn ……Y

MXn-1Y…..X

Dissociative Mechanism

( I- path)

(10)

Associative Mechanism

Interchange Mechanism For dissociation reactions, the activation energy is determined by the requirements of M—X bond dissociation and their mode of activation is called ‘d’ mode, similarly for associative reactions the activation energy is markedly affected by the assistance of incoming group and the activation mode is called ‘a’ mode. For interchange reactions when the incoming group and the leaving group both are weakly held in the coordination sphere, the reaction is classified as Id. If in the transition state both the entering group and leaving group are held firmly in the first coordination sphere, the reaction is called Ia. Since the defining characteristic of the interchange in the absence of an intermediate in which, the primary coordination number of the metal is modified. Following Basolo and Pearson [8] a qualitative equivalence between Langford’s mechanistic designation and Hughes-Ingold’s scheme can be drawn. The A-path of

19

ligand substitution processes would be labeled as SN2(lim) in which the rate determining step involves only bond making. The D-path corresponds to the SN1(lim), in which definite evidence for the existence of intermediate of reduced coordination number can be found. The Ia mechanism corresponds to SN2 path where the rate determining step involves equal bond breaking and bond making. The Id mechanism parallels SN1 process. The rate law of ligand substitution reaction by an interchange mechanism is consistent with an Eigen-Wilkin’s mechanism i.e. an encounter complex is formed in the pre-equilibrium step [10]. The diffusion controlled encounter complex between MXn and the entering group diffuses together and come into contact. They may also separate at diffusion limited rates. The next step is the rate determining reaction of the encounter complex to give products.

KE

XnM + Y

⇌

Xn-1 M X- - -Y

fast

Xn-1 M X- - -Y

Xn-1 M Y- - -X

Outer sphere complex k

Xn-1 M Y- - -X, rate-determining step

Xn-1 M Y + X,

fast

Now, the discussion will be restricted only to ligand substitution reactions of Ru(II/III) and Rh(III) complexes, which may be generally represented in the following way: RuL5X + Y

RuL5Y + X

(10)

RhL5X + Y

RhL5Y + X

(11)

where Y is the solvent or any other nucleophile. In aqueous medium and in the absence of any other nucleophile, H2O and OH- may be regarded as the competing nucleophiles present in the system and then the reaction may be written as: -d[complex]/ dt = k1 [RuL5X] + k2 [RuL5X] [OH-]

(12)

-d[complex]/ dt = k1 [RhL5X] + k2 [RhL5X][OH- ]

(13)

20

If the reaction is studied in aqueous medium below pH 3, the reaction product is usually aqua complex and it is designated as acid hydrolysis or aquation. When the reaction is carried out in pH range 3 to 10, the reaction product will be the equilibrium mixture of aqua and hydroxo complexes, and it is termed as simple hydrolysis. If the reaction is studied above pH 10, the product is usually hydroxo-complexes and the reaction is known as base hydrolysis. When both X and Y is nucleophiles other than H2O and OH-, the reaction will be termed as ligand exchange reaction. If X is water and Y is any other nucleophile, the reaction is called anation reaction.

IUPAC

recommendations

for

the

representation

of

reaction

mechanisms The IUPAC commission on Physical Organic Chemistry recommended a set of proposal for the naming of reaction mechanisms. In short they are discussed below. This nomenclature was not so much popular, but a new system of nomenclature for inorganic reactions over organic reactions is essential. Ingold proposed the term, for example, SN2 to describe a bimolecular nucleophilic substitution. It was not designed to describe reaction mechanism, although it has been widely used for that purpose even by Ingold himself. The Ingold code states the type of transformation and the observed molecularity, but this does not necessarily specify the reaction mechanism. A significant fraction of the controversy about reaction mechanisms arises because of ambiguities in the definition of the reaction mechanisms. In some cases identical names refer to different mechanisms; in others, different names are used for the same mechanism. The IUPAC recommendation is a system for naming reaction mechanisms. The system simply lists the bonds made and broken, with punctuation to separate reaction steps and subscripts to indicate electron apportionment. It removes ambiguities of the traditional system and may stimulate disciplined thought about the nature of molecular change [46].

21

Comparison of Ingold System Names with IUPAC Recommendation for the Representation of Reaction Mechanisms Ingold System Name

IUPAC Proposed Name

SUBSTITUTION MECHANISMS SN2

ANDN

SE2

D EA E

SEC or SE2 coord

An + cyclo-DEAEDn

AAC2

Ah + AN + AhDh + DN +Dh

SN1 or BAL1

DN + A N

SNi

DN + D + A N ADDITION MECHANISMS

Ad3

ANAE

none ( cyclo addition )

cyclo-ANAEDn or cyclo-AA

ELIMINATION MECHANISMS E2 or E2H

AnDEDN or AxhDHDN

Ei

cyclo-DEDNAn

E1

DN + D E

E1 cA

Ac + DN + AnDE (or Ah + DN + A2hDH )

E1 cB

AnDE + DN ( or AxhDH + DN ) REARRANGEMENT MECHANISMS

none ( intramolecular rearrangement )

1/DN + intra-1/AN + intra-2/DN + 2/AN

22

Mechanism of ligand substitution in octahedral ruthenium(II/III) and rhodium(III) systems Most of the transition metals of the periodic table have the coordination number six, it follows that much of the work on substitution reactions of metal complexes has been done on these systems. Furthermore, most of these complexes have a nearly octahedral structure and one is dealing with octahedral substitution reactions. Complexes of the first row transition metal ions with the exception of Cr3+ and Co3+ are generally labile, whereas most second and third row transition metal ions are inert. So Much work has been performed and reported in literature on the kinetics of ligand substitution in cobalt(III) and chromium(III) centre. It has been observed that cobalt(III) complexes proceed by dissociative mechanism, while corresponding reactions of chromium(III) are associative in nature. In detailed discussion that follows we shall be concerned mainly with the substitution reactions of ruthenium(II/III) and rhodium(III) complexes.

AQUATION OR ACID HYDROLYSIS Usually hydrolysis means the cleavage of chemical bonds by the addition of water. Or we say hydrolysis is a chemical process in which a molecule of water is added to a substance. Aquation or acid hydrolysis refer to the reaction carried out in acidic solutions and are represented by the following equation: [MA5X]( m-n )+ + H2O

[MA5(H2 O)]m+ + Xn-

(14)

The aquation studies are extensively started first with octahedral complexes [47] of cobalt(III) and chromium(III). The general observation is the decrease of rate with increase in chelation of the mother complex and a dissociative mechanistic path is followed. Afterwards, Swaddle and Guastalla [48] have explained the same using LFER plots where bond breaking and bond making are equally important. The dissociative nature of these reactions is also supported by many authors [49, 50] using evidences of pressure dependence of reaction rates, which are interpreted in terms of volume of activation (ΔV). However, aquations of Cr(III) complexes follow the associative path. Aqauation of bis-bipyridine di(1,2,4-triazole) ruthenium(II) in perchloric acid were studied by Biswanath Chakraborty and Utpal Kumar Kar [51].

23

Reactions of pentaammine ruthenium(II/III) complexes The investigation on the rates of hydrolysis of [Ru(NH3)5Cl]2+ show that the base hydrolysis is about 106 times faster than acid hydrolysis [34]. No single mechanism is adequate to explain the data for acid hydrolysis. According to Kane Maguire and Thomas [52], the aquation of [Ru(NH3)5Cl]2+ in a variety of waterorganic solvent follow the SN1 mechanism. Fairhurst and Swaddle [53] determine the volume of activation for aquation of the [Ru(NH3)5Cl]2+ and propose a limiting associative mechanism(Ia). The aquation kinetics of [Ru(NH3)5L]2+ (where L = formate, acetate, glycinate etc.), the dissociative mechanism has been proposed [54] though this proceeds through two different paths; one of which takes place involving Ru – O bond breaking and another by C – O bond breaking. Sutton and Taube [55] studied the aquation kinetics of (4-aminopyridine) petaammineruthenium(II) as a function of acidity of the medium and propose a rate law: -d[RuL]/dt = k1Ka[H+] [RuL]/ (1+Ka[H+])

(15)

where [RuL] represents total concentration of the substrate complex and the observed rate constant (kobs) is given by kobs = k1Ka[H+] / (1+Ka[H+])

(16)

The rate constants for aquation of [Ru(NH3)5(DMSO)]2+ and its ruthenium(III) analogue are 10 s-1 and 7.7 x 10-5 s-1 respectively, the large difference reflecting the ease of departure of DMSO ligand from ruthenium(II) species [56]. Measurements of the rate of aquation of [Ru(NH3)5(BzNC)]2+compared with earlier measurements for [Ru(NH3)6]2+show that BzNC (as compared to ammonia) labilises a trans ammonia by a factor of 40 [57]. In weakly acidic solutions (pH 3), petaammine ruthenium(III) complexes of glycinamide and parallel complexes show a rate law of the form: k = k/+ k //[H+] The first term corresponds to chelate ring closure and the second to aquation [58].

(17)

24

The activation parameters for the acid hydrolysis of petaammine ruthenium(III) complexes of acetonitrile, benzonitrile and 1-adamantylcarbonitrile show same mechanism where bond formation is important [59]. In aqueous acid, [(NH3)5Ru{OC(NH2)2}]3+ and some other O-donor ligands show a predominantly dissociative mode of activation for aquation of ruthenium(III) and cobalt(III) [60].

Reactions of tetraamine and other releted amine complexes of ruthenium(II/III) Kinetics of aquation of [RuL4X2], with L4 = (NH3)4, en2, 2, 3, 2-tet or cyclam and X = Cl- or Br-, has been followed by cyclic voltametry. Rate constants and activation parameters (ΔH≠ and ΔS≠) indicate a limiting dissociative(D) mechanism with square-pyramidal geometry for the transient intermediate [61]. A dissociative mechanism is proposed for the aquation of the complexes trans[Ru(NH3)4{P(OR)3}2]2+ and trans-[Ru(NH3)4{P(OEt)3}{P(OR)3}]2+ with R = methyl, isopropyl and butyl [62]. Phosphite ligand appears to be exerting a large trans-effect for the replacement of carbonyl by water in trans- [Ru(NH3)4{P(OEt)3}(CO)]2+ [63]. Broomhead and Kane Maguire [64] have done a lot of investigations on the acid hydrolysis studies of ethylenediamine complexes of ruthenium(III). An SN2 mechanism is proposed for the complexes cis-[RuX2(en)2] (X = Cl-, Br- or I-), cis[RuCl2(pn)2]Cl, cis-α-[RuCl2(trien)]Cl and [RuCl2(NH3)4]Cl. The complex cis[Ru(en)2(H2O)Cl]2+ also shows a mechanism with more associative character [65]. In aqueous acid solution (pH 1-3) (glycinamide-N, O) tetraammineruthenium(III) reacts about 5 orders of magnitude faster than analogous cobalt(III) complexes indicating a much stronger interaction of the carbonyl oxygen with ruthenium(III) than with cobalt(III) which can be explained by a significant ligand to metal π-charge transfer from the oxygen to the half-filled t2g orbital of ruthenium(III) [66].

Reactions of other ruthenium(II/III) complexes The complex [Ru(bpy)(tpy)(DMSO)]2+ undergoes aquation at a specific rate of 1.46 ± 0.05x10-5 s-1 at 50 oC, independent of H+. The parental thioether complex [Ru(bpy)(tpy){S(CH3)2}]2+ does not aquate at all [67]. A dissociative process is

25

indicated [68] for aquation of cis-[Ru(bpy)2 Cl2]. The stability and inertness of chloride ligands for aquation in [Ru(bpy)2XCl]n+ complexes increase as X varies in the order NO2 ~ Cl- < H2O < NO+. This is due to a significant increase in positive charge on X [69]. The kinetics of hydrolysis of cis-[Ru(bpy)2(NO)NOH]2+ to cis-[Ru(bpy)2(NO2)(H2O)]+ were studied by Nikolskii et.al. [70]. Constable and Seddon [71] proposed the SN1CB mechanism for the deuterium exchange reactions of [Ru(bpy)3 ]2+ in DMSO-NaOH solutions. Synitsyn et.al. [72] studied the hydrolysis of [Ru(CO)Cl5 ]2- in aqueous solution at 25oC. The kinetics of hydrolysis indicates that the hydrolytic stability of [Ru(CO)Cl5]2- is lower than that of its analogue [Ru(NO)Cl5]2+. According to Chevalier et.al. [73] [Ru(CN)5(NO2)]4- decays by an aquation process with a rate constant 2 x 10 -4 s-1 at 25 oC. More recently Kung et.al. [74] studied hydrolysis of the tumor-inhibiting ruthenium complexes trans-[RuCl4(im)2] and trans-[RuCl4(ind)2] by means of HPCE and HPLC-MS. High performance capillary electrophoresis (HPCE) as well as high performance liquid chromatography-mass spectrometry (HPLC-MS) have been applied to the separation, identification and quantification of the tumor-inhibiting ruthenium compounds HIm trans-[RuCl4(im)2] (im = imidazole) and HInd trans[RuCl4(ind)2] (ind = indazole) and their hydrolysis product. The decomposition follows pseudo-first-order kinetics. The rate constants in water at 25 oC are 1.102 ± 0.091 x 10-5 s-1 for HIm trans-[RuCl4(im)2] and 0.395 ± 0.014 x 10-5 s-1 for HInd trans[ RuCl4(ind)2]. K.Q. Ferreira, F.G. Doro and E. Tfouni [75] studied aquation reactions of Ru(II) and Ru(II) dichloro complexes with 1- (3-propylammonium) cyclam. The syntheses

and

characterization

of

trans-[(RuClL)-Cl-III(1-(3-

propylammonium)cyclam)]n+ (L = Cl-, trifluoromethanesulfonate, H2O; 1-(3propylammonium)cyclam =1-(3-propylammonium)-1,4,8,11-tetraazacyclotetradecane) are described. The complex trans-[(RuCl2)-Cl-III(1-(3-propylammonium)cyclam)]2+ releases

one

Cl-

forming

trans-[(RuCl2)-Cl-III(H2O)(1-(3-

2+

propylammonium)cyclam)] in aqueous solution at pH 1 (k = 8.2 x 10-5 s-1; 25oC. The reduced

complex

trans-[(RuCl2)-Cl-II(1-(3-propylammonium)cyclam)]+

aquates

chloride by pseudo-first-order kinetics with k = 0.29 s-1. Those rates are larger than in the corresponding cyclam complexes and are explained on the basis of the decrease of

26

cyclam nitrogen-hydrogen bonding interactions with the chloro ligands in the substituted cyclam.

Aquation of rhodium complexes Rhodium(III) forms octahedral complexes with halides [76] that present a complex speciation in chloride solutions due to the formation of a variety of aqua/chloro complexes following the reaction: [RhCl6]3− + nH2O⇌ [RhCl6−n(H2O)n](3−n)− + nCl−

(18)

The extent of this aquation reaction depends on the chloride concentration, temperature, time after preparation, and the pH of the solution [77]. Anionic complexes of rhodium are extracted more easily than cationic and neutral complexes [76]. Palmer and Harris [78] found that [RhCl6]3− undergoes stepwise aquation until the stable RhCl3(H2O)3 complex is formed. This species shows no tendency to lose additional chloride even when refluxed for several hours. These aqua/chloro complexes may also undergo hydrolysis at pH > 3 as follows [79]: [RhCl6−n(H2O)n](3−n)− + H2O ⇌ [RhCl6−n(H2O)n−1 OH](4−n)− + H3O+

(19)

This reaction, which is pH dependent, may lead to association or precipitation. A high pressure study of the rate of water exchange with [Rh(NH3)5(OH2)]3+ favoured an Ia mechanism [80]. On the other hand, ΔV± for the anation of this species indicated that an Id mechanism is operative [81]. A limiting D mechanism for the aquation and anation reaction of [RhCln(OH2)6-n](3-n)+ has also been proposed [82-87], where the involved transition state is square pyramidal. The aquation of [Rh(NH3)5SO4]+ and analogous cobalt(III) complexes have also been studied and essentially dissociative mechanism was proposed [88]. Comparison of aquation reaction of nitratopentaamminerhodium(III) and iridium(III) with cobalt(III) suggests primarily a dissociative way but some degree of associative character cannot be excluded [89]. Aquation of [RhXL(LH)2]n+ where X = Cl-, Br-, I- ; L = SO3H-, SO3= or NO2- and LH = dimethylglyoxime, along with complexes of the type [Rh(Cl)(LH)2(tu)], where tu = thiourea were studied by Systrova et.al. in aqueous organic solvent and dissociative interchange mechanism have been proposed [90].

27

Rate constants for the solvolysis of [M(NH3)5(OSO2CF3)]2+ where M = Co, Rh, Ir have been determined in the range of pure solvents (e.g. water, methanol, dimethyl sulphoxide, dimethyl formamide, acetonitrile, pyridine etc). They are in the ratio 90:40:1 for Co:Rh:Ir in each solvent compared to [M(NH3)5Cl]2+ analogues in water where the ratio is 17000:600:1. For all solvents except water, the progressively slower rate constants from Co > Rh > Ir arise in the activation entropy term. For water, the principal variation is in the activation enthalpy term suggesting a mechanistic uniqueness for this solvent. An Ia mechanism governed chiefly by the ability of the solvent molecule to associate in a nucleophilic manner with the metal ion may operate. Alternatively a modified Id mechanism involving both specific Lewis base solvation of the amines with concomitant electronic effects on the M 3+ O-SO2CF3 bond and some Lewis acid interaction of the solvent with the leaving group have been proposed [91]. A fast and effective method to study the aquation of rhodium chloro complex in hydrochloric acid solution using capillary zone electrophoresis (CZE) has been developed. At least five species, some of which seem to be oligomeric, are found in solution during the aquation process at pH Co(III) > Cr(III) > Rh(III). An SN1CB path was suggested for [Ru(NH3)5Cl]2+. Waysbort and Navon [95] have studied the base catalyzed aquation of [Ru(NH3)6]3+. The reactivity of [Ru(NH3)5(C2Cl4)]2+ has been studied in neutral, acidic and alkaline media. At pH 7 or less, there is very slow aquation, but in alkaline media there is fast attack by OH- at the coordinated ethylene ligand. A σ-bonded intermediate [Ru(NH3)5(CCl2CCl2)]2+ is suggested [96]. A dissociative nature of mechanism was proposed for [Ru(NH3)5(2CO2im)] at pH 11. Base hydrolysis studies of related amine complexes involve mostly the ethylenediamine complexes of ruthenium. Broomhead and Kane Maguire [97] studied the base

hydrolysis reaction of cis-[Ru(en)2X2]+,

cis-[Ru(en)2X(OH)]+ and

30

[Ru(NH3)5X]2+ (X = Cl-, Br- or I-). The observed rate data fit with the second order rate equation: -d [complex]/dt = k[OH-][complex]

(31)

An amido group – ruthenium pπ-dπ interaction was suggested. Poon and Isabirye [98] proposed SN1CB mechanism for [RuL4Cl2]+ (L4 = (NH3)4, en2, 2,3,2-tet or cyclam). The base hydrolysis of trans- [RuL4(A)Cl]+ (L4 = teta, tetb or cyclam; A = OH- or Cl-) were studied by Poon and Lau [99] and same mechanism were proposed. The kinetics of

base

hydrolysis

of

cis-[Ru(en)2Cl2 ]+,

cis-α-[Ru(trien)Cl2 ]+

and

cis-α-

[Ru(trien)(OH)Cl]+ were studied by Broomhead and Pasha [100] and observed a second order rate equation. Kinetic, mechanistic study of the nitrosyl complexes containing mainly ruthenium and different coligands (polypyridines, amines, pyridines, cyanides) with hydroxide were studied by Olabe et.al. [101]. According to a first-order rate law in each reactant, they proposed a fast ion pair formation equilibrium, followed by addition of OH- to the [MX5NO]n moieties, with formation of the [MX5NO2H]n-1 intermediates. Additional attack by a second OH- gives the final products, [MX5NO2]n-2.

Base hydrolysis of rhodium complexes The base hydrolysis of [Rh(NH3)5Br]2+ was studied by Lamb and second order rate was observed [102]. Later, base hydrolysis of several Rh(III) chloramine and chlorooxalato complexes have been studied [103, 104]. At constant pH, a general equation for all these systems may be written, kobs = kH2O + kOH- [OH-]

(32)

kH2O is the rate constant for the acid hydrolysis and kOH- is the second order rate constant for the reaction with OH- ion. It is observed that the rate of base hydrolysis for all trans-[RhA4Cl2 ]+ were independent of [OH- ] when the base concentration was as high as 0.10(M). Hydrolysis of cis-[RhA4Cl2]+ and [Rh(NH3)5Cl]2+ were dependent on [OH- ] with resrect to an order vary between zero and one. But the hydrolysis of CoA4Cl2+ are strictly first order in OH- above pH 8 or so, where A = NH3, en/2, trien/4, m-bn/2, dl-bn/2, bpy/2, C2O42-/2 etc. For the base hydrolysis of pentaamminehalogenorhodium(III) and cobalt(III), a similar mechanism have been adduced [105,106]

31

The kinetics of the reactions [Rh(NH3)5X]2+ + OH-

[Rh(NH3)5OH]2+ + X-

(X = Cl-, Br-, I-) have been studied over a wide range of temperatures under conditions which allow the calculation of second order rate constants at zero ionic strength; the reaction rate increases in the order Cl- > Br- > I- which is the reverse of cobalt ammines (I-> Br- > Cl-). A possible explanation has been put forward in terms of ligand field effects [103]. For comparison, the solid state reactions between [Co(NH3)5(H2O)]Br3 and [Cr(NH3)5(H2O)](NO3)3 with KX (X = Cl, Br, I) have been studied and the activation energies of deaquation reactions are independent of added anions, which could be interpreted by an SN1 dissociative mechanism. The activation energy of the deammination reactions are found to be dependent of the incoming group and decreases in the order Cl-> Br- > I- for Co(III) complex and I- > Br- > Cl- for Cr(III) complexes [107] Base hydrolysis of [Rh(NH3)5SO4]+ [88] and [Rh(NH3)5NO3]2+ [89] have been studied and compared with the analogous cobalt(III) and iridium(III) complexes. Both SN1CB and SN2CB mechanisms are consistent with the observations, however the lower activation entropies for the later members than Co(III) leads to the suggestions that for heavier metals SN2CB is more favored. Base hydrolysis of trans-[Rh(en)2X2]+ ( X = Cl-, Br- and I-) does occur if sufficiently high [OH-] are used [108]. It seems probable that the reactions, which lead to extensive stereochemical rearrangement, occur via SN1CB mechanism but the reactions of complexes further down the isokinetic plot may well have a mechanism closer to SN1IP. Chung and Bounsall found that trans-[Rh(cyclam)XY]+ (cyclam = 1,4,8,11-tetraazacyclotetradecane ; X- and Y- = Cl-, Br-, I-) undergoes base hydrolysis and the rate constants and activation parameters are consistent with SN1CB mechanism [109] The pressure dependence of the rate of base hydrolysis of [Rh(NH3)5X]2+ ( X = Cl-, Br-, I- and NO3- ) at 313.2o K at µ = 1M studied in the pressure range 1-1.5 k bar showed that the volume of activation values are 19.3, 20.2, 20.4 and 22.3 cm3 mol-1, compared to the analogous cobalt(III) complexes, an SN1CB mechanism has been proposed [34]. The [OH-] dependent path is afforded by kinetics of the reaction of the trans-[Rh(en)2ICl]+ cation [110].

32

For the hydrolysis of trans-[Rh(tn)2Cl2]+(where tn = propane-1,3-diamine) in aqueous solution, the pseudo first order rate constant is given by kobs = k1+k2[OH-] for [OH-] up to 1.0 mol dm-3. The later term is assigned to the expected SN1CB process.

Reactivity’s of tn, en and (NH3)4 complexes are observed to be

comparable [111]. A rate law: Rate = {k2[OH-] + k3[OH-]2} [Complex] have been proposed to obey for the base hydrolysis of [M(NH3)5L]n+ where M = Rh(III) and Ir(III) and L = MeCN or DMF. Coordination of the solvent to pentacoordinated pentaammine complex, [M(NH3)5]3+ shows a 106 order acceleration when compared to base hydrolysis rates of free solvent [112]. Base hydrolysis of [Rh(RNH2)5Cl]2+ ( R = Me, Et or npr) shows a first order dependence on [OH-] and the kinetic parameters have been compared with analogous Co(III) and Cr(III) cations. An S N1CB mechanism has been proposed. However Ia mechanism has been suggested for the base hydrolysis of [Rh(NH3)5Br]2+ [113] and for [Rh(RNH2)5Cl]2+ and [Rh(RNH2)4Cl2]+ [114]. Base hydrolysis of [M(NH3)5(OSO2CF3)]2+, (M = Co, Rh, Ir, Cr) and its Nmethylated amine derivatives were studied at 25oC and I = 1.0 M. It is observed that N-methylation of ammine ligand causes a marked enhancement of the rate of base hydrolysis reactions with kMe / kOH of >10 3(Co), 150(Rh) and 800(Cr). Positive activation entropies of [M(NH3)5(OSO2CF3)]2+ (M = Co, Ir) and competition experiments with N3- ion in base solutions as well as in the absence of the competing ion in the rate law allow a dissociative conjugate base mechanism for all complexes. The variation of rate enhancement from ammine to methylamine compounds and competition studies in base with N3- ion chiefly reflects differences in steric interactions due to different metal-ligand bond lengths rather than any mechanistic diversity. Variation in the competition behaviour for Rh(III), Cr(III) and Co(III) appear to reflect relative life time of the intermediate of reduced coordination number. The variation in aquation is much smaller and do not allow any certainity in mechanistic assertions. Marked accelerations of the rate of both acid and base hydrolysis (~10 3–106 folds) occur consistently for all trifluoro methane sulphonato complexes compared with those of halo analogues [115].

33

Survey of literature shows that different interesting observations are made by different workers in the field of base hydrolysis of rhodium(III) complexes. It is clear that though majority of data support conjugate base mechanism but controversy still persists regarding mechanistic conclusion in base hydrolysis of these reactions.

ANATION REACTIONS Anation reactions of pentaamine and tetraamine complexes of ruthenium(II/III) Armor and Taube [116,117] observed an overall second order kinetics for the anation of [Ru(NH3)5(H2O)]2+ by N2O, CO, py, isn and N2. Afterwards, Allen and Ford [118] have done a lot of investigations on the anation of the same complex by various substituted pyridines and by several organonitriles. Then Shepherd and Taube [119] have done anation kinetic studies on the same complex by using py, pyridinium ion, pyrazine, 3-picoline, acetonitrile, cyanoacetate ion and imidazole as incoming ligands. The rate data obtained in these studies fit the same second order rate law: d[{Ru(NH3)5L}2+]/dt

= kL[{Ru(NH3)5L}2+][L]

(33)

For a wide variety of neutral unhindred ligands the anation rates vary only over a very small range, from 0.056 to 0.30 dm3 mol-1 s-1 at 25oC (Table 1). The activation enthalpies are in the range of 70.3 ± 6.3 kJ mol-1 for the class of ligands under discussion. These observations are consistent with the view that activation for anation is largely a bond breaking process and that dissociative mechanism operates. On the basis of this view, the reaction scheme may be written as in equations (34) and (35).

[Ru(NH3)5(H2O)]2+

[Ru(NH3)5]2+ + L

k1 ⇌ k-1 k2

[Ru(NH3)5]2+ + H2O

(34)

[Ru(NH3)5L]2+

(35)

The rate law then becomes

k1 k2[{Ru(NH3)5(H2O)}2+][L] Rate =

________________________________________

k-1 + k2 [L]

(36)

34

Under the conditions of these investigations, k-1 >> k2[L]. Hence, equation (36) reduces to equation (37). Rate =

(k1k2/ k-1) [{Ru(NH3)5L}2+][L]

(37)

The same observation is made by Ojo et.al. [120] using another set of ligands like SCN-, CH3COOH, CN- and oxalato (H2C2O4 - HC2O4-) in acidic solution on the same complex. It also reveals that the reaction is independent of pH. Although second order kinetics is observed, the rates are insensitive to the nature of the ligand proving it to follow the dissociative pathway. Table 1 Summary of second order rate constants (at 25oC) and activation parameters for anation of [Ru(NH3)5(H2O)]2+ by various ligands Ligands

10 2k 3

-1 -1

ΔH≠

ΔS≠ -1

-1

Ref -1

(dm mol s )

(kJ mol )

(JK mol )

N2 O

7.2

74

-21

116

N2

7.1

77

-10

117

Py

9.1

64

-54

118

4Mepy

11.0

63

-54

118

C6H5CN

26.8

66

-33

118

CH3CN

26.2

68

-29

118

PyH+

0.31

71

-54

119

Pyr

5.6

73

-24

119

Pico

9.1

71

-28

119

Cya

1.2

63

-33

119

SCN-

20.8

88

-36

120

HCN

11.3

51

-94

120

35

The substitution reactions of a number of pyridines with electrostatically bound [Ru(NH3)5(H2O)]2+ complex have been investigated extensively [121, 122]. The partition- coefficient rate law is found to be first order in Nafion-bound [RuII] and first order in ligand concentration in the polymer phase. The variation in the intrinsic bimolecular rate constant and ΔS≠ for pyridine ligands in Nafion, combined with the 30-fold rate increase for 2-methyl pyridine in Nafion as compared to H2O, suggests that the substitution reaction in Nafion proceed with a degree of associative character. The activation volume for anation of [Ru(NH3)5(H2O)]3+ by Cl- is –20 cm3 mol-1, for the reverse reaction, aquation of [Ru(NH3)5Cl]2+, it is –30 cm3 mol-1 (at 333 K). In order to explain these very large values, a limiting associative mechanism(A) is proposed for both anation and aquation. In a way the anation value is more striking, since release of electrostricated water on forming dipositive transition state from the tripositive and uninegative reactants will make significant positive contribution to the initial state to transition state volume change. The intrinsic (i.e., ignoring solvent) activation volume may there be larger than –30 cm3 mol-1 for the anation reaction. The assignment of A mechanism for these substitutions is in line with proposals for other substitutions at ruthenium(III); only base hydrolysis gives evidence, which might indicate a different mechanism [53]. Analysis of the concentration dependence of rate constants for formation of the binuclear products from [Ru(NH3)5(H2O)]3+ and [Fe(CN)6]4- yield values of 2000 (molar scale) and 6.9 × 10-4 s-1 for KOS and k1 respectively for an Eigen-Wilkins interchange mechanism [123]. Isied and Taube [124] have studied the anation of cisor trans-[RuII(NH3)4L(H2O)] with isonicotinamide as entering ligand. The order of increasing lability is CO ≈ N2 < isn < py < imN ≈ NH3 < OH- < CN- < SO32- < imC and the range of specific second order rate constant was < 3 × 10 -6 (L = CO) to 60 dm3 mol1 -1

s (L = imC). Brown et.al. [125] have measured the rates and equilibrium for the

equation (38). k1 [Ru(NH3)4(SO3)(H2O)] + L ⇌ [Ru(NH3)4(SO3)(L)] + H2O k-1

(38)

where L is any one of the imidazole and purine derivatives. The observed pseudo-first order rate constant is expressed as in equation (39) kobs

= k1[L] + k-1

(39)

36

All the substitution rates(k1) are within a factor of about 4, provided the reaction site on the ligand is not sterically hindered. The narrow range (13.5 – 57.4 dm3 mol-1s-1) of rate constants is consistent with a process in which bond breaking is more important than bond formation. [Ru(NH3)4(H2O)Cl]2+ suffers the anation through dissociative pathway [126]. Anation reaction of [Ru(NH3)4{P(OEt)3}(H2O)]2+ with a series of ligands such as isn, imN, pyr, P(OEt)3, Mepyr + and SO32- have been investigated by Franco and Taube [127]. The second order specific rate constants are in the range 7.5 × 10-1 dm3 mol-1 s-1 {L= P(OEt)3} to 6.1 × 102 dm3 mol-1 s-1 { L= (SO32-)}. Bond making by the entering groups in the activated complexes for anation appears to be substantial for SO32- and imN but not for isn, pyr and Mepyr+. In the latter cases there is noticeable outer-sphere complex formation with the entering ligand. The reactivity order of the entering ligands towards the monophosphite complex ion are SO32- ≈ P(OEt)3 > imN > isn > pyr > Mepyr. Anation of this complex with CN-, N3- and SCN- have also been studied by Neiva et.al. [128]. The

second

order

specific

rates

k1

for

the

reaction

of

trans-

[Ru(NH3)4{P(OR)3}(H2O)]2+ with isn are 1.2, 2.3, 7.4 and 8.1 dm3 mol-1 s-1 (25 oC, µ= 0.10 mol dm-3 NaCF3COO/CH3COOH) for R = Me, pr, ipr and Bu respectively [129]. There is steady but small increase in rate as the group R increases in size from Me up to Bu. A good linear relation is observed in the plot of ΔH1 ≠ vs ΔS1 ≠. The substitution proceeds by a dissociative mechanism with a significant outer sphere association of trans-[Ru(NH3)4{P(OR)3}(H2O)]2+ with isn. The proposed reaction scheme is represented in equations (40) and (41). [Ru(NH3)4{P(OR)3}(H2O)]2+ + isn [Ru(NH3)4{P(OR)3}(H2O)]2+. isn

Kos

[Ru(NH3)4{P(OR)3}(H2O)]2+. isn

(40)

k1 ⇌ [Ru(NH3)4{P(OR)3}(isn)]2+ + H2O k-1

(41)

+ k-1

(42)

kobs is expressed as in equation (42) kobs =

k1 Kos [isn] __________________________________ Kos [isn] + 1

Trabuco and Franco [130] have measured the anation rate constant of [Ru(NH3)4L(H2O)] with 1, 2, 3, 4-thiatriazole-5-thiolate ion (CS2N3-) as 2.2 × 102, 1.8 × 10 and 1.3 × 102 dm3 mol-1 s-1 for L = SO32-, HSO3- and P(OEt)3 respectively (25 oC,

37

µ= 1.0 mol dm-3 NaCF3COO). Although no evidence for rate saturation has been observed for the systems under study, these reactions, by analogy with data observed for other Ru(II) systems [124, 125], are supposed to occur by a dissociative mechanism. The affinity of the L-Ru(II) centers with respect to the CS2N3- ion decreases with increasing π-acidity of the auxiliary ligand L, and the affinity order is SO32- > HSO3- > P(OEt)3 > SO2. Rate constants for reaction of [Ru(NH3)4L(H2O)]2+ with isn [131] indicate a significant trans- effect of the ligands L, in the order PPh3 >> AsPh3 >> SbPh3. Franco and coworkers [132] have also determined the relative sequence of trans-effect of L for the substitution reactions of [Ru(NH3)4L(H2O)]2+ with pyr as P(Oph)3 < PPh3 < P(OEt)3 < P(Obu)3 < PBu 3 < PEt3. The following relative order of increasing trans-influence of L is also assessed: PEt3 < PBu 3 < P(OBu)3 < P(OEt)3 ≈ PPh3 < P(OPh)3.

Reactions of other related amine complexes The

anation 2+

[RuCl(H2O)(trien)] [133,134].

The

reactions

of

cis-α-

[Ru(H2O)2(trien)]3+

and

cis-α-

by chloride have been studied spectrophotometrically by Pasha kinetics

fit

the

second

order

rate

-

- d[Complex]/dt = k [Complex][Cl ]

law, (43)

cis-α-[RuCl(H2O)(trien)]2+ shows slower anation rate than cis-α-[Ru(H2O)2(trien)]3+. A possible mechanism involving outer sphere association complex is suggested. The anation kinetics of the pentadentate edta complex of Ru(II) with different ligands are studied as a function of pH, temperature and the nature of incoming ligands [135]; it is observed that at the wide pH range 0.8 to 8.5 [Ru III(edta)(H2O)]- is the sole reactive species. It is also established that the anation of [Ru III(edta)(H2O)]- proceeds through the associative process in contrast to that of [Ru II(edta)(H2O)]2-, which follows the dissociative path. Toma et.al. [136] have studied the anation of [Ru(edta)(H2O)]by 2-mercaptopyridine (Hspy). The substitution rate for this complex and the corresponding activation parameters depend on the entering ligands [Table 2] and are consistant with an associative mechanism, as previously proposed by Matsubara and Creutz [135].

38

Table 2 Summary of kinetic parameters for anation of [Ru(edta)(H2O)]- by different ligandsa Ligands

kf (dm3 mol-1 s-1)

a

ΔH≠ (kJ mol-1)

ΔS≠ (JK-1 mol-1)

Reference No

Pyr

2.0 × 104

24

-84

135

CH3CN

3.0 × 104

35

-101

135

Isn

8.3 × 103

28

-79

135

SCN-

2.7 × 102

37

-75

135

HSpy

1.1 × 104

24

-84

136

Tu

3.0 × 103

22

-105

137

DMPb

7.8 × 103

29

-76

139

25 oC ; b 30oC The kinetics of the substitution reactions of [Ru(edta)(H2O)]- with (N3-),

thiocyanate (SCN-), thiourea and substituted thiourea have been studied as a function of pH (2 - 9), temperature (20 – 45 oC) and pressure (0.1 - 100 Mpa) by Bajaj and van Eldik [137]. Activation entropies and volumes for anation of [Ru(edta)(H2O)]- by above ligands lie in the range -99 to -105 JK-1 mol-1 and -7 to -12 cm3 mol-1 respectively. The associative mechanism thus indicated is attributed to hydrogen bonding between carboxylate groups and coordinated water pulling the latter away from its expected position and thus leaving more space for the entering group, thereby facilitating formation of the transition state. The results are discussed in terms of the extraordinary lability of the [Ru(edta)(H2O)]- species and arguments are presented in favour of an Ia mechanism. Taqui Khan and coworkers [138-140] have also investigated the anation of III

[Ru (edta)(H2O)]- by thiourea, 4,6 dimethyl 1-2-mercaptopyrimidine and CN- as a function of ligand concentration, temperature (30 – 45oC) and pH (1.4 – 9.0). It is seen from Table 2 that the low values of ΔH≠ and high negative values of ΔS≠ for these anation reactions clearly support the associative character of the anation process and

39

are in close agreement with those reported for other anation reactions. An associative interchange (Ia) mechanism is suggested for the anation of [Ru(edta)(H2O)]- by 4,6 dimethyl 1-2-mercaptopyrimidine followed by the displacement of coordinated carboxylate group in which deprotonation of coordinated ligand and reorganization of coordination sphere of the metal ion takes place. The slightly higher value of ΔH≠ as compared to 2-mercaptopyrimidine may be due to the presence of two methyl groups which cause some steric hindrance in forming activated species, which is also indicated by a larger value of ΔS≠ (Table 2). The kinetics of anation of [RuIII(edtaH)(H2O)] by CO is found to follow first order dependence in the concentration of this complex, as well as in [CO], over a wide range of concentration (10 -5 – 10-3 mol dm-3) of either reactant [141]. These experimental results are consistent with a mechanism given in equations (44-46) [Ru(edtaH)(H2O)] + CO

⇌ [Ru(edtaH)(CO)] + H2O

[Ru(edta)(H2O)]- + CO

⇌

[Ru(edta)(CO)]- + H2O

[Ru(edta)(CO)]- + [Ru(edta)(H2O)]- ⇌ [Ru(edta)2(CO)(OH)]3- + H+

(44) (45) (46)

Bajaj and van Eldik [142] have investigated the anation of [Ru(hedtra)(H2O)] by SCN-, N3-, thiourea and substituted thiourea as a function of pH (2 – 8), temperature (20 – 45 oC) and pressure (0.1 – 100 Mpa). The observed rate constants observed a characteristic decrease with increasing pH in the range 3.5 – 6.0 but remain constant in the range 2.0 – 3.5 and 6.0 – 8.5. It follows from Table 3 that the studied reactions are all characterized by low values of ΔH≠ and significantly negative values of ΔS≠ and ΔV≠. An increase in steric hindrance on the entering ligand (introduction of methyl substituents on thiourea) results in a significant decrease in k1, which is accompanied by an increase in ΔH≠ and a constant ΔS≠. The ΔH≠ and ΔS≠ values for the substitution by SCN-, N3- do not exhibit a significant dependence on pH, which means the substitution mechanism of [Ru(hedtra)(H2O)] and [Ru(hedtra)(OH)]- are indeed similar. The values of ΔV≠ in Table 3 underline the operation of an associative mechanism. The more negative ΔV≠ found for the reactions with substituted thiourea nicely demonstrates the dependence of the volume decrease during bond formation on the partial molar volume of the entering ligand. The more negative ΔV≠ values for the substitution by SCN-, N3- at pH 8.3 are ascribed to solvational changes resulting from

40

charge concentration, which will be accompanied by an increase in electrostriction and a decrease in volume. Table 3 Summary of data for anation of [Ru(hedtra)(H2O)] by different ligands at 25 oC [142] Ln+

pH

k (dm3 mol-1 s-1)

tu

ΔH≠ (kJ mol-1)

ΔS≠

ΔV≠

(JK-1 mol-1)

(cm3 mol-1)

3.0

22.6

34

-105

-4.1

8.3

2.8

-

-

-7.1

dmtu

3.0

9.4

37

-99

-6.2

tmtu

3.0

2.1

39

-108

-10.4

SCN-

3.0

6.8

39

-100

-7.3

8.3

1.1

40

-105

-10.8

5.0

18.5

38

-92

-

8.3

2.6

45

-86

-14.1

N3 -

The substitution reactions of [Ru(hedtra)(H2O)] with Br -, CH3CN, SCNand pyridine are found to be unusually rapid [143]. The observed rate constants for the reactions with pyridine are separated into two rate constants; the rate constant of the forward reaction of [Ru(hedtra)(H2O)] with py (18 ± 2 dm3 mol-1 s-1) and that of [Ru(hedtra)(OH)]- with py (3.0 ± 1.0 dm3 mol-1 s-1). Bajaj and van Eldik [137] concluded that the hydrogen bonding between the coordinated water and free carboxylate oxygen is responsible for the high lability of the water molecule in [Ru(edta)(H2O)]-. The transient coordination of the pendant carboxylate or N'- (2hydroxyethyl) group to a central metal ion weakens the metal-OH2 bond. [Ru(edta)(H2O)]- is more reactive towards Cl- anation than the corresponding hedtracomplex [144]. The low ΔH≠ (52 ± 1 kJ mol-1) and large negative ΔS≠ (-81 ± 3 JK-1 mol-1) values for anation of [Ru(hedtra)(H2O)] by DMSO are also consistent with the operation of an associative mode of activation [145].

41

Following earlier studies in the substitution behaviour of edta and related complexes of Ru(III), Bajaj and van Eldik [146] extended the series to include data for the N-methylethylenediaminetriacetate complex. Substitution reactions of the aqua and hydroxo complexes with SCN- and thiourea exhibit remarkably different activation volumes, which suggest the substitution mechanism, may change from Ia to A for the aqua and hydroxo complexes respectively. Ghosh and Chatterjee [147] have investigated the anation reaction of pentadentate pdta complex of Ru(III) with sulphur containing ligands like thiourea, 2mercaptopyrimidine, etc. and the following reaction scheme is proposed.

k1

[Ru(pdtaH)(H2O)] + L

k2

[Ru(pdta)(H2O)]- + L

k3

[Ru(pdta)(OH)]2- + L

[Ru(pdtaH)(L)] + H2O

(47)

[Ru(pdta)(L)]- + H2O

(48)

[Ru(pdta)(L)]- + OH-

(49)

The rate expression is given by the equation (50) kobs =

k1[H+]2 + k2K1[H+] +k3K1K2 __________________________________ + 2

(50)

+

[H ] + K1[H ] + K1K2 where K1 and K2 are first and second acid dissociation equilibrium constants of [Ru(pdtaH)(H2O)]. The low values of ΔH≠ and large negative values of ΔS≠ suggest an associative mechanism. The same mode of activation is proposed by these authors for the aqua ligand substitution on [Ru(edtaH)(H2O)]- by [Fe(CN)6]3- [148]. The same type of reaction scheme and the rate expression are given to explain the rate data. It is clear from the activation parameter data of the two complexes [Ru(edtaH)(H2O)]- and [Ru(pdta)(H2O)]- against the same nucleophiles thiourea and 2- mercaptopyrimidine, the nucleophilic attack is more feasible in the first complex. Taqui Khan et.al. [149] have studied the anation kinetics of [Ru(pdtaH)(H2O)] by tu and SCN-. The rate constant does depend on the nucleophilicity of the entering ligand, but does not vary over more than one order of magnitude for the nucleophilic substitution. These observations underline the operation of an Ia mechanism. A comparison of the substitution rate constants in Table 4 clearly indicates that the pdta and edta complexes are more reactive than the hedtra complex, at least by one or two

42

orders of magnitude. The rate and activation parameters for the anation of [(NH3)5Ru III(edta)RuIII(H2O)]2+ by thiourea [150] are found to be consistent with an associative interchange mechanism. The significant difference in rate constants for thiourea substitution of [Ru(edta)(H2O)]- and for [(NH3 )5Ru(edta)Ru(H2O)]2+ may be attributed due to the large size of the pendent group i.e. [Ru(NH3)5]3+ which strictly prevents the entering ligand from approaching the Ru(III) centre. Chatterjee et.al. [151] have also proposed an associative mode of activation for the substitution of [RuIII(edta)(H2O)]- with [Fe(CN)6]4-. The ΔH≠ and ΔS≠ values for this reaction are 28 ± 3 kJ mol-1 and -112 ± 8 J K-1 mol-1 respectively. Table 4 Rate and activation parameters of ligand substitutions with thiourea and thiocyanate at 25oC System

ΔH≠

k (dm3 mol-1 s-1)

(kJ mol-1)

ΔS≠

Ref

(JK-1 mol-1)

[Ru(edta)(H2O)]- / tu

2970

22

-105

137

[Ru(edta)(H2O)]- / SCN-

270

37

-75

137

[Ru (hedtra)(H2O)] / tu

22.6

23

-105

142

[Ru(hedtra)(H2O)]- / SCN-

6.8

39

-100

142

[Ru(pdta)(H2O)]- / tu

3470

25

-94

149

[Ru(pdta)(H2O)]- / SCN-

400

35

-79

149

[(NH3)5Ru(edta)Ru(H2O)]2+ / tu

48.8

49

-50

150

[(NH3)5Ru(edta)Ru(OH)]+ / tu

3.9

51

-63

150

Reactions of arylazo and bipyridine complexes Kinetics

and

mechanism

of

cis-[Ru(tap)(H2O)2]2+

(tap

=

2-[m-

tolylazo]pyridine) by various ligands viz. 1,10-phenanthroline, 2,2’-bipyridine, 8hydroxyquinoline, pyridine-2-aldoxime, salicylaldoxime and thiourea as a function of substrate complex concentration, ionic strength, pH, incoming ligand concentration, temperature and medium dielectric constant were studied by B. Mahanti and G.S. De

43

[152]. The reaction rate is found to be first order with respect to the substrate complex concentration when other parameters are fixed. Again increase in pH increases the reaction rate. As pH increases the percentage of deprotonated ligands also increases which have higher donor ability. So the reaction rate increases. The acid dissociation equilibrium of the substrate complex can be represented as: K1 [Ru(tap)(H2O)2]2+ ⇌ [ Ru(tap)2(H2O)(OH)]+ + H+

(51)

where the pK1 value is 6.6 at 25oC. The reactivity of hydroxoaqua complex is usually higher than that of diaqua complex by well known labilising effect of the coordinated hydroxide ion. Hence the reaction rate increases again with the increase in pH. Ruthenium complexes of 2, 2' - bipyridine, its substituted derivatives and analogues are of recent interest because of their fascinating redox, photophysical, photochemical and biochemical properties and for many years the only reported instances of chelate amine complexes of ruthenium are these types of complexes. The prototype bpy complex is the red tris chelate cation [RuII(bpy)3]2+ reported by Burstell in 1936. The thermal substitution reactions of ruthenium(II) coordinated to heteroatomic chelates were not reported so much in those days. In 1967 and 1968, Davies and Mullins [153, 154]

have

reported

the

substitution

reactions

of

[Ru(bpy)(tpy)]2+

and

[Ru(bpy)2(H2O)2]2+ with a number of nucleophilic reagents. The reactions were observed to be second order and rates fall in the sequence N3- > NO2- > SCN- > py. The diaqua complex appears to undergo substitution leading to disubstituted derivatives in a single step. The interesting observation is that the simplest amino acid does not react with the complex and the amino acid selectivity was not checked, though De and coworkers [155] have extensively studied the amino acid selectivity and also the anation kinetics of the aforesaid complex, and it reveals that the complex is active towards amino acid, and further the anation is no longer associative in nature. However, at low concentration of the ligands, it follows the second order rate law, but as the concentration of the nucleophile increases, it becomes first order. Allen et.al. [156] have extensively investigated the anations of a series of complexes of the general form [Ru(NN)2(H2O)X]m+ (where NN = bpy or phen and X= a monodentate ligand) by a variety of entering nucleophiles in aqueous solution and found to exhibit well-behaved second order kinetics. For the cis- and trans- isomers, the second order rate constants for anation by CH3 CN are found to be dependent on the nature of the X ligand in the sequence SO2 > OH- ⋍ PPh3 > H2O > CH3CN ⋍ py >

44

CO. In general, the reactions involving neutral ligands appear well behaved and predominantly dissociative. The lack of sensitivity to the nature of incoming ligand and the narrow range of ΔH≠ values suggest a considerable degree of bond breaking in the transition state. Leising et.al. [157] have proposed a dissociative interchange mechanism (Id) for the anations of a series of complexes of the form cis-[Ru(bpy)2(PR3)(H2O)]2+ (where PR3 = trialkyl phosphine) by acetonitrile, 4 – acetylpyridine and chloride in non-aqueous solution. The second order rate constants are found to be dependent on the steric and electronic nature of the coordinated phosphate ligands. The natural logarithms of the second order rate constants for anation by CH3CN decrease as a linear function of the Hammet parameters of the para substituents of tris – (para – substituted phenyl) phosphine in the following order: N(CH3)2 > OCH3 > CH3 > H > F > CF3 By using various trialkylphosphines, the steric effect of the ligand has been examined. In this case, the increase in ligand cone angles results in a linear increase in natural logarithms of the second order rate constants for the anation by CH3CN. The mechanism is illustrated as in equatios (52) and (53). [Ru(bpy)2(PR3)(H2O)]2+ + NCCH3 [Ru(bpy)2(PR3)(H2O)]2+….. NCCH3

KE ⇌ [Ru(bpy)2(PR3)(H2O)]2+…… NCCH3 ka

[Ru(bpy)2(PR3)(NCCH3)]2+ + H2O

(52) (53)

The pseudo-first order rate constants are derived as kobs = KEka[NCCH3 ] / (1 + KE[NCCH3])

(54)

The kinetics of anation of trans-[RuIII(bpy)2(H2O)(OH)]2+ by acetonitrile has been studied by Chang et.al. [158]. The rate is a strong function of pH with no observable contribution from the diaqua species below pK1 (1.5) or from the dihydroxo species above pK2 (5.2). K1 and K2 are the acid dissociation constants for the diaqua and the aquahydroxo complexes respectively. Ru(III) complex catalyzes the substitution reactions of [Ru(NN)2(H2O)]2+ (where NN = bpy or phen) and a catalytic mechanism is defined. Das (Karfa) et.al. [159] have investigated the anation reaction of [RuII(bpy)2(H2O)2]2+ by three vicinal dioximes (dimethylglyoxime(L1H), 1,2-

45

cyclohexane dionedioxime(L2H) and -furil dioxime(L3H)) spectrophotometrically in the 45 to 60 oC temperatures range. Rate constants increase with increase in ligand concentration and approach a limiting condition. Following rate law have proposed for the reaction in the 3.5-5.5 pH range: Rate = k2KE[Ru(bpy)2(H2O)2 ]2+ [LH]/(1+KE[LH]), where k2 is the interchange rate constant from outersphere to innersphere complex, K E is the outersphere association equilibrium constant. An associative interchange mechanism is proposed for the substitution process. Thermodynamic parameters calculated from the temperature dependence of the outersphere association equilibrium constants give negative G0 values for all the systems studied at all the temperatures studied, which also supports this proposition. Ghosh et.al. [160, 161] have proposed a associative interchange mechanism(Ia) for the anation of [(H2O)(tap)2RuORu(tap)2(H2O)]2+ {tap = 2-(m-tolylazo)pyridine}by thioglycolic acid and DL-penicilamine as a function of concentration of substrate complex and ligand, pH and temperature. In the studied pH range the reaction is a two step process. For thioglycolic acid both the process are ligand dependent. For DLpenicilamine first step is ligand dependent but the second step is ligand independent. Das

(Karfa)

et.al.

[162, 2+

[(H2O)(tap)2RuORu(tap)2(H2O)]

163] by

have

studied

thiosemicarbazide

the

interaction

and

of

glutathione 2+

spectrophotometrically as a function of [(H2O)(tap)2RuORu(tap)2(H2O) ], [ligand], pH and temperature at constant ionic strength. The interaction reaction followed two parallel paths: both the paths are dependent on [ligand] and showed a limiting nature at higher concentration of the ligand for both the ligands. A mechanism involving the prior formation of an outer sphere complex followed by associative interchange(Ia) is proposed for both the paths where bond making and bond breaking are equally important in the transition state for both the ligands.

Anantion reactions of aquapentaamminerhodium(III) ion Most

studies

have

been

devoted

to

[Rh(NH3)5(H2O)]3+, in this category of reactions.

aquapentaamminerhodium(III), The kinetics of anation of

[Rh(NH3)5(H2O)]3+ with bromide ion have been studied [102]. Both direct and reverse transformations exhibit first order reaction rates including unimolecular mechanism in spite of the fact that the conversion of aqua to acido ammines two reactions are

46

involved. This anomalous behavior is explained as due to changes in ionic strength of the solution during the reaction. Thus the reaction is actually second order overall, first order in aqua complex and first order in bromide ion. For reactions between two oppositely charged ions, ionic strength has reverse effect [164]. Accordingly as bromo complex is formed, with a drop in ionic strength as charges are neutralized, the second order rate constant increases. This compensates partly for the normal decrease in rate for a second order process and the net effect is close to that for a first order process. Other H2O exchange studies on [Rh(NH3)5(H2O)]3+ [165–169] shows that the process in each case proceeds through significant amount of bond making between the metal and the incoming nucleophile in the transition state; i.e. the mechanism is SN2 or Ia. Previous studies had failed to assign the mechanism of reactions of such rhodium(III) complexes [170]. The equilibrium constant for the formation of an associated pair (KE) involving the nucleophile X and the complex for [Rh(NH3)5OH2.Cl]2+ is less than 1/10 of that [Co(NH3)5OH2.Cl]2+. The overall charge of the complex appears to have little effect on the values of KE as seems to be true also for other rhodium(III) [171] and cobalt(III) [172] complexes. The kinetics of the formation of the azido, acetato and glycinato product from the reaction of [Rh(NH3)5OH2 ]3+ cation with N3-, CH3COO- and glycine have been monitored in weakly acidic aqueous solution [173, 174]. Activation parameters are reported in Table 5. Table 5 Activation parameters for the reactions of [Rh(NH3)5OH2]3+ ion System

ΔH≠

ΔS≠ Ref.

(k cal mol-1)

(e.u.)

23.9 ± 0.3

-3.0

165

/glyH

22.2 ± 1.0

-9.2

174

/CH3COO-

25.5 ± 0.5

+1.16 ± 0.30

173

/N3-

23.0 ± 0.1

-4.77 ± 0.02

173

[Rh(NH3)5OH2]3+/18OH2

Comparison of these with activation parameters for analogous reactions at cobalt(III) suggests that the most likely mechanism is the standard Eigen-Wilkins mechanism, but here with considerable associative character to the interchange step. Similar conclusion apply to the reactions of [Rh(NH3)5OH2]3+ with propionate or propionic acid according to pH [175], of trans-[Rh(NH3)4(OH2)2]3+ and probably of

47

[Rh(NH3)5(OH)]2+ with ammonia [176]. Here the pH dependence of the rate constants indicates that OH2 rather than OH- is the leaving group. Rate constants for the reaction of [Rh(NH3)5OH2]3+ with H2PO4- and with H3PO4 are 1.7×10-3 and 2.1×10 -4 at 353 K. Comparison of these rate constants with others for reaction of this aqua-complex with other ligands as summarized below (Table 6), suggests that the interchange mechanism is probably more associative in character than equivalent reactions of [Cr(NH3)5OH2]3+ [177]. Table 6 Summary of rate constants for anation of [Rh(NH3)5OH2]3+ by different entering ligands, at 65oC Entering ligand

104 k1

104 k

( s-1)

(M-1 s-1)

Ref.

N3 -

50.0

10.00

173

SO42-

17.0

12.10

168

AcO-

15.0

5.24

173

GlyH

3.72

174

PropH

2.70

175

Prop-

6.13

9.56

175

Ox2-

1.74

12.40

183

HOx-

1.77

4.20

183

1.79

183

H2Ox Cl-

39.7

7.15

169

Br-

79.0

6.32

168

H2PO4-

2.87

177

H3PO4

0.35

177

H2O

14.9

165, 183

48

In the solid state anation reactions of [M(NH3)5OH2 ]3+ in their [Co(CN)6]3salts, a dissociative mechanism is claimed to operate for cobalt(III), rhodium(III) and iridium(III) [178]. Rate constants and activation parameters for water exchange at cisand trans- isomer both of [Rh(NH3)4(OH2)2]3+ and [Rh(NH3)4(OH2)(Cl)]2+, compared with the published data on the water exchange at [Rh(NH3)4(OH2)2]3+ shows that for a fixed set of cis- ligands, the kinetic trans- effect series emerges as OH2 2-thiouracil. The sensitivity of the reaction rate towards donor properties of the entering ligands are in the line with that expected for an associative mode of activation. Due to the higher steric effect, the reactivity of the ligands used, 2-thiouracil decreases which is reflected in the rate constant values.

4.70 4.65 4.60 4.55

lnKE

4.50 4.45 4.40 4.35 4.30 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 13 Plot of lnKE versus 1/T for the reaction of thioglycolic acid interaction with complex 1

83

A plausible mechanism is shown as below:

2+ N

N

OH2 Ru

N

OH2

N

N

O-

+ HS

N

+

H O

KE

H H

Ru

O

N

N

Thioglycolic acid

O

H

O-

H

Complex(1)

..S ..

O

Outer sphere complex k1 -H2O

+

H N

N O Ru

N

N k2

H .. ..SH

S +

Ru

Chelation

O N

N

O

N

O N

H3O+

O

(2)

(B)

+ N

N S Ru

N

NH N

N

O

(3)

Figure 14 Plausible mechanisms for the substitution of aqua ligands from [Ru(bipy)2(H2O)2]2+ by thioglycolic acid (2) and 2-thiouracil (3)

84

References 1. N.R. Davies and T.L. Mullins, Aust. J. Chem., 21, 915 (1968). 2. A.E. Shilov, A.K. Shilova, and Y.G. Borod'ko, Kinetika i Kataliz, 7, 768 (1966). 3. T.W. Kallan and J.E. Earley, J. Chem. Soc. Chem. Commun., 851 (1970). 4. D. Mallick and G.S. De, Transition Met. Chem., 16, 289 (1991). 5. D. Mallick and G.S. De, Indian J. Chem., 30A, 509 (1991). 6. A. Mukherjee (Goswami) and K. De, Transition Met. Chem., 32, 419 (2007) and reference therein. 7. A.K. Ghosh, Transition Met. Chem., 31, 912 (2006). 8. T. Das (Karfa), B.K. Bera, A.K. Datta and A.K. Ghosh, (2009) Transition Met. Chem. 34, 247 (2009) and references therein. 9. D. Mallick and G.S. De, Transition Met. Chem., 17, 491 (1992). 10. M.J. Clarke, in: A.E. Martell (Ed.) Inorganic Chemistry in Biology and Medicine, ACS Symp, Ser 140, American Chemical Society, Washington DC, P-157, (1980) and references cited therein. 11. F.P. Pruchink, M. Bien and T. Lachowicz, Met. Based Drugs, 3, 185 (1996). 12. M.J. Clarke Met. Ions Biol. Syst., 11, 231 (1980). 13. R.E. Yasbin, C.R. Matthews and M.J. Clarke, Chem. Biol. Interact., 31, 355 (1980). 14. N.W. Leudtke, S.J. Hwang, E.C. Glazzer, D. Gut, M. Kol, and Y. Tor, Chem. Biochem., 3, 766 (2002). 15. E. Allessio, E. Iengo, B. Serli, G. Mestroni and G. Sava, J. Inorg. Biochem, 86, 21 (2001). 16. C. Pifferi, and R. Cini, J. Chem. Soc., Dalton Trans., 2679 (1998).

85

17. (a) M. Sulu, H. Kucukba, R. Durmaz and S. Gunal, Microbiologica, 23, 73 (2000), (b) Q.X. Zhen, B.H. Ye, J.G. Liu, Q.L. Zhang, L.N. Ji, and L. Wang, Inorg. Chim. Acta. 303, 141(2000). 18. (a) V.R. Dela, P. Perez, R. Pradogotor and F. Sanchez, J. Chem. Phys., 297, 163 (2004) and references therein, (b) K. Vaderschilden, A.H. Veldees, J.G. Haasnoot and J. Reedjjik, J. Inorg. Biochem. 86, 460 (2001). 19. (a) P. Munshi and T.N.G. Row, Acta Cryst., B62, 612 (2006), (b) I. Bratsosa, S. Jednera, T. Gianferrarab and E. Alessio, Chimia, 61, 692 (2007), (c) J. Reedjik, Chem. Commun., 801 (1996). 20. E.C. Jhonson, B.P. Sullivan, D.J. Salmon, S.A. Adeyemi and T.J. Meyer, Inorg. Chem., 17, 2211 (1978). 21. N.R. Davies and T.L. Mullins, Aust. J. Chem., 20, 657 (1967). 22. (a) G. Pneumatikakis, and N. Hadjiliadis, J. Inorg. Nucl. Chem., 41, 429 (1979), (b) C.M. Che, T.F. Lai and K.Y. Wong, Inorg. Chem., 26, 2289 (1987). 23. J.R. Durig, W.A. Mcallister, J.N. Willis and Jr. E.E. Mercer, Inorg. Chem., 5, 1881 (1966). 24. J.A. Weyh and R.E. Hamm, Inorg. Chem., 8, 2298 (1969). 25. ‘Stability Constants’ Special Publication No 17, The Chemical Society, London 376 (1964). 26. D. Wen, X. Zhu, F. Zhao, L. Huang and B. Zeng, Solid state Electrochemistry, 10, 69 (2006). 27. L.R. Allen, B. Durhan and J. Walsh, Inorg. Chem. 26, 53 (1987).

86

CHAPTER 2

87

Chapter 2

Kinetic and mechanistic studies on the interaction of azide with cis-diaqua-bis(bipyridyl) ruthenium(II) in aqueous medium a) Introduction The interest on ruthenium(II) complexes is increasing due to its application in diverse filds [1-7]. Ruthenium complexes of 2, 2'- bipyridine and its substituted derivative have redox, photophysical, and biochemical properties. For the last three decades anticancer chemotherapy has concentrated on cisplatin derivates. In spite of their consistent side effects, cisplatin derivates have a central part in most anticancer treatments [8]. In the search for drugs with fewer side effects other metal complexes have been examined over the past few years. Recent research shows that ruthenium complexes have interesting anticancer properties in vivo and they might be a good alternative to platinum-based drugs for anticancer therapy [9-15]. Ru(II) complexes are generally more reactive that Ru(III) complexes. As cancer cells are generally growing and multiplying much more rapidly than normal healthy cells, this creates an environment that is less oxygen rich due to the raised metabolic rate. When this is paired with the tendency of cancerous cells to contain higher levels of glutathione and a lower pH, a chemically reducing environment is created. This allows for ruthenium complexes to be administered as much less active, non-toxic Ru(III) compounds (as a prodrug), which can be activated solely at the site of the cancerous cells [9]. The reduction is thought to occur by mitochondrial proteins or microsomal single electron transfer proteins, though it may also occur by trans membrane electron transport systems which reside outside the cell – implying that entry to the cancerous cells may not be required for the drug to be effective. In theory it is also possible for the ruthenium compounds to be oxidized back to its inactive form if it leaves the cancerous environment. In

this

chapter 2+

we

extend

our

investigation

to

the

anation

of

[Ru(bipy)2(H2O)2] by azide ligand with monodenticity. Azide is an important ligand.

88

Azide inhibits cytochrome oxidase by binding irreversibly to the heme cofactor in a process similar to the action of carbon monoxide.

b) Materials and methods Experimental [Ru(bpy)2CO3].2H2O was prepared by the method of Meyer et.al. [16] and [Ru(bpy)2(H2O)2]2+ (complex 1) was prepared in situ by acidification of the carbonato species with p-toluene sulfonic acid since it did not oxidize the substrate complex to Ru(III) complexes. The experimental condition was such that > 90% of the salt was present as the diaqua species. The pH of the solution was maintained in the acidic region to prevent oxidation of Ru(II) to Ru(III) [17] and pH adjustments were done with the help of a Sartorius pH meter (model PB11) with an accuracy of ± 0.01 unit. Doubly distilled water was used to prepare all the kinetic solutions. All the chemicals used were of AR quality. The reactions were carried out at constant ionic strength and the ionic strength of the medium was adjusted by adding recrystallised sodium ptoluene sulfonate. A typical kinetic run was given using acetate as a ligand to confirm that acetate would not act as a ligand; and thus acetate buffer was used to maintain the pHs of the reaction mixtures The reaction product with azide was obtained by mixing them in different molar ratios, viz., 1:1, 1:2, 1:3, 1:4, 1:5 and 1:10 and thermostated at 50 oC for 10 hours. The complete complexation by the ligand was indicated by exhibiting the more or less same absorbance at same max (491 nm). The spectra of the product complex (2) and the reactant complex (1) are shown in Figure 1. The 1:2 metal-ligand composition of the substituted product in solution was determined by Job’s method of continuous variation (Figure 2).

89

1 2

Figure 1 Spectra of reactant complex (1), and azide substituted complex (2): [Ru(bipy)2(H2O)2]2+ = 1  10-4 mol dm-3, [azide] = 2  10-3 mol dm-3, pH= 4.5

0.75

0.70

abs

0.65

0.60

0.55

0.50

0.45 0.0

0.2

0.4

0.6

0.8

[L] / ( [L]+[M] )

Figure 2 Job’s plot of complex (1) with azide

1.0

90

When [Ru(bipy)2(H2O)2]2+ and azide were mixed in 1:1 ratio product 2 was obtained. The IR spectrum of the product 2 in the KBr disc shows sharp bands at 2035 cm-1 and 636 cm-1. Band appeared at 2035 cm-1 is due to antisymmetric stretching of azide. The additional band at 2146 cm-1 shows substitution occurs with terminal azide, indicating Ru-N=N=N structure. The band at 636 cm-1 indicates that Ru-N bond is present in the product complex (2) [18]. The aqueous solution of [Ru(bipy)2(H2O)2]2+ and azide were mixed in a 1:1 molar ratio and the mixture was thermostated at 60 oC for 48 hours and used for ESIMS measurement. The ESI- mass spectrum of the resulting product (2) is shown in Figure 3. It is clear from this spectrum that the ion at m/z 272 has become the precursor ion species in the mixture solution and this is tentatively attributed to (Ru(II) +2bipy +2N3- +2 Na+)2+. The precursor ion is shown in Figure 4.

Figure 3 ESI-mass spectrum of the reaction product

91

2+

N N3

N

+

Ru

N

2Na+

N3 N

Figure 4 Plausible structure of the molecular ion peak from the ESI-mass spectrum for the product (2) Physical measurements Physical measurements were carried out in the same way as explained in chapter 1 and also same instruments were used to record the kinetic data. Kinetic studies The kinetic measurements were carried out at wavelength 510 nm where the spectral difference between the reactant complex and product (2) is large. Before each kinetic run the pH of each reactant complex and ligand was adjusted to 4.5 and a pseudo first order conditions were employed throughout. Plots of ln(A∞-At) against time(t) gave the rate constants k2(obs), where At and A∞ are the absorbances at time t and at infinite time respectively (Figure 5). The k1(obs) values were calculated graphically (Figures 5 and 6) using the method of Weyh and Hamm [19] and as discussed in chapter 1 and other calculations were done using Origin software. The rate data represented as an average of duplicate runs were reproducible within ± 4%.

92

-1.0

-1.5

X -2.0



t

ln(A -A)

 -2.5

Y

-3.0

-3.5

-4.0 0

20

40

60

80

100

time (min)

Figure 5 Typical plot of ln(A∞ -At) versus time(t). [Ru(bipy)2(H2O)2]2+] = 1  10 -4 mol dm-3, [azide] = 2  10-3 mol dm-3, pH= 4.5, temperature = 65 oC

0.2 0.0 -0.2

ln

-0.4 -0.6 -0.8 -1.0 -1.2 -1.4 0

1

2

3

time (min)

Figure 6 Plot of ln∆ versus time

4

5

93

c) Results and discussion The pKa value [20] of the azide is 4.59 at 25ºC. Thus at pH=4.5 the ligand exists ~50% in the anionic form(N3-), which is the reacting species. HN3 ⇌ N3 - + H+ On the

other

hand

(1) first

acid

dissociation equilibrium of the

complex,

2+

[Ru(bipy)2((H2O)2] is 8.9 [21] Ka [Ru(bipy)2(H2O)2]2+ ⇌ [Ru(bipy)2(H2O)(OH)]+ + H+

(2)

At constant temperature, pH (4.5) and fixed concentration of complex (1), the ln(A∞-At) verses time(t) plots for different ligand concentrations indicate a two step process. Both the steps are dependent on ligand concentration and with increasing ligand concentration a limiting rate are reached for both the steps. The rate constant for such process can be evaluated by assuming scheme 1. (1)

k1

k2 B

(2)

KE1 [Ru(bipy)2(H2O)2]2+ + N3- ⇌ [Ru(bipy)2(H2O)2]2+ . N3(1) Outersphere association complex k1 [Ru(bipy)2(H2O)2]2+. N3- → [Ru(bipy)2(H2O)(N3)]+ + H2O B KE2 [Ru(bipy)2(H2O)(N3)]+ + N3- ⇌ [Ru(bipy)2(H2O)(N3)]+. N3Outersphere association complex

k2 [Ru(bipy)2(H2O)(N3)]+ . N3- → [Ru(bipy)2(N3)2] + H2O (2) Scheme 1 Here k1 is the anation rate constant for the first step i.e. for the interchange of the outer sphere to inner sphere complex and KE1 is the outersphere association

94

equilibrium constant for the first step. k2 is the rate constant for second step and KE2 is the outersphere association equilibrium constant for the second step. Calculation of k 1 for the first step (1→B) The k1(obs) values were calculated according to the same procedure mentioned in chapter 1 (Figures 5 and 6) and k1(obs) values were tabulated in table 1. The pseudo-first order rate constants (k1(obs)) were found to increase with increase in ligand concentration and show a limiting condition which is probably due to the completion of the outer sphere association complex formation (Figure 7).

6.5 6.0

D

5.5 5.0

C

4.5

3

10 k

1(obs)

-1

(s )

4.0

B

3.5

A

3.0 2.5 2.0 1.5 1.0 0.5 0.0 0

1

2

3 3

4

5

-3

10 [ligand] (mol dm )

Figure 7 Plots of k1(obs) (s-1) versus [azide] at different temperatures, A = 50, B = 55, C = 60 and D = 65ºC

95

Table 1 10 3k1(obs) (s-1) values for different ligand concentrations at different temperatures; [complex 1] =1.0×10−4 mol dm−3, pH = 4.5, ionic strength = 0.1 mol dm3

of sodium p-toluene sulfonate 103 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

1.0

0.95

1.28

1.72

2.36

2.0

1.71

2.24

2.91

4.16

3.0

2.34

3.00

3.85

4.84

4.0

2.77

3.49

4.36

5.51

5.0

3.12

3.91

4.81

5.84

Considering the kinetic results, the mechanism shown below can be proposed for the anation of [Ru(bipy)2(H2O)2]2+ by azide. KE1 1 + azide ⇌ 1. azide Outersphere association complex

k1 1.azide → B Scheme 2 Based on this pathway a rate expression can be derived: Rate = k1 KE1[ [Ru(bipy)2(H2O)2]2+][ azide]/ (1+ KE1[azide])

(5)

= k1(obs).[Ru(bipy)2(H2O)2]2+]T T stands for total concentration of Ru(II). We can write k1(obs) = k1KE1 [azide] / (1+KE1[azide])

(6)

1/k1(obs) = 1/ k1 + 1/ (k1KE1[azide])

(7)

A plot of 1/k1(obs) verses 1/[azide] should be linear (Figure 8) with an intercept of 1/k1 and slope 1/ k1KE1. where k1 is the anation rate constant for the 1 → B step,

96

and KE1 is the outer sphere association equilibrium constant. The k1 and KE1 values obtained from the intercept and intercept to slope ratios are given in Table 2.

A

1.1 1.0 0.9

B

0.8

3

1/10 k1(obs) (s)

0.7

C

0.6 0.5

D

0.4 0.3 0.2 0.1 0.0 0.2

0.4

0.6 3

0.8 3

1.0

-1

1/10 [ligand] (dm mol )

Figure 8 Plots of 1/k1(obs) against 1/[azide], A = 50, B = 55, C = 60 and D = 65ºC Table 2 103k1(s-1) and KE1 values for different ligands at different temperatures. [complex 1] = 1.0 ×10−4 mol dm−3, pH = 4.5, ionic strength = 0.1 mol dm-3 of sodium p-toluene sulfonate Temperature (°C)

103k1 (s−1)

KE 1 (dm3 mol−1)

50

7.71

141

55

8.34

182

60

9.15

232

65

10.01

314

Calculation of k2 for the second step (B →2) For the second step the rate constants are again dependent on ligand concentration and show a limiting value at higher concentration of the ligand. A new azide ligand attacks the ruthenium(II) center. The intermediate here also possibly

97

stabilised through hydrogen bonding between coordinated H2O and the approaching azide. Based on the experimental findings a two-step associative interchange mechanism is proposed for the substitution process. The rate constants (k2) were calculated from latter linear portions of the graphs and are collected in Table 3. The pseudo-first order rate constants (k2(obs)) were found to increase with increase in ligand concentrations and show a limiting condition which is probably due to the completion of the outer sphere association complex formation (Figure 9). A plot of 1/k2(obs) verses 1/ [azide] should be linear (Figure 10) with an intercept of 1/k2 and slope 1/ k2KE2. Where k2 is the anation rate constant for the B→2 step, and KE2 is the outer sphere association equilibrium constant for the second step. The k2 and KE2 for the B → 2 step is calculated similar to equation (7) and collected in Table 4.

5.5 5.0

D

4.5 4.0

C

3.0

B

2.5

4

-1

10 k2(obs) (s )

3.5

2.0

A

1.5 1.0 0.5 0.0 0

1

2

3 3

4

5

-3

10 [ligand] (mol dm )

Figure 9 Plots of k2(obs) (s-1) versus [azide] at different temperatures, A = 50, B = 55, C = 60 and D = 65ºC

98

Table 3 10 4k2(obs) (s-1) values for different ligand concentrations at different temperatures; [complex 1] =1.0×10−4 mol dm−3, pH = 4.5, ionic strength = 0.1 mol dm3

of sodium p-toluene sulfonate 103 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

1.0

0.51

0.86

1.41

2.02

2.0

0.97

1.56

2.40

3.33

3.0

1.34

2.12

3.12

4.26

4.0

1.63

2.49

3.62

4.80

5.0

1.84

2.79

4.06

5.03

A

2.0 1.8 1.6

B

1.2 1.0

4

1/10 k2(obs) (s)

1.4

0.8

C

0.6

D

0.4 0.2 0.0 0.2

0.4

0.6 3

0.8 3

1.0

-1

1/10 [ligand] (dm mol )

Figure 10 Plots of 1/k2(obs) (s) against 1/[azide], A = 50, B = 55, C = 60 and D = 65ºC

99

Table 4 104k2(s-1) and KE2 values for different ligands concentrations at different temperatures. [complex 1] = 1.0 ×10−4 mol dm−3, pH = 4.5, ionic strength = 0.1 mol dm-3 of sodium p-toluene sulfonate Temperature (°C)

10 4k1 (s−1)

KE2 (dm3 mol−1)

50

6.05

93

55

6.87

144

60

7.70

225

65

8.67

305

Effect of pH on the reaction rates Effect of pH was studied with the ligand. The kobs values at [(1)] (1.0 x 10-4 mol dm-3), [azide] (2.0 x 10-3 mol dm-3), ionic strength (0.1 mol dm-3, sodium salt of ptoluene sulphonic acid) temperature 60oC were found to increase with increase in pH. The kobs(s-1) values at different pHs are collected in Table 5. When we increase the pH, the proportion of the deprotonated forms of the complex ([Ru(bipy)2(H2O)(OH)]+) and ligand (azide) increase, and the reaction rate may have a slight response to the pH variation. Table 5

The 103k1(obs) and 10 4k2(obs) values at different pHs; [complex 1] = 1.0 × 10 -4

mol dm-3, [ligand] =2.0 × 10 -3 mol dm-3, temperature = 60 oC, ionic strength = 0.1 mol dm-3 of sodium p-toluene sulfonate 103k1(obs) (s-1)

pH

10 4k2 (obs) (s-1)

3.0

1.50

1.90

4.0

2.02

2.22

4.5

2.91

2.40

5.0

3.59

2.99

6.0

4.15

3.43

100

Effect of temperature on the reaction rates The reactions were studied at four different temperatures for different ligand concentrations, and the results are listed in Tables 1 to 5. The activation parameters for both the steps (1)→B and B→(2) are evaluated from the linear Eyring plots (Figures11 and 12) and are collected in Table 6.

-34.15

ln(k1h/kBT)

-34.20

-34.25

-34.30

-34.35

-34.40

2.94

2.96

2.98

3.00

3.02

3.04

3

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 11 Eyring plot ln(k1 h/kBT) versus (1/T) for the 1 → B step of azide interaction with complex 1 -36.60 -36.65

-36.70

ln(k2h/kBT)

-36.75

-36.80

-36.85

-36.90

-36.95 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 12 Eyring plot ln(k2 h/kBT) versus (1/T) for the B→2 step of azide interaction with complex 1

101

Table 6 Activation parameters for substitution of [complex 1] by azide in aqueous medium, pH = 4.5 ∆H1 ≠

∆S1≠

(kJ mol-1)

(JK-1 mol-1)

12.8 ± 0.7

-246 ± 2

∆H2 ≠

∆S2≠

(kJ mol-1)

(JK-1 mol-1)

18.4 ± 0.6

-250 ± 2

Mechanism and conclusion From the experimental results it is indicated that the anation on [Ru(bpy)2(H2O)2]2+ by azide proceed via two distinct substitution steps. Each step proceeds by an associative interchange(Ia) mode of activation. The proposition is supported by the following facts: a) With an increase in ligand concentration saturation in rate is observed for both the steps. This is possible only when an outer sphere association complex is formed and that complex is possibly stabilized through H-bonding. As the ligands react in the immediate vicinity of the complex, thus an increase in concentration of the ligand can not increase the rate. b) The lower value of enthalpy of activation and large negative value of entropy of activation strongly suggest the ligand participation in the transition state. c) From the temperature dependence of the KE1 and KE2 values the thermodynamic parameters are calculated (Figures 13 and 14): ΔH10 = 46.7 ± 3.3 kJ mol-1, ΔS10 = 186 ± 9 JK-1 mol-1 and ΔH20 = 71.3 ± 1.5 kJ mol-1, ΔS20 = 259 ± 4 JK-1 mol-1. The ΔG0 values, calculated at all temperatures studied, have a negative magnitude which is once again in favour of the spontaneous formation of an outer sphere association complex. From the Job’s method of continuous variation molar ratio of metal-ligand (1:2) and the ESI-mass spectrum of the product it is confirmed that the here azide acts as a monodentate ligand and no ring formation occurred.

102

5.8

5.6

lnKE1

5.4

5.2

5.0

4.8 2.94

2.96

2.98

3.00

3.02

3.04

3

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 13 Plot of lnKE1 versus 1/T for the reaction of azide with complex 1

5.8

5.6

lnKE2

5.4 5.2

5.0 4.8

4.6 4.4 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 14 Plot of lnKE2 versus 1/T for the reaction of azide with complex 1

103

Based on the above fact, a plausible mechanism for the substitution has been proposed and shown below (Figure 15).

2+

+

N

N

OH2

N

N

_ N

+

Ru

+ N

KE1

_ N

N

Complex (1) k1 _H O 2

+

_ N

Outersphere association complex

N

N3

N3

N _ N

+

Ru

+ N

_ N

KE2

N

N

(B)

k2

_ N

Ru

OH2

N

N+

OH2

N

N N

_ N

H Ru

OH2

N

H O

N

N

H _ N O H

N+

Outersphere association complex

N N3

N Ru

N

+

H2O

N3 N Product Complex (2)

Figure 15 Proposed mechanism for the interaction of azide with complex 1

104

References 1. R. delaVega, P. Perez, R. PradoGotor and F. Sanchez, J. Chem. Phys., 297, 163 (2004). 2. K. Vaderschilden, A.H. Velders, J.G. Haasnoot and J. Reedjjik, J. Inorg. Biochem., 86, 460 (2001). 3. H.K. Izumi and W.L. Smith, Abstracts of paper of the Am. Chem. Soc., 219, 727 (2000). 4.

Z.M. Wang and L.N. Ji, Prog. Chem., 14, 296 (2002).

5.

F. Roncaroli, M.E. Ruggiero, D.W. Franco, G.L. Estiu and J.A. Olabe, Inorg. Chem., 41, 5760 (2002).

6.

I. Turel, M. Pecanac, A. Golobic, E. Allessio and B. Serli, Eur. J. Inorg. Chem., 1928 (2002).

7. N.W. Leudtke, J.S. Hwang, E.C. Glazer, D. Gut, M. Kol and Y. Tor, Chembiochem, 3, 766 (2002). 8. A. Bergamo, C. Gaiddon, J.H.M. Schellens, J.H. Beijnen and G. Sava, J. Inorg.

Biochem., 106, 90 (2012). 9. E.S. Antonarakis and A. Emadi, Cancer Chemotherapy and Pharmacology, 66, 1 (2010). 10. M.J. Clarke, in: A.E. Martell, (Ed.)

Inorganic Chemistry in Biology and

Medicine, ACS Symp, Series #190, American Chemical Society, Washington DC, 157 (1980) and references cited therein. 11. R.V. Brabec and O. Novakova, DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity, Drug Resistance Updates, 9, 111 (2006). 12. I. Kostova, Ruthenium complexes as anticancer agents, Cur. Med. Chem., 13, 1085 (2006) and references therein. 13. M.J. Clarke, Coord. Chem. Review, 236, 209 (2003). 14. C.G. Hartinger, S. Zorbas-Seifried, M.A. Jakupee, B. Kynart, H. Zorbas, and B.K. Keppler, J. Inorg. Biochem, 100, 891 (2006). 15. W.H. Ang and P.J. Dyson, Eur. J. Inorg. Chem, 20, 4003 (2006).

105

16. E.C. Jhonson, B.P. Sullivan, D.J. Salmon, S.A. Adeyemi and T.J. Meyer, Inorg. Chem., 17, 2211 (1978). 17. G.M. Bryant, J.E. Ferguson and H.K.J. Power, Aust. J. Chem., 24, 257 (1971). 18. J.R. Durig, W.A. McAllister, J.N. Willis and E.E. Mercer, Inorg. Chem., 5, 1881 (1966). 19. J.A. Weyh and R.E. Hamm, Inorg. Chem., 8, 2298 (1969). 20. L.G. Sillen and A.E. Martell, Stability Constants of Metal Ion Complexes, The Chemical Society, London Special Publication No. 17, Table no. 31, 160 (1964). 21. L.R. Allen, B. Durhan and J. Walsh, Inorg. Chem., 26, 53 (1987).

106

CHAPTER 3

107

Chapter 3

Kinetics and mechanism of the ligand substitution reaction of [(H2O)(tap)2RuORu(tap)2(H2O)]2+{tap=2-(m-tolylazo)pyridine} with diethyldithiocarbamate anion in aqueous solution at pH 7.4 a) Introduction The studies [1-5] on the bioactivity and the DNA-binding capability of Ru(II/III) complexes are emerging as an interesting area because of their lower toxicity compared to platinum complexes, such as cisplatin, carboplatin and others. Cisplatin [6] and carboplatin [7] are well known drugs for cancer chemotherapy, but certain tumors are resistant to them and furthermore platinum complexes can also induce toxic effects. Different studies reveal that a numbers of ruthenium compounds serve as bacterial mutagens and are capable of damaging genetic material [8-12]. A series of ruthenium complexes exhibit antitumour [13-16], anticancer [17], antileukemic [18], anti-HIV [19] and antifungal activity [20, 21]. The ligand sodium diethyldithiocarbamate (NaDDTC) has been investigated as a biochemical modulator of the toxicity associated with clinically used cancer chemotherapeutic agents [22]. The effect of diethyldithiocarbamate anion (DDTC-) of chelating Zn inhibits metallo-proteinases, which in turn prevents the degradation of extracellular matrix, which is an initial step in cancer metastasis and angiogenesis [23]. The aim of the present work is to study the complex formation of diethyldithiocarbamate(DDTC) anion with the title complex in aqueous medium, where ruthenium(II), which is a pro-drug, is stable even at biological pH 7.4 due to the presence of the strong pi-acceptor ligand tap {2-(m-tolylazo) pyridine }[24].

b) Metrials and methods Experimental The

compound

cis-diaqua-bis-{2(m-tolylazo)pyridine}

ruthenium(II)

diperchlorate, monohydrate, cis-[Ru(tap)2(H2O)2](ClO4)2,H2O and the reacting complex ion [(H2O)(tap)2RuORu(tap)2(H2O)]2+ (1) was prepared following the literature method [25, 26]. The product [(tap)2Ru(µ-O)(µ-DDTC)Ru(tap)2]+ (2) of the reaction between complex (1) and DDTC- was prepared by mixing the reactants in different ratios, specifically 1:1, 1:2, 1:3, 1:5, 1:10 and thermostated at 50 oC for 72

108

hours. The spectrum of 2 (Figure 1) shows good complexation between DDTC- and (1). The composition of 2 in solution was determined by the Job’s method of continuous variation and the metal:ligand ratio was found to be 2:1(Figure 2). The pH of the solution was adjusted by adding NaOH/HClO4 and the measurements were carried out with the help of a Sartorius digital pH meter (PB 11) with an accuracy of ± 0.01 unit. Doubly distilled water was used to prepare all the kinetic solutions. All chemicals used were of AR grade available commercially. The reactions were carried out at constant ionic strength of 0.1 (M) NaClO4.

1

2

Figure 1 Spectra of reactant complex (1) and product complex (2). [1] = 1.0 x 10-4 mol dm-3, [DDTC-] = 2.0 x 10 -3 mol dm-3, pH = 7.4

109

0 .3 5

0 .3 0



absorbance

0 .2 5

0 .2 0

0 .1 5

0 .1 0 0.1

0 .2

0 .3

0 .4

0 .5

0 .6

0.7

0 .8

0 .9

[ L ] / ( [ L ]+ [ M ] )

Figure 2 Job’s plot of complex 1 with DDTCThe IR spectrum of the product in the KBr disk showed prominent band at 1092 cm-1 and 382 cm-1. The C=S stretching frequency of the non bonded DDTCoccurs at 1132 cm-1 which shifted 41 cm-1 downwards to 1092 cm-1 indicating the coordination of the C=S group to Ru+2 through the S atom of C=S group. The two S atoms of the ligand DDTC- are nonequivalent [27]. The IR spectrum of free ligand displays a sharp peak near ~2500 cm-1 assignable to free –SH group but there is no peak at near ~2500 cm-1 (stretching frequency of free –SH group) in the final product complex. So we can say both S atoms of the ligand involved in bonding. The band at 382 cm-1 is therefore assigned to Ru-S stretching frequency. From the ESI-mass spectrum (Figure 3) of the product, it is clear that the peak at m/z ~ 635 has become the molecular ion species in the mixture solution and this is tentatively attributed to (DDTC- + 2Ru + O + 4 tap + 2H2O + Na+)2+. The precursor ion is shown in Figure 4.

110

Figure 3 ESI-mass spectrum of DDTC- substituted product

2+ O (tap)2Ru

Ru(tap)2

S

S

+

Na+

+ 2H2O

C

N Et

Et

m/z = ~635 Figure 4 Plausible structure of the molecular ion peak from the ESI-mass spectrum

111

Kinetic and physical measurements Physical measurements were carried out in the same way as explained in chapter 1 and also same instruments were used to record the kinetic data. The progress of the reaction was monitored by measuring the decrease in absorbance at 560 nm, where the difference in spectra between the substrate and the product complex is maximum. The plots of ln(At -A∞) against time t, where At and A∞ are the absorbance at time t and at infinite time (after the completion of the reaction) were found to be non-linear; being curved at the initial stage and subsequently of constant slope (Figure 5). The rate constants for two consecutive steps were calculated using the Weyh and Hamm method [28] as discussed in chapter 1. From the linear second portion, k2(obs) values were obtained. The k1(obs) values were available from the plots of lnΔ versus time. A typical plot is shown in Figure 6. The rate data represented as an average of duplicate runs were reproducible within ± 4%.

-0.14 -0.16 -0.18

X

-0.20

ln(At-A)

-0.22



-0.24

Y

-0.26 -0.28 -0.30 -0.32 -0.34 0

20

40

60

80

100

time (min)

Figure 5 A typical plot of ln(At -A) versus time. [complex]= 1.0×10 −4 mol dm−3, [ligand] = 4.0×10 −3 mol dm−3; pH = 7.4, temperature = 65ºC

112

-2.6 -2.8 -3.0

ln

-3.2 -3.4 -3.6 -3.8 -4.0 0

1

2

3

4

5

time (min)

Figure 6 A typical plot of ln versus time. [complex]= 1.0×10−4 mol dm−3, [ligand] = 4.0×10−3 mol dm−3; pH = 7.4, temperature = 65ºC

c) Results and discussion First acid dissociation equilibrium of the complex [Ru(tap)2(H2O)2]2+ is 6.6 [29] at 25◦C. At pH 7.4, the complex ion exists in dimeric oxo-bridged form, [(H2O)(tap)2RuORu(tap)2(H2O)]2+ [30–33]. At pH 7.4, the mononuclear species exists in the hydroxoaqua form. Two such species assemble to form the dinuclear oxobridged diaqua complex due to thermodynamic force mainly arising from pi-bonding [34] (O2− donor, RuII acceptor) which is favorable for 4d ion, Ru II. Now, such strong covalency reduces the acidity of the coordinated water. The oxobridge formation is solely dependent on pH. Electrochemical studies show that there is pH potential domain, where the µ- oxo structures stay intact. Variable temperature study does not show any effect, which is in line with the fact that oxo-bridge formation is solely pHdependent [35-36]. Ka [Ru(tap)2(H2O)2]2+ ⇌ [Ru(tap)2(H2O)(OH)]+ + H+

(1)

113

2+ O

(tap)2Ru

Ru(tap)2

H2O

OH2

Dimeric oxo-bridged form The pKa value of the ligand sodium diethyldithiocarbamate is 3.37 at 25 oC [37], so that at pH 7.4, the major species involved in the kinetic process is the anionic form of the ligand which is DDTC-. At constant temperature, pH (7.4) and fixed concentration of complex (1) the ln(At-A) versus time(t) plots for different ligand concentration indicates a two step process. Both are dependent on the incoming ligand concentration, and with increasing ligand concentration a limiting rate is reached. Job’s method of complexation indicates a 2:1 metal–ligand ratio in the product complex. This is possible only when the reaction follow a parallel path. The rate constant for such a process can be evaluated by assuming the following scheme 1. [(H2O)(tap)2RuORu(tap)2(H2O)]2+ + DDTC(1) ⇅ KE/ & KE // [(H2O)(tap)2RuORu(tap)2(H2O)]2+• DDTCOutersphere association complex

k1 & k2 [(tap)2RuO(DDTC)Ru(tap)2]+ + 2H2O (2) Scheme 1 In the starting complex there are two equivalent ruthenium(II) centers. Now the ligand has two donor centers. During the ligation two donor centers attack in two parallel speeds (k1 and k2) which is shown in the mechanism and conclusion section.

114

Calculation of k1 value The k1(obs) values were calculated according to the same procedure mentioned in chapter 1 (Figures 5 and 6) and k1(obs) values were tabulated in table 1. The rate increases with increase in [ligand] and reaches a limiting value (Figure 7). The limiting rate constant is probably due to the completion of outer sphere association complex formation. Since the metal ion reacts with its immediate environment, further change in [ligand] beyond the saturation point will not affect the reaction rate. The outer sphere association complex may be stabilized through Hbonding. Table 1 10 3k1(obs) (s-1) values for different DDTC- concentrations at different temperatures; [complex] = 1.0 × 10-4 mol dm-3, pH = 7.4, ionic strength = 0.1 mol dm-3 NaClO4 103 [ligand] (mol dm−3)

Temperature (oC) 50

55

60

65

1.0

0.81

1.14

1.40

1.79

2.0

1.53

2.08

2.50

3.03

3.0

2.13

2.77

3.45

4.16

4.0

2.50

3.22

4.00

4.76

5.0

2.76

3.85

4.35

5.55

115

6.0

D

5.5 5.0 4.5

C B

3.5 3.0

A

2.5

3

-1

10 k1(obs) (s )

4.0

2.0 1.5 1.0 0.5 0.0 0

1

2

3

3

4

5

-3

10 [ligand] (mol dm )

Figure 7 Plots of 103k1(obs) versus [ligand], A=50 o, B=55o, C=60o and D=65 oC Based on the experimental findings, the following Scheme 2 may be proposed for the path (1) → (2) (k1 path);

(1) + (DDTC-) ⇌ (1)·(DDTC-) K E/ (1)· (DDTC ) → (2) Outersphere association complex

Scheme 2 Based on the above scheme a rate expression can be derived. k1 d[2]/dt= k1KE/ [{(H2O) (tap)2RuORu(tap)2(H2O)}2+][DDTC- ] / (1+ KE/ [DDTC-]) or, d[2]/dt = k1(obs) [{(H2O) (tap)2RuORu(tap)2(H2O)}2+] T

(3) (4)

Where T stands for total concentration of Ru(II).We can then write, k1(obs) = k1KE/ [DDTC-]/(1+ KE/ [DDTC-] )

(5)

Where k1 is the rate constant for the first path, i.e., the rate constant for the interchange of outer sphere complex to the inner sphere complex; KE/ is the outer sphere association equilibrium constant for the first path.

116

The equation can be represented as: 1/k1(obs) = 1/k1 +1/k1 KE/ [DDTC-]

(6)

The plot of 1/k1(obs) against 1/[DDTC-] should be linear with an intercept of 1/k1 and slope 1/k1KE/. This was found to be the case at all temperatures studied. The k1 and KE/ values were calculated from the intercept and slope (Figure 8) and are collected in Table 3.

1.4

A

3

1/10 k1(obs) (s)

1.2

1.0

B

0.8

C

0.6

D

0.4

0.2

0.0 0.2

0.4

0.6 3

0.8 3

1.0

-1

1/10 [ligand] (dm mol )

Figure 8 Plots of 1/k1(obs) against 1/ [ligand], A=50o, B=55o,C=60 o, and D=65oC Calculation of k2 value The rate constants for second path were calculated from the latter linear portions of the graphs and are collected in Table 2. This is again dependent on [DDTC-] and shows a limiting value at higher ligand concentrations (Figure 9). The intermediate here is also possibly stabilised through H-bonding between coordinated water and the approaching DDTC ion. In a parallel reaction two paths overlap each other. But during the calculation of the first path (k1~10 -3 s-1) the contribution from second path (k2 ~10 -5 s-1) is negligible. On the other hand, when we are calculating the rate constant for the second path the first path is already complete. Thus there is no problem in calculating k1 and k2.

117

For second path the rate equation can be written as similar as equation 6. i.e. 1/k2(obs) = 1/k2 +1/k2 KE// [DDTC-]

(7)

Where k2 is the rate constant and KE// is the outer sphere association equilibrium constant for the second parallel path. Table 2 105k2(obs) (s-1) values for different DDTC- concentrations at different temperatures; [complex] = 1.0 × 10-4 mol dm-3, pH = 7.4, ionic strength = 0.1 mol dm-3 NaClO4 103 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

1.0

0.39

0.5

0.66

0.85

2.0

0.71

0.91

1.12

1.49

3.0

0.97

1.20

1.54

2.04

4.0

1.10

1.45

1.85

2.32

5.0

1.27

1.61

2.10

2.63

2.8

D

2.6 2.4 2.2

C

2.0

B

1.6 1.4

A

1.2

5

-1

10 k1(obs) (s )

1.8

1.0 0.8 0.6 0.4 0.2 0.0 0

1

2 3

3

4

5

-3

10 [ligand] (mol dm )

Figure 9 Plots of 105k2(obs) versus [ligand], A=50 o, B=55o, C=60o and D=65 oC

118

The k2 and KE// for the second path is calculated in a manner similar to Equation (6) (Figure 10) and data are collected in Table 3.

A

2.8 2.6 2.4

B

2.2 2.0

5

1/10 k1(obs) (s)

1.8

C

1.6 1.4

D

1.2 1.0 0.8 0.6 0.4 0.2 0.0 0.2

0.4

0.6 3

0.8 3

1.0

-1

1/10 [ligand] (dm mol )

Figure 10 Plots of 1/k2(obs) against 1/ [ligand], A=50 o, B=55 o,C=60o, and D=65 o

Table 3 The k1, KE/, k2 and KE// values

Temp (oC)

103k1 (s-1)

KE/ (dm3 mol-1)

105k2 (s-1)

KE// (dm3 mol-1)

50

8.33

109

3.16

140

55

9.09

143

3.87

149

60

10.0

164

4.60

165

65

11.11

191

5.70

177

Based on the experimental findings, a two step interchange associative mechanism is proposed for the substitution process. An outersphere association complex is formed between the ligand and the two ruthenium(II) centers, which is

119

stabilised by the H-bonding between the incoming ligand and the coordinated aqua molecules. Now the interchange of the ligand from the outersphere to the inner sphere occurs. Effect of pH on the reaction rates The reaction was studied at five different pH values. The kobs values increase with increase in pH. With increasing pH, the proportion of the more reactive DDTCform increases which accounts for the increase in rate with increasing pH. The complex also changes its form, from aqua to hydroxo aqua and then to the oxobridged dimer. The hydroxo species is more reactive due to the well-known labilising effect of the -OH group via its -bonding ability and strong electromeric effect.

Table 4 The 103k1(obs) and 105k2(obs) values at different pH values; [1] = 1.0 x 10 -4 mol dm-3, [ligand] = 2.0 x 10-3 mol dm-3, temperature = 60 o C ionic strength = 0.1 mol dm-3 NaClO4 pH

103k1(obs) (s-1)

105k2(obs) (s-1)

5.5

0.21

0.30

6.0

0.69

0.48

6.5

1.10

0.63

7.0

1.98

0.91

7.4

2.50

1.12

Effect of temperature on the reaction rates

120

To study the effects of temperature, the reaction was studied at four different temperatures for different DDTC- concentrations and the results are listed in Tables 1 and 2. The activation parameters for both the steps were evaluated from the linear Eyring plots. (Figures 11 and 12) giving values of ∆H1 ≠ = 14.1 ± 0.9 kJ mol-1, ∆S1≠ = 241 ± 3 JK-1 mol-1, ∆H2 ≠ = 31.9  1.9 kJ mol-1, ∆S2≠ = -233  6 JK-1 mol-1. The low ∆H≠ values are in support of the ligand participation in the transition state for both the paths. The high negative ∆S≠ values for both the paths suggest a more compact transition state, than the starting complex which also corroborates the assumption of a ligand participating transition state.

-34.05

-34.10

ln(k1h/kBT)

-34.15

-34.20

-34.25

-34.30

-34.35 2.94

2.96

2.98

3.00

3.02 3

3.04 -1

10 /T (K )

Figure 11 Eyring plot for the first path

3.06

3.08

3.10

3.12

121

-39.3

-39.4

ln(k2h/kBT)

-39.5

-39.6

-39.7

-39.8

-39.9 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 12 Eyring plot for the second path

Mechanism and conclusion The interaction of sodium diethyldithiocarbamate (NaDDTC) with the ruthenium complex (1) at physiological pH (7.4) proceeds through two distinct consecutive steps of substitution of aqua molecules (k1~10 -3 s-1 and k2~10 -5 s-1), each one step proceeds via an associative interchange activation. At this pH most of the ruthenium complexes are oxidised to Ru(III); but this Ru(II) complex is quite stable due its attached tap {2-(m-tolylazo) pyridine} ligands. At the outset of each path an outer sphere association complex is formed, which is stabilized through H-bonding, this is followed by an interchange from outer sphere to inner sphere complex. The outer sphere association equilibrium constants, a measure of the extent of H-bonding for each path at different temperatures are collected in Table 3. From the temperature dependence of the KE/ and KE// the thermodynamic parameters calculated (Figures 13 and 14) are: ∆H10 = 32.3 ± 3.3 kJ mol-1, ∆S10 = 139 ± 9 JK-1 mol-1, ∆H20 = 13.9 ± 1.0 kJ mol-1 and ∆S20 = 84 ± 1 JK-1 mol-1. For both the paths ∆G0 values calculated at all temperatures studied have a negative value which once again support in favour of the

122

spontaneous formation of outer sphere association complex. The six membered ring structure of the product is also possible by the coordination of N and S atoms of DDTC- with the two Ru(II) centers. But from the IR study it was confirmed that the two S atoms of DDTC- react to form the six membered ring.

5.3

5.2

5.1

lnKE'

5.0

4.9

4.8

4.7

4.6 2.94

2.96

2.98

3.00

3.02

3.04

3

3.06

3.08

3.10

3.12

-1

10 /T ( K )

Figure 13 Plot of lnKE/ versus 1/T for the first path

5.20

5.15

lnKE''

5.10

5.05

5.00

4.95

4.90 2.94

2.96

2.98

3.00

3.02 3

3.04 -1

10 /T (K )

3.06

3.08

3.10

3.12

123

Figure 14 Plot of lnKE// versus 1/T for the second path

A plausible mechanism for the substitution process has been proposed and shown below (Figure 15).

124

2+

_ S

O (tap)2Ru H2O

Ru((tap)2

NEt2

C

+ S

OH2

Complex (1) KE"

KE'

1+ O (tap)2Ru

Ru(tap)2

O H

_ S

O H

H

H

S

C

NEt2 Outersphere complex k1 k2 1+ O (tap) 2Ru

Ru(tap)2 S

S

+

2H2O

C

NEt2 (2)

Figure 15 Proposed mechanism for the interaction of DDTC- with complex 1

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125

3. L. Mishra, A.K. Yadav, R. Sinha and A.K. Singh, Indian J. Chem., 40A, 913 (2001). 4. K. Haas and W. Beck, Z. Anorg. Allgem. Chem., 628, 788 (2002). 5. B.T. Patterson, J.G. Collins, F.M. Foley and F.R. Keene, J. Chem. Soc., Dalton Trans., 4343 (2002). 6. B. Rosenberg, L. Vancamp, J.E. Trosko and V.H. Mansour, Nature (London), 225, 385 (1969). 7. P. Umapathy, Coord. Chem. Rev., 95, 129 (1989). 8. J. Reedijk, Pure and Appl. Chem., 59, 181 (1987). 9. M. Zhao and M.J. Clarke, J. Biol. Chem., 4, 325 (1999). 10. E. Galardon, P.L.

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127

CHAPTER 4

Chapter 4

128

Interaction

of

thiourea

and

L-cysteine

with

[(H2O)(tap)2RuORu(tap)2(H2O)]2+{tap=2-(m-tolylazo)pyridine} in aqueous medium: kinetic and mechanistic studies a) Introduction All chemotherapeutic drugs have drawbacks, including intrinsic or acquired resistance, toxicity, and consequent side effects. Cisplatin [1, 2] is no exception. The anticancer drug cisplatin, or cis-DDP is well known but its toxicity has led to the search for second and third generation drugs with the same therapeutic activity comparable to that of cisplatin but with reduced toxicity [3]. Efforts to mitigate the drawbacks have prompted chemists to synthesise a variety of analogues, but only a handful of new drugs have resulted that have been shown to be suitable for clinical application. Improved understanding of the mechanism of action of cisplatin, resulting from the efforts of many research groups during the last three decades, has rationalised the design of new platinum drugs, and drugs based on other metals such as ruthenium. This overview will begin with a brief introduction to the molecular, kinetic and thermodynamic details of the coordination chemistry of medicinally relevant metals, focusing on platinum, ruthenium and other noble metals that have been shown to possess important biological properties Now it is established that among the metal complexes ruthenium complexes have considerable antibacterial power like other platinum, rhodium and palladium complexes [4, 5]. Work with nucleosides and nucleic acids indicate that the coordination of ruthenium(II) such ligands are similar to that of cisplatin or its analogues. Ruthenium complexes are an order of magnitude less toxic than cisplatin [6, 7]. Trans-[Cl4(Me2SO)(Im)Ru(III)]- (Im = imidazole) is the first ruthenium compound that successfully entered phase I clinical trial [8]. The studies on the bioactivity of ruthenium(II/III) complexes are still a developing area. Molecules containing sulphur are currently under study as chemoprotectants in platinum based chemotherapy. However the metal sulphur compounds such as thioethers could perhaps serve as a drug reservoir for metal ion at DNA [9]. Thiourea and L-cysteine are sulphur containing ligands. Thiourea derivatives are potentially very versetile ligands, able to coordinate to a range of metal centres as neutral ligands, monoanions or dianions. The oxygen, nitrogen and sulphur donor

129

atoms of thiourea derivatives provide a multitude of bonding possibilities. Both the free thioureas and their metal complexes display a wide range of biological activity, including

antibacterial,

antifungal,

antitubercular,

antithyroid,

antihelmintic,

rodenticidal, insecticidal, herbicidal and plant-growth regulator properties [10-14]. L-Cysteine is a nonessential amino acid that is required by our body in many different biochemical reactions. Cysteine is marketed in nutritional supplements as an antioxidant and immune system booster and has been reported to improve muscle recovery following vigorous exercise and soft tissue recovery following injury or surgery. In view of the above, in the present chapter we present mechanistic aspects of the interaction of thiourea and L-cysteine with the title complex in aqueous medium, where ruthenium(II) is stable even at biological pH 7.4 due to the presence of an excellent π-acceptor ligand, tap{2-(m-tolylazo)pyridine} [15].

b) Materials and methods Experimental The

compound

cis-diaqua-bis-{2-(m-tolylazo)

pyridine}

ruthenium(II)

diperchlorate, monohydrate, cis-[Ru(tap)2(H2O)2](ClO4)2.H2O was prepared following the

literature

method

[16,

17],

and

the

reacting

complex

ion

[(H2O)

(tap)2RuORu(tap)2(H2O)]2+ (1) was prepared in situ at pH 7.4. The reaction product of thiourea and L-cysteine (2 and 3) with complex 1 were prepared by mixing the reactants in 1:1, 1:2, 1:3, 1:5, and 1:10 ratios and thermostated at 50ºC for 72 hours. The electronic spectra of 2, 3 (Figure 1) show complete complexation between the complex 1 with the two ligands namely thiourea and L-cysteine.

130

2

3

1

Figure 1 Spectra of complex 1, thiourea substituted complex (2), L-cysteine substituted complex (3). [complex 1] = 1×10−4 mol dm−3, [ligands] = 2.0×10 −3 mol dm−3, pH = 7.4

The compositions of the products were determined by Job’s method of continuous variation, which indicate a 2:1 metal-to-ligand ratio in the complex for all two products (2 and 3) (Figure 2).

Figure 2 Job’s plot for the reaction of complex 1 with thiourea

131

When complex 1 and thiourea were mixed in 2:1 molar ratio at pH 7.4 a violet product (2) was obtained. The IR spectrum of free thiourea displays two sharp bands at 3,402 and 3,295 cm-1, assignable to asymmetric and symmetric –NH2 group modes, respectively. These remain at almost the same positions in the product complex (2), suggesting that the amino group is not involved in coordination. The IR spectrum of product complex, in KBr disc shows prominent bands at 1114 cm-1. The C=S stretching frequency of the free thiourea occurs at 1206 cm-1 which is shifted 92 cm-1 downwards to 1114 cm-1 indicating the coordination of the C=S group of thiourea to Ru2+ through the S atom. The spectrum suggests that the final product is a S coordinated chelate. When complex 1 and L-cysteine were mixed in 2:1 molar ratio at pH 7.4 a violet product (3) was obtained. The IR spectrum of the product, in KBr disc shows strong bands at the region 3000-3380 cm-1 together with medium bands at 1570 cm-1. The asymmetric COO- stretching frequency (νasym) of the free ligand (L-cysteine) occurs at 1575 cm-1 which remains in the almost same position (1568 cm-1) in the product complex indicating that the COO group of L-cysteine is not involved in bonding with metal. The asymmetric COO- stretching frequency (νasym) of the acid occurs at 1580-1660 cm-1, when the group is coordinated to metal, where as a non coordinated COO- group has the νasym(COO-) stretching at lower frequencies [18]. The I.R spectrum of free ligand (L-cysteine) displays a sharp peak near ~2500 cm-1 assignable to free –SH group but there is no peak at near ~2500 cm-1(stretching frequency of free –SH group) in the final product complex. This fact indicates that bonding occurred through S atom of L-cysteine. The band at 3000-3380 cm-1 is assigned to an NH stretching frequency which is also observed in the I.R spectrum of the free ligand. The spectrum suggests that bonding not occurred through the carboxyl group or amino group but bonding occurred through S atom of L-cysteine. From the ESI-mass spectrum (Figure 3) of the product 2 it is clear that the ion at m/z ~542 has become the precursor ion species in the mixture solution and this is tentatively attributed to [2Ru(II) + O + 4 tap + thiourea]2+. The precursor ion is shown in Figure 4. ESI-mass spectrum (Figure 5) of the product 3 suggests that the ion at m/z ~582 has become the molecular ion species in the mixture solution and this is tentatively attributed to [2Ru(II) + O + 4 tap + L-cysteine-H + H2O +H3O+]2+. The precursor ion is shown in Figure 6.

132

Figure 3 ESI-mass spectrum for thiourea substituted product (2)

2+ O Ru(tap)2

(tap)2Ru S C H2N

NH2

Figure 4 Plausible structure of the precursor ion peak from the ESI-mass spectrum for thiourea substituted product (2)

133

Figure 5 ESI-mass spectrum for L-cysteine substituted product (3)

2+ O

(tap)2Ru

Ru(tap)2

+

H2O + H3O+

_ R = OOC

CH

+ NH3

S

H2C R

Figure 6 Plausible structure of the precursor ion peak from the ESI-mass spectrum for L-cysteine substituted product (3)

134

Kinetic and physical measurements Physical measurements were carried out in the same way as explained in chapter 1 and also same instruments were used to record the kinetic data. For L-cysteine the progress of the reaction was followed by measuring the decrease in absorbance at 560 nm, and for thiourea the progress of the reaction was followed by measuring the increase in absorbance also at 560 nm where the spectral difference between the substrate and the product complexes is maximum. The conventional mixing technique was followed and pseudo-first-order conditions were employed throughout. The plots of ln(A∞−At), (where At and A∞ are the absorbances at time t and after completion of the reaction) against time were found to be non-linear, being curved at the initial stage but subsequently of constant slope (Figure 7). The method of Weyh and Hamm [19] was adopted to calculate rate constants for the two consecutive steps as discussed in chapter 1. We took the help of Origin 6.0 for other calculations. From the linear second portion, k2 values were obtained. The k1(obs) values were obtained from the plots of lnΔ versus time. A typical plot is shown in Figure 8. Rate data represented as an average of duplicate runs are reproducible within ± 4%.

135

-0.4 -0.6 -0.8

X

-1.0 -1.2

Y



t

ln(A -A )



-1.4 -1.6 -1.8 -2.0 0

10

20

30

40

50

60

70

80

time (min)

Figure 7 A typical plot of ln(A∞ - At) versus time. [complex]= 1.0×10 −4 mol dm−3, [thiourea] = 1.0×10−3 mol dm−3; pH = 7.4, temperature = 60ºC -0.6 -0.7 -0.8

ln

-0.9 -1.0 -1.1 -1.2 -1.3 -1.4 0

1

2

3

4

5

time (min)

Figure 8 A typical plot of ln versus time. [complex]= 1.0×10−4 mol dm−3, [thiourea] = 1.0×10 −3 mol dm−3; pH = 7.4, temperature = 60oC

136

c) Results and discussion The first acid dissociation equilibrium of the complex [Ru(tap)2(H2O)2]2+ is 6.6 [20] at 25 oC. At pH 7.4, the complex ion exists in a dimeric oxo-bridged form, [(H2O)(tap)2RuORu(tap)2(H2O)]2+ [21 – 25]. At pH 7.4, the mononuclear species exists in the hydroxoaqua form. Two such species assemble to form the dinuclear oxo-bridged diaqua complex due to thermodynamic force, mainly arising from π-bonding [26] (O2- donor, Ru(II) acceptor) which is favourable for the 4d ion, Ru(II). Now, such strong covalency reduces the acidity of the coordinated water. The oxo-bridge formation is solely dependent on pH. Electrochemical studies show that there is a pH potential domain, where the µ -oxo structures stay intact. A variable temperature study does not show any effect, which is in line with the fact that the oxo-bridge formation is solely pH-dependent [27, 28]. 2+ O

(tap)2Ru

H2O

Ru(tap)2 OH2

Dimeric oxo-bridged form (1) The pKa value of thiourea is 2.0 at 25oC [29], so that at pH 7.4 it exists in the neutral form. On the other hand the pK1, pK2 and pK3 values of L-cysteine are 1.71, 8.33, and 10.78 respectively at 25oC [30], which refer to the following dissociation processes: HS-CH2-CH(NH3)+COOH ⇌ HS-CH2-CH(NH3)+COO- + H+,

pK1 = 1.71

HS-CH2-CH(NH3)+COO- ⇌

pK2 = 8.33

-

S-CH2-CH(NH3)+COO- ⇌ So

at

pH

7.4,

the

-

S-CH2-CH(NH3)+COO- + H+,

-

S-CH2-CH(NH2 )COO- +

ligand

L-cysteine

exists

H+, as

pK3 = 10.78 zwitterionic

form,

HS¬CH2¬CH(NH3)+COO-. At constant temperature, pH, and fixed concentration of complex (1), the ln(A∞−At) versus time plots for different ligand concentrations indicate that the reaction involves a two-step consecutive process; the first step is dependent on ligand concentration, whereas the second step is independent of ligand concentration.

137

The rate constant for such a process can be evaluated by assuming Scheme 1, where A is the oxo-bridged diaqua complex, B is the intermediate with ligand, and C (2/3) is the final chelate product complex [(tap)2Ru(µ-O)(µ- L)Ru(tap)2]2+. k1 k2 A→B→C Scheme 1

Calculation of k1 for the A→B step The k1(obs) values were calculated according to the same procedure mentioned in chapter 1 (Figures 7 and 8) and k1(obs) values were tabulated in table 1. Table 1 10 3k1(obs) (s-1) values for different ligand concentrations at different temperatures; [complex] = 1.0 × 10-4 mol dm-3, pH = 7.4, ionic strength = 0.1 mol dm-3 NaClO4 Ligand

10 3 [ligand] (mol dm−3)

Thiourea

L-cysteine

Temperature (oC) 50

55

60

65

1.0

1.40

1.71

2.38

2.84

2.0

2.48

2.94

4.00

4.79

3.0

3.35

3.90

5.08

6.01

4.0

3.83

4.55

5.81

6.71

5.0

4.27

5.06

6.28

6.97

1.0

0.75

1.01

1.23

1.55

2.0

1.39

1.92

2.40

2.79

3.0

1.94

2.47

3.05

3.95

4.0

2.20

2.93

3.42

4.22

5.0

2.54

3.25

3.84

4.50

The rate increases with an increase in ligand concentration and reaches to a limiting value (Figure 9). The limiting rate is probably the result of the completion of outer sphere association complex formation. Because the metal ion reacts with its immediate environment, a further change in ligand concentration beyond the saturation point will not affect the reaction rate. The outer sphere association complex may be

138

stabilised through H bonding. Based on the experimental findings, Scheme 2 may be proposed for the path A→B. KE A + L ⇌ A.L (Outer sphere association complex) k1 A.L → B (Where L= thiourea or L-cysteine) Scheme 2 Based on Scheme 2, a rate expression can be derived: d[B]/dt = k1KE[A][L]/(1+KE[L]), d[B]/dt = k1(obs)[A]T where subscript T stands for total concentration of Ru(II). Thus it can be written as k1(obs) = k1KE[L]/(1+KE[L])

(1)

where k1 is the rate constant for the A→B step; that is, the rate constant for the interchange of outer-sphere complex to the inner-sphere complex. KE is the outersphere association equilibrium constant. Equation can be represented as: 1/k1(obs) = 1/k1 +1/k1KE[L]

(2)

The plot of 1/k1(obs) against 1/[L] should be linear with an intercept of 1/k1 and slope 1/k1KE. This was found to be the case at all temperatures studied. The k1 and KE values were calculated from the intercept and slope (Figure 10) and are collected in Table 2.

139

Figure 9 Plots of k1(obs) (s-1) versus [thiourea] at different temperatures, A = 50, B = 55, C = 60 and D = 65ºC

0.8

A 0.7

B 0.5

C 0.4

D

3

1/10 k1(obs) (s)

0.6

0.3

0.2

0.1 0.2

0.4

0.6 3

0.8 3

1.0

-1

1/10 [thiourea] (dm mol )

Figure 10 Plots of 1/k1(obs) (s) against 1/[ thiourea], A = 50, B = 55, C = 60 and D= 65ºC

140

Table 2 10 3k1 (s-1) and KE values for different ligands at different temperatures. [complex] = 1.0 ×10−4 mol dm−3, pH = 7.4, and ionic strength = 0.1 mol dm−3 NaClO4 Ligand Thiourea

L-cysteine

10 3k1 (s−1)

Temperature (°C)

KE (dm3 mol−1)

50

9.38

176

55

10.18

202

60

11.12

273

65

12.13

309

50

6.94

122

55

8.24

141

60

9.42

153

65

10.53

174

Calculation of k 2 for the B→C step At a particular temperature, the slopes of ln(A∞-At) versus time plots at different ligand concentrations were found to be constant in the region where the plots are linear (Figure 7). For different temperatures, the k2 values are obtained directly from the limiting slopes and are collected in Table 3. Table 3 105k2 (s-1) values for different ligand concentrations at different temperatures, [complex] = 1.0 ×10−4 mol dm−3, pH = 7.4 and ionic strength = 0.1 mol dm-3 NaClO4 Temperature (oC)

Ligand 50

55

60

65

Thiourea

14.17

17.28

20.58

23.80

L-cysteine

2.86

3.45

4.19

5.32

141

Effect of pH on the reaction rates The reactions were studied at five different pH values. The k(obs) values are found to increase with increase in pH in the studied pH range. The k(obs) values are collected in Table 4. In the studied pH range (pH 5.5 to 7.4) with increase in pH the percentage of diaqua species of the complex is reduced and the percentage of the dimer is increased, and the dimer having two metal centers may be more acceptable to the incoming ligand. On the other hand with increase in pH the percentage of more reactive deprotonated ligand species increases which accounts for the increase in rate with increasing pH. We did not add any buffer in the kinetic solutions to maintain pH, because the buffer components may act as ligands.

Table 4

The 103k1(obs) and 105k2(obs) values at different pH values; [complex] = 1.0×

10 -4 mol dm-3, [ligand] =2.0 × 10-3 mol dm-3, temperature = 60oC, ionic strength = 0.1 mol dm-3 NaClO4 Ligand Thiourea

L-cysteine

pH

103k1(obs) (s-1)

10 5k2 (obs) (s-1)

5.5

2.70

15.09

6.0

2.91

15.70

6.5

3.27

16.25

7.0

3.81

17.02

7.4

4.00

20.58

5.5

1.76

2.01

6.0

1.89

2.12

6.5

2.06

2.68

7.0

2.21

3.57

7.4

2.40

4.19

142

Effect of temperature on the reaction rates The reactions were studied at four different temperatures for different ligand concentrations and the anation rate constants for both A → B (k1) and B → C (k2) steps are given in Tables 2 and 3. The activation parameters calculated from Eyring plots (Figures 11 and 12) are given in Table 5.

-34.00

ln(k1h/kBT)

-34.05

-34.10

-34.15

-34.20

2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 11 Eyring plot ln(k1 h/kBT) versus (1/T) for the A→B step of thiourea interaction with complex 1

-37.9

ln(k2h/kBT)

-38.0

-38.1

-38.2

-38.3

-38.4

2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 12 Eyring plot ln(k2h/kBT) versus (1/T) for the B→C step of thiourea interaction with complex 1

143

Table 5 Activation parameters for substitution of [complex 1] by ligands in aqueous medium, pH = 7.4

Ligand

∆H1 ≠

∆S1≠

(kJ mol-1)

(JK-1 mol-1)

∆H2 ≠ (kJ mol-1)

∆S2≠ (JK-1 mol-1)

Thiourea

12.4 ± 0.5

-246 ± 2

28.0 ± 0.6

-232 ± 2

L-cysteine

21.8 ± 1.1

-219 ± 3

33.4 ± 2.8

-229 ± 8

Mechanism and conclusion Our results indicate that the first step, i.e. the attack by the incoming ligands (both for thiourea and L-cysteine) proceeds by an associative interchange(Ia) mechanism. This proposition is supported by the following observations. First, with an increase in ligand concentration, saturation in the rate is observed. This indicates that an outer sphere association complex is formed. Second, the low enthalpy of activation and large negative value of entropy of activation strongly suggest that the ligands participate in the transition state. From the I.R data of both thiourea substituted product (2) and L-cysteine substituted product (3), it is clear that the only S atom of both the ligands are participating in bonding. The S atom in C=S group of thiourea and S atom in –SH group of L-cysteine are involved in bonding with metal. This is consistent with the soft nature of both sulphur and ruthenium(II). Both thiourea and L-cysteine act as bridging ligand and in both the cases four membered ring are formed with the complex 1. In the first step a rapid equilibrium is established, giving an outer sphere complex between complex 1 and the ligands. The second step is the intramolecular ring closure which is independent on the incoming ligand concentration. Hence, the rate constant (k2) for this step was independent of ligand concentration. The activation parameters for the first and second steps suggest an associative mode of activation for the substitution processes. From the temperature dependences of the KE values (Figure 13) the thermodynamic parameters are calculated ΔH0 = 35.2 ± 4 kJ mol-1, ΔS0 = 152 ± 11 JK-1 mol-1 (for thiourea), ΔH0 = 20.2 ± 1.6 kJ mol-1, ΔS0 = 103 ± 5 JK-1 mol-1 (for L-cysteine). The ΔG0 values, calculated at all temperatures

144

studied, have a negative magnitude which is once again in favour of the spontaneous formation of an outer sphere association complex. The rate of reaction also depends on steric effect. In case of L-cysteine the steric effect is more than thiourea which is reflected on the rate constant values (k1 and k2).

5.8

5.7

5.6

lnKE

5.5

5.4

5.3

5.2

5.1 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 13 Plot of lnKE versus 1/T for thiourea interaction with complex 1

145

A plausible mechanism is shown as below

2+

2+ O

O S KE

Ru(tap)2

(tap)2Ru

+

C O

OH2

H2O

NH2

H2N

Complex (A)

Ru(tap)2

(tap)2Ru

H

H

H

O

S

H

Thiourea C H2N

NH2

Outersphere complex

k1

_H O 2

2+ 2+ O H2O

+

O Ru(tap)2

(tap)2 Ru

k2 ring closure

S

H2O

C

Ru(tap)2

(tap)2Ru S C

NH2

H2N (C)

Figure 14

H2N

NH2 (B)

Proposed mechanism for the interaction of thiourea with complex 1

146

2+

2+

O O (tap)2Ru

+

Ru(tap)2

H2O

R

KE

SH

(tap)2Ru

OH2

O L-Cysteine

Complex (A)

Ru(tap)2 H

O

H

H

H S H

R Outersphere complex k1 _ H2O

+

2+

O + H3O + (tap)2Ru

O Ru(tap)2

k2

(tap)2Ru

Ru(tap)2

ring closure

S

H2O

R

S H R

(C)

(B) _ R = OOC

CH

+ NH3

H2C -

Figure 15 Proposed mechanism for the interaction of L-cysteine with complex 1

147

References 1. B. Rosenberg, L. Vancamp and T. Krigas, Nature (London), 205, 698 (1965). 2. B. Rosenberg, L. Vancamp, J.E. Trosko and V.H. Mansour, Nature (London), 222, 385 (1969). 3. J.A. Broomhead, D.P. Fairlie and M.W. Whitehouse, Chem. Biol. Interact., 31,113 (1980). 4. M.J. Clarke, in: A.E. Martell, (Ed.) Inorganic Chemistry in Biology and Medicine, ACS Symp, Series #190, American Chemical Society, Washington DC, 157 (1980) and references cited therein. 5. F.P. Pruchink, M. Bien and T. Lachowicz, Met. Based Drugs, 3, 185 (1996).

6. M.J. Clarke, Met. Ions. Boil. Syst., 11, 231 (1980). 7. R.E. Yasbin, C.R. Matthews and M.J. Clarke, Chem. Biol. Interact., 31, 355 (1980). 8. N. Katsaros and A. Anagnostopoulou, Crit. Rev. in Oncol/Heamatol., 42, 297 (2002). 9. J. Reedijk, Chem. Rev., 99, 2499 (1999). 10. Y.F. Yuan, J.T. Wang, M.C. Gimeno, A. Laguna and P.G. Jones, Inorg. Chim. Acta, 324, 309 (2001). 11. Y.M. Zhang, T.B. Wei, L. Xian and L.M. Gao, Phosphorus, Sulfur Silicon Relat. Elem., 179, 2007 (2004). 12. Y.M. Zhang, T.B. Wei, X.C. Wang and S.Y. Yang, Indian J. Chem., (Sect B) 37, 604 (1998). 13. W.Q. Zhou, B.I. Li, I.M. Zhu, G.J. Ding, Z. Yong, I. Lu and X.J. Yang, J. Mol. Struct., 690, 145 (2004). 14. M. Eweis, S.S. Elkholy and M.Z. Elsabee, Int. J. Macromol., 38, 1 (2006). 15. B.K. Ghosh and A. Chakravorty, Coord. Chem. Rev., 95, 239 (1989).

148

16. Goswami, A.R. Chakraborty and A. Chakravorty, Inorg. Chem., 20, 2246 (1981). 17. S. Goswami, A.R. Chakraborty and A. Chakravorty, Inorg. Chem., 22, 603 (1983). 18. G. Pneumatikakis and N. Hadjiliadis, J. Inorg. Nucl. Chem., 41, 429 (1979). 19. J.A. Weyh and R.E. Hamm, Inorg. Chem., 8, 2298 (1969). 20. B. Mahanti and G.S. De, Transition. Met. Chem, 17, 23 (1992). 21. S.J. Raven and T.J. Meyer, Inorg. Chem., 27, 4478 (1988). 22. W. Kutner, J.A. Gilbert, A. Tomaszewski, T.J. Meyer and R.W. Murray, J. Electroanal Chem, 205, 185 (1986). 23. S.W. Gersten, G.J. Samuels and T.J. Meyer, J. Am. Chem. Soc., 104, 4029 (1982). 24. P. Ghosh and A. Chakravorty, Inorg. Chem., 23, 2242 (1984). 25. N. Bag, A. Pramanik, G.K. Lahiri and A.Chakravorty, Inorg. Chem., 31, 40 (1992). 26. F.A. Cotton, G. Wilkinson, C.A. Murrilo and M. Bochmann, Adv. Inorg. Chem. New York. USA: John Wiley & Sons, 6th edition (1999). 27. J.A. Gilbert, D.S. Eggleston, W.R. Murphy, Jr. D.A. Geselowitz, S.W. Gersten, D.J. Hodgson and T.J. Meyer, J. Am. Chem. Soc., 107, 3855 (1985). 28. J.A. Gilbert, D. Geselowitz and T.J. Meyer, J. Am. Chem. Soc., 108, 1493 (1986). 29. D.R. Goddard, B.D. Lodam, S.O. Ajayi and M.J. Campbell, J. Chem. Soc. A, 506 (1969). 30. A.E. Martell and M. Calvin, Chemistry of metal chelate compounds, 1st Edn (Prentice Hall, New Jersey), 524 (1962).

149

CHAPTER 5

150

Chapter 5

Mechanistic

aspects

of

ligand

substitution

on

hydroxopentaaquarhodium(III) ion in aqueous solution by sulphur containing bioactive ligands a) Introduction Researchers have either isolated from natural sources, or, synthesised, literally hundreds of compounds that possess anti-tumour activity. Many of these used to treat cancer in humans. The discovery by Rosenberg et.al. [1, 2] that some platinum complexes exhibit carcinostatic properties gave special impetus to the research on interaction of the metal ion with biomolecules. One of the most widely prescribed of these is cisplatin [3]. Regardless of the achievements of current platinum drug (cisplatin), there are some major drawbacks: they are efficient only for a limited range of cancers; some tumors can have acquired or intrinsic resistance; and they often cause severe side-effects, such as nausea, bone marrow suppression and kidney toxicity [4, 5]. Due to severe side-effects, chemists have prepared several analogues of it. Carboplatin is prominent among them. The cis relationship between Cl ligands (or Xtype ligands in general) is essential to the antitumor activity of all the Pt-based chemotherapy drugs. Cisplatin and its relatives inhibit tumour cell growth by covalently interacting with one of the two strands of DNA in the nucleus of a cancerous cell. This event occurs as the results of two ligands substitution reactions in which chloride ligands (or X-type ligands occupying analogous cis-positions) are displaced by neighbouring guanine bases, both in are strand. Toxic side effects in varying degrees accompany all chemotherapy regimens. Apart from platinum complexes, other metal complexes specially ruthenium, rhodium, iridium and palladium complexes also have carcinostatic properties [6, 7]. Complexes of the early and middle transition metals have been at the centre of the search for non-platinum anti-tumour agents. Ruthenium(II) and rhodium(III), the 4d 6 congeners of two body friendly metals (being the higher members of iron and cobalt, two widely used metals by the body) are promising in this regard. Different studies reveal that ruthenium(II /III) complexes have antibacterial behaviour [8-11]. Dimeric-

151

-acetato complexes of rhodium(II) as well as monomeric square planar rhodium(I) and octahedral rhodium(III) complexes also showed antitumor activities [12]. Some rhodium(III) complexes are reported to have considerably greater cytostatic activity than cisplatin [13] specially when their action against HCV29T tumor cells is considered. In this chapter, we present the kinetic and mechanistic aspects of the interaction of a rhodium(III) complex towards sulphur containing ligands namely thioglycolic acid, 2-thiouracil and glutathione. The ability of thioglycolic acid to mimic many biological molecules, like thiol containing proteins and peptides in binding to ruthenium complex is well known. 2-thiouracil is a component in certain nucleic acids and is also a minor component of transfer ribonucleic acid (tRNA). For example, 2thiouracil has been characterized in tRNAGlu isolated from Escherichia coli [14]. Glutathione is a ubiquitous tripeptide (γ-LGlu-L-Cys-Gly) molecule, the predominant non protein thiol, consisting of three amino acids joined together. These are cysteine, glutamic acid and glycine.

b) Materials and methods Experimental [Rh(H2O)6](ClO4)3 was prepared as per the literature method [15] and characterised by chemical analysis and spectroscopic data [16] (max = 396 nm,  = 62 dm3 mol-1cm-1; max = 311 nm,  = 67.4 dm3 mol-1cm-1). The reactant complex [Rh(H2O)5(OH)](ClO4)2 (complex 1) was obtained in situ (yield  90) by adjusting the pH to 4.3. Higher proportions of complex could not be obtained as the solution becomes turbid at higher pH. The reaction products of thioglycolic acid, 2-thiouracil and glutathione with complex 1 were prepared by mixing the reactants in the different ratios: 1:1, 1:2, 1:3, 1:5, and 1:10, and kept at 60oC for 72 hours. The electronic spectra of 2, 3 and 4 (Figure 1) show complete complexation between the complex 1 with the three ligands namely thioglycolic acid, 2-thiouracil and glutathione.

152

2

3 1

4

Figure 1 Spectra of reactant complex (1), thioglycolic acid substituted complex (2), 2thiouracil substituted complex (3), glutathione substituted complex (4). [complex 1] = 1.25×10 −4 mol dm−3, [ligands] = 2.5×10 −3 mol dm−3, pH = 4.3

The compositions of the products in the reaction mixture were determined by Job’s method of continuous variation (Figure 2). The metal-ligand ratio was found to be 1:1 for all the three products (2, 3 and 4).

153

Figure 2

Job’s plot for the reaction of complex 1 with glutathione

[Rh(H2O)5OH]2+(1) and the ligands were mixed separately in 1:1 molar ratio at pH 4.3 and a pale yellow product was obtained in each case, which was isolated in the solid form. When [Rh(H2O)5OH]2+ and thioglycolic acid were mixed in 1:1 ratio product 2 was obtained. The IR spectrum of the product 2 in the KBr disc shows strong bands at 1615 cm-1 and 416 cm-1. The asymmetric COO- stretching frequency (asym) of the acids occurs at 1580-1660 cm-1 when the group is coordinated to metals, where as a nonbonded COO- group has the asym(COO-) stretching at lower frequency [17]. The band at 1615 cm-1 is therefore due to the asym(COO-) of the metal bound carboxyl group. The band at 416 cm-1 is assigned to (Rh-O) bond formation [18]. The IR spectrum of the free thioglycolic acid ligand shows sharp peak near ~ 2500 cm-1 assignable to free SH group but there is no peak at near ~2500 cm-1 (stretching frequency of free –SH group) in the final product 2. This fact indicates that the SH group of thioglycolic acid is coordinated to Rh3+ through S atom. From the assignments of these bands, it can be presumed that the product 2 is a (S, O) coordinated chelate.

154

When [Rh(H2O)5OH]2+ and 2-thiouracil were mixed in 1:1 ratio product 3 was obtained. The IR spectrum of the product 3 in the KBr disc shows prominent bands at 1114 cm-1 and 549 cm-1. The C=S stretching of the non bonded 2- thiouracil occurs at 1166 cm-1 which shifted 52 cm-1 downwards to 1114 cm-1 indicates that the coordination of C=S group Rh(III) ion, through ‘S’ atom. The band at 549 cm-1 is assigned to (Rh-N) bond formation .The spectrum suggests that the final product is a (N, S) coordinated chelate and the 2-thiouracil behaves as bidentate ligand. The [Rh(H2O)5OH]2+ and glutathione when mixed in 1:1 ratio product 4 was obtained. The IR spectrum of the product 4 in the KBr disc shows sharp bands at 3395 cm-1 and 539 cm-1. The IR spectrum of the free glutathione shows sharp peak near ~ 2500 cm-1(stretching frequency of free –SH group). But the IR spectrum of the glutathione substituted product 4 does not show any peak near 2500 cm-1. This is due to the involvement of the S atom of SH group of glutathione in bonding with Rh(III). The intense band at 539 cm-1 is assigned to (Rh-N) bond formation [18]. The presence of a strong band at 3395 cm-1 indicates that the product is hydrated. The aqueous solution of [Rh(H2O)5(OH)]2+ and the ligands were mixed separately in a 1:1 molar ratio and the mixtures were thermostated at 60 oC for 48 hours and used for ESI-MS measurement. The ESI mass spectra of the resulting products (2, 3 and 4) are shown in Figures 3, 5 and 7. It is clear from the first mass spectrum (Figure 3) that the ion at m/z ~ 409 has become the molecular ion species in the mixture solution. (complex 1 with thioglycolic acid) and this is attributed to (Rh(III) + 3H2O + OHˉ+ thioglycolate anion – H+ + Na+ + NaClO4)+. The structure of precursor ion is shown in Figure 4. It is clear from the second mass spectrum (Figure 5) that the ion at m/z 319 has become the molecular ion species. (complex 1 with 2-thiouracil) and this is attributed to (Rh(III) + 3H2O + OHˉ+ 2-thiouracil – H+ + H2O)+. The structure of precursor ion is shown in Figure 6. The third mass spectrum (Figure 7) reveals that the ion at m/z ~ 515 has become the molecular ion species. (complex 1 with glutathione) and this is attributed to (Rh + 3H2O + OHˉ+ glutathione – 2H+ + H3O+ + H2O)+. The structure of precursor ion is shown in Figure 8.

155

Figure 3 Mass spectrum for thioglycolic acid substituted product (2)

+

OH H2O

S

CH2

Rh H2O

+ O

C

+ Na

+

NaClO4

O OH2

Figure 4 Plausible structure of the molecular ion peak from the ESI-mass spectrum for thioglycolic acid substituted product (2)

156

Figure 5 Mass spectrum for 2-thiouracil substituted product (3)

+ OH H2O

S Rh

H2O

+

NH N

H2O

O

OH2

Figure 6 Plausible structure of the molecular ion peak from the ESI-mass spectrum for 2-thiouracil substituted product (3)

157

Figure 7 Mass spectrum for glutathione substituted product (4)

+ OH H2O

S

CH2

Rh H N

H2O

C O

OH2

O H N

_ O

+

2H2O

+

H+

O

+ H3N O _ O

Figure 8 Plausible structure of the molecular ion peak from the ESI-mass spectrum for glutathione substituted product (4)

158

Kinetic and physical measurements Physical measurements were carried out in the same way as explained in chapter 1 and also same instruments were used to record the kinetic data. The progress of the reaction was monitored by the UV absorbance measurements at different intervals of time with the equipment described above at 352 nm, 327 nm and 340 nm where the difference in absorbances between the reactant and product complexes (2, 3 and 4) are maximum. Before each kinetic run the pH of each solution of reactant complex and the ligands were adjusted to 4.3 and a pseudo-first order condition were maintained throughout. The plots of ln(A∞- At) (where A∞ and At are absorbances after completion of reaction and at time t) against time (Figure 9) were found to be nonlinear; being curved at the initial stage and subsequently linear in nature indicating that the reaction proceeds via two steps mechanism. From the limiting linear portion of the curve, the values of k2(obs) were obtained. The k1(obs) values were obtained from the slopes of lnΔ versus time plots (Figure 10).

0.4

X

0.3

0.2



t

ln(A-A)

 0.1

Y

0.0

-0.1

-0.2 -0.3 0

20

40

60

80

100

time (min)

Figure 9 A plot of ln(A∞-At) versus time. [complex 1] = 2.5 × 10-4 mol dm-3, [glutathione] =7.5  10 3 mol dm3, pH = 4.3, temperature = 60 oC

159

-1.3

ln

-1.4

-1.5

-1.6

-1.7

0

1

2

3

4

5

time (min)

Figure 10 Plot of ln∆ versus time. [complex 1] = 2.5×10 -4 mol dm-3, [glutathione] = 7.5 10 3 mol dm3, pH = 4.3, temperature = 60oC

c) Results and discussion The pK1 and pK2 [19] values of thioglycolic acid are 3.58 and 9.78 at 25 oC. The pK1 and pK2 values [20] of 2-thiouracil are 9.78, 12.7 respectively at 25 oC and the pK1, pK2, pK3 and pK4 values [21, 22] of glutathione are 2.05, 3.4, 8.72 and 9.49 respectively at 25˚C. From the pK values of the ligands we can say that at pH = 4.3, thioglycolic acid and glutathione remain in the anionic form and 2-thiouracil exists in neutral form. On the other hand the ionization of [Rh(H2O)6]3+ may be given as: Ka (1) [Rh(H2O)6]3+ ⇌ [Rh(H2O)5OH]2+

H+

+

Ka (2) [Rh(H2O)5OH]2+ ⇌ [Rh(H2O)4(OH)2]+

+

(1) H+

(2)

The First and second acid dissociation equilibrium of the complex [Rh(H2O)6]3+ are 3.6 and 4.7 respectively at 25ºC [23]. Other reports on the pKa(1)

160

value are 3.2, 3.4 and 3.45 [23]. i.e., at pH 4.3 the complex [Rh(H2O)6]3+ mainly exist as [Rh(H2O)5(OH)]2+. The plots of ln(A∞-At) verses time(t) for the three different ligands concentration indicate that the reaction is not a single step process, a two step consecutive process may be assumed with the first step being dependent and the final step is independent of the concentration of the ligands. The rate constant for such a process can be evaluated by assuming scheme 1. k1 1

k2

B

2/3/4

KE [Rh(H2O)5(OH)] + LH ⇌ [Rh(H2O)5(OH)]2+ . LHn(Outersphere association) 1 2+

n-

k1 [Rh(H2O)5(OH)]2+. LHn- → [Rh(H2O)4(OH)(LH)](2-n)+ -H2O B k2 [Rh(H2O)4(OH)(LH)](2-n)+ → [Rh(H2O)3(OH)(L)](1-n)+ + H3O+ (chelation) 2 /3 /4 Scheme 1 Where n is 1 for thioglycolic acid and glutathione and 0 for 2-thiouracil. Here k1 is the anation rate constant for the slow step i.e. for the interchange of the outer sphere to inner sphere complex and KE is the outersphere association equilibrium constant. k2 is the rate constant for intramolecular ring closure step. Calculation of k1 for the 1 → B step The k1(obs) values were calculated according to the same procedure mentioned in chapter 1 (Figures 9 and 10) using the Weyh and Hamm [24] equation and k1(obs) values were tabulated in table 1. The pseudo-first order rate constant (k1(obs)) were found to increase with increase in ligand concentration and show a limiting condition which is probably due to the completion of the outer sphere association complex formation (Figure 11). The outer sphere association complex may be stabilised through H-bonding [25-26].

161

Figure 11 Plots of k1(obs) (s-1) versus [glutathione] at different temperatures, A = 50, B = 55, C = 60 and D = 65ºC

162

Table 1 103k1(obs)(s-1) values for different ligand concentrations at different temperatures; [complex 1] =2.5×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 Ligand

Thioglycolic acid

2-thiouracil

Glutathione

103 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

2.5

1.71

1.92

2.21

2.77

5.0

2.69

3.03

3.34

4.24

7.5

3.09

3.48

3.94

4.88

10.0

3.28

3.63

4.22

5.21

12.5

3.38

3.76

4.31

5.39

2.5

0.41

0.64

0.94

1.36

5.0

0.68

0.99

1.42

2.00

7.5

0.79

1.19

1.64

2.22

10.0

0.89

1.26

1.71

2.37

12.5

0.95

1.32

1.77

2.41

2.5

0.33

0.43

0.71

0.97

5.0

0.53

0.72

1.05

1.56

7.5

0.66

0.83

1.29

1.74

10.0

0.73

0.94

1.44

1.91

12.5

0.78

0.99

1.55

2.02

From the experimental findings, the following Scheme 2 may be proposed for the step 1 → B; Considering the kinetic results, the mechanism shown below can be proposed for the anation of [Rh(H2O)5(OH)]2+ by LHn-. KE 1 + LHn- ⇌ 1. LHnOutersphere association complex

1. LHn-

k1 → B Scheme 2

163

Based on this pathway a rate expression can be written as d[B]/dt = k1KE[1][ LHn-]/(1 + KE[LHn- ])

(5)

or, d[B]/dt = k1(obs)[1]

(6)

We can write k1(obs)=k1KE[LHn-]/(1+KE[LHn-])

(7)

where k1 is the anation rate constant for first step, i.e., the anation rate constant for the interchange of the outer sphere complex to the inner sphere complex; KE is the outer sphere association equilibrium constant. This equation can be represented as 1/k1(obs) = 1/k1 + 1/k1KE[LHn- ]

(8)

The plot of 1/k1(obs) versus 1/[ LHn-] should be linear (Figure 12) with an intercept of 1/k1 and slope 1/k1KE. This was found to be so at all temperatures studied. The k1 and KE values obtained from the intercept and intercept to slope ratios are given in Table 2.

A

3.2 3.0 2.8 2.6

B

2.4

3

1/10 k1(obs) (s)

2.2 2.0 1.8 1.6

C

1.4 1.2

D

1.0 0.8 0.6 0.4 0.2 0.05

0.10

0.15

0.20 3

0.25

0.30 3

0.35

0.40

0.45

-1

1/10 [ligand] (dm mol )

Figure 12 Plots of 1/k1(obs) (s) against 1/[glutathione], A = 50, B = 55, C = 60 and D = 65ºC

164

Table 2 103k1(s-1) and values for different ligands at different temperatures. [complex 1] = 2.5 ×10 −4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 10 3k1 (s−1)

KE (dm3 mol−1)

Ligand

Temperature (°C)

Thioglycolic acid

50

4.81

226

55

5.33

231

60

6.03

236

65

7.46

140

50

1.45

162

55

1.90

205

60

2.40

265

65

3.13

314

50

1.22

150

55

1.55

157

60

2.15

198

65

2.86

212

2-thiouracil

Glutathione

Calculation of k2 for the B → 2 / 3 / 4 step The B→ 2 /3 / 4 step, which means the second step is intermolecular ring closure and is independent of the ligand concentration. At a particular temperature the slopes of ln(A∞-At) versus time plots at different ligand concentrations were found to be constant in the region where the plots are linear (Figure 9). For different temperatures, the k2 values are obtained directly from the limiting slopes and are collected in Table 3.

165

Table 3 105k2 (s-1) values for different ligand concentrations at different temperatures, [complex 1] = 2.5 ×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 Temperature (oC)

Ligand 50

55

60

65

Thioglycolic acid

8.87

11.32

14.20

17.90

2-thiouracil

4.43

6.66

10.00

14.21

Glutathione

2.48

4.08

6.61

9.04

Effect of pH on the reaction rates The reaction was studied at five different pH values (3.0, 3.3, 3.6, 4.0 and 4.3). The kobs values were found to increase with increase in pH in this range. The kobs values are collected in Table 4. The enhancement in rate may be explained by the acid dissociation equilibria of the reactants. A rate expression may be given as

k(obs) =

k1KEKc(1)Ka [ligand]t Ka Kc(1)(1 +KE [ligand]t)+ [H+](Ka + Kc(1)) + [H+]2

Where k1 and KE are rate constant and outer-sphere association equilibrium constant, and Kc(1) and Ka are acid dissociation constants of [Rh(H2O)6]3+ and for the ligand respectively. In order to explain the observed pH dependence it may be suggested that during the ring closure step proton liberation occurs. At a higher pH, this process would be favoured, which would in turn enhance the reaction rate. With increasing pH the complex changes its form from aqua to hydroxoaqua. Similarly on increasing pH the proportion of the deprotonated forms of ligands increase, and the reaction rate have a slight response to the pH variation. Further study of the substitution reaction was avoided above pH 4.3 due to complications caused by adding an additional parameter [H+] to the rate equation. At pH higher than 4.5, precipitation of Rh3+ takes place.

166

Table 4

The 103k1(obs) and 10 5k2(obs) values at different pH values; [complex 1] = 2.5

× 10-4 mol dm-3, [ligand] =7.5 × 10 -3 mol dm-3, temperature = 60oC, ionic strength = 0.1 mol dm-3 NaClO4 10 3k1(obs) (s-1)

10 5k2 (obs) (s-1)

Ligand

pH

Thioglycolic acid

3.0

2.50

12.33

3.3

2.89

12.86

3.6

3.01

13.37

4.0

3.42

13.78

4.3

3.94

14.20

3.0

0.65

7.95

3.3

0.89

8.68

3.6

1.07

9.05

4.0

1.21

9.64

4.3

1.64

10.00

3.0

0.46

4.87

3.3

0.74

5.09

3.6

1.01

5.46

4.0

1.17

5.90

4.3

1.29

6.61

2-thiouracil

Glutathione

Effect of temperature on the reaction rates Four different temperatures were chosen for study and the results are listed in Table 1, 2, and 3. The activation parameters for the steps 1→ B and B→ 2 /3/ 4 were evaluated from linear Eyring plots (Figures 13 and 14) and are collected in Table 5. The low values of ∆H≠ and the large negative ∆S≠ values in both the steps suggest significant associative character of the substitution process for all the three ligands. The breaking of Rh-OH2 bond, already present and the formation of the new Rh-LHn- bond are equally important. The energy required to break the Rh-OH2 bond is partially compensated by the formation of Rh-LHn- bond. The significant drop in entropy values indicates that both leaving and entering groups are attached in the transition state; as a result a more compact transition state than the original starting situation is obtained resulting in a decrease in entropy values.

167

Table 5 Activation parameters for substitution of [complex 1] by ligands in aqueous medium, pH = 4.3 Ligand

∆H1 ≠ (kJ mol-1)

∆S1≠

∆H2 ≠

∆S2≠

(JK-1 mol-1)

(kJ mol-1)

(JK-1 mol-1)

Thioglycolic acid

22.4 ± 3.0

-220 ± 11

38.5 ± 1.3

-204 ± 4

2-thiouracil

42.2 ± 2.0

-169 ± 6

66.1 ± 0.5

-124 ± 2

Glutathione

47.2 ± 1.7

-155 ± 5

73.5 ± 1.1

-105 ± 3

Table 6 Activation parameters for related system with [Rh(H2O)5OH]2+ System

∆H≠ (kJ mol-1)

∆S ≠ (JK-1 mol-1) References

Glycyl-L-valine

∆H1 ≠ = 22 ±1.2 ≠

Glycyl-L-glutamine

Glycyl-glycine

1-

∆S2 = -47± 10

∆H1 ≠ = 34.7± 1.3

∆S1≠ = -189 ± 4

∆H2 ≠ = 94.1± 1.1

∆S2≠ = -37 ± 3

∆H1 ≠ = 26.7 ± 0.3

∆S1≠ = -207 ± 1

∆H2 ≠ = 92.4 ±1.3

∆S2≠ = -42 ± 4

∆H1 ≠ = 40.7± 3.8

∆S1≠ = -156± 12

∆H1 ≠ =22.4 ± 3.0 ≠

2-thiouracil

Glutathione

[27]

≠

∆H2 = 90.7± 3.2

≠ hydroxybenzotriazole ∆H2 = 78.7 ± 3.8

Thioglycolic acid

∆S1≠ = -220±4

[27]

[28]

[29]

∆S2≠ = -95 ± 12 ∆S1≠= -220 ±11

This work

≠

∆H2 =38.5 ± 1.3

∆S2 = -204 ± 4

∆H1 ≠ = 42.2 ± 2.0

∆S1≠ = -169 ± 6

∆H2 ≠ = 66.1 ± 0.5

∆S2≠ = -124 ± 2

∆H1 ≠ = 47.2 ± 1.7

∆S1≠ =-155 ± 5

∆H2 ≠ = 73.5 ± 1.1

∆S2≠ = -105 ±3

This work

This work

168

-35.4

ln(k1h/kBT)

-35.6

-35.8

-36.0

-36.2

-36.4

2.94

2.96

2.98

3.00

3.02

3.04

3

-1

3.06

3.08

3.10

3.12

10 /T (K )

Figure 13 Eyring plot ln(k1h/kBT) versus (1/T) for the 1→ B step of glutathione interaction with complex 1

-3 8 .8

-3 9 .0

ln(k2h/kBT)

-3 9 .2

-3 9 .4

-3 9 .6

-3 9 .8

-4 0 .0

-4 0 .2 2 .9 4

2 .9 6

2 .9 8

3 .0 0

3 .0 2 3

3 .0 4

3 .0 6

3 .0 8

3 .1 0

3 .1 2

-1

1 0 /T (K )

Figure 14 Eyring plot ln(k2h/kBT) versus (1/T) for the B → 2 step of glutathione interaction with complex 1

169

Mechanism and conclusion Our results indicate that for all the three ligands the first step, i.e. the attack by the incoming ligands proceed by an associative interchange(Ia) mechanism. This proposition is supported by the following observations. First, with an increase in ligands concentrations, saturation in the rate is observed. This indicates that an outersphere association complex is formed which is stabilised through H-bonding. Second, the low enthalpy of activation and large negative value of entropy of activation strongly suggest that ligands participate in the transition state. The second step is the intramolecular ring closure which is independent on the incoming ligand concentration.Which is supported by the value of the rate constants (k2) for this step which is actually found to be independent of the ligand concentration. From the temperature dependences of the KE values (Figure 15) the thermodynamic parameters are calculated ΔH0 = 3.60 ± 0.03 kJ mol-1, ΔS0 = 56 ± 1 JK-1 mol-1 (for thioglycolic acid), ΔH0 = 39.7 ± 0.9 kJ mol-1, ΔS0 = 165 ± 3 JK-1 mol-1 (for 2thiouracil) and ΔH0 = 22.4 ± 3.1 kJ mol-1, ΔS0 = 111 ± 9 JK-1 mol-1 (for glutathione). The ΔG0 values, calculated at all temperatures studied for all three ligands, have a negative magnitude which is once again in favour of the spontaneous formation of an outer sphere association complex. When [Rh(H2O)5(OH)]2+ reacts with thioglycolic acid, the five membered ring formation occurs. It (five membered ring) is also formed when [Rh(H2O)5(OH)]2+ reacts with glutathione. In case of thioglycolic acid chelation occurred by the coordination of the O- of carboxylate group and S atom with the Rh(III) center. Now as electron density on O- is greater it first attacks the Rh(III) centre by the removal of one water molecule i.e., follows the k1 path and then the S atom finishes the ring closing process. In case of glutathione the five membered ring was formed by the attack of S and N atoms. At first the S atom attacks Rh(III) centre follows the k1 path and then N atom attacks Rh(III) to form five membered ring in the chelation step. As the result of Job’s method of continuous variation indicates 1:1 molar ratio of metalligand and the IR spectrum of the solid product suggest that 2-thiouracil behave, as a bidentate ligand. Finally ESI-mass spectrum provides a qualitative picture of the composition i.e. the ligational sites are the sulfur and nitrogen ends of 2-thiouracil. The affinity of nitrogen atom of the 2-thiouracil provides the driving force for the ring formation. At first the S atom attacks to Rh(III) centre follows the k1 path and then N atom completes the chelation step by attacking Rh(III) to form four membered ring.

170

From a comparison of the ligands used, it can be concluded that the variation in size, bulkiness and electronic effect of the entering ligands reflects their properties as nucleophiles. The reactivity of the incoming ligands follow the order: thioglycolic acid > 2-thiouracil > glutathione. The rate of reaction also depends on steric effect. In case of glutathione the steric effect is much more than thioglycolic acid and 2-thiouracil which is reflected on the rate constant values (k1 and k2).

5.40 5.35 5.30

lnKE

5.25 5.20 5.15 5.10 5.05 5.00 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 15 Plot of lnKE versus 1/T for the reaction of glutathione with complex 1

171

A plausible mechanism is shown in the following: +

2+ OH

OH H2O

H2O

OH2 Rh

_ O

+

H2O

H O

KE SH

OH2

H

H2O

O

O

Complex 1

:S :

_ O

H

OH2

OH2

H

H

Rh

O

Outersphere association complex

Thioglycolic acid

+ + OH

H

H2O

H

H

Rh

H

O

:S:

H2O

O

+

H2O

O OH2

H

H .. :SH

Rh

k1

_

O OH2

H

H2O

O

H2O

OH

O

O

(B)

+ OH

H

H2O

O

H .. :SH

Rh H2O

O OH2

OH H2O k2

S

H2O O

CH2

Rh

Chelation

+ O

H3O+

C O

OH2 (2)

Figure 16 Plausible mechanisms for the substitution of aqua ligands from complex 1 by thioglycolic acid (2), 2-thiouracil (3) and glutathione (4)

172

References 1. B. Rosenberg, L. Vancamp and T. Krigas, Nature (London). 205, 698 (1965). 2. B. Rosenberg, L. Vancamp, J.E. Trosko and V.H. Mansour, Nature (London), 222, 385 (1969). 3. M.M. Shoukry, M.R. Shehata, A. Abdel-Razik and A.T.I. Abdel-Karim, Monatshefte für Chemie, 130, 409 (1999). 4. R. Zaludova, A. Zakovaska, J. Kasparkova, Z. Balcarova, V. Kleinwachter, O. Vrana, N. Farrel and V. Brabec, Eur. J. Biochem, 246, 508 (1997). 5. B. Lippert, (Ed.), Cisplatin-Chemistry and Biochemistry of Leading Anticancer Drug; Wiley VCH: Weinheim, (1999). 6. M.J. Clarke, Inorganic chemistry in Biology and Medicine, A.E. Martell, (Ed), (ACS Symp. SER. 140) American Chemical Society, Washington DC, p 157 (1980) and references cited therein. 7. F.P. Pruchink, M. Bien and T. Lachowicz,. Met. Based Drugs, 3, 185 (1996). 8. J. Reedijk, Pure and Appl. Chem., 59, 181 (1987). 9. M. Zhao and M.J. Clarke, J. Biol. Chem., 4, 325 (1999). 10. D.R. Frasca and M.J. Clarke, J. Am. Chem. Soc, 121, 8523 (1999). 11. V.G. Povsc and J.A. Olabe, Transition Met. Chem., 23, 657 (1998). 12. N. Katsaros and A. Anagnostopoulou, Crit Rev in Oncol/Heamatol., 42, 297 (2002). 13. F.P. Pruchnik, P. Jakimowicz, Z. Cuinik, J. Zakrzewskaczerwinska, A. Opolski, J. Weitrzyk and E. Wojdat, Inorg. Chim. Acta, 334, 59 (2002). 14. P. Munshi and T.N.G. Row, Acta Cryst., B62, 612 (2006). 15. G.H. Ayres and J.S. Forrester, J. Inorg. Nucl. Chem., 3, 365 (1957). 16. W.C. Wolsey, C.A. Reynolds and J. Kleinberg, J. Inorg. Chem., 2, 463 (1963). 17. G. Pneumatikakis and N. Hadjiliadis, J. Inorg. Nucl. Chem., 41, 429 (1979). 18. D. Steel and P.F.M. Verhoeven, Vib. Spectroscopy, 25, 29 (2001). 19. Stability Constants, Special publication, No. 17, The Chemical Society London, p 376 (1964).

173

20. D. Wen, X. Zhu, F. Zhao, L. Huang and B. Zeng, Solid state Electrochemistry, 10, 69 (2006). 21. Z.D. Burgacic, G. Liehr and R.V. Eldik, Dalton Trans., p 2825 (2002). 22. D.L. Rabenstein, J. Am. Chem. Soc., 95, 2797 (1973). 23. I. Banyai, J. Glaser, M.C. Read and M. Sandstroem, Inorg. Chem., 34, 2423 (1995). 24. J.A. Weyh and R.E. Hamm, Inorg. Chem., 8, 2298 (1969). 25. G.A. Jeffrey, An Introduction to Hydrogen Bonding. Oxford University Press, Oxford (1997). 26. G.R. Desiraju and T. Steiner, The Weak Hydrogen Bonding in Structural Chemistry and Biology. Oxford University Press, Oxford (1999). 27. B.K. Bera, S. Mondal, S. Mallick, A. Mandal, P. Karmakar and A.K. Ghosh, J. Solution Chem., 41, 741 (2012). 28. B.K. Bera, S. Mallick, A. Mandal, S. Mondal, P. Karmakar and A.K. Ghosh, Prog. React. Kinet. Mech., 36, 371 (2011). 29. B.K. Bera, A. Mandal, B. Maity, S. Mallick, S. Mondal, P. Karmakar and A.K. Ghosh, J. Chem. Sci., 124, 791 (2012).

174

CHAPTER 6

175

Chapter 6

Displacement of aqua ligand from the hydroxopentaaqua rhodium(III) ion by azide: A kinetic and mechanistic approach a) Introduction The interactions of metal ions with biomolecules and the functions of the metal ions in physiological system are very complex and the most part of the precise nature of these interactions are unknown. The accidental discovery by Rosenberg and coworker [1, 2] in 1969 of the powerful anticancer properties of cisplatin, a pure inorganic compound created interest among the chemotherapists leading to investigation of the anticancer properties of inorganic metal complexes. It is established [3] that cisplatin at first hydrolysed in the biological condition and the aqua variety is the active species. Some of the hydrolysed products are also responsible for toxicity. Thus it is expected that aqua complexes if used directly will be of less toxicity. Now it is also established that among the metal complexes of 4d and 5d series rhodium complexes are also promising in connection with the antiblastoma activity. The interaction of rhodium(II) and other platinum group metal antitumoral compounds with serum albumin had been reported by Esposito and Najjar [4] where rhodium was thought to react mainly through coordination with the imidazole group of histidine residues. The mer-isomer of [Rh(NH3)3Cl3 ] as well as trans [Rh(py)4Cl2]Cl and trans [Rh(en)2Cl2 ]NO3 are effective against the growth of Sarcoma-180 and Walker carcinosarcoma. Rhodium(III) complexes preferentially bind with the adenine and its nucleotides and nucleosides [5-7]. In order to examine the bioactivity of rhodium(III) complexes, studies on the interaction of rhodium(III) with DL-methionine [8], pyridine-2-aldoxime [9], Lcysteine [10], adenosine [11], cytidine [12], uridine [13], thymidine [14], DLpenicillamine [15], inosine [16] have already been reported. In this chapter we extend our investigations to the anation of the hydroxopentaaqua rhodium(III) complex by azide ligand. Azide is a useful probe

176

reagent, mutagen, and preservative. Azide inhibits cytochrome oxidase by binding irreversibly to the heme cofactor in a process similar to the action of carbonmonoxide.

b) Materials and methods Experimental [Rh(H2O)6](ClO4)3 was prepared as per the literature method [17] and characterised by chemical analysis and spectroscopic data [18] (max = 396 nm,  = 62 dm3 mol-1cm-1; max = 311 nm,  = 67.4 dm3 mol-1cm-1). The reactant complex [Rh(H2O)5(OH)](ClO4)2 (complex 1) was obtained in situ (yield  90) by adjusting the pH to 4.3. Higher proportions of complex could not be obtained as the solution becomes turbid at higher pH. The reaction product of azide with complex 1 was prepared by mixing the reactants in the different ratios: 1:1, 1:2, 1:3, 1:5, and 1:10, and kept at 60oC for 72 hours. The electronic spectrum of 2 (Figure 1) shows complete complexation between the complex 1 with the ligand. The composition of the product in the reaction mixture was determined by Job’s method of continuous variation (Figure 2). The metal-ligand ratio was found to be 1:2. Doubly distilled water was used to prepare all the kinetic solutions. The pH of the solution was adjusted by adding NaOH/HClO4 and the measurements were carried out using a Sartorius digital pH meter (model PB-11) with an accuracy of ±0.01 unit. All chemicals used were of A.R grade available commercially. The reactions were carried out at constant ionic strength 0.1 mol dm−3 NaClO4.

177

2 1

Figure 1 Spectra of complex 1, azide substituted complex (2). [Rh(H2O)5(OH)]2+ = 2.5  104 mol dm3, [ligand] = 5.0  103 mol dm3, pH = 4.3

1.1

1.0

0.9

abs

0.8

0.7

0.6

0.5 0.0

0.2

0.4

0.6

[L] / ( [L]+[M] )

Figure 2 Job’s plot for reaction of complex 1 with azide

0.8

1.0

178

[Rh(H2O)5OH]2+(1) and the azide were mixed in 1:1 molar ratio at pH 4.3 and a pale yellow product(2) was obtained, which was isolated in the solid form. The IR spectrum of the product (2) in the KBr disc shows sharp bands at 2030 cm-1 and 546 cm-1. Band appeared at 2030 cm-1 is due to antisymmetric stretching of azide. The additional band at 2146 cm-1 shows substitution occurs with terminal azide, indicating Rh-N=N=N structure. The band at 546 cm-1 indicates that Rh-N bond is present in the product complex (2). The aqueous solution of [Rh(H2O)5(OH)]2+ and the azide were mixed in a 1:1 molar ratio and the mixture was thermostated at 60oC for 48 hours and used for ESI-MS measurement. The ESI mass spectrum of the resulting product (2) is shown in Figure 3. It is clear from the mass spectrum (Figure 3) that the ion at m/z 317 has become the molecular ion species. (complex 1 with azide) and this is attributed to (Rh(III) + 3H2O + OHˉ+ 2N3- + Na+ + 2H2O) +. The structure of precursor ion is shown in Figure 4.

Figure 3 Mass spectrum for azide substituted product (2)

179

+

OH H2O

N3 Rh

H2O

+

Na+

+ 2 H2O

N3 OH2

Figure 4 Plausible structure of the molecular ion peak from the ESI-mass spectrum for azide substituted product (2) Physical measurements and kinetic studies Physical measurements were carried out in the same way as explained in chapter 1 and also same instruments were used to record the kinetic data. The kinetic measurements were carried out at wavelength 288 nm where the spectral difference between the reactant complex and product(2) is large. Conventional mixing technique was followed and pseudo first-order conditions with respect to metal ion concentration were maintained throughout the course of the reaction. The plots of ln(A∞−At) (where At and A∞ are absorbance at time t and after completion of reaction) against time t (Figure 5) are found to be nonlinear; it is curved at initial stage and subsequently of constant slope, indicating that the reaction proceeds via two consecutive steps. From the limiting linear portion of ln(A∞−At) versus time curves, k2(obs) values were obtained. The k1(obs) values were obtained from the plots of lnΔ versus time, where t is small (Figure 6). Origin software was used for computational works. Rate data, represented as an average of duplicate runs, were reproducible within ± 4%.

180

1.2

X 1.0

ln(A-At)

 0.8

Y

0.6

0.4

0

20

40

60

80

100

time (min)

Figure 5 A plot of ln(A∞- At) versus time. [complex 1] = 2.5 × 10-4 mol dm-3, [azide] =10.0  10 3 mol dm3, pH = 4.3, temperature = 50oC

-1.0 -1.2 -1.4

ln

-1.6 -1.8 -2.0 -2.2 -2.4 -2.6 0

1

2

3

4

5

time (min)

Figure 6 Plot of ln∆ versus time. [complex 1]= 2.5×10-4 mol dm-3, [azide] = 10.0 103 mol dm3, pH = 4.3, temperature = 50 oC

181

c) Results and discussion The pKa value [19] of the azide is 4.59 at 25ºC. Thus at pH=4.3 the ligand exists ~50% in the anionic form(N3-), which is the reacting species. HN3 ⇌ N3 - + H+ ;

(1)

On the other hand the ionization of [Rh(H2O)6]3+ may be given as: Ka (1) [Rh(H2O)6]3+ ⇌ [Rh(H2O)5OH]2+ Ka (2) [Rh(H2O)5OH]2+ ⇌ [Rh(H2O)4(OH)2]+

H+

+

+

(2) H+

(3)

The First and second acid dissociation equilibrium of the complex [Rh(H2O)6]3+ are 3.6 and 4.7 respectively at 25ºC [20]. Other reports on the pKa(1) values are 3.2, 3.4 and 3.45 [20]. Thus we see that in the studied pH range the complex changes its protonation state and the actual reacting form of the complex is [Rh(H2O)5OH]2+. At constant temperature, pH (4.3) and fixed concentration of complex (1), the ln(A∞-At) verses time(t) plots for different ligand concentrations indicate a two step process. Both the steps are dependent on ligand concentration and with increasing ligand concentration a limiting rate are reached for both the steps. The rate constant for such process can be evaluated by assuming scheme 1. k1 k2 A→B→C Where A is stating complex (1), B is as intermediate with azide and C is the final product complex [Rh(H2O)3(OH)(N3)2] (2) KE1 [Rh(H2O)5(OH)]2+ + N3- ⇌ [Rh(H2O)5(OH)]2+ . N3(1) Outersphere association complex k1 2+

-

[Rh(H2O)5(OH)] . N3 → [Rh(H2O)4(OH)(N3)]+ +H2O B K E2 [Rh(H2O)4(OH)(N3)]+ + N3- ⇌ [Rh(H2O)4(OH)(N3)]+. N3Outersphere association complex

182

k2 [Rh(H2O)4(OH)(N3)]+. N3- → [Rh(H2O)3(OH)(N3)2] + H2O (2) Scheme 1 Calculation of k1 for the first step (A → B) The k1(obs) values were calculated according to the same procedure mentioned in chapter 1 (Figures 5 and 6) using the Weyh and Hamm [21] equation as discussed in chapter 1. k1(obs) values were tabulated in table 1. The pseudo-first order rate constant (k1(obs)) were found to increase with increase in ligand concentration and show a limiting condition which is probably due to the completion of the outer sphere association complex formation (Figure 7). The outer sphere association complex may be stabilised through H-bonding [22-23].

Figure 7 Plots of k1(obs) (s-1) versus [azide] at different temperatures, A = 50, B = 55, C = 60 and D = 65ºC

183

Table 1 10 3k1(obs) (s-1) values for different ligand concentrations at different temperatures; [complex 1] =2.5×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 103 [ligand] (mol dm−3)

Temperature (oC) 50

55

60

65

2.5

2.00

2.43

3.13

3.97

5.0

3.30

3.82

4.96

5.85

7.5

3.96

4.57

5.61

6.90

10.0

4.31

4.97

6.14

7.14

12.5

4.43

5.31

6.39

7.34

Based on Scheme 2, a rate expression (7) can be derived for the A→B step: KE1 A + N3- ⇌ A. N3Outersphere association complex - k1 A. N3 → B Scheme 2 d[B]/dt = k1KE1 [Rh(H2O)5(OH)]2+ [N3-] / (1+ KE1[N3-])

(6)

d[B]/dt = k1(obs).[Rh(H2O)5(OH)2+]T

(7)

where T stands for total concentration of Rh(III). We can then write: k1(obs) = k1KE1[N3-]/(1 +KE[N3-])

(8)

where k1 is the rate constant for the A→B step; that is, the rate constant for the interchange of outer-sphere complex to the inner-sphere complex. KE1 is the outersphere association equilibrium constant for the first step. Equation 8 can be represented as: 1/k1(obs) = 1/k1 +1/k1KE1[N3-]

(9)

The plot of 1/k1(obs) against 1/[ N3-] should be linear with an intercept of 1/k1 and slope 1/k1KE1. This was found to be the case at all temperatures studied. The k1 and KE1 values were calculated from the intercept and slope (Figure 8) and are collected in Table 2.

184

A 0.50 0.45

B

0.35

C

0.30

3

1/10 k1(obs) (s)

0.40

D

0.25 0.20 0.15 0.10 0.05

0.10

0.15

0.20

0.25

3

0.30 3

0.35

0.40

0.45

-1

1/10 [azide] (dm mol )

Figure 8 Plots of 1/k1(obs) (s) against 1/[azide], A = 50, B = 55, C = 60 and D = 65ºC Table 2 103k1 (s-1) and KE1 values for different ligands at different temperatures. [complex 1] = 2.5 ×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 Temperature (°C)

103k1 (s−1)

KE1 (dm3 mol−1)

50

7.02

162

55

7.80

183

60

9.07

215

65

9.88

273

Calculation of k2 for the second step (B→C) The second step is again dependent on azide concentration and shows a limiting value at higher concentration of the ligand. A new azide ligand attacks the rhodium(III) center. The intermediate here also possibly stable through hydrogen bonding between coordinated H2O and the approaching azide. Based on the experimental findings a two-step associative interchange mechanism is proposed for

185

the substitution process. The rate constants were calculated from latter linear portions of the graphs and are collected in Table 3. The k2 and KE2 for the B→C step is calculated similar to equation (9) and collected in Table 4. The pseudo-first order rate constant (k2(obs)) were found to increase with increase in ligand concentrations and show a limiting condition which is probably due to the completion of the outer sphere association complex formation (Figure 9). A plot of 1/k2(obs) verses 1/ [azide] should be linear (Figure 10) with an intercept of 1/k2 and slope 1/ k2KE2.

Figure 9 Plots of k2(obs) (s-1) versus [azide] at different temperatures, A = 50, B = 55, C = 60 and D = 65ºC

186

Table 3 10 5k2(obs) (s-1) values for different ligand concentrations at different temperatures; [complex 1] =2.5×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 103 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

2.5

4.28

5.49

7.14

8.39

5.0

7.08

9.06

11.94

13.74

7.5

8.79

11.17

14.31

16.34

10.0

9.58

12.25

15.34

17.87

12.5

10.24

12.70

16.10

19.12

A

0.24 0.22 0.20

B

5

1/10 k2(obs) (s)

0.18 0.16

C

0.14

D

0.12 0.10 0.08 0.06 0.04 0.02 0.05

0.10

0.15

0.20 3

0.25

0.30 3

0.35

0.40

0.45

-1

1/10 [azide] (dm mol )

Figure 10 Plots of 1/k2(obs) (s) against 1/[azide], A = 50, B = 55, C = 60 and D = 65ºC

187

Table 4 105k2 (s-1) and KE2 values for different ligands concentrations at different temperatures. [complex 1] = 2.5×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4 Temperature (°C)

10 5k2 (s−1)

KE2 (dm3 mol−1)

50

16.80

138

55

20.76

146

60

25.66

157

65

30.30

162

Effect of pH on the reaction rates The reactions were studied at five different pH values (3.0, 3.3, 3.6, 4.0 and 4.3). The k1(obs) and k2(obs) values increase with increasing pH at fixed concentration of complex 1, and ligand. The 10 3k1(obs) and 10 5k2(obs) values at 60°C are collected in Table 5. The enhancement in rate may be explained by the acid dissociation equilibria of the reactants.

k(obs) =

k1KEKc(1)Ka [ligand]t Ka Kc(1)(1 +KE [ligand]t)+ [H+](Ka + Kc(1)) + [H+]2

Where k1 and KE are rate constant, and outer-sphere association equilibrium constant, and Kc(1) and Ka are acid dissociation constants of [Rh(H2O)6]3+ and for the ligand respectively. At pH = 4.3, the complex exists mainly in the hydroxopentaaqua form and the contribution due to the hexa aqua species is negligible. With increasing pH the complex changes its form from aqua to hydroxoaqua and the proportion of the more labile hydroxopentaaquarhodium(III) ion increases. As the pH increases the proportion of the more reactive anionic form of the ligand increases and since the ligating capability of the deprotonated ligand is always higher than its neutral form, the rate increase with increasing pH is partly accounted for. Further study of the substitution reaction was avoided above pH 4.3 due to complications caused by adding an additional parameter [H+] to the rate equation. At pH higher than 4.5, precipitation of Rh3+ takes place.

188

Table 5

The 10 3k1(obs) and 105k2(obs) values at different pHs; [complex 1] = 2.5×10−4

mol dm-3, [azide] =7.5 × 10-3 mol dm-3, temperature = 60oC, and ionic strength = 0.1 mol dm−3 NaClO4

pH

103k1(obs) (s-1)

105k2(obs) (s-1)

3.0

3.72

10.87

3.3

4.21

11.39

3.6

4.67

11.75

4.0

4.99

13.22

4.3

5.61

14.31

Effect of temperature on the reaction rates The reactions were studied at four different temperatures for different ligand concentrations, and the results are listed in Tables 1 to 5. The activation parameters for both the steps A → B and B → C are evaluated from the linear Eyring plots (Figures11 and 12) and are collected in Table 6. The low Hvalues are in support of the ligand participation in the transition state for both the steps. The positive energy required for the bond breaking process is partly compensated by the negative energy obtained from bond formation in the transition state and hence, a low value of His observed. The highly negative Svalues, on the other hand, suggest a more compact transition state than the starting complexes and this is also in support of the assumption of a ligand participated transition state. H2is higher than H1 which is quite expected for the second step which is slower than the first step.

189

-34.20

-34.25

ln(k1h/kBT)

-34.30

-34.35

-34.40

-34.45

-34.50 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 11 Eyring plot ln(k1 h/kBT) versus (1/T) for the A→B step of azide interaction with complex 1

-37.6

-37.7

ln(k2h/kBT)

-37.8

-37.9

-38.0

-38.1

-38.2

-38.3 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 12 Eyring plot ln(k2h/kBT) versus (1/T) for the B→C step of azide interaction with complex 1

190

Table 6 Activation parameters for substitution of [complex 1] by azide in aqueous medium, pH = 4.3

∆H1 ≠

∆S1≠

∆H2 ≠

∆S2≠

(kJ mol-1)

(JK-1 mol-1)

(kJ mol-1)

(JK-1 mol-1)

18.1 ± 1.1

-230 ± 3

32.4 ± 0.2

-217± 1

Mechanism and conclusion The interaction of azide with the [Rh(H2O)5(OH)]2 complex proceeds via two distinct consecutive substitution steps of aqua molecules (k1 ~ 10-3 s-1 and k2 ~ 10-5 s1

). Each step proceeds via an associative interchange activation and both the steps

dependent on ligand concentration. At the outset of each step outer sphere association complex results, this is stabilized through H-bonding and is followed by an interchange from the outer sphere to the inner sphere complex. The outer sphere association equilibrium constants, a measure of the extent of H bonding for each step at different temperatures are evaluated are collected in Tables 2 and 4. From the Job’s method of continuous variation (1:2 molar ratio of metalligand) and the ESI-mass spectrum of the product it is confirmed that here azide acts as a monodentate ligand and no ring formation occurred. From the temperature dependence of the KE1 and KE2 values, the thermodynamic parameters are calculated (Figures 13 and 14): ΔH10 = 30.2 ± 4.4 kJ mol-1, ΔS10 = 136 ± 13 JK-1 mol-1 and ΔH20 = 9.9 ± 0.7 kJ mol-1, ΔS20 = 71 ± 2 JK-1 mol-1. The negative ΔG0 values, calculated for both the steps at all temperatures studied, support the spontaneous formation of an outer sphere association complex.

191

5.7

5.6

5.5

lnKE1

5.4

5.3

5.2

5.1

5.0 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 13 Plot of lnKE1 versus 1/T for the reaction of azide with complex 1

5.10 5.08 5.06 5.04

lnK

E2

5.02 5.00 4.98 4.96 4.94 4.92 2.94

2.96

2.98

3.00

3.02 3

3.04

3.06

3.08

3.10

3.12

-1

10 /T (K )

Figure 14 Plot of lnKE2 versus 1/T for the reaction of azide with complex 1

192

Based on the above facts, a plausible mechanism is shown in Figure 15.

2+

+

OH

OH

H2O

OH2

H2O

Rh

_ N

+ H2O

_ N

+ N

KE1

OH2

_ N N+ _ N

OH2

Azide OH2

Complex (1) k1 _

Outersphere association complex H2O

+

OH

OH

H2O

H2O

N3 Rh

+

_ N

+ N

_ N

H

O OH2

H H

Rh H2O

OH2

H2O

O

KE2

N3

_ N

Rh H2O

O

H

H H

_ N

+ N

OH2 k2

(B)

Outersphere association complex

OH H2O

N3 Rh

H2O

+

H2O

N3 OH2 Product Complex (2)

Figure 15 Plausible mechanism for the substitution of aqua ligand from complex 1 by azide

193

References 1. B. Rosenberg, L. Vancamp and T. Krigas, Nature (London), 205, 698 (1965). 2. B. Rosenberg, L. Vancamp, J.E. Trosko and V.H. Mansour, Nature (London), 222, 385 (1969). 3. J. Reedijk, Pure and Appl. Chem., 59, 181 (1987). 4. B.P. Esposito and R. Najjar, Coord. Chem. Rev., 232, 137 (2002). 5. M.J. Clarke and P.C.

Hydes, in: H .Siegel (Ed) Metal ions in biological

systems, vol 2. Marcel Dekker, New York, pp 1–62, (1980). 6. C. Monti-Bragadin, L. Ramani, L. Samer, G. Mestroni and G. Zassinovich, Antimicrob Agents Chemother, 7(6), 825 (1975). 7. G. Mestroni, E. Alessio, G. Zassionovich and A. Bontempi, Inorg. Chim. Acta, 63, 138 (1987). 8. A.K. Ghosh, S. Ghosh and G.S. De, Indian J. Chem., 35A, 342 (1996). 9. A.K. Ghosh, S. Ghosh and G.S. De, Transition Met. Chem., 21, 358 (1996). 10. A.K. Ghosh, P.S. Sengupta and G.S. De, Indian J. Chem., 36A, 611 (1997). 11. A.K. Ghosh, Transition. Met. Chem., 23, 269 (1998). 12. S.K. Mukhopadhyay, A.K. Ghosh and G.S. De, Indian J. Chem., 38A, 895 (1999). 13. S.K. Mukhopadhyay and A.K. Ghosh, Indian J. Chem., 41A, 489 (2002). 14. S.K. Mukhopadhyay and A.K. Ghosh, Transition Met. Chem., 30, 141 (2005). 15. S.K. Mukhopadhyay and A.K. Ghosh, Transition Met. Chem., 30, 107 (2005). 16. S.K. Mukhopadhyay and A.K. Ghosh, Inorg. React. Mech., 5, 255 (2005). 17. G.H. Ayres and J.S. Forrester, J. Inorg. Nucl. Chem., 3, 365 (1957). 18. W.C. Wolsey, C.A. Reynolds and J. Kleinberg, Inorg. Chem., 2, 46 (1963). 19. L.G. Sillen and A.E. Martell, Stability Constants of Metal Ion Complexes, The Chemical Society, London Special Publication No. 17, Table no. 31, 160 (1964).

194

20. I. Banyai, J. Glaser, M.C. Read and M. Sandstroem, Inorg. Chem., 34, 2423 (1995). 21. J.A. Weyh and R.E. Hamm, Inorg. Chem., 8, 2298 (1969). 22. G.A. Jeffrey, An introduction to hydrogen bonding, OxfordUniversity Press, Oxford, (1997). 23. G.R. Desiraju and T. Steiner, The weak hydrogen bonding in structural chemistry and biology. Oxford University Press, Oxford, (2001).

195

SUMMARY AND CONCLUSION

196

Summary and Conclusion Kinetics and mechanism of ligand substitution in octahedral ruthenium(II) and rhodium(III) complexes Our present study relates to the kinetic behaviour of the interactions of two aqua ruthenium(II) and one aqua rhodium(III) complexes and their reactions with some biologically important ligands as a function of substrate complex concentration, ligand concentration, pH and temperature. Ruthenium(II) and rhodium(III) both are 4d6 metal ion and it is observed that being a 4d congenor of iron and cobalt (the most important biological metals in the periodic table), ruthenium and rhodium complexes are less toxic. We have divided our summary and coclusion portion in main two sections. One is kinetic and mechanistic studies of substitution reaction of Ru(II) complexes. Another section is kinetic and mechanistic studies of substitution reaction of Rh(III) complexes. Lastly we have compered the kinetics, mechanism and reactivity of ruthenium(II) and rhodium(III) system. General Discussion The reactive forms of the ligands derived from the consideration of pKa values in the said pH range are presented in Table 1.

197

Table 1 Actual forms of the ligands at studied pH Ligand

Azide

Dissociation

Actual form of the ligand during

Constant (s)

Complexation

(25o C) pK = 4.59

_ N

M:L

1:2 (Both for the

_ N

+ N

[Ru(bipy)2 (H2O)2]2+ complex

and

[Rh(H2O)5(OH)]2+ complex) Thioglyc

pK1 = 3.58

olic acid

HS

1:1 (Both for the

_ COO

CH2

[Ru(bipy)2 (H2O)2]2+

pK2 = 7.75

complex

and 2+

[Rh(H2O)5(OH)] complex)

2-

pK1= 9.78

1:1 (Both for the

O

[Ru(bipy)2 (H2O)2]2+

thiouracil

NH

pK2=12.7

complex

and 2+

[Rh(H2O)5(OH)]

N H Glutathio

complex)

pK1= 2.05

SH

ne

pK3= 8.72 pK4=9.49

pK= 2.0

O

O

pK2= 3.4

Thiourea

S

_ O

H2N

_ O

complex)

2:1

(For

the

[(H2O)(tap)2RuORu(t ap)2(H2O)]2+

S

the

O

NH2 C

(For

[Rh(H2O)5(OH)]2+

H N N H

+ NH3

1:1

O

complex)

198

Sodium

pK= 3.37

_ S

diethyldit

C

hiocarba mate

(For

the

[(H2O)(tap)2RuORu(t

N

ap)2(H2O)]2+ complex)

CH2CH3

S

L-

2:1

CH2CH3

pK1= 1.71

2:1

cysteine

(For

the

[(H2O)(tap)2RuORu(t pK2= 8.33

ap)2(H2O)]2+ complex)

pK3= 10.78

Kinetic and mechanistic studies of substitution reaction of Ru(II) complexes We have chosen [Ru(bpy)2(H2O)2]2+ and [(tap)2(H2O)RuORu(tap)2(H2O)]2+ complexes for kinetic and mechanistic studies. Though a lot of work [1-7] has been done on the ligand substitutions of octahedral ruthenium(II) complexes, but persisting controversy [8-17] regarding mechanism necessitates further study of these reactions in details. The thesis contains the report of the kinetics and mechanism of [Ru(bpy)2(H2O)2]2+ by three ligands viz. thioglycolic acid, 2-thiouracil and azide in aqueous medium and at pH 4.5. These reactions are studied within the temperature range 50oC to 65oC at pH 4.5 but not at 7.4, because in this condition ruthenium(II) is oxidized

to

a

mixed

valence n+

[(H2O)(bpy)2RuORu(bpy)2(H2O)] ,

n

varies

oxo-bridged with

the

complex

oxidation

state,

like two

2+

ruthenium(II) center adopts [18]. The complex exists as [Ru(bpy)2(H2O)2] at pH 4.5. The reactive forms of the ligands derived from the consideration of pKa values in the said pH range are presented earlier. [Ru(bpy)2(H2O)2]2+ was prepared [19, 20] in situ by acidification of the carbonato species with p-toluene sulfonic acid since it did not oxidize the substrate complex to Ru(III) complex. The pH of the solution was maintained in the acidic region to prevent oxidation of Ru(II) to Ru(III). The ionic strength of the medium was adjusted by adding recrystallised sodium p-tolene sulfonate.

199

The products of the reactions have been characterized by IR and ESI-mass spectroscopic analysis. The compositions of the products in the reaction mixture were determined by Job’s method of continuous variation. The metal-ligand ratio was found to be 1:1 for thioglycolic acid and 2-thiouracil but for azide the ratio was 1:2. The effect of pH variation on rate constant was studied in the 3.5-5.5 pH range. The observation can be explained considering the following equilibria: The first acid dissociation equilibrium of the complex, [Ru(bipy)2((H2O)2]+2 is 8.9 [21] [Ru(bipy)2(H2O)2]2+ ⇌ [Ru(bipy)2(H2O) (OH)]+ + H+

(1)

Thus we see that in the studied pH range the complex exists as diaqua form and among the ligands thioglycolic acid and azide exist as anionic form but 2-thiouracil exists as neutral form. As we increase the pH the percentage of the deprotonated form of complex and ligands slightly increased and the reaction rates may have a slight response to the pH variation. The k(obs) values increase with the increase in ligand concentrations and at higher ligand concentration a limiting rate was observed in all the cases studied. The parameters studied for different ligands were kept identical for comparison. The observations were in accordance with the associative interchange mechanism, where an outersphere association complex is first formed between the ligand and the complex, followed by the interchange of the ligand from outer to innersphere with the displacement of one coordinated aqua ligand from the complex which has been designated as anation step. At pH 4.5, the reaction has been found to proceed via two distinct consecutive steps. For thioglycolic acid and 2-thiouracil, the first step is [ligand] dependent and the second step is [ligand] independent and it is chelation step. For azide both the steps are [ligand] dependent and no ring formation occurred as azide is a monodentate ligand. For thioglycolic acid and 2-thiouracil the rate constant can be evaluated by assuming the following scheme 1.

200

KE [Ru(bipy)2(H2O)2]2+ + LHn- ⇌ [Ru(bipy)2(H2O)2]2+. LHn(1)

Outersphere association complex k1

[Ru(bipy)2(H2O)2]2+. LHn-

[Ru(bipy)2(H2O)(LH)](2-n)+.

-H2O

k2

[Ru(bipy)2(H2O)(LH)](2-n)+ (B)

(B)

Ring closure

[Ru(bipy)2(L)](1-n)+ + H3O+ (2) / (3)

Scheme 1 Where n is 1 for thioglycolic acid and 0 for 2-thiouracil. Here k1 is the anation rate constant for the slow step i.e. for the interchange of the outersphere to innersphere complex and KE is the outer sphere association equilibrium constant. k2 is the rate constant for intramolecular ring closure step. Based on scheme 1 a rate expression can be derived for (1) → (B) step. k1KE[Ru(bipy)2(H2O)22+][LHn-] Rate =

(1+KE[LHn-])

(2)

= k1(obs).[Ru(bipy)2(H2O)22+]T T stands for total concentration of Ru(II). We can write k1(obs) =

k1KE [LHn- ] . (1+KE[LHn-])

or, 1/k1(obs) = 1/ k1 + 1/ (k1KE[LHn- ])

(3)

(4)

A plot of 1/k1(obs) verses 1/ [LHn-] should be linear with an intercept of 1/k1 and slope 1/k1KE.

201

For thioglycolic acid and 2-thiouracil the second step is intramolecular ring closure and is independent of ligand concentration. At a particular temperature the slopes of ln(At - A∞) versus time plots at different ligand concentrations were found to be constant in the region where the plots are linear. For different temperatures the k2 values are obtained directly from the limiting slope. For azide the rate constant can be evaluated by assuming the following scheme 2. KE1 2+

[Ru(bipy)2(H2O)2] + N3 ⇌ [Ru(bipy)2(H2O)2]2+ . N3(1)

-

Outersphere association complex

k1 [Ru(bipy)2(H2O)2]2+. N3- → [Ru(bipy)2(H2O)(N3)]+ + H2O (B) K E2 [Ru(bipy)2(H2O)(N3)]+ + N3- ⇌ [Ru(bipy)2(H2O)(N3)]+. N3Outersphere association complex

k2 [Ru(bipy)2(H2O)(N3)]+ . N3- → [Ru(bipy)2(N3)2] + H2O (2) Scheme 2 Here k1 and k2 are the anation rate constants for the first step and second step, i.e. for the interchange of the outersphere to innersphere complex. KE1 and KE2 are the outer sphere association equilibrium constants for first and second steps. Based on scheme 2 a rate expression can be derived for (1) → (B) step. The rate equation can be written as similar as equation 4, i.e. 1/k1(obs) = 1/ k1 + 1/ (k1KE1[azide])

(5)

A plot of 1/k1(obs) verses 1/[azide] should be linear with an intercept of 1/k1 and slope 1/ k1KE1. For azide the second step is again dependent on ligand concentration and shows a limiting value at higher concentration of the ligand. A new azide ligand attacks the ruthenium(II) center. The rate constants (k2) were calculated from latter linear portions of the graphs and are collected in Table 3. The pseudo-first order rate constant (k2(obs)) were found to increase with increase in ligand concentrations and show a limiting

202

condition which is probably due to the completion of the outer sphere association complex formation. The rate equation can be written as similar as equation 5, i.e. 1/k2(obs) = 1/ k2 + 1/ (k2KE2[azide])

(6)

A plot of 1/k2(obs) verses 1/[azide] should be linear with an intercept of 1/k2 and slope 1/ k2KE2. The k values are the interchange rate constants dependent on the donor ability of the ligands and the activation parameters such as enthalpy of activation (H) and entropy of activation (S) are related to the transition state of a reaction and play an important role to point out the mechanism. The H and S are related by Eyring equation such as: ln(kh/kBT) =  H/RT + S/R Where k is the anation rate constant, kB is Boltzmann constant, h is Planck’s constant, T is temperature in Kelvin scale and R is universal gas constant. For dissociative activation H value is high positive and S value is positive and for associative activation H value is low positive and S shows large negative values. Again, from the temperature dependence of KE values and using the well known thermodynamic relationship G0 = H0 - TS0 or, – RT ln KE = H0 - TS0 or, ln KE = - H0/RT + S0/R, the H0 and S0 are calculated. Thus the plot of lnKE versus 1/T is straight line with slope H0/R and intercept S0/R. So we will calculate H0, S0 and G0 using this plot. The rate constant values (k(obs)), kinetic parameter values (k, ∆H≠ and ∆S≠) and thermodynamic parameter values (KE, ∆H0 and ∆S0) for the interaction of [Ru(bpy)2(H2O)2]2+ complex with azide, thioglycolic acid and 2-thiouracil are collected in Tables 2 to 5.

203

Table 2 10 3 k1(obs) (s-1) values for the interaction of [Ru(bpy)2(H2O)2]2+ complex by three different ligands at different ligand concentrations and at different temperatures for the first step, [substrate complex] = 1.00 10-4 mol dm-3, pH=4.5, ionic strength = 0.1 mol dm-3 of sodium p-toluene sulfonate Ligand

10 3 [ligand] (mol dm−3)

Azide

Thioglycolic acid

2-thiouracil

Temperature (oC) 50

55

60

65

1.0

0.95

1.28

1.72

2.36

2.0

1.71

2.24

2.91

4.16

3.0

2.34

3.00

3.85

4.84

4.0

2.77

3.49

4.36

5.51

5.0

3.12

3.91

4.81

5.84

1.0

0.36

0.41

0.54

0.72

2.0

0.70

0.85

1.08

1.35

3.0

0.99

1.14

1.37

1.76

4.0

1.21

1.37

1.75

2.29

5.0

1.34

1.50

1.92

2.56

1.0

0.22

0.31

0.44

0.67

2.0

0.39

0.54

0.75

1.12

3.0

0.53

0.76

0.98

1.45

4.0

0.65

0.87

1.19

1.64

5.0

0.74

0.91

1.32

1.82

204

Table 3 Comparison of kinetic and thermodynamic parameters, at different temperatures for the anation of [Ru(bpy)2(H2O)2]2+ complex by three different ligands in aqueous medium for the first step Ligand

Azide

Thioglyc olic acid

2thiouraci l

Temp

103 k1

( oC )

(dm3 mol1s1)

(dm3mol-1)

50

7.71

141

55

8.34

182

60

9.15

232

65

10.01

314

50

5.24

74

55

5.81

82

60

6.55

91

65

7.51

106

50

1.80

139

55

2.07

176

60

2.62

202

65

3.23

263

KE1

ΔH1≠ (kJ mol-1)

ΔS1≠ (JK-1 mol-1)

ΔH10

ΔS10

(kJ mol-1)

(JK-1 mol-1)

12.8 ±0.7 -246 ± 2

46.7±3.3

186 ± 9

19.1± 1.2 -230 ± 4

21.4±1.6

102 ± 5

32.4± 2.9 -198 ± 9

36.1±3.9

153 ± 12

205

Table 4 104k2(obs) (s-1) values for the interaction of [Ru(bpy)2(H2O)2]2+ complex by three different ligands at different ligand concentrations and at different temperatures for the second step, [substrate complex] = 1.00 10-4 mol dm-3, pH=4.5, ionic strength = 0.1 mol dm-3 of sodium p-toluene sulfonate Ligand

10 3 [ligand] (mol dm−3)

Azide

Thioglycolic acid

2-thiouracil

Temperature (oC) 50

55

60

65

1.0

0.51

0.86

1.41

2.02

2.0

0.97

1.56

2.40

3.33

3.0

1.34

2.12

3.12

4.26

4.0

1.63

2.49

3.62

4.80

5.0

1.84

2.79

4.06

5.03

1.0

0.96

1.25

1.55

1.85

2.0

0.98

1.24

1.54

1.84

3.0

0.99

1.28

1.56

1.86

4.0

0.99

1.24

1.55

1.85

5.0

0.97

1.29

1.55

1.90

1.0

0.74

1.01

1.26

1.65

2.0

0.73

1.02

1.25

1.65

3.0

0.75

1.02

1.27

1.67

4.0

0.74

1.01

1.28

1.63

5.0

0.72

1.00

1.26

1.66

206

Table 5 Comparison of kinetic and thermodynamic parameters, at different temperatures for the anation of [Ru(bpy)2(H2O)2]2+ complex by three different ligands in aqueous medium for the second step Ligand

Temp

Thioglyc olic acid

2thiouraci l

KE2

(dm3 mol-1s1)

(dm3 mol-1)

50

6.05

93

55

6.87

144

60

7.70

225

65

8.67

305

50

0.98

55

1.26

60

1.55

65

1.86

50

0.74

55

1.01

60

1.26

65

1.65

( oC )

Azide

10 4 k2

ΔH2≠ (kJ mol-1)

ΔS2≠ (JK-1 mol-1)

18.4 ±0.6 -250 ± 2

ΔH20 (kJ mol-1)

71.3±1.5

ΔS20 (JK-1mol-1)

259 ± 4

36.0± 1.6 -192 ± 5

43.7± 2.4 -189 ± 7

For all the three reactions (thioglycolic acid, 2-thiouracil and azide) studied, an associative activation mechanism is proposed, in which both the formation of the new metal-ligand bond and the rupture of metal-OH2 bond are equally important. The low ∆H≠ values are in support of the ligand participation in the transition state for both the paths. The high negative ∆S≠ values for both the steps suggest a more compact transition state, than the starting complex which also corroborates the assumption of a ligand participating transition state. The ΔG0 values, calculated at all temperatures studied, have a negative magnitude which is once again in favour of the spontaneous formation of an outer sphere association complex.

207

For thioglycolic acid and 2-thiouracil the first steps proceeds via associative interchange activation and the second steps are the ring closure. At the outset of first steps outer sphere association complexes result, which are stabilized through Hbonding and followed by an interchange from the outer sphere to the inner sphere complex. For azide both the steps proceed by an associative interchange mode of activation and both the steps are dependent on ligand concentration. The sensitivity of the reaction rate towards donor properties of the entering ligands are in the line with that expected for an associative mode of activation. The reactivity of the incoming ligands follow the order: azide > thioglycolic acid > 2thiouracil. Steric effect and electronic effect play an important role to point out the mechanism. Azide is less sterically crowded than thioglycolic acid and which is less sterically crowded than 2-thiouracil. Azide and thioglycolic acid exist as anionic form at the studied pH, but 2-thiouracil exists as neutral form which is reflected in the rate constant values. The another systems studied was the interaction of three sulphur containing ligands

diethyldithiocarbamate,

thiourea

[(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex.

[tap

and

L-cysteine

= 2-(m-tolylazo)pyridine,

with an

unsymmetrical bidentate N,N-chelator with azoimine function (-N=N-C=N-)] in an aqueous medium at pH 7.4. The importance of the work lies in the fact that it has been done in an aqueous medium and at the physiological pH under which conditions most of the ruthenium(II) complexes are oxidised to ruthenium(III); but the +2 state of the metal ion in this complex ion is quite stable due to the presence of an excellent acceptor ligand, tap [22, 23]. The products of the reactions have been characterized by IR and ESI-mass spectroscopic analysis. The compositions of the products in the reaction mixture were determined by Job’s method of continuous variation. The metal-ligand ratio was found to be 2:1 for all the three ligands. First acid dissociation equilibrium of the complex [Ru(tap)2(H2O)2]2+ is 6.6 [24] at 25oC. At pH 7.4, the complex ion exists in dimeric oxo-bridged form, [(H2O)(tap)2RuORu(tap)2(H2O)]2+ [25–28]. At pH 7.4, the mononuclear species exists in the hydroxoaqua form. Two such species assemble to form the dinuclear oxo-

208

bridged diaqua complex due to thermodynamic force mainly arising from pi-bonding [29] (O2 − donor, Ru II acceptor) which is favorable for 4d ion, Ru II.

Ka [Ru(tap)2(H2O)2]2+ ⇌ [Ru(tap)2(H2O)(OH)]+ + H+

(7)

2+ O

(tap)2Ru

Ru(tap)2

H2O

OH2

Dimeric oxo-bridged form

The pKa value of the ligand sodium diethyldithiocarbamate (DDTC-) is 3.37 at 25 oC [30], so at pH 7.4 it exists as anionic form. The pKa value of thiourea is 2.0 at 25 oC [31], so that at pH 7.4 it exists in the neutral form. On the other hand the pK1, pK2 and pK3 values of L-cysteine are 1.71, 8.33, and 10.78 respectively at 25 oC [32]. So

at

pH

7.4,

the

+

-

ligand

L-cysteine

exists

as

zwitterionic

form,

HS¬CH2¬CH(NH3) COO . For all the three ligands, at constant temperature, pH (7.4) and fixed concentration of complex the ln(A∞−At) versus time(t) plots for different ligand concentrations indicate a two step process and with increasing ligand concentration a limiting rate is reached. For diethyldithiocarbamate both the steps are dependent on the incoming ligand concentration. For thiourea and L-cysteine first step is dependent on ligand concentration but the second step is independent on ligand concentration. For diethyldithiocarbamate the rate constant can be evaluated by assuming the following scheme 3.

209

[(H2O)(tap)2RuORu(tap)2(H2O)]2+ + DDTC(1) ⇅ KE/ & KE // [(H2O)(tap)2RuORu(tap)2(H2O)]2+• DDTCOutersphere association complex

k1 & k2 [(tap)2RuO(DDTC)Ru(tap)2]+ + 2H2O (2) Scheme 3 In the starting complex there are two equivalent ruthenium(II) centers. Now the ligand has two donor centers. During the ligation two donor centers attack in two parallel speeds (k1 and k2). Based on the above scheme a rate expression can be derived for the first path (k1) d[2]/dt = k1KE/ [{(H2O)(tap)2RuORu(tap)2(H2O)}2+][DDTC- ]/(1+KE/ [DDTC-])

(8)

or, d[2]/dt = k1(obs) .[{(H2O) (tap)2RuORu(tap)2(H2O)}2+] T

(9)

Where T stands for total concentration of Ru(II).We can then write, k1(obs) = k1 KE/ [DDTC-]/(1+ KE/ [DDTC-] )

(10)

Where k1 is the rate constant for first path, i.e., the rate constant for the interchange of outer sphere complex to the inner sphere complex; KE/ is the outer sphere association equilibrium constant for the first path. The equation can be represented as: 1/k1(obs) = 1/k1 +1/k1 KE/ [DDTC-]

(11)

The plot of 1/k1(obs) against 1/[DDTC-] should be linear with an intercept of 1/k1 and slope 1/k1KE/. This was found to be the case at all temperatures studied. For second path the rate equation can be written as similar as equation 11. i.e. 1/k2(obs) = 1/k2 +1/k2 KE// [DDTC-]

(12)

A parallel reaction scheme was proposed to explain the experimental findings. The rate constant values for such a parallel reaction are widely different. In a parallel reaction two paths overlap each other. But during the calculation of the first

210

path (k1~10 -3 s-1) the contribution from second path (k2 ~10-5 s-1) is negligible. On the other hand, when we are calculating the rate constant for the second path the first path is already complete. Thus there is no problem in calculating k1 and k2. For thiourea and L-cysteine scheme 4 have been proposed. KE [(H2O)(tap)2RuORu(tap)2(H2O)]2+ + L → [(H2O)(tap)2RuORu(tap)2(H2O)]2+.L (1) (Outer sphere association complex) k1 [(H2O)(tap)2RuORu(tap)2(H2O)]2+.L → [(H2O)(tap)2RuORu(tap)2L]2+ -H2O [B] k2 [(H2O)(tap)2RuORu(tap)2L]2+ →

[(tap)2RuORu(tap)2L]2+ + H2O

Ring closure

[B] (Where L= thiourea or L-cysteine)

Scheme 4 Based on Scheme 4, a rate expression can be derived: d[B]/dt = k1KE[(H2O)(tap)2RuORu(tap)2(H2O)]2+][L]/(1+KE[L]), d[B]/dt = k1(obs)[ [(H2O)(tap)2RuORu(tap)2(H2O)]2+]T where subscript T stands for total concentration of Ru(II). Thus it can be written as k1(obs) = k1KE[L]/(1+KE[L])

(13)

where k1 is the rate constant for the first step. KE is the outer-sphere associatioequilibrium constant. Equation can be represented as: 1/k1(obs) = 1/k1 +1/k1KE[L]

(14)

The plot of 1/k1(obs) against 1/[L] should be linear with an intercept of 1/k1 and slope 1/k1KE. For thiourea and L-cysteine the second step is intramolecular ring closure and is independent of ligand concentration. At a particular temperature the slopes of ln(At A∞) versus time plots at different ligand concentrations were found to be constant in the region where the plots are linear. For different temperatures the k2 values are obtained directly from the limiting slope.

211

For all the three ligands from the temperature dependence of the anation rate constants (k1), using Eyring equation we calculate the ∆H≠ and ∆S≠ values and from the temperature dependences of the KE values the thermodynamic parameters (H0 and S0) are calculated. The k values are the interchange rate constants dependent on the donor ability of the ligands. The low enthalpy of activation (∆H1 and ∆H2) values and negative entropy of activation (∆S1 and ∆S2) values imply a good degree of ligand participation in the transition state. The higher the nucleophilicity of the ligand, the smaller the activation enthalpy because of stabilization of the transition state. For all the three ligands, with an increase in ligand concentration saturation in rate is observed. This is possible only when an outer sphere association complex is formed and that complex is possibly stabilised through H-bonding. The ΔG0 values, calculated at all temperatures studied, have a negative magnitude which is once again in favour of the spontaneous formation of an outer sphere association complex. The rate constant values (k(obs)), kinetic parameter values (k, ∆H≠ and ∆S≠) and thermodynamic parameter values (KE, ∆H0 and ∆S0) for the interaction of [(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex with thiourea, diethyldithiocarbamate and L-cysteine are collected in Tables 6 to 9. Table 6 10 3k1(obs) (s-1) values for the interaction of [(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex by three different ligands at different ligand concentrations and at different temperatures for the first step, [complex] = 1.0 × 10 -4 mol dm-3, pH = 7.4, ionic strength = 0.1 mol dm-3 NaClO4 Ligand

10 3 [ligand] (mol dm−3)

Temperature (oC) 50

55

60

65

1.0

1.40

1.71

2.38

2.84

2.0

2.48

2.94

4.00

4.79

3.0

3.35

3.90

5.08

6.01

4.0

3.83

4.55

5.81

6.71

5.0

4.27

5.06

6.28

6.97

Sodium

1.0

0.81

1.14

1.40

1.79

diethyldithio

2.0

1.53

2.08

2.50

3.03

carbamate

3.0

2.13

2.77

3.45

4.16

4.0

2.50

3.22

4.00

4.76

Thiourea

212

L-cysteine

5.0

2.76

3.85

4.35

5.55

1.0

0.75

1.01

1.23

1.55

2.0

1.39

1.92

2.40

2.79

3.0

1.94

2.47

3.05

3.95

4.0

2.20

2.93

3.42

4.22

5.0

2.54

3.25

3.84

4.50

Table 7 Comparison of kinetic and thermodynamic parameters, at different temperatures for the anation of [(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex by three different ligands in aqueous medium for the first step Ligand

Thiourea

Sodium diethyldi thio carbamat e

Lcysteine

Temp

103 k1

( oC )

(dm3 mol-1s1)

(dm3mol-1)

50

9.38

176

55

10.18

202

60

11.12

273

65

12.13

309

50

8.33

109

55

9.09

143

60

10.00

164

65

11.11

191

50

6.94

122

55

8.24

141

60

9.42

153

65

10.53

174

KE1

ΔH1 ≠ (kJ mol-1)

ΔS1≠ (JK-1 mol-1)

ΔH10 (kJ mol-1)

ΔS10 (JK-1 mol-1)

12.4 ±0.5 -246 ± 2

35.2 ± 4

152 ± 11

14.1± 0.9 -241 ± 3

32.3±3.3

139 ± 9

21.8± 1.1 -219 ± 3

20.2±1.6

103 ± 5

213

Table 8 10 5k2(obs) (s-1) values for the interaction of [(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex by three different ligands at different ligand concentrations and at different temperatures for the second step, [complex] = 1.0 × 10-4 mol dm-3, pH = 7.4, ionic strength = 0.1 mol dm-3 NaClO4 Ligand

10 3 [ligand] (mol dm−3)

Temperature (oC) 50

55

60

65

1.0

14.17

17.28

20.57

23.78

2.0

14.20

17.29

20.57

23.82

3.0

14.15

17.28

20.58

23.79

4.0

14.16

17.28

20.59

23.80

5.0

14.19

17.27

20.57

23.83

Sodium

1.0

0.39

0.5

0.66

0.85

diethyldithio

2.0

0.71

0.91

1.12

1.49

carbamate

3.0

0.97

1.20

1.54

2.04

4.0

1.10

1.45

1.85

2.32

5.0

1.27

1.61

2.10

2.63

1.0

2.87

3.46

4.22

5.32

2.0

2.85

3.45

4.17

5.34

3.0

2.85

3.47

4.19

5.32

4.0

2.86

3.44

4.16

5.30

5.0

2.85

3.43

4.21

5.32

Thiourea

L-cysteine

214

Table 9 Comparison of kinetic parameters, at different temperatures for the anation of [(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex by three different ligands in aqueous medium for the second step Ligand

Thiourea

Sodium diethyldith io carbamate

L-cysteine

Temp

10 5 k2

( oC )

(dm3 mol-1s1)

ΔH2≠

KE2 (dm3mol-1)

50

14.17

55

17.28

60

20.58

65

23.80

50

3.16

140

55

3.87

149

60

4.60

165

65

5.70

177

50

2.86

55

3.45

60

4.19

65

5.32

ΔS2≠

ΔH20

ΔS20

(kJ mol-1)

(JK-1 mol-1)

(kJ mol-1)

(JK-1mol-1)

28.0 ±0.6

-232± 2

31.9± 1.9

-233 ± 6

33.4± 2.8

-229 ± 8

13.9±1.0

84 ± 1

The relative reactivity order for the system [(H2O)(tap)2RuORu(tap)2(H2O)]2+ is: thiourea  diethyldithiocarbamate  L-cysteine. Thiourea is less strically crowded than diethyldithiocarbamate and L-cysteine which is reflected in rate constant and activation parameter values. Again diethyldithiocarbamate exists as anionic form at studied pH but L-cysteine is neutral ligand. So reactivity of L-cysteine is less than that of diethyldithiocarbamate. The

interaction

of

diethyldithiocarbamate

with

the

[(H2O)(tap)2RuORu(tap)2(H2O)]2+ complex proceeds via two distinct parallel

215

substitution steps of aqua molecules (k1~10-3 s-1 and k2 ~10 -5 s-1). Each step proceeds via an associative interchange activation. At the outset of each step outer-sphere association complex results, this is stabilised through H-bonding and is followed by an interchange from the outer-sphere to the inner-sphere complex. The activation parameter values for both the steps suggest an associative mode of activation for the substitution process. From the I.R. study it is confirmed that the two S atoms of the ligand DDTC- are non-equivalent. In the starting complex there are two equivalent ruthenium(II) centers. During the ligation two S atoms of the ligand DDTC- attack in two parallel speeds (k1 and k2) and a six membered ring is formed. In case of thiourea and L-cysteine, in the first step a rapid equilibrium is established, giving an outer sphere complex between complex and the ligands. The second step is the intramolecular ring closure which is independent on the incoming ligands concentrations. Based on the experimental findings an associative mechanism is proposed for the substitution process. From the IR data of both thiourea substituted product and L-cysteine substituted product, it is clear that the only S atom of both the ligands are participating in bonding. The S atom in C=S group of thiourea and S atom in –SH group of L-cysteine are involved in bonding with metal. This is consistent with the soft nature of both sulphur and ruthenium(II). Both thiourea and L-cysteine act as bridging ligand and in both the cases four membered rings are formed with the complex. Kinetic and mechanistic studies of substitution reaction of Rh(III) complex The thesis also contains the report of the kinetics and mechanism of hydroxopentaaquarhodium(III)

ion,

[Rh(H2O)5 (OH)]2+ by some

ligands viz.

thioglycolic acid, 2-thiouracil, glutathione and azide as a function of substrate complex concentration, pH, incoming ligand concentration and temperature at constant ionic strength. The interactions of all these ligands with [Rh(H2O)5(OH)]2+ were studied within the temperature range 50oC to 65oC at pH 4.3 in aqueous medium, except in case of pH variation. The products of the reactions have been characterized by IR and ESI-mass spectroscopic analysis. The composition of the product in the reaction mixture was determined by Job’s method of continuous variation. The metal-ligand ratio was found to be 1:1 for thioglycolic acid, glutathione and 2-thiouracil but for azide the ratio was 1:2.

216

The complex, [Rh(H2O)6](ClO4)3 was prepared as per the literature method [33] and characterised by chemical analysis and spectroscopic data [34] (max = 396 nm,  = 62 dm3 mol-1cm-1; max = 311 nm,  = 67.4 dm3 mol-1cm-1). The procedure of the preparation is

HClO4

→

RhCl3.xH2O [Rh(H2O)6](ClO4)3 Repeated evaporation The needle shaped light yellow crystals of [Rh(H2O)6](ClO4)3 was washed with ice cold HClO4. The crystals were dried in vacuum over P2O5. The temperature was kept at 110 oC by boiling toluene. The substrate complex [Rh(H2O)5(OH)]2+ was obtained in situ (yield  90%) by adjusting the pH of the solution at 4.3. Further higher pH was not suitable for study because at pH higher than 4.3 the solution became turbid. The ionization of [Rh(H2O)6]3+ may be given as: [Rh(H2O)6]3

+

Ka (1)

⇌

[Rh(H2O)5OH]2+

+

Ka (2) [Rh(H2O)5OH]2+ ⇌ [Rh(H2O)4(OH)2]+

H+

+

(15) H+

(16)

The First and second acid dissociation equilibrium of the complex [Rh(H2O)6]3+ are 3.6 and 4.7 respectively at 25ºC [35]. Other reports on the pKa(1) value are 3.2, 3.4 and 3.45 [35], i.e at pH 4.3 the complex [Rh(H2O)6]3+ mainly exist as [Rh(H2O)5(OH)]2+ species. From the pK values of the ligands we can say that at pH = 4.3, thioglycolic acid, glutathione and azide remain in the anionic form and 2thiouracil exists in neutral form. The interaction of [Rh(OH2)5(OH)]2+ with the above mentioned ligands were studied at four different temperatures and at different ligand concentrations. The k(obs) values increase with the increase in ligand concentrations and at higher ligand concentration a limiting rate was observed in all the cases studied. The parameters studied for different ligands were kept identical for comparison. The observations were in accordance with the associative interchange mechanism, where an outersphere association complex is first formed between the ligand and the complex, followed by an interchange of the ligand from outer to inner sphere with the displacement of one

217

coordinated aqua ligand from the complex which has been designated as anation step. The plots of ln(A∞-At) verses time(t) for the four different ligand concentrations indicate that the reaction is not a single step process, a two step consecutive process may be assumed. For thioglycolic acid, glutathione and 2-thiouracil the first step being dependent on ligand concentration and the final step is independent of the concentration of the ligands. For azide both the steps are dependent on ligand concentration. For thioglycolic acid, glutathione and 2-thiouracil the rate constant for such a process can be evaluated by assuming scheme 5. 1

k1

B

k2

2/3/4

KE [Rh(H2O)5(OH)]2+ + LHn- ⇌ [Rh(H2O)5(OH)]2+ . LHn(Outersphere association) 1 k1 [Rh(H2O)5(OH)]2+. LHn- → [Rh(H2O)4(OH)(LH)](2-n)+ -H2O B k2 [Rh(H2O)4(OH)(LH)](2-n)+ → [Rh(H2O)3(OH)(L)](1-n)+ + H3O+ (chelation) 2 /3 /4 Scheme 5 Where n is 1 for thioglycolic acid and glutathione and 0 for 2-thiouracil. Here k1 is the anation rate constant for the slow step i.e. for the interchange of the outer sphere to inner sphere complex and KE is the outersphere association equilibrium constant. k2 is the rate constant for intramolecular ring closure step. Based on this pathway a rate expression can be written as d[B]/dt = k1KE[[Rh(H2O)5(OH)]2+][ LHn-]/(1 + KE[LHn-])

(17)

or, d[B]/dt = k1(obs)[Rh(H2O)5(OH)]2+] T

(18)

where T stands for total concentration of Rh(III). We can then write: k1(obs)=k1KE[LHn-]/(1+KE[LHn-])

(19)

218

where k1 is the anation rate constant for the first step, i.e., the anation rate constant for interchange of the outer sphere complex to the inner sphere complex; KE is the outer sphere association equilibrium constant. This equation can be represented as 1/k1(obs) = 1/k1 + 1/k1KE[LHn- ]

(20)

The plot of 1/k1(obs) versus 1/[ LHn-] should be linear with an intercept of 1/k1 and slope 1/k1KE. This was found to be so at all temperatures studied. For thioglycolic acid, glutathione and 2-thiouracil the second step is intramolecular ring closure and is independent of ligand concentration. Due to steric hindrance, this step is slower. At a particular temperature, the k2 values were calculated from the limiting linear portion (where t is large) of the ln(A∞ - At) versus time curve. For different temperatures, k2 values obtained directly from the limiting slope of ln(A∞ - At) versus time plots. For azide the rate constant can be evaluated by assuming the following scheme 6 . k1 k2 A→B→C Where A is complex (1), B is as intermediate with azide and C is the final product complex [Rh(H2O)3(OH)(N3)2] .

KE1 [Rh(H2O)5(OH)]2+ + N3- ⇌ [Rh(H2O)5(OH)]2+ . N3(1) Outersphere association complex k1 [Rh(H2O)5(OH)]2+ . N3- → [Rh(H2O)4(OH)(N3)]+ +H2O B KE2 [Rh(H2O)4(OH)(N3)]+ + N3- ⇌ [Rh(H2O)4(OH)(N3)]+. N3Outersphere association complex k2 [Rh(H2O)4(OH)(N3)]+. N3- → [Rh(H2O)3(OH)(N3)2] + H2O C Scheme 6

219

Based on Scheme 6, a rate expression can be derived: d[B]/dt = k1KE1 [Rh(H2O)5(OH)]2+ [N3-] /(1 +KE1[N3-])

(21)

d[B]/dt = k1(obs).[Rh(H2O)5(OH)2+]T

(22)

where T stands for total concentration of Rh(III). We can then write: k1(obs) = k1KE1[N3-] /(1 +KE1[N3-])

(23)

where k1 is the rate constant for the A→B step; that is, the rate constant for the interchange of outer-sphere complex to the inner-sphere complex. KE1 is the outersphere association equilibrium constant for the first step. Equation 23 can be represented as: 1/k1(obs) = 1/k1 +1/k1KE1[N3-]

(24)

The plot of 1/k1(obs) against 1/[ N3-] should be linear with an intercept of 1/k1 and slope 1/k1KE1. This was found to be the case at all temperatures studied. For azide the second step is also dependent on ligand concentration and shows a limiting value at higher concentration of the ligand. A new azide ligand attacks the rhodium(III) center. The rate constants (k2) were calculated from latter linear portions of the graphs. The pseudo-first order rate constants (k2(obs)) were found to increase with increase in ligand concentrations and show a limiting condition which is probably due to the completion of the outer sphere association complex formation. The rate equation can be written as similar to equation 24, i.e. 1/k2(obs) = 1/ k2 + 1/ k2KE2[N3-]

(25)

A plot of 1/k2(obs) verses 1/[ N3-] should be linear with an intercept of 1/k2 and slope 1/ k2KE2. For all the four ligands from the temperature dependence of the anation rate constants (k1), we calculate the ∆H≠ and ∆S≠ values and from the temperature dependences of the KE values the thermodynamic parameters (H0 and S0) are calculated. The rate constant values (k(obs)), kinetic parameter values (k, ∆H≠ and ∆S≠) and thermodynamic parameter values (KE, ∆H0 and ∆S0) for the interaction of [Rh(H2O)5(OH)]2+ complex with azide, thioglycolic acid, 2-thiouracil and glutathione are collected in Tables 10 to 13.

220

Table 10 10 3k1(obs) (s-1) values for the interaction of [Rh(H2O)5(OH)]2+ complex by the four different ligands at different ligand concentrations and at different temperatures for the first step, [complex] =2.5×10−4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4

Ligand

Azide

Thioglycolic acid

2-thiouracil

Glutathione

10 3 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

2.5

2.00

2.43

3.13

3.97

5.0

3.30

3.82

4.96

5.85

7.5

3.96

4.57

5.61

6.90

10.0

4.31

4.97

6.14

7.14

12.5

4.43

5.31

6.39

7.34

2.5

1.71

1.92

2.21

2.77

5.0

2.69

3.03

3.34

4.24

7.5

3.09

3.48

3.94

4.88

10.0

3.28

3.63

4.22

5.21

12.5

3.38

3.76

4.31

5.39

2.5

0.41

0.64

0.94

1.36

5.0

0.68

0.99

1.42

2.00

7.5

0.79

1.19

1.64

2.22

10.0

0.89

1.26

1.71

2.37

12.5

0.95

1.32

1.77

2.41

2.5

0.33

0.43

0.71

0.97

5.0

0.53

0.72

1.05

1.56

7.5

0.66

0.83

1.29

1.74

10.0

0.73

0.94

1.44

1.91

12.5

0.78

0.99

1.55

2.02

221

Table 11 Comparison of kinetic and thermodynamic parameters, at different temperatures for the anation of [Rh(H2O)5(OH)]2+ complex by the four different ligands in aqueous medium for the first step

Ligand

Temp

Thioglycol ic acid

2thiouracil

Glutathion e

KE1

ΔH1≠

ΔS1≠

ΔH10

ΔS10

(dm3 mol-1s1)

(dm3 mol-1)

(kJ mol-1)

(JK-1 mol-1)

(kJ mol-1)

(JK-1mol-1)

50

7.02

162

18.1 ±1.1

-230 ±3

30.2 ± 4.4

136 ± 13

55

7.80

183

60

9.07

215

65

9.88

273

50

4.81

226

22.4± 3.0

-220±11

3.60 ±0.03

56 ± 1

55

5.33

231

60

6.03

236

65

7.46

240

50

1.45

162

42.2± 2.0

-169 ± 6

39.7±0.9

165 ± 3

55

1.90

205

60

2.40

265

65

3.13

314

50

1.22

150

47.2± 1.7

-155 ± 5

22.4±3.1

111 ± 9

55

1.55

157

60

2.15

198

65

2.86

212

( oC )

Azide

10 3 k1

222

Table 12 10 5k2(obs) (s-1) values for the interaction of [Rh(H2O)5(OH)]2+ complex by the four different ligands at different ligand concentrations and at different temperatures for the second step, [complex] =2.5×10 −4 mol dm−3, pH = 4.3, and ionic strength = 0.1 mol dm−3 NaClO4

Ligand

Azide

Thioglycolic acid

2-thiouracil

Glutathione

10 3 [ligand]

Temperature (oC)

(mol dm−3)

50

55

60

65

2.5

4.28

5.49

7.14

8.39

5.0

7.08

9.06

11.94

13.74

7.5

8.79

11.17

14.31

16.34

10.0

9.58

12.25

15.34

17.87

12.5

10.24

12.70

16.10

19.12

2.5

8.88

11.32

14.20

17.92

5.0

8.89

11.30

14.18

17.93

7.5

8.85

11.34

14.20

17.87

10.0

8.88

11.33

14.20

17.89

12.5

8.86

11.31

14.22

17.91

2.5

4.45

6.68

9.98

14.21

5.0

4.46

6.64

10.01

14.20

7.5

4.40

6.67

10.00

14.21

10.0

4.42

6.65

9.99

14.21

12.5

4.44

6.67

10.02

14.22

2.5

2.50

4.11

6.63

9.02

5.0

2.47

4.08

6.58

9.04

7.5

2.45

4.06

6.60

9.04

10.0

2.49

4.07

6.62

9.06

12.5

2.47

4.09

6.60

9.04

223

Table 13 Comparison of kinetic and thermodynamic parameters, at different temperatures for the anation of [Rh(H2O)5(OH)]2+ complex by the four different ligands in aqueous medium for the second step Ligand

Azide

Thioglycol ic acid

2thiouracil

Glutathion e

ΔH2 ≠

ΔS2≠

ΔH20

(dm3mol-1)

(kJ mol-1)

(JK-1 mol-1)

(kJ mol-1)

16.70

138

32.4 ±0.2

-217±1

9.9 ± 0.7

55

20.76

146

60

25.66

157

65

30.30

162

50

8.87

38.5± 1.3

-204 ± 4

55

11.32

60

14.20

65

17.90

50

4.43

66.1± 0.5

-124 ± 2

55

6.66

60

10.00

65

14.21

50

2.48

73.5± 1.1

-105 ± 3

55

4.08

60

6.61

65

9.04

Temp

105 k2

( oC )

(dm3 mol-1s1)

50

KE2

ΔS20 (JK-1 mol-1)

71 ± 2

224

From the experimental results it is indicated that the anations on [Rh(H2O)5(OH)]2+ complex by four ligands proceed via an associative interchange(Ia) mode of activation. The proposition is supported by the following facts: With an increase in ligand concentration saturation in rate is observed for all the ligands. This is possible only when an outer sphere association complex is formed and that complex is possibly stabilized through H-bonding. As the ligands react in the immediate vicinity of the complex, thus an increase in concentration of the ligand can not increase the rate. The lower value of enthalpy of activation and large negative value of entropy of activation strongly suggest the ligand participation in the transition state. The ΔG0 values, calculated at all temperatures studied, have a negative magnitude which is once again in favour of the spontaneous formation of an outer sphere association complex. Summing up all the results, it may be concluded that for all the four ligands the reactions proceed through a two step consecutive process. For thioglycolic acid, glutathione and 2-thiouracil the first step is dependent on the ligand concentration and second one is ligand independent intramolecular ring closure. For azide both the steps proceed by an associative interchange mode of activation and both the steps are dependent on ligand concentration. When thioglycolic acid and glutathione react with [Rh(H2O)5(OH)]2+ the five membered ring is formed. In case of 2-thiouracil a four membered ring is formed. But when azide interacts with [Rh(H2O)5(OH)]2+ no ring formation is occurred as azide is a monodentate ligand. The activation parameters for anation by different incoming ligands on the same substrate are given for comparison. It is observed that the values are changing depending on the ligand, which strongly suggests an associative nature for the reactions. The reactivity of the incoming ligands follow the order: azide > thioglycolic acid > 2-thiouracil > glutathione. This reactivity order indicates that steric effect and electronic effect are two important factors for assigning the reactivity order. Azide is less sterically crowded than other ligands and thioglycolic acid is also less strically crowded than 2-thiouracil and glutathione. The steric effect in case of 2-thiouracil is also less than glutathione. Azide, thioglycolic acid and glutathione exist in anionic form whereas 2-thiouracil exists as neutral form during interaction with the ([Rh(H2O)5(OH)]2+) complex. This fact also affects the reactivity order.

225

Comparison of reactivities of ruthenium(II) and rhodium(III) complexes We have compared the rate constants and activation parameters of [Ru(bpy)2(H2O)2]2+

and

[Rh(H2O)5(OH)]2+ complexes using the same ligands

(thioglycolic acid, 2-thiouracil and azide) at common temperatures 50-65 oC. For these two complexes kinetic studies have been done at nearer pH. i.e at 4.5 for [Ru(bpy)2(H2O)2]2+ complex and at 4.3 for [Rh(H2O)5(OH)]2+ complex. For this reason we have easily compared the reactivity parameters of these two systems. We can not compare the [(H2O)(tap)2RuORu(tap)2(H2O)]2+ [Ru(bpy)2(H2O)2]2+

rate constants and activation parameters of complex

with

[Rh(H2O)5(OH)]2+,

and 2+

[(H2O)(tap)2RuORu(tap)2(H2O)]

these

two

because

in

systems, case

of

complex the kinetic studies have been done at

physiological pH (pH 7.4) under which conditions most of the ruthenium(II) complexes are oxidised to ruthenium(III); but the +2 state of the metal ion in this complex ion is quite stable due to the presence of an excellent -acceptor ligand, tap (2-(m-tolylazo)pyridine). In case of [Ru(bpy)2(H2O)2]2+ the reactions have been carried out at pH 4.5. Because at higher pH (pH  7) ruthenium(II)

is oxidised to

6

ruthenium(III) which is not a 4d system. Again Ru(II) compounds are better than the corresponding ruthenium(III) since the latter is a prodrug, to be reduced to Ru(II) in a reducing enviorment of the affected area of the cells. For [Rh(H2O)5(OH)]2+ complex kinetic studies have done at pH 4.3 because at higher pH (pH  4.5) precipitation of rhodium(III) occurred. The rate constant values (k1 and k2), and activation parameter values (∆H≠ and ∆S≠ ) for the interactions of [Rh(H2O)5(OH)]2+ and [Ru(bpy)2(H2O)2]2+ complexes with azide, thioglycolic acid and 2-thiouracil are collected in Tables 14 and 15.

226

Table 14 Comparison of kinetic parameters, at different temperatures for the anation of [Ru(bpy)2(H2O)2]2+ and [Rh(H2O)5(OH)]2+ complexes using the same ligands in aqueous medium for the first step

Ligand

Azide

System

[Ru(bpy)2(H2O)2]2+

[Rh(H2O)5(OH)]2+

Thioglycoli

[Ru(bpy)2(H2O)2]2+

c acid

[Rh(H2O)5(OH)]2+

ΔH1 ≠

ΔS1≠

Temp

10 3 k1

(oc )

( s-1)

(kJ mol-1 ) (JK-1 mol-1)

50

7.71

12.8 ± 0.7

-246 ±2

55

8.34

60

9.15

65

10.01

50

7.02

18.1 ± 1.1

-230 ± 3

55

7.80

60

9.07

65

9.88

50

5.24

19.1±1.2

-230 ± 4

55

5.81

60

6.55

65

7.51

50

4.81

55

5.33

60

6.03

65

7.46

22.4 ± 3.0

-220 ± 11

227

2-thiouracil

[Ru(bpy)2(H2O)2]2+

[Rh(H2O)5(OH)]2+

50

1.80

55

2.07

60

2.62

65

3.23

50

1.45

55

1.90

60

2.40

65

3.13

32.4 ± 2.9

-198 ± 9

42.2 ± 2.0

-169 ± 6

Table 15 Comparison of kinetic parameters, at different temperatures for the anation of

[Ru(bpy)2(H2O)2]2+ and [Rh(H2O)5(OH)]2+ complexes using the same ligands in

aqueous medium for the second step Ligand

Azide

System

[Ru(bpy)2(H2O)2]2+

[Rh(H2O)5(OH)]2+

Temp

10 4 k1

(oc )

( s-1)

50

6.05

55

6.87

60

7.70

65

8.67

50

1.68

55

2.07

60

2.56

65

3.03

ΔH2 ≠

ΔS2≠

(kJ mol-1 ) (JK-1 mol-1) 18.4 ± 0.6

-250 ± 2

32.4 ± 0.2

-217 ± 1

228

Thioglycoli

[Ru(bpy)2(H2O)2]2+

c acid

[Rh(H2O)5(OH)]2+

2-thiouracil

[Ru(bpy)2(H2O)2]2+

[Rh(H2O)5(OH)]2+

50

0.98

55

1.26

60

1.55

65

1.86

50

0.89

55

1.13

60

1.42

65

1.79

50

0.74

55

1.01

60

1.26

65

1.65

50

0.44

55

0.66

60

1.00

65

1.42

36.0 ± 1.6

-192 ± 5

38.5 ± 1.3

-204 ± 4

43.7 ± 2.4

-189 ± 7

66.1 ± 0.5

-124 ± 2

From the rate constant and activation parameter values it may be concluded that reactivity of [Ru(bpy)2(H2O)2]2+ complex are higher than [Rh(H2O)5(OH)]2+ complex when they interact with the same ligands using the same experimental conditions. This result is quite expected because due to presence of -acceptor ligand bpy the positive charge on the central metal ion (ruthenium) increases which is reflected in the kinetic parameters.

229

References 1. D.H. Macartney in ‘Mechanisms of Inorganic and Organometallic Reactions’, edited by M.V. Twigg, Vol 1-8, Plenum Press, New York and London, (1989). 2. R.B. Jordan, Reaction Mechanisms of Inorganic and Organometallic Systems’, 2/e, Oxford University Press, New York, (1998). 3. F. Basolo and R.G. Pearson, Mechanisms of Inorganic Reactions, 2nd Edn., John Wiley and Sons, New York (1967). 4. C.H. Langford and H.B. Gray, Ligand Substitution Dynamics, Benzamin, New York (1973). 5. R.G. Wilkins, The Study of Kinetics and Mechanism in Transition Metal Complexes, Allyn and Bacon, Boston (1974). 6. (a) I. Kostova, Ruthenium complexes as anticancer agents, Cur. Med. Chem., 13, 1085 (2006) and references therein, (b) I. Kostova, Recent patents on Anti-Cancer Drug Discovery, 1, 1 (2006). 7. E.A. Seddon and K.R. Seddon, The Chemistry of Ruthenium, Elsevier, New York (1984). 8. D. Mallick and G.S. De, Transition Met. Chem., 17, 491 (1992) and references therein. 9.

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21. L.R. Allen, B. Durhan and J. Walsh, Inorg. Chem., 26, 53 (1987). 22. S. Goswamy, A.R. Chakraborty and A. Chakraborty, Inorg. Chem., 20, 2246 (1981). 23. S. Goswami, A.R. Chakraborty and A. Chakravorty, Inorg. Chem., 22, 602 (1983). 24. B. Mahanti and G.S. De, Transition Met. Chem., 17, 521 (1992). 25. S.J. Raven and T.J. Meyer, Inorg. Chem., 27, 4478 (1998). 26. W. Kutner, J.A. Gilbert, A. Tomaszewski, T.J. Meyer and R.W. Murray, J. Electroanal. Chem., 205, 185 (1986). 27. S.W. Gersten, G.J. Samuels and T.J. Meyer, J. Am. Chem. Soc., 104, 4029 (1982). 28. P. Ghosh and A. Chakravorty, Inorg. Chem., 23, 2242 (1984). 29. F.A. Cotton, G. Wilkinson, C.A. Murrilo and M. Bochman, Adv. Inorg. Chem., John Wiley & Sons, NY, USA, 6th edition (1999). 30. K.I. Aspila, S.J. Joris and C.L. Chakrabarti, J. Phys. Chem., 74, 3625 (1970). 31. D.R. Goddard, B.D. Lodam, S.O. Ajayi and M.J. Campbell, J. Chem. Soc. A, 506 (1969). 32. A.E. Martell and M. Calvin, Chemistry of metal chelate compounds, 1 st Edn (Prentice Hall, New Jersey), 524 (1962). 33. G.H. Ayres and J.S. Forrester, J. Inorg. Nucl. Chem., 3, 365 (1957). 34. W.C. Wolsey, C.A. Reynolds and J. Kleinberg, J. Inorg. Chem., 2, 463 (1963). 35. I. Banyai, J. Glaser, M.C. Read and M. Sandstroem, Inorg. Chem., 34, 2423 (1995).

231

LIST OF PUBLICATIONS

1. Kinetics and mechanism of the interaction of bio-active ligands with cis-diaquabis(bipyridyl)ruthenium(II) in aqueous medium, Subala Mondal, Arup Mandal, Parnajyoti Karmakar, Biplab K. Bera, Subhasis Mallick, Sumon Ray and Alak K. Ghosh, J. Indian Chem. Soc., 90, 153 (2013). 2.

Kinetics

and

mechanism

of

the

ligand

substitution

2+

[(H2O)(tap)2RuORu(tap)2(H2O)] {tap=2-(m-tolylazo)pyridine}

reaction

of with

diethyldithiocarbamate anion in aqueous solution,Subala Mondal, Debabrata Nandi, Arup Mandal, Biplab Kumar Bera, Parnajyoti Karmakar, Sumon Ray, Subhasis Mallick and Alak K Ghosh, J. Indian Chem. Soc., 90, 903 (2013). 3. Kinetic and mechanistic studies on the interaction of azide with cis-diaquabis(bipyridyl) ruthenium(II)complex and hydroxopentaaqua rhodium(III) complex in aqueous medium. Subala Mondal, Sumon Ray, Animesh Chattopadhyay, Debabrata Nandi, Roshni Sarkar (Sain) and Alak K Ghosh, Prog. React. Kinet. Mech., (Accepted). 4. Mechanistic aspects of ligand substitution on hydroxopentaaquarhodium(III) ion in aqueous solution by sulphur containing bioactive ligands. Int. J. Chem. Kinet., (Revised). 5. Interaction of Thiourea and L-Cysteine with [(H2O)(tap)2RuORu(tap)2(H2O)]2+ {tap=2-(m-tolylazo)pyridine}

in

aqueous

medium:

kinetic

and

mechanistic

studies.(Communicated). 6. Kinetic Study of the Interaction of Three Glycine-Containing Dipeptides with Hydroxopentaaquarhodium(III) Ion in Aqueous Medium, Biplab K. Bera, Subala Mondal, Subhasis Mallick, Arup Mandal, Parnajyoti Karmakar, Alak K. Ghosh, J. Solution Chem., 41, 741 (2012). 7. Kinetics and mechanism of the ligand substitution reaction of di-µhydroxobis(bipyridyl)dipalladium(II) ion with thiourea in aqueous solution, Subhasis Mallick, Subala Mondal, Biplab K. Bera, Parnajyoti Karmakar, Sankar C. Moi and Alak K. Ghosh, Transition Met. Chem., 35, 469 (2010). 8.

Mechanistic Aspects of Ligand Substitution on [(H2O)(tap)2RuORu(tap)2(H2O)]2+

{tap = 2-(m-tolylazo)pyridine}, by Some Amino Acids in Aqueous Medium at Physiological pH, Arup Mandal, Subala Mondal, Parnajyoti Karmakar, Subhasis

232

Mallick, Biplab K Bera, and Alak K. Ghosh, Int. J. Chem. Kinet., DOI 10.1002/kin.20701. 9. Kinetic study of the interaction of three glycine-containing dipeptides with diaquaethylenediamineplatinum(II)

in aqueous medium. Subhasis Mallick, Subala

Mondal, Arup Mandal, Biplab K Bera, Parnajyoti Karmakar, and Alak K Ghosh, Int. J. Chem. Kinet., 43, 498 (2011). 10. Interaction of glutathione (reduced) with [(H2 O)(tap)2RuORu(tap)2(H2O)]2+ {tap = 2-(m-tolylazo)pyridine}, ion at physiological pH in aqueous medium. Tandra Das(Karfa), Subala Mondal, Asok K Datta, Biplab K. Bera, Parnajyoti Karmakar, Subhasis Mallick, Arup Mandal, and Alak K. Ghosh, I. J. LSc. Phar. Ras., 2, 76 (2012). 11. Mechanistic aspects of ligand substitution on [(H2O)(tap)2RuORu(tap)2(H2O)]2+ {tap = 2-(m-tolylazo)pyridine}ion by three glycinecontaining dipeptides in aqueous medium at physiological pH. Arup Mandal, Subala Mondal, Parnajyoti Karmakar, Biplab K Bera, Subhasis Mallick and Alak K. Ghosh, J. Chem. Sci., 124, 587 (2012). 12. Kinetics and mechanism of the ligand substitution reaction of di-µhydroxobis(bipyridyl)dipalladium(II) ion with diethyldithiocarbamate anion aqueous solution. Subhasis Mallick,

in

Biplab K. Bera, Subala Mondal, Parnajyoti

Karmakar, Arup Mandal and Alak K. Ghosh , J. Chem. Sci., 123, 1 (2011). 13. Kinetics and Mechanism of the interaction of Adenosine with cis-diaqua(cis-1,2diaminocyclohexane)platinum(II) perchlorate in aqueous medium, Parnajyoti Karmakar, Subhasis Mallick, Subala Mandal, Biplab K. Bera, Arup Mandal, Sudip K. Mukhopadhyay and Alak K. Ghosh, Int. J. Chem. Kinet., 43, 219 (2011).

14. Interaction of glycyl-glycine with hydroxopentaaquarhodium (III) ion in aqueous medium: Kinetic and mechanistic studies, Biplab K. Bera, Subhasis Mallick, A. Mandal, S. Mondal, P. Karmakar and A.K. Ghosh, Prog. React. Kinet. Mech., 36, 371 (2011). 15. Kinetic and mechanistic studies on the interaction between azide and cis-diaquachloro-tris-(dimethyl sulfoxide)-ruthenium(II) complex in aqueous medium, Alak K. Ghosh, Arup Mandal, Biplab K Bera, Subhasis Mallick, Subala Mondal, Parnajyoti Karmkar, Inorganic Chemistry : Chem. : Indian J., 5, 176 (2010). 16. Kinetics and mechanism of the ligand substitution reaction of di-µhydroxobis(bipyridyl)dipalladium(II) ion with some bio-relevant ligands. Subhasis

233

Mallick, Biplab K. Bera, Arup Mandal, Subala Mondal, Parnajyoti Karmakar and Alak K. Ghosh, J. Solution Chem., 40, 532 (2011). 17. Kinetics and mechanism of the ligand substitution reaction of di-µhydroxobis(bipyridyl)dipalladium(II) ion with dipeptides in aqueous solution. Subhasis Mallick, Biplab K. Bera, Arup Mondal, Subala Mandal, Parnajyoti Karmakar and Alak K. Ghosh, Prog. React. Kinet. Mech., 36, 272 (2011). 18. Kinetic Studies of substitution on cis-diaqua-chlorotris-(dimethyl sulfoxide)ruthenium(II) complex with glycylglycine in aqueous medium. Arup Mandal, Biplab K Bera, Subhasis Mallick , Subala Mondal, Parnajyoti Karmakar, and Alak K Ghosh I. J. LSc. Phar. Res., 1, 110 (2011). 19. Kinetic and mechanistic studies on the interaction of

diethyldithiocarbamate

anion with diaquaethylenediamineplatinum(II) ion in aqueous medium.

Subhasis

Mallick, Arup Mondal, Biplab K. Bera, Subala Mandal, Parnajyoti Karmakar and Alak K. Ghosh, Prog. React. Kinet. Mech., 37, 18 (2012). 20. Kinetic and mechanistic studies on the interaction of DL-penicillamine with di-hydroxobis(bipyridyl)dipalladium(II) ion in aqueous solution. Subhasis Mallick, Arup Mandal, Biplab K. Bera, Subala Mandal, Parnajyoti Karmakar , S. C. Moi and Alak K. Ghosh, J. Indian Chem. Soc., 88, 859 (2011). 21. Kinetics and mechanism of the ligand substitution reaction of hydroxobis(bipyridyl)dipalladium(II)

ion

with

N,N'-diethylthiourea

di-µinaqueous

solution. Subhasis Mallick, Debabrata Nandi, Arup Mandal, Subala Mondal, Biplab K. Bera, Parnajyoti Karmakar and Alak K Ghosh, Int. J. Res. Chem. Environ., 2, 275 (2012). 22.

Mechanistic

aspects

of

diaminocyclohexane)platinum(II)

ligand by

substitution

Glycine-L-Leucine.

on

cis-diaqua(cis-1,2-

Parnajyoti

Karmakar,

Subhasis Mallick, Biplab K. Bera, Arup Mandal, Subala Mondal, Sudip K. Mukhopadhyay and Alak K. Ghosh, Transition Met Chem., 35, 911 (2010).