Citation preview
SYNTHETIC AND ANAL YTICAL STUDIES
OF
810MIMETIC METAL COMPLEXES
THESIS
Submitted in fulfilment of the requirements for the Degree of
DOCTOR OF PHILOSOPHY
of Rhodes University
by
KEVIN WAYNE WELLINGTON
Department of Chemistry
Rhodes University
June 1999
TABLE OF CONTENTS
page
1 INTRODUCTION 1
1.1 METALLOENZYMES 1
1 . 1 .1 Background 1
1.1.2 The structure of metalloenzymes 2
1.1.3 Functions of metalloenzymes 3
1.2 TYROSINASE 5
1.2.1 Background 5
1.2.2 The active sites of tyrosinase and haemocyanin 8
1.2.3 Studies of the active site of haemocyanin 9
1.2.3. 1 Early studies 9
1.2.3.2 More recent studies 10
1.2.4 Similarities between tyrosinase and haemocyanin 11
1.2.5 A possible mechanism of oxidation by tyrosinase 13
1.2.6 Applications of the enzyme tyrosinase 15
1.3 THE BIOMIMETIC APPROACH TO TYROSINASE ANALOGUES 16
1.3.1 The selection of ligands for dinuclear copper complexes ' 18
1.3.2 Coordination considerations in the reaction of copper
complexes with dioxygen 20
1.3.3 The mode of binding of dioxygen in oxyhaemocyanin and
oxytyrosinase 22
1.3.4 Synthetic biomimetic models of haemocyanin and
tyrosinase 24
1.4 THE IMPORTANCE OF METAL-DIOXYGEN BONDING 37
1.5 OBJECTIVES OF THE PRESENT INVESTIGATlON 41
II
2 DISCUSSION 42
2.1 LIGAND DESIGN AND RATIONALE 42
2.2 LIGAND SYNTHESES 43
2.2.1 Biphenyl ligands 44
2.2.2 1,1 O-Phenanthroline ligands 54
2.2.3 Schiff base ligands prepared from diketones 59
2.2.4 The Baylis-Hillman approach to ligand syntheses 64
2.2.5 Macrocycle syntheses 70
2.2.6 Dendrimer synthesis 73
2.3 COMPLEXATION AND COMPUTER MODELLING STUDIES 78
2.3.1 Complexation Studies 78
2.3.2 Copper Complexes 80
2.3.3 Computer Modelling Studies 90
2.3.4 Other Transition Metal Complexes 101
2.3.4.1 Cobalt Complexes 101
2.3.4.2 Nickel Complexes 114
2.3.4.3 Platinum Complexes 127
2.4 ELECTROCHEMICAL STUDIES: CYCLIC VOL TAMMETRY~ 136
2.4.1 Copper Complexes 1137
2.4.2 Cobalt Complexes 142
2.4.3 Nickel Complexes 145
2.5 BIOMIMETIC EVALUATION OF THE CATALYTIC ACTIVITY OF
COPPER COMPLEXES 150
2.6 CONCLUSIONS 155
iii
3 EXPERIMENTAL 157
3.1 GENERAL 157
3.2 PROCEDURES FOR LIGAND SYNTHESES 158
3.2.1 Biphenyl ligands 158
3.2.2 1,1 O-Phenanthroline ligands 167
3.2.3 Schiff base ligands prepClred from diketones and
2-(2-aminoethyl)pyridine 172
3.2.4 The Baylis-Hillman approach to ligand synthesis 177
3.2.5 Macrocycle syntheses 181
3.2.6 Dendrimer synthesis 185
3.3 SYNTHETIC PROCEDURES FOR THE PREPARATION OF
COMPLEXES 185
3.3.1 Copper Complexes 185
3.3.2 Cobalt Complexes 190
3.3.3 Nickel Complexes 193
3.3.5 Platinum Complexes 195
3.4 PROCEDURE FOR THE COMPUTER MODELLING OF
COMPLEXES 198 !
3.5 ELECTROCHEMICAL STUDIES: CYCLIC VOL TAMMETRY 199
3.6 METHOD FOR THE EVALUATION OF THE CATALYTIC
ACTIVITY OF COPPER COMPLEXES 205
4 REFERENCES 206
5 APPENDIX: CRYSTAL STRUCTURE DATA 220
IV
ACKNOWLEDGEMENTS
I am grateful to my supervisor Prof. Perry Kaye for granting me the opportunity to
work with him and also for the advice, support and encouragement over the years.
Also to Prof. Nyokong, my co-supervisor who has, over the years, been a source
of inspiration and encouragement, for her support and advice with the
electrochemistry. I would also like to thank Dr. Cheryl Sacht for informative
discussions concerning coordination chemistry. Special thanks go to Dr. Gary
Watkins, also for informative discussions, but most of all for his generous support
and guidance with the coordination chemistry section despite not being one of my
supervisors.
I am also grateful to my colleagues, who over the years, have made my stay in the
department a pleasant one, for their support and encouragement. I want to thank,
in particular, Andre Daubinet who has always been very willing to assist with the
molecular modelling programme Cerius2.
\ I am very grateful to Mintek and, also to the FRO and DAAD for their financial
J support. I want, in particular, to thank Mr. Bob Tait, Dr. Kathy Sole and Dr. Brian
Green at Mintek.
I also want to thank the technical staff (Mr Aubrey Sonne man and Mr. Andre
Adriaan), the secretaries (Mrs. Margie Kent and Mrs. Bernita Tarr), and the
storeman (Mr. Johan Buys) for their support, and Ms Leanne Cook (University of
the Witwatersrand) for X-ray structure determinations.
Most of all, I would like to thank my parents for their support and encouragement
over the years. I dedicate this thesis to my parents in appreciation of their support
and encouragement.
v
ABSTRACT
Several series of novel diamido, diamino and diimino ligands containing different
spacers and heterocyclic donors have been synthesised. The spacers include the
flexible biphenyl, the rigid 1,1 O-phenanthroline and various acyclic moieties, while
the heterocyclic donors comprise pyridine, imidazole or benzimidazole groups.
These ligands have been designed to complex copper and act as biomimetic
models of the active site of the enzyme, tyrosinase, and their complexes with
copper, cobalt, nickel and platinum have been analysed using microanalytical, IR,
UV-Visible and cyclic voltammetric techniques. Attempted reduction of the
biphenyl-based diimino ligands resulted in an unexpected intramolecular
cyclisation affording azepine derivatives, the structures of which were elucidated
with the aid of single crystal X-ray analysis of cobalt and nickel complexes.
Computer modelling methods have been used to explore the conformational
options of the copper complexes, and to assess the accessibility of the dinuclear
copper site to substrate molecules. Computer modelling has also been used, in
conjunction with the available analytical data, to visualise the possible structures
of selected ligands and complexes. I
The copper complexes, although predominantly polymeric, were evaluated as
biomimetic catalysts using 3,5-di-t-butylphenol and 3,5-di-t-butylcatechol as
substrates. Some of the complexes clearly displayed biomimetic .. potential,
exhibiting both phenolase and catecholase activity.
vi
ABBREVIA TIONS
COl carbonyldiimidazole
CH2CI2 dichloromethane
CHCI3 chloroform
CT charge transfer
CV cyclic voltammetry
OTSC 3,5-di-tert-butylcatechol
OTSP 3,5-di-tert-butylphenol
OMF N, N-dimethylformamide
OMSO dimethylsulfoxide
Et3N triethylamine
Et20 diethyl ether
EPR electron paramagnetic resonance
EXAFS extended X-ray absorption fine structure
HCSO hexachlorobutadiene
IR infrared
MeCN acetonitrile
NMR nuclear magnetic resonance .I
THF tetrahydrofuran
UV ultraviolet
1
INTRODUCTION
1.1. METALLOENZYMES
1.1.1. Background
Metal ions are often found as constituents of proteins and enzymes. In fact,
approximately one third of enzymes known require metal ions for activitY,1 and it
is apparent that nature has utilized the special properties of metal ions to perform
a wide variety of specific functions which may be crucial in life processes. In
Australia, for example, the deficiency of copper in certain areas adversely affected
the nervous system of sheep and caused ,pnaemia and wool deterioration.1
Metal ions in proteins and enzymes can be roughly divided into two classes, viz.,
chemical and structural metals. Metals which enter directly into biological reactions
in a chemical manner are referred to as chemical metals, e.g. iron(ll) in its role in
the oxidation-reduction reactions catalysed by peroxidases and ferrodoxins or the
bonding of oxygen by haemoglobin. Those metals that stabilise ~the protein for
biological function (e.g. calcium(lI) in thermolysin) or indirectly promote c9talysis
by inducing a required orientation of th.e substrate or catalytic group in the protein
(e.g. magnesium(lI) in phosphoglucomutase) are referred to as structural metals.1
It has also been observed2 that metal ions in proteins and enzymes are able to
perform in two ways: i) as an integral part of the protein, removable only by
extreme chemical attack and exhibiting high metal-ion specificity in function, or ii)
loosely bound to the substrate or enzyme, readily dialysable and exhibiting low
metal-ion specificity in catalytic function.
Introduction 2
1.1.2. The Structure of Metalloenzymes
Metalloenzymes contain metal ions that are tightly bound and always isolated with
the protein. The structure of the enzyme is destroyed upon removal of the metal
ions. The metals ions are mainly responsible for electron transfer. Alcohol
dehydrogenase (containing Zn2+),3 arginase (containing Mn2+),4 ferredoxin
(containing Fe2+),5 haemocyanin (containing CU2+)5 and urease (containing Ni2+)6
are all metalloenzymes. In the case of the proteins, haemoglobin and the
cytochromes, however, the metal (Fe2+ or Fe3+) is part of the haeme prosthetic
group (non-protein). Metal ions frequently occur within the active site of the
enzyme and resemble protons in that they are electrophiles, which are able to
accept an electron pair for the formation of a coordinate-covalent bond with anionic
or neutral ligands to yield complexes of various geometries, e.g., linear, square
planar, tetrahedral or octahedral. 7
The ability of free amino and carboxyl groups in proteins to bind to metals allows
for the establishment of an active conformation, as in the case of carboxypeptidase
A 8 This enzyme, which promotes hydrolysis, has Zn2+ in its active site. When the
ester substrate fits into the hydrophobic pocket of the enzyme, the,zinc stabilises
the enzyme-substrate complex by coordinating to the developing oxygen allion as
the water attacks the carbonyl carbon of the ester substrate. In carbonic
anhydrase, zinc binds to water making it sufficiently acidic to permit the loss of a
proton and formation of a nucleophilic-hydroxyl group.
It is known that the biological role of metals in metalloenzymes is highly specific,
and that the same metal ion in a different protein is able to perform different
functions. The range of functions promoted, however, is largely dictated by the
protein environment.
Introduction 3
1.1.3. Functions of Metalloenzymes
Metalloenzymes function in many essential physiological processes. They effect
a variety of important chemical transformations, often involving small molecule
substrates or products such as molecular oxygen, hydrogen, nitrogen and water.
The transformations occur with exceptional substrate regio- and stereoselectivity
under mild conditions. Various metal clusters or ions have been observed at the
active sites, and living systems have utilised rudimentary recurring, structures that
have been modified or adapted for particular purposes. The role of
metalloenzymes is to perform specific catalytic functions. Dioxygen metabolism is
vital to aerobic organisms, mainly as a primary energy source having a
thermodynamically favourable reduction to water [standard potential, EO = 0.82 V
(1 atm 02, pH = 7)], and metalioenzymes have been used for the insertion of
dioxygen into biological substrates.9 This insertion occurs through mono- or
dioxygenation processes. The functions of various metalioproteins and
metalloenzymes are summarised in Table 1.10
Metalloenzymes may be controlled by changing the pH, thus disrupting the flow of
electrons which the enzyme would normally regulate. Metalloenzym~s can also be
inhibited by using transition state analogs which mimic the structure! of the
transition state in the reaction of the enzyme with a particular substrate.
Introduction 4
Table 1: Functions of various metalloenzymes and metalloproteins. 10
Metal Protein Source Function
Mo nitrogenase Cl.pasteurium electron transfer
nitrate reductase N. crassa electron transfer
Co methionine micro-organisms methionine biosynthesis, transfer
synthetase of a methyl group
Fe haemerythrin blood cells of marine worms oxygen storage and/or transport
haemoglobin mammalian erythrocytes oxygen storage and/or transport
myoglobin mammalian muscle oxygen storage and/or transport
cytochrome band c animal and plant tissue, liver, electron transfer in mitochondrial
catalase eryth rocytes respiration
peroxidase plant roots ~> oxidation of H20 2 to 02
cytochrome oxidase yeast and animal tissue reduction of HP2 to HP
Fe, Cu haemocyanin blood of molluscs electron transfer in O2 reduction
Cu tyrosinase mushrooms oxygen transport
dopamine-~- adrenal medulla mixed function oxidase
hydroxylase
\
Cu, Zn erythrocuprein erythrocytes mixed function oxidase .I
Zn carboxypeptidase pancreas superoxide dismutation
carbonic anhydrase erythrocytes protein hydrolysis
alcohol liver acid-base control, CO2 hydration-
dehydrogenase dehydration metabolism and
oxidation of alcohols
Zn, Ca thermolysin B. thermoproteolyticus Zn, protein hydrolysis; Ca,
thermal stability
Mn pyruvate carboxylase liver formation of pyruvic acid from
Acetyl CoA
Mn, Ca conconavalin A jack bean cell mitogen
- <
Ca a-amylase B.subtilis, saliva carbohydrate hydrolysis
-
Introduction 5
1.2 TYROSINASE
1.2.1 Background
Tyrosinase is a metalloenzyme which was discovered in 1895, when a black pigment
was observed in the mushroom, Russulla nigricans. 11 The enzyme was named
tyrosinase in reference to the substrate tyrosine, oxidation which affords a black
pigment. As the structures of most tyrosina~es and their modes of action have not
been fully elucidated, tyrosinase remains the subject of wide-ranging research by
many biologists and chemists. Tyrosinase is found widely in microorganisms, plants
and animals. In microorganisms and animals, tyrosinase catalyses the initial step in
the biochemical formation of the highly coloured pigment, melanin, from tyrosine. 11
In plants, the physiological substrates comprise a variety of phenolics, which are
oxidised by tyrosinase in the browning reaction observed when apples, bananas,
mushrooms etc. are injured and exposed to dioxygen. Although the function of this
reaction has not been established, it is believed that it may offer protection of the
wound from pathogens or insects. It has also been suggested that tyrosinase may be
involved in wound healing and, possibly, sclerotisation of the cuticle in insects. 11
OH OH II 0 " ¢ ~,2H+ qOH H2O ¢r0+ ~ I . ~ 2H+ (eq. 1)
tyrosinase ~ tyrosinase
R R R R=Me
tyrosine DOPA DOPAquinone
Tyrosinase catalyses both the o-hydroxylation of monophenols (cresolase activity)
and the two-electron oxidation of the o-diphenol (catecholase activity) to the 0-
quinone using molecular O2 .11 The substrate supplies the two electrons required for
the reduction of the second oxygen atom to H20 and, thus, functions as an internal
monooxygenase. The hydroxylation reaction (I) is faster than the oxidation reaction
Introduction 6
(II) (k(,) = 103 S-1, k(ll) = 107 S-1; eqn.1).12 The rate determining step is believed to be
the hydroxylation of the substrate to DOPA (dihydroxyphenylalanine). The pigment,
melanin, is obtained via a series of non-enzymatic polymerisation reactions of the
DOPAquinone product. Other common names for tyrosinase are phenolase and
polyphenol oxidase.
Table 2: Properties of some tyrosinases which have been well characterised. 13
* * Absorption nm Circular dichroism I Amino
Source No. of MW/subunits (x 10-3 M-1cm-1)
nm (x 10-3 M-1 cm2 acid
subunits (KDa) dmol-1 ) sequence
Streptomyces 1 30.9 345 (17.4) 345 (-32.5) yes
g/augescens 640 (1.5) 470 (2.1) "" ...
575 (-1.7)
740 (5.0)
Neurospora 1 46 345 (18) 345 (-27) yes
crassa 425 (0.5) 520 (0.6)
600 (1.0) 600 (1.0)
750 (3)
Agaricus 2 13.4 345 (18) 353 no
bisporus 2 43 600 (1.2)
(Mushroom) \
*Absorption and Circular Dichroism of OXY form
Tyrosinases isolated from the eubacteria Streptomyces glaucescens and the fungi
Neurospora crassa and Agaricus bisporus are the best characterised (See Table 2).
Although tyrosinase is the most widely studied multicopper oxygenase, there are
many other important copper proteins (see Table 3) which are involved in the
reactions of dioxygen or its derivatives.
Introduction 7
Table 3: Other important copper proteins 14,15
Protein Enzyme Source Function
"Blue" electron carriers Azurin Algae, green leaves and Electron transfer (Photosynthesis)
Plastocyanin other plants
Stellacyanin
Umecyanin
"Blue" oxidases Laccase Tree, Fungal Oxidation of phenols and diamines
Ceruloplasmin Human, animal serum Weak oxidase activity
Fe and Cu transport
Ascorbate Oxidase Plants Oxidation of L-Ascorbic acid
Oxygen carrier Haemocyanin Molluscs and arthropods Oxygen transport
Copper monooxygenases Phenol o-monooxygenase Animal skin, plants, tyrosine oxidation to melanin
insects, melanoma
Dopamine beta-hydroxylase Adrenals Converts dopamine to
norepinephrine
Introduction 8
1.2.2 The active sites of tyrosinase and haemocyanin
There are inherent difficulties in purifying multi-subunit enzymes, and the elucidation
of the protein structure of tyrosinases has been hampered by such multiplicity. As a
result, there is no complete structure presently available for any tyrosinase enzyme.
However, some understanding of the nature and function of the active site can be
obtained by correlations with haemocyanins,16 for which crystal structures of both the
deoxy17 and oxi8 forms of the active sites have been obtained. Based on
spectroscopic properties (mainly EPR), the copper proteins have been divided into
three main groups (see Table 4).
Table 4: The groups of copper proteins and their characteristics. 19
Group Characteristics Examples
Type I Mononuclear copper having a trigonal basal plane with an N28 ligand donor set Plastocyanin
(8 denotes thiolate sulfur from cysteine); exhibits unusual spectroscopic Azurin
properties. viz.,
(1) a strong absorption band at ca. 600nm (an intense blue colour),
(2) a small All value «70 G), and
(3) a high reduction potential (generally >250 mV).
Type II Mononuclear copper site exhibiting a normal EPR spectrum. ) . I
Phenylalanme hydroxy ase,
Three sub-groups have been identified, viz., IIA, liB and IIC. galactose oxidi!se,
superoxide dismutase.
Type IIA The ligands comprise ordinary protein residues, such as histidine imidazole,
cysteine thiolate and water (or hydroxide).
Type liB The ligand donors include unusual protein side chains.
Type IIC The copper is bridged to another metal ion, forming a hetero-dinuclear metal
site.
Type III EPR silent dinuclear site which binds dioxygen as peroxide and exhibits Tyrosinase and
unusual physicochemical characteristics, viz., haemocyanin
(1) diamagnetism,
(2) two characteristic absorption bands at 350 and 580 nm, and
(3) a low 0-0 vibratiQ!) stretching frequency (ca. 750 cm").
Introduction 9
Tyrosinase and haemocyanin have been classified as Type III copper proteins. Such
proteins are characterised by a dinuclear copper active site, the copper atoms being
anti-ferromagnetically coupled in the oxidised state and, therefore, EPR silent. 20
1.2.3 Studies of the active site of haemocyanin
1.2.3.1 Early studies
Haemocyanins function as oxygen carriers in the haemolymph of molluscs and
arthropods. They have a dinuclear copper active site which bind oxygen, as a
peroxide, to give oxyhaemocyanins. Volbeda and Hol21 were the first to determine the
three-dimensional structure of the deoxygenated form of haemocyanins from
Panuiirus interruptus, and found that the two Cu(l) ions of the active site are
embedded in a protein matrix with three histidine residues coordinating each copper
ion.
Table 5: Data for haemocyanin derivatives with different active site arrangements of the copper ions. 29
Derivative Name Properties
Cu(I) .. Cu(l) deoxy Coupled, colourless ,
CU(II).02·Cu(II) oxy Coupled, absorbs at 330 and 650 nm J
Cu(II) .. Cu(l) half-met EPR-active
Cu(II) .. Cu(II) met Coupled, EPR-silent
Cu(II) .. - met-apo Paramagnetic
Cu(II) Cu(II) dimer Paramagnetic, not coupled
Earlier, chemical and spectroscopic evidence suggested that each cuprous ion in
deoxyhaemocyanin was coordinated to two or three imidazole ligands from
histidine. 22-28 The spectral.!eatures of various forms of haemocyanin, generated with
different active site arrangements, were investigated by-Lang and Holde29 '(Table 5).
The charge transfer spectra and magnetic properties of the oxy derivatives indicated
Introduction 10
that oxygen was bound as an end-to-end peroxide (02-) bridge across the two copper
atoms. It was proposed that the oxygen bridge was positioned in the equatorial plane
between the two copper atoms, as in Figure 1.
Figure 1
~N HiS" 0 His H" / 'c / IS-CU u, His
/ \ / , His 0-0 His
From an X-ray crystallographic study of Panulirus interruptus haemocyanin, the Cu(I)
Cu(l) distance in the deoxy form was found to be 3.8 A.30 Upon reaction of the
deoxyhaemocyanin with O2, significant coordination takes place giving rise to
tetragonally coordinated copper(II) ions separated by 3.6 A. These copper(II) ions are
bridged by 0/-and an endogenous oxygen-containing group.31
1.2.3.2 More recent studies
Crystals of haemocyanin and oxyhaemocyanin from Limulus po/iphemus have also
been analysed.32,33 High resolution X-ray crystal data for the oxyhaemocyanin
indicated that each copper atom is tightly coordinated in a square\planar geometry
to both atoms of the oxygen molecule and to the nitrogen atoms of the two closer
histidine ligands (Figure 2). Each copper atom is also weakly coordinated to the third
histidine ligand which is in an axial position. Molecular oxygen lies in a side-on (IJ
rtf() configuration with respect to the Cu-Cu axis. The two copper, the two oxygen,
and the four nitrogen atoms lie approximately in the same plane. The two copper
atoms are 3.54 A apart while the two oxygen atoms are 1.41 A apart. The relative
positions of the copper atoms and histidine residues in this structure are very similar
to those found by Volbeda and HoI. 21
Figure 2
Introduction
His \ N
H" I IS-N : 0 N-His "", //' / /Cu, /C;;u,
His-N 0: N-His I
N 'His
11
The data obtained for the deoxygenated form of the haemocyanin obtained from L.
po/iphemus, however, are rather different from those reported for the P. interruptus
protein. Each copper atom exhibits trigonal geometry and is coordinated to three
histidines, while the two copper atoms are 4.6 A apart - a distance greater than the
value found for the deoxygenated P. interruptus haemocyanin (3.8 A).21
The structural difference between these two deoxy forms of haemocyanin has been
explained in terms of a two-state model. The haemocyanin hexamer may adopt
conformational states of high (R-state) or low (T-state) oxygen affinity, either of which
may be oxygenated or deoxygenated. It has been postulated that the deoxygenated
L poliphemus haemocyanin is in the T-state, while that of P. interruptus haemocyanin
assumes the deoxygenated R-state. 32
J
1.2.4 Similarities between tyrosinase and haemocyanin
Chemical and spectroscopic studies indicate that tyrosinase has a coupled dinuclear
copper active site very similar to that of haemocyanin. Studies performed on a series
of derivatives of mollusc and arthropod haemocyanins34-41 and fungal tyrosinase, 42-46
have shown that the active sites of these proteins are remarkably similar and include
examples of the deoxy [Cu(l) Cu(l)], oxy [Cu(lI) O2 Cu(II)], mixed-valent half-met [Cu(I)
Cu(II)], met [Cu(II)-Cu(II)]and the dimer [Cu(II)' "Cu(II)] arrangements (seeTable 5).
- The met derivative is considered to be the resting form of tyrosinase but,
Introduction 12
unfortunately, there is currently no crystal structure available for the corresponding
met haemocyanin. The EPR silence of the met form is due to antiferromagnetic
coupling between the two copper(lI) ions, which requires a super-exchange pathway
involving a bridging ligand. 40 The crystal structure of P. interruptus haemocyanin
reveals that it is not possible for the protein residues, in the vicinity of the copper site,
to provide such bridging; in this case, the bridging ligand is presumed to be a water
hydroxyl group.21
It is believed that a similar situation exists at the active site in met tyrosinase. It
appears that only one water-derived ligand is bound terminally to the two copper(lI)
ions as the met tyrosinase Cu-Cu distance of 3.4 A (as determined by EXAFS
analysis) is too large for two, single atom hydroxide bridges. 16 Oxytyrosinase is
produced from met tyrosinase by the addition of peroxide, or by two electron
reduction to the deoxy state followed by the reversible binding of dioxygen.43,44,47 As
oxytyrosinase reacts with both the monophenol and the diphenol, 17,18 the geometric
and electronic structures are important in understanding the hydroxylation chemistry
of this enzyme. For oxyhaemocyanin, the following spectroscopic features are
observed:- (i) an intense absorption band at 350 nm (8 -20000 M-1 cm-1);36 (ii) a low
0-0 stretching frequency of ca. 750 cm-1; 19 and (iii) a Cu-Cu distance of 3.6A (from
EXAFS16 and X-ray crystallography48). The spectral features observed for oxtyrosinase
are essentially the same,16,43,44,46,47 and are characteristic of the side-on I-J-r{ r]2
peroxide bridging mode (see Figure 3).
Figure 3: The geometric arrangement of the side-on 1-J-r]2: r]2 peroxide bridging mode in oxyhaemoq~anin and oxytyrosinase.
Introduction 13
In view of the similarities in the spectroscopic features of these oxy states, it is
believed that oxytyrosinase has a similar dinuclear copper active site to that of
oxyhaemocyanin. These spectroscopic features are quite well understood. 21 -23 The
intense absorption band at 350 nm indicates that the side-on peroxide is a very
strong a-donor ligand to the two copper(lI) atoms, while the low 0-0 stretching
frequency (at ca. 750 nm) indicates a weak 0-0 bond. The weakness of the 0-0
bond derives from the ability of the peroxide to act as a n-acceptor ligand; the n-back
bonding shifts electron density into the peroxide a* orbital, which is highly anti
bonding with respect to the 0-0 bond, thus activating it for cleavage.
1.2.5 The proposed mechanism of oxidation by tyrosinase
A mechanism, which takes into account the: geometric and electronic characteristics
of oxyhaemocyanin, has been proposed to account for the phenolase and
catecholase activity of tyrosinase. 18 While earlier mechanisms have interpreted the
complex kinetics of tyrosinase in terms of allosteric effects and two binding sites, 44,48,49
the mechanism outlined in Figure 4 accounts for all the kinetic and inhibition patterns
observed for this enzyme. 18 In the first step of the phenolase cycle (A), a phenol binds
in an axial position to one of the copper atoms of the oxy site. A trigonal bipyramidal \
rearrangement towards the equatorial plane then occurs, which orients the artha-J
position af the phenol for hydroxylation by peroxide. The resulting o-diphenolate
(met-D) is then oxidised to the quinone releasing the deoxy site for a further oxidation
cycle. In the catecholase cycle (8), the a-catechol is oxidised to the quinone after
reacting with the oxy site. From kinetic studies it has been found that bulky
substituents on the phenol ring dramatically reduce the cresolase activity, but not the
catecholase activity.18 It has been deduced that monophenolic substrates require
axial-to-equatorial rearrangement for artha-hydroxylation, but this is not a necessity
for diphenolic substrates undergoing simple electron transfer. The bridged bidentate
_ coordination mode illustrated for the met-D form in Figure 4 is supported by the fact
8
met
Introduction
Q~ oxy-D
o 0 N" I Il,O,,1 II,N
,;Cu 1 Cu ...... N "o~ N
~7'\ o
N"I II ,0" ",N Cu' i 'Cil
N" "'O~"N Y OH
I A
Q HO OH
N, II ,0, II ,N .CU~i .. Cu'" NON
oxy
~ Q
deoxy
met-O
o 0
A - cresolase cycle B - catecholase cycle
Figure 4: A mechanism proposed by Solomon et al. for the cresolase and catecholase activity of tyrosinase, 50
J
14
that o-diphenol, but not the m- and p-diphenol (0- and p-diphenol have approximately
the same redox potential) is oxidised by tyrosinase,50 It has been noted that bidentate
coordination to one copper atom is also a possibility,50
Notwithstanding the similarities, a major difference between the active sites of
haemocyanin and tyrosinase is indicated by the fact that tyrosinase can react with
Introduction 15
substrates whereas haemocyanin cannot. An explanation for this difference IS
provided by sequence comparisons of tyrosinases with the structurally defined
haemocyanins, from which it is apparent that an additional domain in the larger
haemocyanin protein blocks access to the dinuclear copper site.
1.2.6 Applications of the enzyme tyrosinase.
Current interest in applications of the tyrosinase enzyme is reflected in publications
which have appeared in the recent literature. Atlow et al. 51 have reported use of the
enzyme in the removal of phenols from industrial, aqueous effluents. The phenols are
converted to the corresponding o-quinones, which then undergo non-enzymatic
polymerisation to form water-insoluble aggregates. Another study has been
concerned with the removal of aromatic amines from industrial waste-water. 52
Following treatment with the enzyme, a colour change from colourless to dark-brown
was observed, but no precipitation occurred; however, treatment of the coloured
compounds with a combination of tyrosinase and a catioRic polymer coagulant,
containing an amino group, resulted in the precipitation of the enzymatic reaction
products. For heterogeneous applications, tyrosinase has been immobilised via free
amino groups on cation exchange resins that can be used rep~atedly, 53 a 100%
removal of phenols being achieved after 2 h, with only marginal reduqtion in the
activity even after 10 repeat treatme[1ts.
The development of new biosensors is a rapidly growing research field and the
tyrosinase enzyme has been used as a biosensor for detecting several phenols and
o-diphenols. Studies of this application were first undertaken by Schiller and co
workers,54.55 and involved immobilising the enzyme in a polyacrylamide gel. An
enzyme-spectrometric method was used initially but, subsequently, an enzyme
potentiometric method was developed. Campanella et al. 56 have reported an enzyme-
- amperometric method in which tyrosinase may be immobilised in three different ways
Introduction 16
and coupled to an oxygen gas-diffusion electrode. This method has been used for the
determination of phenol in several environmental matrices, and evaluated as a
promising alternative to more conventional methods.
Introduction 17
1. 3 THE BIOMIMETIC APPROACH TO TYROSINASE ANALOGUES
Metalloenzymes effect a variety of important chemical transformations that often
involve small molecule substrates, such as molecular oxygen, hydrogen, nitrogen
and water. Metalloenzyme-catalysed reactions also function under very mild
conditions, and affect transformations with exceptional efficiency and substrate
regio- and stereoselectivity. As a result, extensive research has been undertaken
in this field to design synthetic processes that approach this efficiency and
selectivity and, thus, mimic the natural systems. A multidisciplinary bioinorganic
approach has been adopted, which encompasses a variety of disciplines such as
inorganic chemistry, synthetic organic chemistry, biochemistry and spectroscopy.
The basic objectives of the biomimetic approach, as applied to the modelling of
metalloenzymes, can be outlined as follows:-
(a) to develop a biomimetic model that will account for the spectroscopic
characteristics and function of the metalloenzyme in terms of its structure;
(b) to compare the observed metalloenzyme properties with those of
the biomimetic model; and
(c) to exploit the use of synthetic models which exhibit catalytic ~ctivity
comparable to the metalloenzyme. 57 J
Two principal strategies exist for the preparation of biomimetic models, viz., total
synthesis and metal template condensation (the self-assembly approach). The
total synthesis method allows for the incorporation of selected properties, such as
geometry, polarity, hydrophil/icity, hydrophobicity and steric characteristics; in this
method, the metal is added after the ligand has been synthesised. In the metal
template condensation method, on the other hand, the complex adopts an optimal
geometry dictated by the f'tature of the metal ion. It is also important to consider the
- - basic premise in bioinorganic chemistry, viz., that ttie chemistry of the metal-
binding site is dependent Qn the immediate ~nvironment of the metal ion. In many
metal/oproteins, the amino acid side chains provide the coordination environment
Introduction 18
and, at times, the coordination-sphere of the metal ion may be completed by a
prosthetic group, such as a porphyrin ring. 58 Once synthesised, the synthetic
model can be compared with the metalloprotein, with respect to spectral and
physicochemical properties, coordination geometry, catalytic activity, and the
mechanism of action. This may then provide information relating to the effects of
the environment on the active site and/or to the intrinsic properties of the active
site.
Besides providing a basis for postulating biological reaction pathways and possible
metal-complex intermediates, extensive modelling efforts may yield small
molecule biomimetic catalysts capable of effecting transformations with practical
applications. Such applications include the following:- (i) the removal of
environmental pollutants, such as pho_sphate ester pesticides or nitrogen
compounds; (ii) the hydrolysis of peptides or nucleic acids in biotechnological
processes; or (iii) selective dioxygen-mediated oxidation in drug and chemical
transformations. 59
1.3.1 The selection of ligands for dinuclear copper complexes
\
To design biomimetic models that will mimic the metalloenzyme, it is essential that
" the structure of the model be as similar as possible to that of the metalloenzyme.
The ligands selected should be chemically similar to those in the enzyme and
should also have the correct number of donor atoms required for coordination to
the metal ions. For tyrosinase biomimetics, the ligands should be similar to the
histidyl-imidazole moieties. The sizes of the ligands are also significant as they
must be able to accommodate not only both copper ions, but also any additional
bridging group essential for reactivity. Thus, the ligands used must be sufficiently
flexible to adapt to different geometries, especially if there is a valence change, as
_ is the case in dioxygen binding. The geometriC and coordination requirements of
Cu(l) and Cu(lI) ions are CLuite different, as i~dicated in Table 2.60 As six-membered
chelate rings are more flexible than five-membered chelate rings, they can more
Introduction 19
readily satisfy coordination changes in the redox process. 61
When selecting ligands which will mimic histidyl-imidazole moieties, it is necessary
that the nitrogen donors be aromatic or, at least, Sp2 hybridised. As a result, imine
nitrogens are preferred to amine - nitrogens. Ligands containing imine nitrogens
can also stabilise copper complexes in the lower oxidation state better than amine
nitrogens, because the unsaturated ligands can delocalise electron density from
the metal ions via l7-back-bonding. 62 Heterocycles containing nitrogen are
particularly favoured.
Another aspect to be considered is the basicity of the donor group in the ligand,
since the reactions under investigation involve electron transfer. 58 A list of ligands
with their corresponding basicity is provid>~d in Table 6.
Table 6: N-donor groups and their p~ values.
Donor group p~
Benzimidazole 8.5
Imidazole 7.0
Histidine 8.0 J
Pyridine 8.7
Pyrazole 11.5
Alkyl-NH2 3.0
Aryl-NH2 9.4
The use of imidazole groups has been hampered by cyclisation, encountered in
the synthesis of ligands in which they have been included. Consequently,
derivatives such as benzimidazole have been used as donor groups as they are ~
less prone to cyclisation and, moreover, their increased steric bulk may be useful
in controlling the metal ion stereochemistry.63 A disadvantage, however, is that the
aromatic ring (fused fo-the imidazole ntlcleus) can affect the spectroscopic
properties of the resulting complex and mask the UV region, so important in
Introduction 20
studying copper(l) complexes. 58
Pyrazole groups have also been incorporated into ligands but, despite their easy
preparation64 and their spectroscopic similarity to imidazole, they are significantly
less basic. Pyridine groups have the advantage that their basicity is similar to that
of the histidyl-imidazole, and models in which pyridine has been incorporated have
been successful in mimicking the reactivity65 of copper proteins.
1.3.2 Coordination considerations in the reaction of copper complexes
with dioxygen.
During the binding of dioxygen to copper, two charge-transfer processes can *
occur, viz., metal-17-to-dioxygen-17 back donation and donation from oxygen to the
metal. This ultimately results in, at least partial, electron transfer to the metal and
weakening of the 0-0 bond. The binding of dioxygen to copper is also
accompanied by changes in both the oxidation state and coordination number of
the metal. The observed coordination numbers and stereochemistry is dependent
upon the oxidation state and, in the dO Cu(l) ion, the coordination number of four
dominates. The Cu(lI) cf ion, however, is the most prevalent oxi~ation state for
copper and, in this state, an octahedral coordination environment domil)8tes. In
this coordination environment, there.are four equatorial ligands that are strongly
bound and two axial ligands that are less strongly bound (Jahn-Teller effect). The
coordination numbers and geometries observed for the two oxidation states of
copper are summarised in Table 7.
The coordination numbers and geometries of the Cu(l) and Cu(ll) ions determine
the resulting redox reactions for the two oxidation states. The redox process which
occurs is also strongly affected by the type of ligand, the chelate ring size and the
- solvent. Six-membered chelate rings stabilise Cu(l),66-while five-membered rings
stabilise CU(II).67 When_polar solvents are used, the Cu(ll) oxidation state is
favoured but, conversely, non-polar solvents favour the Cu(l) oxidation state.68,69
Introduction 21
Table 7: Cu(l) and Cu(ll) coordination numbers and geometries70
ION Observed Observed geometry
coordination
number
Cu(l) 2 Linear
3 Trigonal
4 Tetrahedral
Cu(iI) 4 Square planar
Tetrahedral
5 Square pyramidal
6 Trigonal bipyramidal
Octahedral
Introduction
1.3.3 The mode of binding of dioxygen in oxyhaemocyanin and
oxytyrosinase
22
The dinuclear copper proteins, haemocyanin and tyrosinase, bind dioxygen
reversibly at their active sites. It is believed that these proteins have very similar
oxy active sites,42 involving two copper(lI) atoms (based on X-ray absorption
data71 ,16) and bound peroxide (based on the unusually low Raman 0-0 stretching
band72 ,73 at 750 cm-1). The studies showed that a peroxide ion bridges the
dinuclear copper active site of deoxyhaemocyanin and that oxidation of the metal
ions from copper(l) to copper(lI) occurs upon coordination of dioxygen. Intense
absorption bands due to CT transitions have been observed for both
oxyhaemocyanin and oxytyrosinase at 350 nm (8 = 20 000) and 570 nm
(8 = 1000). In a mononuclear copper-peroxige complex only two CT transitions are
observed.23 For oxyhaemocyanin, however, more than two peroxide-to-copper CT
transitions are observed, which is further evidence that the pair of copper atoms
are bridged. Because oxytyrosinase displays the same spectral features as
oxyhaemocyanin, its active site has been ascribed a similar structure to that of
oxyhaemocyanin.
, Research has been focussed on elucidating the structure of the peroxide ion
I
bridging the copper atoms. Initially, th~three end-on peroxide bridging structures
shown in Figure 5 were considered [(a) 1-1-1,1; (b) cis 1-1-1,2 and (c) trans 1-1-1,2J, but
only the cis 1-1-1,2 structure in (b) was expected to produce spectral features
consistent with those observed for oxyhaemocyanin.36 Several complexes have
been synthesised to mimic the cis 1-1-1,2 bridging in (b), but these were found to
have a trans 1-1-1,2 bridging mode and to exhibit spectral properties which differ
widely from those of oxyhaemocyanin. 74,75
"
Introduction 23
0 0-0 0-0 0
I / \ 0 / \ eu/ I "eu 0 eu eu eu/ \ eu Cu" /Cu c.f 'eu 0/
0 "0/ H
(a) 1-1-1,1 (b) cis 1-1-1,2 (c) trans 1-1-1,2 (d) cis 1-1-1,2 (e) l-I-r{1l2
Figure 5: Possible structural models for the bridging peroxide ion in dicopper complexes.
Strong antiferromagnetic coupling has been observed for oxyhaemocyanin and
oxytyrosinase, indicating that the copper ions are diamagnetic (EPR silent). To
account for this coupling, a cis 1-1 1,2- arrangement [Figure 5 (d)] involving an
endogenous bridge, originating from the protein, was proposed by Solomon. 76 The
two copper atoms were considered to coordinate to two or three histidyl-imidazole
ligands and were assumed to be in a copper(ll) oxidation state (Figure 6). The
endogenous bridge (OR) was thought to involve alkoxide, phenolate, sulphydryl
or hydroxyl groups in the protein or in the medium. The elucidation of the X-ray
crystal structure of haemocyanin77 from the spiny lobster (Panulirus interruptus)
confirmed both the dinuclear nature of the active site and the presence of three
histidine ligands per copper atom. However, the notion of an endogenous bridging
group was discarded as there was no suitable candidate within 12 A of t~ site. 78
N" .. I Io-q I .. "N CU Cu'
N/ I '0/ I "'N R
Figure 6: The dinuclear active site model proposed by Solomon. 76
A model that binds dioxygen in a similar way to that exhibited by oxyhaemocyanin
has been synthesised inthe laboratory of Nobumasa Kitajima. 79 The structure of
- the complex (Figure 7) showed that the dioxygen was bound in the novel 1-1-11 2 :112
bridging mode betweerr the two copper atoms [Figure 5 (e)].79 From the
spectrochemical and magnetic properties it could be seen that this model closely
Introduction 24
resembled the biosite in the protein. The controversy over the mode of dioxygen
bridging was eventually resolved when a crystal structure of oxyhaemocyanin from
the horseshoe crab was elucidated by Karen Magnus.8o A fJ-rt r)2 bridging mode
for dioxygen was, in fact, observed between the two copper atoms, each of which
is associated with three histidine nitrogens.
N, /01\ IN N-Cu Cu-N
I \ / '
NON
Figure 7: A model representing the fJ-r)2:r)2 bridging mode of a complex which emerged from the laboratory of Nobumasa Kitajima. 79
1.3.4 Synthetic biomimetic models of haemocyanin and tyrosinase
1.3.4.1 Early work
Before the X-ray crystal structure elucidation of haemocyanin~, research focussed
on developing systems exhibiting the spectroscopic or physical features which
characterise the biosite, the inference being that such systems reflect the structural
characteristics. Once a good synthetic model (based on spectroscopic and
physical features) was identified, then its X-ray crystal structure could be~sed to
elucidate the structure of the biosite.·
Thus, early research was based on an investigation of the physical and
spectroscopic properties of dioxygen-bridged systems. Key issues addressed in
this research included:- the structure of the deoxy-active site; the nature of the
protein bridge; the nature and geometry of the CU20 2 unit; the factors responsible
for the reversible binding of dioxygen; and the activation of molecular oxygen by
tyrosinase. 58
Introduction 25
1.3.4.2 Mononuclear Complexes
Before the discovery that the active site of haemocyanin was dinuclear, research
focussed on mononuclear copper complexes. The idea was that two mononuclear
complexes could be brought together by dioxygen to produce a structural model
of tyrosinase. Such systems were first reported by Wilson82-85 and later by
Casella,86 complex 1 being an example of the complexes developed by Casella.
R=H,C~H3
1
The red copper(l) complex 1 (R = H; L = pyridine) reacted with dioxygen in a 1:2
(Cu:02) stoichiometry at room temperature to give a green product, formulated as
a dinuclear copper(II)-peroxo species. This reaction may be partially reversed by
purging the solution with nitrogen.
- f ~ ~ I. _
-N N \\ 'I '\ .
~ /; 2 - 3
Complex 2, developed by Jacobson et a/. , 87 was one of the first completely
characterised complexes in which two mononuclear units are bridged by dioxygen.
The results of the spectroscopic analysis revealed that the structural features of
the complex, i.e. the Cu-Cu separation and the geometry around the copper ions,
were different to those in oxyhaemocyanin. It was also found that the peroxide
- bridge was trans rather than cis ~-1 ,2. The fact that the complex is diamagnetic
proves that an endogen9Y..s bridge is not a ~ecessary requirement for coupling of
the copper ions in the protein.
Introduction 26
The copper complex of the ligand 3 is dimeric in solid form, but mononuclear in a
solution of acetonitrile.88 The complex binds dioxygen in a 2:1 ratio (Cu:02) and,
at -BO°C, exhibits similar spectral features to those of complex 2. It has, therefore,
been proposed that the oxygenated dinuclear complex resulting from ligand 3 has
dioxgen bound in a trans 1-1-1,2 fashion. EPR measurements revealed that the
copper ions in the oxygenated complex are magnetically coupled (EPR silent).
4 ---- 5
The mononuclear complex 4 has been found to bind dioxygen reversibly forming
a I-I-peroxo copper(lI) complex 5;58 from the IR spectrum it is apparent that the
dioxygen is bound as peroxide. This reaction is reversible upon addition of
ethylene, but no structural data was reported.
Pyr 0 Pyr \ /1\ / Pyr--Cu Cu--Pyr / ,,/ \
Pyr 0 pyr
7
~N Pyr = I
The synthesis of the dinuclear copper complex 7, prepared from tris(pyrazolyl)
borate ligands 6 by Kitajima and co-workers,79 represented a major breakthrough
in this field. The electronic spectra, magnetic character, Cu-Cu separation as well
the I-I-peroxo IR stretching frequency were all very similar to those observed for
oxyhaemocyanin, and the 1-1-112: 112 bridging mode was confirmed by X-ray
crystallographic analysis:
Introduction 27
1.3.4.3 Dinuclear complexes
Systems based on the model proposed by Solomon 76 (Figure 6) were designed so
that a "reaction space" was provided in which the dioxygenated substrate could
be bound and activated. It was expected that the chemical reactivity and the
physicochemical characteristics of such complexes would be dependent upon the
coordination environment. The ligands were designed to coordinate two copper
atoms in sufficiently close positions to permit bridging by dioxygen.
R = H, Me
R' = H, CO:2Me
Complexes 8 and 9, which reflect this strategy, have been reported by Casella. 81
For complex 8 (R = Hand R' = H) oxidation of copper(l) to copper(ll) occurs when
the complex reacts with oxygen in dry acetonitrile. In methanol,however, the
oxidation of copper(l) is inhibited by the hydroxylation of the aromatic nucleus at , the C-2 position. In complex 9, hydroxylation at C-2 occurs on treatment with
J
oxygen, the resulting hydroxyl group acting as a bridge between the two copper
atoms.
~ HN~~ Ip' NH
ON-l-CU Cu- -N() I HN"~~ ~~ NH \
~b b~ 10 11
Complex 10 has been reported to react with dioxygen "semi-reversibly",81 while ~ ~ ~
complex 11, which differs only in the nature of the spacer, reacts with oxygen
Introduction
reversibly.
Hydroxide
14
Phenoxide and alkoxide
Alkoxide
(r ,~/
r-N. /0, /N, <.. Cu Cu ) N-N' 'I 'N-N V N3V
Phenoxide
28
13
15
In some cases, the ligand has been designed to have a hydroxyl group as part of
its structure, while in others an exogenous hydroxide bridge is inserted between
the copper atoms upon reaction with dioxygen. Several synthetic complexes (12-, 15) with different peroxide bridges are shown above. 58
Compared to their mononuclear analogues, dinuclear complexes have enhanced
reactivity and specificity in catalytic oxidation.89 Ligands that are binucleating have
the advantage of offering greater control over electronic and magnetic properties
than dimeric systems,90 and this has led to attention being focussed on the design
and synthesis of ligands that can coordinate two copper atoms. Karlin and co
workers91 ,92 reported the synthesis of ligand 16; the resulting copper complex
reacts with dioxygen at !.ow temperature quaSi-reversibly. From EPR studies it
_ could be seen that the copper complex was dinuclear-and that it was EPR silent,
due to strong anti-ferrollJagnetic coupling be,!Ween the two cupric ions through the
peroxide bridge. It was suggested that the dioxygen was bound in a cis IJ-peroxo
or a bent IJ-112: 112 structure. 93 Although the crystal structure was not successfully
Introduction 29
determined, a Cu-Cu distance of ca. 3.4 A was estimated on the basis of EXAFS
data,93 and more recent studies have shown that the complex is virtually
diamagnetic. 94
Complex 17, reported by Zippel, displays antiferromagnetic coupling between the
two copper(II) atoms, bridged by alkoxy groupS.95 From the X-ray crystal structure
the Cu-Cu distance was found to be 3.033 A. Studies on this complex revealed that
the same structure is present in both the solid state and in solution, but that the
complex does not show any tendency to effect oxidation of c~techol.
Complex 18, reported by MOiler and co-workers,96 adopts an open conformation
resulting in a Cu-Cu distance of 6.16 A in the crystal state. No antiferromagnetic
coupling was observed for the two copper atoms because of the large Cu-Cu
separation. The formation of an oxygenated complex was, however, precluded by
the formation of a coordination polymer.
19
M ((N 0 N\'j py( \C~ \:~~-py
,,/\ ,'\/ py 0-0 py
Introduction
N: /":N 0 /N\l r( (\ / 'p~~) Py 20 Py~CU I o.i ,,/\! '7
Py 0-0'
30
Py = pyridine
The symmetric dinuclear complex 19, having a phenoxo bridging group, binds
dioxygen quasi-reversibly at low temperature yielding an intensely purple coloured
complex.97 The suggestion that dioxygen is a peroxo adduct is based on Raman
spectroscopy [v(O-O) = 803 cm-1] and dioxygen absorption stoichiometry (Cu/02
= 2) data. A Cu-Cu distance of 3.3 A for complex 19 was determined by EXAFS
analysis. Complex 20 is similar in structure to complex 19 but is unsymmetric; it
has been shown that this complex reacts ~ith dioxygen reversibly at -80°C and is
also intense purple in colour.97 The coordination of dioxygen to the copper ions
has been presumed to be the same in both complexes (19 and 20) because of
their spectral similarity. Complex 20 is, however, more stable than complex 19
and, as a result, it has been possible to isolate it in solid form.
21 22
The peroxo adduct @f complex 21, reported by Nishida et a/., shows
- antiferromagnetic coupling. 98 From the X-ray crystal structure, it is apparent that
the copper ions are Gogrdinated in a tri,gonal bipyramidal geometry with the
peroxide in an axial position. The copper(ll) ions in complexes 22 and 23 also
Introduction 31
exhibit antiferromagnetic coupling. 99,10o
R = H, Me, Et.
The dinuclear copper complex of the macrocycle 24 is a bright yellow solid that
changes to green when exposed to dioxygen in solution, and less rapidly in the
solid state. 15 It has been proposed that a ll-peroxo-dicopper(lI) species is
generated during the dioxygen uptake. Oxidative dehydrogenation occurs during
this dioxygen uptake. The structures an,9 properties of some dicopper(l) and
dicopper(ll) complexes of the macrocycle 25 have been reported. They function
as catalysts for the oxidation of several organic substrates, including catechols, in
the presence of oxygen. 101 In the [Cu2(25)(OEt}z(NCS}Z1 complex, each copper(lI)
ion is bonded to two imino nitrogen atoms of the macrocycle, to the nitrogen of
one terminally bound thiocyanate and to two bridging ethoxide groups in an
approximate trigonal bipyramidal geometry. The Cu-Cu distance is 3.003 A and the ~
furan oxygen atoms are not coordinated. The copper(lI) ions are strongly I
antiferromagnetically coupled in the bis(ll-alkoxo) complex and less strongly in the
dihydroxo complex. 15
26
_ Chiral dinuclear copper complexes have been relatively unexplored as catalysts
for enantioselective oxidations. Feringa has reported the chiral dinuclear copper ~ .-. ;>-
complex 26,102 which exhibits square planar geometry around each copper(lI) ion
and a normal Cu-Cu separation of 2.971 A. A trans-orientation of the N-benzyl-
Introduction 32
groups is found in complex 26 which, as a consequence, has C2-symmetry.
1.3.5 Monooxygenase Models
Since tyrosinase is a monooxygenase, a successful model of this enzyme would
be one that can catalyse the hydroxylation of an aromatic ring. Models reported in
the literature have done so in two ways, hydroxylating either an exogenous
substrate or the ligand itself. In the section that follows, attention will focus on
complexes that catalyse the hydroxylation of an exogenous substrate as well as
those that hydroxylate the ligand itself.
Oxidation of exogenous substrates
Several complexes have been reported th~t catalyse the oxidation of exogenous
substrates. Kitajima's fJ-peroxo complex 7 which resembles the tyrosinase enzyme
so closely in its spectroscopic features, has been reported to react with 3,5-di-t
butyl phenol (DTBP) via a radical mechanism to afford couple.d products. 79
27 28
I
Reglier et a/. reported the oxidation of DTBP (2,4-di-t-butylphenol) in the presence
of triethylamine, by the biphenyl dinuclear copper complex 27.103 It is thought that
deprotonation of the phenolic substrate promotes binding to the catalyst. A coupled
product 28 is formed in the absence of triethylamine. Complex 29 (n = 4), which
reacts reversibly with dioxygen to form diamagnetic peroxide bridged structures, 92
has also been reported to give the coupled product 28 via a radical mechanism.
Introduction 33
29
Complex 30 has been reported to catalyse the oxidation of DTBP to the quinone,
and the phenolic substrates 31 to the dihydroxyphenols.104 Evidence for the initial
formation of an intermediate phenolate adduct was obtained.
30
A !VIe r----:N N~!VIe
6'N\\ I "Cu cl '\ ~ ":oN ~N \ / \ / N# I ):::::-N N~ \
A Me--N6 oN-Me "'--
(r0H R 31
R = p-CO:zCHa or DTBP
Complexes of the macrocyclic ligand 32 catalyse the oxidation of exogenous
substrates, 2,6-di-t-butylphenol being oxidised to the coupled product 33. , I
32 =0=0= o 0 - -
33
Reim et al. have reported symmetrical and unsymmetrical dinuclear copper
complexes that catalyse the oxidation of 3,5-di-t-butylcatechol to the o-quinone. 105
The complexes were pr.epared from ligands 34, 35, 36 and 37. The dinuclear
_ copper complex prepared from the symmetric ligand 34 displayed the highest
catecholase activity of pll the dinuclear copper complexes prepared from these
ligands.
--
Introduction 34
Br Br
A A 34 eN) OHeN) eN) OH HN 35
N N ~d I I Me Me Me _ Br Br
A ~ 36 eN) OH HN eN) OH HN 37
l d l J ~N-Me
Hydroxylation of the aromatic ring of the ligand.
From studies conducted on the hydroxylation of the aromatic ring in dinuclear
copper(l) complexes, it seems that the reaction is ligand dependent. Sorrel and his
co-workers prepared complexes 38 and 39 and investigated their reaction with , dioxygen. 58 They found that these copper(l) complexes neither catalyse the
J
hydroxylation of the aromatic ring nor react with dioxygen in dichloromethane.
A A R
~ ~ 38 H Pyr = I ;;
/N 39 CH3 (01u TCJJ (0eu eCJ;
40 R
Py = pyridine Pyr' I I ./ Pyr Pyr'Pyr Pyr Pyr Py Py
Introduction 35
However, when the mixed pyrazole-pyridine copper(l) complex 40 was treated with
dioxygen, a reaction was observed, but no aromatic hydroxylation occurred.
41 42
Dehalogenation reactions are catalysed by various enzymes using hydrolytic,
reductive or oxidative pathways,106 but only a few enzymes are capable of
oxidative dehalogenation of aromatic compounds. The dinuclear copper(ll)
complex 41 has been reported to undergo oxidative debromination to afford
complex 42 upon reaction with dioxygen at room temperature.
A M \ 1
eN>" rf,~ eN 0 J 43 ' I \ / 44 Cu Cu / \ I "'-
R 'R R 0 R
J
Casella and Gullotti have reported mOrJooxygenase activity for complexes of type
43, which are oxidised to the corresponding complexes 44. 107 The hydroxylation
of the ligand is affected by the solvent, the oxygenation reaction being partially or
completely depressed in dry acetonitrile. Protons have been found to enhance the
hydroxylation of some of these systems and, as a result, it has been suggested
that an electrophillic copper-peroxo or copper-hydroperoxo complex is the active
species in the hydroxylation process. A proposed mechanism for the hydroxylation
reaction is illustrated in-5cheme 1, and low-temperature spectral studies have
- been undertaken to characterise the intermediates. 107 -
Introduction 36
M m m 02 H I w I ~ I N H N ---.. ---..
(' I II ) N - N N H, N Cu Cu / \ (' "t III) C ' "f "I ) N N CU- -CU CU- -CU
/ - \ / - \ NON NON
1
MI MI A NON ...-- NON ...-- NON C ' 11/ , IV ) ( \ III , DI ) C ' "I ' "I ) Cu Cu Cu Cu Cu Cu
/ \ / \ / \ \ / \ \ NON N OH2 N NON
; \ , \
H H H H
Scheme 1
Casella and co-workers have also reported aromatic hydroxylation to give the
dinuclear copper(l) complex 45, containing methionine sulfur groupS.108 The .
dinuclear copper(lI) complex 46 forms as a result of hydrolytic clea~age of 45, and
has been characterised by X-ray crystallography. J
o /(l?11
o NON 0
45 I '/' / I
o--C�-o------Cu ~------O--Cl-O 46 I / \ / \ I o NON 0
I~I 17, ~
Introduction 37
1.4 THE IMPORTANCE OF METAL-DIOXYGEN BONDING
The flourishing interest in dinuclear and polynuclear complexes emanates from the
fact that pairs or clusters of metal ions have the capacity to mediate certain
chemical reactions of industrial significance either more efficiently than, or in a
different manner to, isolated metal centres. Dinuclear complexes having metal
centres in close proximity, have been the theme of much recent research since
these structural units are believed to be involved in an array of crucial biochemical
processes, especially oxygen transport and oxygen activation by metal - containing
proteins and enzymes. "l()9 .. 120 Reactions in which one or both atoms of dioxygen are
catalytically inserted into an organic substrate are of significance in the synthesis
of metabolic products and intermediates. Dioxygen also serves as an electron sink
in the oxidation of a variety of small molecul~s such as ascorbic acid, catechol and
amino acids. 121,122 Complexes, both synthetiC and natural, which bind dioxygen
reversibly have been termed oxygen carriers. In addition to their significance as
models for natural oxygen carriers, synthetic dioxygen complexes have potential
applications in dioxygen separation and storage, industrial processes and
catalysis. 122 These complexes may act in catalytic or stoichiometric fashion. The
concepts originating from these studies are expected to contribute to the evolution ~
of practical synthetic systems for the reversible binding of oxygen and~or the
oxidation of organic compounds.
The reduction of dioxygen is of major importance for biological systems and for
oxygenation reactions. The free energy change for the four-electron reduction of
dioxygen to two water molecules is -316 kJmol-1 at pH 7 (eq. 1).
O2 + 4H+ + 4e- --. 2H20 (eq. 1)
P = +0.81 §.V (vs. the normal hydrogen electrode)
The reduction does no( os;cur in a single ~tep, but rather rn a series of steps
involving successive single - electron transfers. The usefulness of the reduction
Introduction 38
is, however, severely restricted. A common pathway for the reduction of dioxygen
involves a one-electron reduction followed by disproportionation to form OH
(under basic conditions) or H20 2 (under acidic conditions). The effective potential
is pH independent and the single-electron reduction is endothermic by 128
kJmol-1.
It has been found that the oxidation of organic compounds is more efficient when
dioxygen is directly involved with dinuclear rather than mononuclear complexes.
The formation of metal hydroperoxides are of fundamental importance during these
oxidations and, as a result, the formation of such species has been investigated.
Copper is a metal which is particularly important in oxidation catalysis. It has been
used extensively in the laboratory and in in~ustry. The synthesis of acetaldehyde
by catalytic oxidation of ethylene, the so-called Wacker process, is of major
importance in the manufacture of organic chemicals from ethylene. The reaction
is shown in equation 2.
(eq.2)
~
Although palladium is the main catalytic component responsible for the oxidation J
of acetaldehyde in the Wacker process, copper is the most effective co-catalyst to
re-oxidise Pdo to P&+with dioxygen.123 The oxidative coupling of acetylene to give
diacetylenes, the Glaser reaction, is another well-known reaction catalysed by
copper (eq. 3). This is synthetically useful124 because many ethynyl compounds
are coupled almost quantitatively. The coupling is effected by bubbling oxygen
through an acetone solution of acetylene in the presence of a copper(l) chloride
tetramethylethylenediamine complex. 125 This reaction is important in the
commercial dimerisation~of acetylene, which is then used as a precursor for
_ chloroprene, the monomer for neoprene rubber. 60
Introduction 39
~ 2 R-G=C-R - R-G=C-G=C-R (eq. 3 )
Aerobic oxidation of 2,6-xylenol with copper(l) in the presence of a N-donor ligand
produces a p-phenylene oxide polymer which is widely used as an engineering
thermoplastic under the trade name PPO (eq. 4).126
(eq. 4)
n
Ethylene glycol is produced directly from ethylene by oxidation in the Teijin
process which utilises a CuBr system as. a catalyst (eq. 5).127,128 This oxidation
process is important since ethylene glycol is a major intermediate in the synthesis
of polyesters and polyurethanes.
(eq. 5)
The copper-mediated oxidative decarboxylation of benzoic acid to\ form phenol is
an industrially useful reaction (eq. 6) as is the catalytic cleavage of catecjlOl (eq.
7).129,130
OH
1/2~ • 6 +~ (eq.6)
(XQ-i
. I ~ Q-i
(eq. 7)
Introduction 40
Acrolein is manufactured by oxidising propene in the presence of heterogeneous
catalysts containing copper or cuprous oxide, while methanol is produced from
synthesis gas by a non-oxidative heterogeneous process using a CuOIZnO
catalyst. Hydroquinone, an important commodity chemical primarily used as an
antioxidant and in photographic chemistry, is produced by the copper-catalysed
oxidation of phenol with dioxygen to afford p-benzoquinone, which is then
reduced. 131 The commercial production of trimethylhydroquinone, a vitamin E
precursor, is based on the copper-catalysed oxidation of 2,3,5-trimethylphenol to
the benzoquinone. 131 It is believed that copper-dioxygen complexes play important
roles in these catalytic oxidation reactions. However, relatively few intermediates
have been isolated and characterised. Furthermore, the structural factors which
determine the catalytic effectiveness of the catalysts are not clearly understood.
There has also been considerable interest in the reactions of dioxygen and
hydrogen peroxide with copper(l) complexes of 1,1 O-phenanthroline (phen),
[Cu(phen)2t and substituted phen derivatives, following .the discovery that
[Cu(phenht cleaves deoxyribonucleic acid (DNA) in the presence of hydrogen
peroxide.so
I
Introduction 41
1.5 OBJECTIVES OF THE PRESENT INVESTIGATION
The primary aim of this study has been to design and prepare synthetic models of
the enzyme, tyrosinase. In previous work in our group, synthetic models which
contained an imine functionality were synthesised. 138 These synthetic models
displayed some biomimetic activity but, unfortunately, the pure complexes could
not be isolated, thus precluding unambiguous identification. It was suspected that
the imine functionality was involved in intramolecular cyclisation resulting in
formation of mixtures. In order to circumvent the problem of intramolecular
cyclisation, attention in this study has been focussed on ligands which do not
contain the imine functionality, and the following objectives were identified.
1. The design and synthesis of novel ligan9s capable of forming dinuclear copper
complexes and acting as biomimetic models of the active site in tyrosinase.
2. The preparation and characterisation of copper complexes of these ligands.
3. An investigation of the copper oxidation state(s) in the re.sulting complexes
using cyclic voltammetry.
4. Evaluation of the phenolase and catecholase activity of the copper
complexes using 3,S-di-t-butylphenol and 3,S-di-t-butylcatechol as \
substrates respectively. , 5. An investigation of complexes of the ligands with other metals, such as
cobalt, nickel and platinum.
--
42
2 DISCUSSION
In the discussion that follows attention will be focussed on: - the synthesis of
biphenyl ligands (Section 2.2.1); 1,1 O-phenanthroline ligands (Section 2.2.2);
Schiff base ligands (Section 2.2.3); ligands prepared via the Baylis-Hillman
reaction (Section 2.2.4); macrocyclic ligands (Section 2.2.5); and a dendrimer
based ligand (2.2.6). This is followed by complexation and computer modelling
studies (Section 2.3). Electrochemical data, which help to elucidate the oxidation
state(s) of the metal in copper, cobalt and nickel complexes, are considered in
Section 2.4. Finally, the biomimetic evaluation of selected copper complexes is
discussed in Section 2.5.
2.1 LIGAND DESIGN AND RATIONALE-
The nature of the hydrocarbon groups (the "spacers") linking the coordinating units
i.n dinuclear copper complexes had to be taken into account as this can markedly
affect the reactivity of the copper complexes. 132 The ligands were designed,
primarily, to incorporate copper(l) and copper(ll) ions (Figure 8).
1\ 1\ N N-R N, , /N-R
'Cu'
,Cu, N N-R N/ 'N-R
~ ~
(a) (b)
Figure 8: (a) The generalised ligand structure; (b) the complex after complexation with copper, but prior to oxygen bridging.
.1 R
0 ~I
N~ LNH
NJ:NH
0
Discussion 43
In these ligand systems, the spacer was varied to explore the effect of complex
structure and geometry on biomimetic activity. For each of the ligands examined,
there are at least two different types of nitrogen donor, one from an amide, amine
or imine functionality attached to the "spacer", and the other from a heterocyclic
system (R = pyridine, imidazole or benzimidazole; Figure 8). The electronic
characteristics of the different nitrogen donors provide for variation in electron
availability at the donor sites in the different complexes.
The incorporation of different nitrogen donor types is justified106 by the fact that, in
haemocyanin, one histidyl imidazole is situated further away from the copper ion
than the other two; 133 it is believed that this is also likely to be the case in
tyrosinase. 134 Additional support is provided by the activity shown by complexes
containing different donor types.13S.136 TheJigands have, typically, been designed
to form 6-membered chelate rings on complexation, because this arrangement is
stable for copper complexes and permits changes in the oxidation state. 61 For the
ligands containing the planar 1,1 O-phenanthroline spacer, however, formation of
a 5-membered chelate ring during complexation with copper is possible - an
arrangement known to favour the stabilisation of the copper(lI) oxidation state. 137
The substrate is expected to gain entry to the copper active site, i~ each case, by
moving between the arms of the ligand. I
In our attempts to develop synthetic models of the active site of the enzyme,
tyrosinase, it was decided to prepare and isolate the organic ligand prior to
complexation rather than use the template approach. This allows for the
independent isolation and characterisation of the ligand without any interference
from the metal ion.
Discussion 44
2.2 LIGAND SYNTHESES
2.2.1 Biphenyl ligands
The biphenyl unit has been used as a spacer to impart flexibility to the organic
ligand and the resulting complex.138 This spacer allows the complex to adopt a
conformation in which the two copper atoms are sufficiently close together to
permit bridging by dioxygen without imposing rigid planar geometry. It has been
shown that if the spacer is too flexible, binding of the substrate may be inhibited. 139
The synthetic routes used to prepare a series of ligands containing the biphenyl
spacer are outlined in Scheme 2. Biphenyl-2,2'-dicarbaldehyde 48140 and biphenyl-
2,2'-dicarboxylic acid 49141 were produced from phenanthrene 47 in separate
reactions following reported methods. Thus, ozonolysis of phenanthrene 47 in
methanol at low temperature [to inhibit formation of a stable peroxide 50 from the
reaction of the intermediate with methanol (Scheme 3)] afforded biphenyl-2,2'
dicarbaldehyde 48 in high yield (93%). The 1H NMR spectrum (Figure 9) of the
dicarbaldehyde 48 is charactersised by the aldehydic proton signal at 09.83 ppm.
J J
I' , 'I' PPIII 10 9
48 g I ~I CHO
OHC I~
b
Figure 9: The 400 MHz 1H NMR spectrum of biphenyl-2,2'-dicarbaldehyde 48 in CDCI
3. ~ -
Discussion 45
Access to the dicarboxylic acid 49 was achieved via H20 2 oxidation of
phenanthrene 47 in glacial acetic acid, the required product being isolated in 67%
yield; the presence of the carboxylic acid group was confirmed by a 1 H NMR signal
at 012.44 ppm and a broad IR absorption band in the region 2500-3500 cm-1.
< > < > 0 3
OHC RNH2 KI Q (> 47 - 48
MeOH NH2
CHO 51
~02 t C~C02H
t RNH2 CHCI3 6 ::::,...1
49
55a-c
NR
H02C NH2
< ~ ( > 54a-c H~N 52 C02H 'I RN
t RNH2 t NaBH4 COl MeOH DMF
NHR NHR 53 UAIH4
* 56a-c
THF RHN RHN I
a b c
Scheme 2: Synthetic routes for obtaining ligands containing the biphenyl spacer.
0
~ \LNH
Discussion 46
OHC KI OHC
MeOH CHO
47 MeOH~ 48
CH-9 50 CH-O
\
OCH3
Scheme 3: Synthesis of biphenyl-2,2'-dicarbaldehyde 48.
The chelating ligand system, 2-(2-aminoethyl)pyridine 51, was available com
mercialy, while histamine 53 had to be released from its dihydrochloride salt by
treatment with sodium methoxide. 2-(2-Aminoethyl)benzimidazole 52 was obtained
by reacting 1 ,2-diaminobenzene 57 with p-alanine 58 (Scheme 4).138 The formation
of the bis-substituted biphenyl derivatives 54a, 54b and 54c containing these
chelating systems, however, presented particular difficulties.
~N~ + ~N~
57 58
6MHCI .. 52
Scheme 4: Preparation of 2-(2-aminoethyl)benzimidazole 52.
J
The formation and subsequent reduction of the diimino derivatives 54a, 54b and
54c of the dialdehyde 48, was expected to afford the required di-amin9 ligands
56a, 56b and 56c. The tendency of imidazolyl imines to undergo intramolecular
cyclisation, observed in our group 138 and reported by Casella ef a/. 135 (Scheme 5),
had prompted us to target the diamines 56a, 56b and 56c as model ligands rather
Discussion 47
than their di-imino precursors 54a, 54b and 54c. However, the reduction step
proved more difficult than expected.
Scheme 5: An intramolecular cyclisation reaction proposed by Casella et al. 135
The di-imino compound 54a, containing pyridyl groups, was prepared using the
procedure employed by Reglier et al. 103 Attempted reduction of this compound
using sodium borohydride in methanol at room temperature, however, failed to
afford the expected product, 56a. The 1H NMR spectrum of the isolated product
(Figure 10) are clearly inconsistent with structure 56a. It was expected that the
signals for the methylene protons at 02.98, 03.13 and 03.48 ppm would each
integrate for four protons but, instead, the integrals at 02.98 and 03.13 ppm are
equivalent to two protons each, while only the signal at 03.48 ppm integrates for
four protons. The 13C NMR spectrum (Figure 11), however, reveals the expected
14 signals (2 overlapping at ca. 55.5 ppm; 3 at ca. 127.5 ppm). \
f"
ppm '0 . ~ 'I' 'I • i. I
7 ,
61a
'I' 5 I""" to 4 3
fr
'I 2
I"" 'i ., , 0
Figure 10: The 400 MHz 1H NMR spectrum of ligand 61a in CDCI3.
I
.'" " " "~a 1Jto I ,60
I
I 140
I
Discussion
i
I
'" I
'00
......
~'
Figure 11: The 13C NMR spectrum of ligand 61a in CDCI3.
I .0
• "1' o
48
When the reaction was repeated at room temperature, the same product was
isolated. Single crystal X-ray analysis (see sections 2.3.4.1.2, p.1 07, Figure 36 and
2.3.4.2.2, p.122, Figure 46) of the cobalt and nickel complexes of this compound
revealed that the ligand was, in fact, the dibenzoazepine (R = pyridine; Scheme ~
54), thus explaining the apparent anomalies in the NMR spectra. I
Formation of ligand 61a may be rationalised in terms of the mechanism outlined
in Scheme 6. It is suggested that one imine functionality is first reduced during the
reaction with NaBH4 . The lone pair on the nitrogen of the resulting amine
functionality 59a then attacks the remaining imine functionality, resulting in
cyclisation and subsequent loss of one arm of the ligand from the intermediate
aminal 60a. Similar reduction of diimines 54b and 54c also failed to yield the
expected products 56b and 56c, affording, instead, the corresponding
dibenzoazepines 61b and 61c. One- and two-dimensional analysis (illustrated for
compound 61 b in Figu~es 12 and 13) pr?vided unambiguous confirmation of the
identity of these cyclised products.
Discussion 49
R ~R NaBl-i4 ..
MeOH a () ~I
54a-c 59a-c HNtN
1 b U C ~N
61a-c N~R HN..!I •
Scheme 6: Proposed mechanism for the intramolecular cyclisation during NaBH4 reduction of the diimine 54a.
~I
61 b ~ N-~-.tD I N~
b
I
\ ----)'----~
pp.
Figure 12: The 400 MHz 1H NMR spectrum of ligand 61b in MeOH-d4.
, -
o
Discussion
, <. , < .•
01
(l 10
Figure 13: The HETCOR spectrum of ligand 61 b in MeOH-d4.
50
In an alternative approach, it was decided to focus attention on ligands containing
amide rather than imine functions and to effect reduction to the corresponding
amine ligands 56a, 56b and 56e using lithium aluminium hydride (Scheme 2). The \
diamides were prepared by reacting the diacid 49 with the coupling agent carbonyl I
diimidazole (CDI),142 at 4(1)C and then treating the resulting intermediate with the
amines 2-(2-aminoethyl)pyridine 51, 2-(2-aminoethyl)benzimidazole 52 and
histamine 53. The diamides were obtained in 54-82% yield and were fully
characterised by elemental (high resolution MS) and spectroscopic analysis.
Broadening and coalescence of certain signals is apparent in the 1 H NMR spectra
of ligands 55b and 55e. These effects are illustrated in the 1H NMR spectrum of
diamide ligand 55e where broad peaks are observed at 02.51 and 03.34 ppm
(Figure 14). The broadening of the peaks are attributed to slow rotation of the
- bonds on the NMR time scale. Unfortunately, numerous attempts to reduce these
diamides (55a, 55b and 55e) with reducjng agents such as lithium aluminium
hydride and Raney Nickel were unsuccessful.
Discussion 51
55c WI H
FN O~ ~ HN~ 0 ~NH
~ I ~ A
- J
Figure 14: The 400 MHz 1H NMR spectrum of diamide ligand 55e in MeOH-d4.
In a third approach, a synthetic route reported by Sorrell and Garrity,143 was
explored. These authors had also been unsuccessful in their attempts to reduce
similar amide derivatives and, as a result, they developed a synthetic route that
involved initial protection of the amine as an amide, followed by de\protection using
acid hydrolysis. A similar synthetic approach (Scheme 7) was investigated for
generating the diamine ligand 56b. "The amide 62 was obtained by condensing
2-(2-aminoethyl)benzimidazole 52 with benzoic acid and using COl as the coupling
agent. This amide was then treated with NaH and 2,2'-dibromomethylbiphenyl to
give the diamide ligand 63. The structure of the ligand was confirmed by elemental
and spectroscopic analysis; the complexity of the aromatic region in the 13C NMR
spectrum can be clearly seen in Figure 15. Attempts to remove the benzoyl
protecting groups by ac:.id hydrolysis proved unsuccessful. Given the unexpected
difficulties in accessing the diamino ligands, we decided to examine the various
amide ligands, which had been obtained, as potential ligands forcomplexing
copper (see section 2.3.2).
Discussion 52
CO:zH
>-0 O:N~NH' 0 ~ O:yN -~ NH DMF I" H
COl ~ NH 62 52
Br
Nr;; qb DMF N2
Br
~ -- 0
<~~ ~i> 63
o~ HN ~ h
~ 6N Hel reftux 10N NaOH
H
Ji> (~~N J 56b
N HN H
Scheme 7: Attempted synthesis of ligand 56b.
Discussion 53
Figure 15: The 400 MHz 13C NMR spectrum of ligand 63 in o fv\SO-d6·
Discussion 54
2.2.2 1,1 O-Phenanthroline ligands
Ligands containing the 1,1 O-phenanthroline unit as spacer were expected to exhibit
some rigidity and planarity. Such rigidity in copper complexes may well favour
binding of the substrate and, thus, enhance their biomimetic potential. The
synthetic routes followed to obtain 1,1 O-phenanthroline-containing ligands are
outlined in Scheme 8.
Neocuproine 64 (2, 9-dimethyl-1 ,1 O-phenanthroline) was used as the starting
material. It has long been known that this compound is a useful analytical reagent
for the determination of copper, 144 forming a bright red copper complex. The Se02
oxidation reactions of neocuproine 64 to 1,1 0-phenanthroline-2,9-dicarbaldehyde
65145 and the subsequent oxidation to 1, t.o-phenanthroline-2, 9-dicarboxylic acid
66 145 using 80% HN03, occurred with relative ease. The 1 H NMR spectrum of 1,10-
phenanthroline-2,9-dicarbaldehyde 65 (Figure 16) reveals the characteristic
aldehydic proton signal at 010.35 ppm.
Condensation of 1,1 0-phenanthroline-2, 9-dicarbaldehyde 65 with the amines 51
and 52 gave the corresponding imines 67a and 67b which, without further
purification, were reduced using NaBH4 to afford the required diamino ligands 68a
and 68b. These ligands were fully characterised, and 1- and 2-D NMR spectra for
compound 68a are illustrated in Figures 17 and 18 respectively. From the 1H NMR
spectrum it can be seen that the formation of the diamine ligand 68a was
successful, the singlet at 04.32 ppm corresponding to the methylene groups. The
HETCOR spectrum of ligand 68a (Figure 18) reveals the requisite correlations
between the carbons and their attached protons.
Discussion 55
0=0 0=0 RNH2
Se02 64 .. 65
1,4-dioxan
6 H3C CH3 OHC CHO 51
% 1 RNH2 80%HN0.3 :::::,...'
~ 0=0 NH2
67a,b 66 H~N 52 HOzC COzH
NHR RH\J 0 t NaBH4• 1 RNH2• MeOH COl,
DMF
~ ~ LiAIH4 53
68a-c -->< 69a-c THF
0 \LNH
0 NHR RH\J NHR RHN
abc
I
Scheme 8: Synthesis of ligands containing the 1,1 O-phenanthroline spacer.
Discussion
0=0 OHC CHO
65 j[-
j Iii i I I I I i j I ! I I I I I iii j i i [ I I , j I , , I f I I Ii! I i I Iii f
ppm 10 ~ B 7
Figure 16: The 400 MHz 1H NMR spectrum of 1, 10-phenanthroline-2,9-dicarbaldehyde 65 in DMSO-d6.
I' ... • I~
68a
~ ,
HN J)
\
" I NHU ~
1 ~ , I " 1 ' .~~
I 0
Figure 17: The 400 MHz 1H NMR spectrum of ligand 6Sa.in CDCI3 .
J
56
Discussion 57
J l 1 , ,
I
. I
~ ,I ,
~ I II
- I ~""'-
.- , , , , , , ,
Figure 18: The HETCOR spectrum of ligand 68a in COCI3 .
In an alternative approach, the dicarboxylic acid 66 was conden~ed with each of
the amines, 2-(2-aminoethyl)pyridine 51, 2-(2-aminoethyl)benzimidazo~ 52 and
histamine 53 using COl as a condensing agent. The resulting diamides 69a, 69b
and 6ge were isolated in yields ranging from 61 to 73% and, in each case, a signal
corresponding to the amide proton was observed at 09.5-9.8 ppm in the 1H NMR
spectrum (illustrated for ligand 69b in Figure 19). Access to the 1,1 O-phenan
throline-based diamino ligands 68b and 68e was then explored via the reduction
of the intermediate diamides 69b and 6ge. Amide carbonyl groups are commonly
reduced using excess LiAIH4. Unfortunately, as was the case with the biphenyl
analogues, attempts to reduce the diamides 69b and 6ge using LiAIH4 were -
unsuccessful. It was decided to evaluate the diamides as potential ligands for
copper, the diamino analogues being available via the diimines.
69b
'" I DP'" 10
I' 7
Discussion
100.0 i '&
6 5 "~ o ~ ,.
Figure 19: The 400 MHz 1H NMR spectrum of ligand 69b in DMSO-d6 o
58
I
Discussion 59
2.2.3 Schiff base ligands prepared from diketones
A series of novel diimine ligands were targeted, which contain acyclic spacers and
which illustrate the effect of varying the length of the spacer chain and the
substituents R\ R2 and R' (Figure 20). As imidazole-containing imino ligands are
prone to intramolecular cyclisation, 2-(2-aminoethyl)pyridine 51 was chosen to
form the coordinating arms of the ligands. Various diketones were used to provide
the required spacer moieties. Furthermore, the ligands were designed to complex
copper via 6-membered chelate rings (see Figure 20b), thus allowing changes in
the oxidation state of copper.61 Additional advantages are that both the imine and
pyridine moieties are able to stabilise copper in the lower oxidation state.
R2 "" ... R2
-A~ RAR' R1 R2 R3
76 Me H Me 77 Me Me Me
cf ~ 8 9 78 Me Et Me Cu Cu
~ 79 Me Ph Me / "-_N N " 80 Ph H Ph
~ N N~ ~ B '1_ 81 Ph H Me (a) (b)
\ Figure 20: (a) Proposed Schiff base ligands and (b) their envisaged complexation
with copper. I
The synthesis of these ligands is outlined in Scheme 9. With the exception of the
diketone 73, which was prepared by the standard benzylation of acetyl acetone
(Scheme 10), the required diketones were available commercially. Reaction of
these diketones with 2-(2-aminoethyl)pyridine 51 gave the expected diimines 76-81
in yields ranging from 25 to 61 %. Similar condensation of the diketone 82 afforded
the diimine 84; numerous attempts to prepare the diphenyl analogue 85 from the
diketone 83 proved ~unsuccessful. The ligands were purified by flash
chromatography and characterised by NMR spectroscopy and by FAB-MS
analysis.
82
R2
RylyR3
0 0
70 -75
H2NU ~ I ~
51
70 71 72 73 74 75
0
H3C~CH3 0
CHCb
Discussion 60
R2
CHCb RhR3
•
dN
N~ ~ N N~
R1 R2 R3
Me H Me Me Me Me Me Et Me Me PHCH2 Me Ph H Ph Ph H 'Me
51
H2NU ~ I ~
76 - 81
76 77 78 79 80 81
0 0
Ph~Ph 83
I
CHCb
Ph~Ph
""i jN N'( "'" C~ fJ
85
Scheme9: Synthesis of Schiff base ligands.
Discussion 61
0 0 NaOMe 0 0
AA ~ Y 70 P~Br 73
Scheme 10: Synthesis of the diketone 73.
The 1 H NMR spectra for ligands 76-81 in which the imine functionalities are
separated by one carbon atom, reveal extensive tautomerism. A broad signal in the
region 012-13 ppm characterises the 1H NMR spectra of these ligands (illustrated
for ligand 78 in Figure 22) and is attributed to the hydrogen-bonded amino proton
in the enamine tautomer (Figure 21). This interpretation is supported by deuterium
exchange data. After the addition of 0 20 to a sample of ligand 78 in COCI3, the 1H
NMR signal at 012.37 ppm virtually disa'ppeared (Figure 23); furthermore, the
methylene signal at 03.65 ppm (observed as a quartet before deuterium exchange)
appeared as a triplet indicating coupling between the amino proton and the
adjacent methylene protons. In the 1H NMR spectrum of ligand 84 (in which the
imine groups are separated by two methylene groups), however, the signal at ca.
012 ppm is absent and the methylene signal at 04.13 appears as a triplet, not as
a quartet (Figure 24). Thus, it may be concluded that significant taMomerism only
occurs when the imine functionalities are separated by one carbon atom~ This is
not surprising since, only in these systems, is the enamine tautomer (Figure 21 )
stabilised by extensive conjugation and by a six-membered, H-bonded chelate.
Figure 21: Tautomerism in the Schiff base ligands 76- 81.
Discussion
r rI '" I"'" """ I'
pp" t2 to
J'J "j
4 1'0' Oi'I' 2 o
Figure 22: The 400 MHz 1H NMR spectrum of ligand 78 in COCI3 _
I 00.
12 1
10
r r r J Jj j J J
.. J.1J_ ... J. 11-,.~,------, r
0" 'I 4 , & " 'A '~ ,
Figure 23: The 400 lVI~z 1H NMR spectrum of ligand 78 in COCI3 after the addition of 0 20 _ <
62
Discussion 63
~CyyCH3
d, N \"---1 ~N 84 fJ
iii. i pp. !O
Figure 24: The 400 MHz 1H NMR spectrum of ligand 84 in CDCI3 _
The Schiff base ligands, derived as they are from acyclic diketone spacers, are
flexible, since rotation about the carbon-carbon bonds separating the two imine \
functionalities is possible. As a result, their copper complexes may be ex~ected to
readily adopt appropriate conformations for binding a substrate molecule_
However, it was hoped that the copper complexes would not be too flexible as this
could actually inhibit the binding of the substrate and result in an absence of
catalytic activity_
Discussion 64
2.2.4 The Baylis-Hillman approach to ligand synthesis
A further approach to the synthesis of ligand systems involved use of the Baylis
Hillman reaction, 146 in which activated alkenes (typically, acrylate esters) react with
aldehydes in the presence of a nucleophilic catalyst, such as DABCO
{diazabicyclo[2.2.2]octane}, to afford multifunctional products 86 (Scheme 11). The
reaction has been the subject of several reviews,147 and has been applied in our
research group to the synthesis of heterocyclic systems, viz., indolizine,148
quinoline, 149 coumarin and chromene derivatives. 150 In the present study, it was
anticipated that application of the Baylis-Hillman reaction to a dialdehyde (e.g.
1, 10-phenanthroline-2,9-dicarbaldehyde 65; Scheme 12) would provide access to
polydentate ligands such as 89 and 90. Thus, reaction of the acetylated Baylis
Hillman product 88 with piperidine or pyrrolidine was expected to lead, via a
conjugate addition-elimination sequence, to the ligands 89 and 90 respectively.
Before applying the Baylis-Hillman reaction to the dialdehyde 66 it was decided to
use pyridine-2-carboxaldehyde 91 (Scheme 13) as a model system to explore the
feasibility of the proposed transformations.
+ '\.-R' DABCO
•
86
Scheme 11: The Baylis-Hillman reaction.
R' = CN, OO;zMe
Discussion 65
~~ <~ OHC CHO
DABCO
87 * ~CN HO OH
65 NC CN
.------ 88 AcO OAc
NC CN
o 89
90
o o I
Scheme 12: Proposed Baylis-Hillman pathway to polydentate ligands.
2.2.4.1 Pyridine-2-carboxaldehyde as a substrate
The Baylis-Hillman product 92 was obtained after 4 days by reacting pyridine-2-
carboxaldehyde 91 with acrylonitrile in the presence of DABCO (Scheme 13).148
- Once this product had been obtained, two routes to compounds 96 and 97 were
considered. In the first, rE?aftion of pyrrolidine< or piperidine with the Baylis-Hillman
product 92 was expected to give derivatives 94 and 95 via an addition reaction,
Discussion 66
subsequent dehydration affording 96 and 97 respectively. Alternatively, acetylation
of the Baylis-Hillman product 92, followed by allylic (SN') displacement of acetate
from the acetylated intermediate 93 by piperidine or pyrrolidine, was expected to
afford compounds 96 and 97 respectively. In the event, the latter synthetic route
involving the acetylated product 93 was attempted first and was found to work well;
as a result, the alternative route was not attempted.
0 ~CN -P AC20 -P .. ... 93 DABCO HO O.5h reflux AcO
OHC CHCI3 4d NC NC
91 92 ,
RH I
THF 1 RH I ,
THF : stir for 3d [-AcO] , 94 -e [-H2 O] e 96
95 ------...
97 HO
NC R NC R
R I
94
95
Scheme 13: Synthesis of model ligands using the Baylis-Hillman reaction.
The purpose of acetylatmg the hydroxyl group in the Baylis-Hillman product is, of
- course, to provide a better leaving group, thus facilitating allylic displacement by
the nucleophilic 2° amine._One drawback o~ the acetylation approach, however, is
that the acetylated product can cyclise at elevated temperature to form an
Discussion 67
indolizine. 148 This cyclisation can be avoided by ensuring a reaction temperature
of less than ca. BO°C. The acetylated product was obtained in 60% yield, and was
readily identified by the characteristic acetate methyl signal at 02.21 ppm in the 1 H
NMR spectrum (Figure 24).
93
~~rrrl ~~I ~'T"~
PPII 10 9
r J JJ f
Figure 24: The 400 MHz 1 H NMR spectrum of the acetylated pr<!>duct 93 in CDCI3 · J
. The 1H NMR spectrum of the substitution product 96, on the other hand, (Figure
25) is characterised by the absence of the acetate methyl signal and the
appearance of a signal at 03.29 ppm corresponding to the allylic methylene
protons; the piperidine methylene protons are responsible for the signals in the
region 01.4-3.3 ppm. The presence of the nitrile group is confirmed by an IR
absorption band at 2217 cm-1. The analogous pyrrolidine derivative 97 was
similarly characterised trom the NMR and IR data.
96
J
2 ~ 0
r r j J __
Discussion
Figure 25: The 400 MHz 1H NMR spectrum of compound 96 in CDCI3 .
68
2.2.4.2 1,10-Phenanthroline-2,9-dicarboxaldehyde 65 as a Baylis-Hillman
substrate.
I Given the success obtained with pyridine-2-carbaldehyde 91, the use of 1,10-
phenanthroline-2,9-dicarbaldehyde 65 as a substrate for the Baylis-Hillman
reaction was investigated (see Scheme 12). Unfortunately, repeated attempts to
react the dicarbaldehyde 65 with acrylonitrile in the presence of DABCO, at room
temperature, in both chloroform and MeOH as solvent, proved unsuccessful. The
substrate 65 is insoluble in both solvents and, consequently, the reactions were
also attempted at reflux temperature in order to improve solubility. However, these
attempts were also uns~ccessful and this approach was abandoned.
An alternative strategy involving the Baylis-Hillman reaction was then explored
(Scheme 13). In this appr;ach, it was intended that the chelating arms of the ligand
Discussion 69
should be attached to a 1 ,3-diaminopropane spacer rather than a 1,1 O-phenan
throline spacer. Unfortunately, attempted condensation of the acetylated 8aylis
Hillman product 93 with 1,3-diaminopropane also proved unsuccessful, as
indicated by the 1 H NMR spectra of the reaction products isolated by
chromatography.
o OHC
91
~CN .. DABCO,
CHCI3,
4d
Q HO~-
NC
92
-P ~ I.
AcO N 0.5 h, reflux
NC
THF
98
Scheme 13: Attempte~ synthesis of the ligand 98. I
Discussion 70
2.2.5 Macrocycle Syntheses
Cyclic polydentate ligands, which exhibit conformational flexibility, have been
found to act as effective hosts in binuclear and polynuclear complexes,151-155 and
such complexes are potential targets as supramolecular catalysts. 156 Macrocycles
with large cavities, in particular, have received attention as inorganic and organic
anion and cation receptors, affording complexes which participate in biological
processes. 157-160
. Representations of a proposed macrocyclic system and possible dicopper
complexes are shown in Figure 26. It is apparent that two coordination possibilities
can occur, viz., tetradentate coordination with the copper atoms aligned "vertically"
(b) and bidentate coordination (the rema}ning coordination sites being filled by
solvent donors) in which the copper atoms are "horizontally" aligned (c).
Spacer Spacer Spacer
F 8 F.\ . , N N N-------Cu-------N N, .N
I I I I I '::CU cli' I J
N N NBN N/ "-N
8 8 I \ I •
N-N
Spacer Spacer Spacer
(a) (b) (c)
Figure 26: Representations of the proposed macrocyclic ligand (a) and possible dicopper coordination options, (b) and (c).
,-
Discussion 71
q:o H2N~NH2
~ 65 -* OHC CHO MeOH N N
"~X) 1 ( ) 100 I MeOH
HzN reflux N N
p=s qp N N a D 99 N N
~ Scheme 14: Synthetic approaches to macrocyclic ligands.
The synthesis of the polydentate macrocycles 99 and 100 was explored, the former
being more rigid and bulkier than the laUer. The intention was to compare the
catalytic activity of a rigid, bulky copper complex with that of a more flexible, less
bulky system. 1,1 0-Phenanthroline-2, 9-dicarbaldehyde 65 was used as a'spacer
and treated with 1 ,2-diaminobenzene and 1 ,2-diaminoethane with a view to
obtaining Schiff base macrocycles 99 and 100 respectively (Scheme 14).
The novel dibenzo analogue 99 was isolated in 30% yield and characterised by
MS and IR spectroscopy. The FAB mass spectrum clearly reveals the molecular
ion peak at m/z 616 (Figure 27), and high resolution MS analysis confirmed the
atomic composition. T~e IR spectrum has a strong band at 1619 cm-\
characteristic of the imine functionality. Interestingly, Jhe 13C NMR signals were
unusually broad, possibly due to conformational flexions which are intermediate
on the NMR time-scale.
Discussion 72
31!
136
49
197 309
41l
Iii
Figure 27: The FAB-MS spectrum of macrocycle 99 showing the molecular ion peak at m/z 616.
Unfortunately, attempts to obtain the known ligand161 100 were unsuccessful; the
products obtained in attempted preparations were insoluble in~ DMSO and are
believed to be polymeric. J
--
Discussion 73
2.2.6 Dendrimer Synthesis
In the last few years, much attention has been given to the preparation and
characterisation of dendrimer-based transition-metal complexes. 162 Such
complexes provide a promising structural concept for new materials. 163-168 Unlike
conventional metal-containing polymers, dendritic (from the Greek word meaning
branched) cascade molecules have the advantage of offering a highly controlled
architecture, which can act as a foundation for dendrimer -supported metal
complexes. 169 Research in this area has blossomed and is currently concerned
with exploring or developing various uses for dendritic molecules; these include:
chemical sensors, magnetic resonance imaging agents, agents for delivering drugs
or genes into cells, micelle mimics, nanoscale catalysts, reaction vessels, immuno
diagnostics, information-processing materjals and high-performance polymers.17o
In our investigation, it was antiCipated that dendrimer moieties could be used to
develop ligand systems which could mimic the macro characteristics of an enzymic
active site, viz., a hydrophilic exterior and a hydrophobic binding pocket. The
account which follows details our first endeavours in this direction. The
trihydroxyamine 105 was identified as a potentially useful dendri(l1er group, and
its synthesis, following Newkome's method,171 is outlined in Scheme 15. I
'-CN CN COzH
~CN HCI ~Co..H C~~ ,... ~ 103
Triton B 101 CN COzH
102 ! BH,.THF
~
~ T-1
~OH Raney Ni 105 H2 OH ~ 02~ OH 104
3 atm OH OH
Scheme 15: Synthesis of the dendrimer moiety 105.
Discussion 74
Nitromethane 101 was reacted with acrylonitrile in the presence of Triton 8 (a
surface active agent) to afford, via a Michael reaction, tris(2-cyanoethyl)
nitromethane 102.171 The nitro triacid 103, prepared by acid-catalysed hydrolysis
of the trinitrile 102, was identified by the absence of a nitrile band (at ca. 2200
cm-1) and the presence of a carbonyl band (at 1721 cm-1) in the IR spectrum and
the appearance of a carbonyl carbon signal at 175.6 ppm in the 13C NMR
spectrum. The reduction of the triacid 103 to the trial 104 was achieved using the
mild reducing system, borane-THF;171 the absence of a carbonyl carbon signal and
the presence of a signal at 60.3 ppm (corresponding to CH20H) in the 13C NMR
spectrum served as evidence for the formation of the trial 104. The final reduction
of the nitro functionality to obtain the amino trial 105 was achieved by
hydrogenation using specially prepared T -1 Raney Nickel172 as a reducing agent.171
The success of this reduction was evidenced by the disappearance of the low-field
(94.0 ppm) C-N02 signal in the 13C NMR spectrum.
With the dendrimer moiety 105 in hand, attention was given to the construction of
dendrimer-based ligands. Several approaches were explored (Scheme 16). The
first route (Path 1) envisaged deprotonation of neocuproine 64, using NaH to
generate a dianion, for reaction with acrolein to produce the lialdehyde 106.
Subsequent reaction with the aminotriol 105 was then expected to afford the
dendrimer ligand 107 via a Schiff base reaction. Unfortunately, this synthetic
pathway was complicated by the formation of what appeared to be a polymeric
product (insoluble in DMSO) during the reaction with acrolein.
In further approaches (Paths 2 and 3), the tri- and tetracarbonyl derivatives 108
and 110 were expected to react with the amino trial 105 to afford the
corresponding dendrimer-based ligands 109 and 111, respectively. Numerous
attempts to oxidise the central ring in neocuproine 64, _using methods reported for
1,1 O-phenanthroline, 173-175 proved unsuccessful.
--
Discussion 75
106 107
a a
Path 1
Q KMnO" KOH -X-ii) Se02 Path 2 " Path 3 * i) HNQ"H,sO"KBr
ii) Se02
a a a
dt~ ~R~ 110 108
OHC CHO OHC CHO
1 RNH2 RNH21 \
I
NR a a
~ -N N- 111 109 ~
NR RN
~H R = OH
OH
Scheme 16: Attempted pathways to d~ndrimer-based ligands containing the 1,1 O-phenanthroline spacer.
Discussion 76
Finally, selenium dioxide oxidation of neocuproine' 64 afforded the dialdehyde 65,
which on treatment with the amino triol105, gave the dendrimer-based ligand 112
in 96% yield (Scheme 17). This ligand was characterised by IR, 1H and 13C NMR
spectroscopy. The 1H NMR spectrum (Figure 2S) is characterised by the imine
proton signal at oS.09 ppm and the broad upfield signals corresponding to the
dendrimer methylene groups. The FAB mass spectrum of ligand 112 did not exhibit
the expected molecular ion peak at m/z 610 but, rather, a peak at m/z 633
corresponding to attachment of a sodium cation (633.3627; M + Na+); such ions
are not unusual in the FAB-MS spectra.
64 o Q 65 OHC CHO
h'0H ~~OH
OH
112
Scheme 17: Synthesis of the dendrimer -based ligand 112.
I
A mononuclear copper complex of this ligand was considered unlikely to be a good
biomimetic model since two copper ions are found in the active site of the
-. - tyrosinase enzyme, whereas the coordination cavity in-ligand 112 would probably
only accommodate a single copper ion. Complexation with a metal would, however,
establish whether coordination involves the aromatic nitrogen atoms or whether the
Discussion
hydroxyl groups of the dendrimer moieties compete as donors.
pp.
112 ~
~:JfN ~OH HO OH OH
I 10
77
. :
\ Figure 28: The 400 MHz 1H NMR spectrum of the dendrimer-based ligand 112.
I
Discussion 78
2.3 COMPLEXATION AND COMPUTER MODELLING STUDIES
2.3.1 Complexation Studies
While the ligands synthesised in this study were designed to form dinuclear copper
complexes, they may also coordinate with metals other than copper, e.g.
manganese(II), iron(II), cabalt(ll), nickel(II), platinum(II), palladium(ll) and lead(II).
Consequently, some attention was also given to the complexation of ligands
containing the biphenyl and 1,1 O-phenanthroline spacers (Schemes 2 and 8) with
cobalt(II), nickel(II), platinum(lI) and paliadium(II).
Hard metals, which include copper(II), cobalt(ll) and nickel(lI) are known to
coordinate with amide oxygen,176-178 but the resulting metal-oxygen bonds are
weaker than the corresponding metal-amide nitrogen bonds. Coordination of
metals to nitrogen donors occurs over a wide pH range, but the ability of metals to
deprotonate and complex with amide nitrogen is pH-dependent. From
potentiometric titration studies of divalent metal ion-dipeptide systems, the
following pH preferences have been obtained for the coordination of metals to
peptide nitrogen donors:- copper(II), pH 5 - 6;179.180 nickel(II), RH 8 _ 9;181.182
platinum(II), pH < 5; 183 and paliadium(II), pH 2.5 _ 3.5.184.185
It must, however, be emphasised that in the present complexation studies, the pH
was not tuned to specifically achieve coordination of the metal with the amide
nitrogen donors, and coordination of the metal could involve either the oxygen or
nitrogen atom of the amide functionality.
The analysis of these complexes was expected to reveal:
(i) whether dinuclear complexes were formed;
-. - (ii) whether coordination of the metal occurs through-the. nitrogen or oxygen
atom of the amide Ijgsnds; and
(iii) the preferred geometry of the resulting complexes.
Discussion 79
Ligands containing amide, imidazole and benzimidazole moieties should provide
coordination environments that are similar to those in biological systems, such as
enzymes, and the resulting complexes of cobalt and nickel could prove to be good
synthetic models of metalloproteins in which these metals are found. The
structures proposed for the various complexes, which have been isolated, are
based on a consideration of the IR, NMR, UV-Vis, microanalytical and computer
modelling data. Unfortunately in only two cases were crystals obtained which were
suitable for X-ray crystallographic analysis.
2.3.2 Copper Complexes
Copper is present at low concentrations in many enzymes and proteins. 18G In larger
quantities, copper is toxic to humans and its salts are highly toxic to lower
organisms. 187 Copper ions instantly form complexes with a wide variety of ligands
and exhibit a range of oxidation states in the coordination compounds in which
they occur. The copper(l) and (II) oxidation states are the most prevalent, but the
copper(lll) and (IV) oxidation states are also known. Copper(III) and copper(IV)
oxidation states are, however, rare. Copper(l) is readily oxidised to copper(II),
which is the most stable oxidation state of copper under standard cpnditions. l88, 189
A wealth of copper complexes have been generated,189and the crystal stgJctures
of many of these have been deterrT)ined. These structures have permitted the
characterisation of various regular and distorted geometries of the copper(II)
ion, 190,191 which are associated with the Jahn-Teller effect. 192 Copper(I), a d10 ion,
behaves as a soft acid and favours coordination to soft sulfur and phosphorus
bases,193whereas copper(II), a d9 ion, is considered to be a border-line hard acid
which favours oxygen and nitrogen donors.l94 Diamagnetic, colourless complexes
are formed by copper(l) with its closed shell configuration, 190,195 while copper(II)
produces highly coloured paramagnetic complexes. 190,194, 195
Discussion 80
2.3.2.1 Synthesis of Copper complexes
The complexation of copper with the various ligands occurred with ease [see
Experimental section (3.3.1 )]. Depending on the solubility of the ligand, dry DMF
or dry MeCN were used as solvents in these complexation reactions.
Biphenyl and 1,10-Phenanthroline Complexes
The biphenyl (Scheme 18) and 1,1 O-phenanthroline (Scheme 19) ligands were
reacted with [Cu(MeCN)4]PFs, a Cu(l) reagent, at room temperature under N2 in
dry, degassed solvent; in some cases, the solutions had to be heated to dissolve
the ligands. The ligand solution was added dropwise to the solution of the
copper(l) reagent to obtain dinuclear copper(l) complexes. The biphenyl
complexes, obtained using this procedur~, were green, indicating the copper(lI)
oxidation state. The 1,1 O-phenanthroline complexes, however, were brown in
colour and there was some uncertainty as to whether this was an indication of the
copper(l) or (II) oxidation state, since colourless complexes are formed for
copper(l) and green complexes are formed for copper(II). Microanalysis data for
these complexes (Table 8, p.85) show that the biphenyl and 1,1 O-phenanthroline
complexes are, typically, dinuclear and of acceptable purity; the d~ta for complex
117 appears to be a mixture of mononuclear and dinuclear complexes (9ata not
included in Table 8). The results also ~ndicate that two PFs- anions are present as
counter ions- except for complex 119 which has four. This suggests either that
protons from the amide, benzimidazole or imidazole moieties are generally
removed during complexation, or that both copper atoms are in a copper(l)
oxidation state in these complexes. All the complexes, except complex 119, were
insoluble in DMSO due, it is believed, to the formation of polymers. The structures
proposed for the copper complexes detailed in Schemes 18 and 19, while
necessarily tentative, are-based on a consideration of the spectroscopic (Sections
-. - 2.3.2.2-4) and microanalytical data.
Discussion
+ a b C ~N
---+--+-±-+ ~N~ 0 -
R N~; HN "N ; r-(~ I N ~ b V
~ b TN - \ ~ b H N
f' N~h ~U(MeCNZ4PF6 - 0 \ ./"N~
DMF CU
0' [for 55b] QN/ \ R ...............
HN ~ 0 ~ /I N~ DI'vF
o ~ NH~R + I~
55a-c
MeCN * [for 55a] [Cu(MeCN)4lPF 6
117
yU~N)4PF6 DMF ~for 55e]
115
Scheme 18: Complexation of the biphenyl amide ligands with copper.
81
Discussion 82
a b c
69a-c
ICU(MeCNl4II'FSl OMF
118a-c
I
68a 119
Scheme 19: Complexation of selected 1,1 O-phenanthroline ligands with copper.
Schiff base complexes
It was felt that it would be better to react the Schiff base ligands with a copper(lI)
reagent as the formation of mixtures of copper(l) or ~II) complexes might have
caused complications during the isolation and purification of the biphenyl- and the <
1,10-phenanthroline-based complexes. Consequently, the ligands were treated
with CU(N03)2.3H20 in MeCN (Scheme 20), without the precautions used
Discussion 83
previously for the copper(J) complexes, viz., pre-drying and degassing the solvent
and conducting the reaction under N2. The resulting complexes 120, 121 and 123
were green in colour and tended to be hygroscopic; from their microanalysis data
(Table 8), it can be seen that these complexes were dinuclear. However, the data
obtained for the complexes with ligands 74, 75, 78 and 84 (not included in Table
8) suggest formation of mixtures of mononuclear and dinuclear complexes. While
a structure has been proposed for complex 120 (Scheme 20), the complexity of the
spectroscopic data for complexes 121 and 123 preclude the confident assignment
of structures.
:l4+ YI( H~ YI( OH2 4N03
X,Z \ / 76 fNH N'l .. Cu fNH Nt Cu
MeCN H~-- \ / "-Py Py ~ Py Py O~
R 120
yY X,Z fNH N'l .. 121 123
MeCN R Me Benzyl
Py Py
77 79
R Me Benzyl J
Py = © x = Py ~N~ Z = CU(N0:Y2' 3 H2O
Scheme 20: Complexation of the Schiff base ligands with copper.
The Macrocyclic complex
When a solution of the macrocycle 99 in DMF was added dropwise to a solution
of the copper(lI) reagent Cu(N03)z.3H20, the coloL!r of the reaction .mixture
changed from turquoise to red-brown. Microanalysis of the resulting complex 124
(Table 8) indicated it to be dinuclear and "of acceptable purity and, due to the
presence of four nitrate anions, to contain two copper(lI) cations.
Discussion
p=ts N N a 0 DMF
N N
Q9 99
R814+
f_~ :_' I 4N~ \ I
.---Cu-.. N N a 0 N-.. __ N
Cu / \
-N N-
124
84
Scheme 21: Complexation of macrocycle 99 with copper.
Table 8: Micro-analytical data for the copper complexes followed, in parentheses, by the calculated values.
Complex Complex
Stoich iometry
%Carbon %Hydrogen %Nitrogen
---------------------------------------------------------------------------------------
115 Cu2( 55b )(PF 6h.2DMF 41.9 (41.9) 3.9 (3. 7) ~ 10.0 (10.3)
116 Cu2(55c)(PF6h·5Hp 30.8 (30.9) 3A (3.5) 8.8 (9.0) J
118a Cu2(69a)(PF6h· 5Hp 37.7 (37.3) 2.0 (2.7) 9.7 (9A)
118b Cu2(69b )(PF 6h 6H2O 35A (35.6) 3.2 (3.6) 10.3 (10A)
118c Cu2(69c)(PF6h·5Hp 29.5 (30.0) 3.0 (3.2) 12.3 (11.7)
119 Cu2(69a)(PF6)4 30.2 (29.2) 2.7 (2.3) 7A (7.3)
120 Cu2(76)( N03)4' 7H2O 28.2 (28.2) 3.9 (4.7) -13.7 (13.8)
121 Cu2(77)(N03)4· 8Hp 29.0 (28.6) 4.1 (5.0) 13.0 (13.3)
123 Cu2(79)(N03 )4· 9Hp 32.8 (33A) 3.6 (5.2) 12.0 (12.0)
124 Cu2(99)(N03)4' H2O 47.5 (47.6) 3.0 (2.6) 16.6 (16.7)
Discussion 85
2.3.2.2 NMR Studies of the copper complexes
Upon coordination of copper the ligand nuclei are deshielded relative to the free
ligand, and the magnitude of the downfield shift may reflect, to some extent, the
proximity of a specific nucleus to the coordinated copper cation. 92 While copper(l)
complexes can be readily analysed by NMR spectroscopy, copper(lI) complexes
are paramagnetic, and the signals for the nuclei close to the copper tend to be
broadened, thus complicating analysis. This difference provides a quick and
simple distinction between copper(l) and copper(lI) complexes.
It was not possible to distinguish, on the basis of colour, whether copper(l) or (II)
1,1 O-phenanthroline complexes were obtained. From the 1H NMR spectra of these
complexes, however, it could be seen that the copper(l) oxidation state was not
dominant as the signals in the 1 H NMR spectra were broad. Thus, it seems, that
at least one copper atom in the 1,1 O-phenanthroline copper complexes may be in
a copper(lI) oxidation state; magnetic susceptibility studies- will be required to
determine whether copper(l) is present in these complexes.
2.3.2.3 IR studies of the copper complexes
J
These studies were undertaken to determine whether coordination of the ligands
with copper occurs through the nitrogen or oxygen of the amide functionality, or
through the secondary or tertiary amine groups of the imidazole and benzimidazole
units. The spectra were also expected to show whether the amide proton is
removed during complexation. It was, however, not possible to establish whether
coordination involves the 1,1 O-phenanthroline nitrogen donors because the
aromatic bands overlap in the region of interest (1600-1500 cm-1).
- Biphenyl- and 1, 10-Phenanthroline-based complexes
It can be seen from the €lata in Table 9 that copper coordinates with either the
amide oxygen or nitrogen in the 1,1 O-phenanthroline- and biphenyl-based copper
complexes. A negative carbonyl shift indicates coordination through the carbonyl
Discussion 86
oxygen, while a positive NH shift indicates coordination through the nitrogen of the
amide group. Thus, for complexes 118a and 118b, coordination involves the amide
oxygen and, due to the absence of an amide NH band, through the amide nitrogen.
For complexes 115 and 116 coordination appears to involve the amide nitrogen
due to the positive NH shift. In the case of complex 118c, coordination also
involves the amide nitrogen since the amide NH band is absent indicating that
deprotonation of the amide NH had occurred upon complexation with copper; the
fact that f1vc=o is zero, however, casts some doubt on the carbonyl oxygen
coordination depicted in the structure proposed for complex 118c (Scheme 19).
For the PFe- anion a P-F stretching band between 840-850 cm-1 is observed for
each of these copper complexes. 196
Table 9: Selected IR data for the amide copper complexes of the biphenyl- and 1,10-phenanthroline-based ligands .
Copper complexes .6V a/cm -1 NH .6Vc=Oa/cm -1 VPFs
b/cm-1
115 65 33 845
116 55 29 846
118a - -21 842
118b - -13 ~ 846
118c - 0 845 I
a Frequency shift for amide apsorption on complexation. A positive value indicates a frequency increment and a negative value a decrement relative to the free ligand.
b P-F stretching band for the PFe- counterion.
In the spectra of the biphenyl complex 115 and the 1,1 O-phenanthroline complex
118b, the benzimidazole NH band (at ca. 3171 cm-1) is absent, indicating that this
proton has been removed suggesting that coordination with copper occurs through
the secondary nitrogen -<:Ionor of benzimidazole. The fact that the amide protons
_ are not removed on formation of complex 115, suggests that the pKa of the
benzimidazole protons in the ligand 55b is lower than that of the pKa of the amide ~ ,;a.. ;:
protons. In the IR spectrum of the biphenyl complex 116 the imidazole NH band
is present (at 3156 cm-1), but the frequency of the amide NH band is increased by
Discussion 87
55 cm-1 to 3242 cm-1 on complexation. The presence of the imidazole NH is an
indication that the tertiary imidazole nitrogens as well as the amide nitrogens (see
above) are, coordinated to copper. For complex 116, it seems that the reaction
conditions do not favour deprotonation of either the imidazole secondary amine or
the amide groups .
.,. 1248.2
" 1216.9
1361.9 /
" \
1492.!!-
\il ...1.\
1;2'92.2
J Figure 29: IR spectrum of complex 115 in hexachlorobutadiene.
A band at 3273 cm-1 in the IR spectrum of the bis(amino) 1,1 O-phenanthroline
complex 119 is attributed to the secondary amine NH stretch, indicatfng that the
amine protons are not removed upon coordination with copper. A band at 853 cm-1
is observed for the PF 6' anions in this complex.
Schiff base complexes
The IR spectra of the copper complexes prepared from the Schiff base ligands are
more complicated than expected. This complexity is attributed to the presence of
the nitrate anion, which can act in its own right as an un identate or bidentate ligand
or simply be present as an uncoordinated counterion.202 All these possibilities have
Discussion 88
been found to occur in the Schiff base copper complexes.
The complex 121 exhibits a number of significant bands (Figure 30). These
include:-
i) the imine C=N band at 1637 cm-1;
ii) bands at 1480 and 1283 cm-1 characteristic of the nitrate anion coordinated
as a bidentate ligand;
iii) a band at 1445 cm-1 indicating un identate coordination of nitrate; and
iv) a band at 1013 cm-1 which suggests that the nitrate anion is coordinated as a
un identate ligand;197 a second band expected at ca. 1315 cm-1may be
masked by the band occurring at 1383 cm-1 and indicates the presence of
free nitrate ion.
It is concluded that, in addition to the presence of the nitrate ion, unidentate and
bidentate coordination of the nitrate ion occurs in this copper complex.
'" "
v1'.\ r ,,;,., \
"".' \ 804 8 " "
2926.6 IJ\ /;" \ '/ \
"T • I
71'0.1
; \
JOn.3 29-12.9
3413.1
\ \ " / \\ \\"''-'" 1292.8
1653.0 "-
I, lO!J.5 1393.1 11;31.5 \
I i 1444.9
'. ·1
... 1606.7 1560.4
Figure 30: IR spectrum of complex 121 in KBr.
Discussion 89
The IR spectrum of the copper complex 123 exhibits bands corresponding to the
imine moiety and the free and bis-coordinated nitrate anion. In the case of the
macrocyclic complex 124, however, no un identate or bidentate coordination of the
nitrate anion is apparent; the band at 1383 cm-1 reveals the presence of free nitrate
anions, while the imine C=N band appears at 1653 cm-1. All of the Schiff base
copper complexes examined proved to be hygroscopic and, consequently, the
assignment of the NH band is precluded by the presence of a broad H20 hydroxyl
band.
2.3.2.4 UV-Vis studies of the copper complexes
It was decided to use UV-Vis spectroscopy to detect whether the two copper atoms
are in the same or different coordination environments within the dinuclear
complexes. Different geometrical arrangements of the copper atom give rise to
different absorption characteristics and, as the copper(l) and (II) oxidation states
favour different geometries, it was expected that the UV-Visible absorption data
would reflect the oxidation state(s) involved. Due to the insolubility of the
complexes in DMF, DMSOwas used as solvent but, unfortunately, the regions of
interest were masked by solvent absorption bands, thus precludi~g comparison
with the UV data reported for the enzyme, tyrosinase. J
Discussion 90
2.3.3 Computer Modelling Studies
Molecular mechanics is now a routine tool in organic chemistry,198,199 and has
become increasingly important in the field of drug design200 and in studying the
matching of bases in nucleic acids. 201 Its use is also well established in
coordination chemistry,202,203 where it has been used for the analysis of disordered
structures,204 the prediction of unknown structures,205 the determination of isomer
and conformer ratios206 and metal ion selectivities. 207
Molecular modelling and molecular mechanics
The basis of molecular modelling is that all the important molecular properties (i.e.
stabilities, reactivities and electronic properties) are related to the molecular
structure. A computational study can only be carried out once a molecular model
has been established, and because of its computational simplicity and efficiency, -
molecular mechanics is commonly used to construct such models. Typically, the
energy-minimised model, which is obtained, represents an idealised gas-phase
structure of the molecule that is independent of solvent effects in solution, or of
lattice interactions in the solid state. I
The molecular modelling of transition' metal complexes is complicated, however,
by the presence of partially filled, metal ion d-orbitals, which are responsible for
the multifarious structures of coordination compounds, which exhibit a ,variety of
coordination numbers and geometries. Moreover, metal-ligand bonds can become
elongated during steric crowding, especially when small metal ions are
coordinated. In cases where the ideal bond lengths have not been determined, it
is considered acceptable to use an average force constant. 203
In the computer models illustrated in this section, the following colour key applies:
carbon: light-blue; nitrogen: dark-blue; oxygen: red; hydrogen: white; copper
yellow.
Discussion 91
2.3.3.1 Computer modelling of the dinuclear copper complexes
Computer modelling studies were undertaken to explore the structures of proposed
dinuclear copper complexes and their potential as biomimetic tyrosinase
analogues. Bernhardt and Comba have published a force field for copper(lI) in
organometallic complexes. 62 This has been determined by modelling a series of
amine and imine complexes and correlating the results with X-ray crystal
structures. A close similarity was observed for these correlations, thus providing
support for the validity of computer modelling of copper complexes. The discussion
that follows focusses on the modelling of possible monomeric structures for the
dinuclear copper complexes 120, 128 and 130t. The aim, in each case, was to
determine:- (i) the most likely conformation for the ligand and the complex; (ii) the
Cu-Cu distance in the complex; (iii) the fe~sibility of a dioxygen peroxide bridge
between the two copper atoms; and (iv) the accessibility of the Cu-02-Cu unit for
binding phenolic substrates.
The distance between the copper atoms is, of course, crucial since the initial
stage of the enzyme-catalysed reaction involves the binding of dioxygen across
the dinuclear copper site. For rigid, planar molecules, a Cu-Cu distance of 5 A is
required for a good steric match; less for more flexible systems. 20B lt is beneved
that the Cu-Cu distance in the tyrosinase enzyme is 3.5 A,32,33 and models
reported to have displayed successful biomimetic activity have a similar Cu-Cu
separation. 101 ,217 Initially, it was thought that the dioxygen in tyrosinase was bridged
in a cis fJ-1,2 fashion209 but, in fact, it is coordinated in a fJ-rj-:rj- side-on bridging
mode.210,211 The binding of the substrate appears to be accompanied by a change
in coordination from tetragonal copper(l) to trigonal bipyramidal copper(II).212 It is
also believed that the peroxide moiety is in an equatorial plane when the phenolic
substrate binds axially to one copper atom in the active site.213 However, in order
for the electron transfer to occur most readily at the active site of tyrosinase, the
t While the apparent polymeric nature of the copper complexes has already been indicated (p.81 and p.82) it is possible that, in solution, catalytically active monomeric complexes may exist in equilibrium with polymeric complexes.
Discussion 92
phenolic substrate has to be in an equatorial plane to permit maximum overlap of
the substrate donor orbitals with the half empty d/./ orbitals of the copper(ll)
ions.211 Such rearrangement from axial to equatorial binding is not required for
catechols and, as a result, their oxidation is less geometrically and sterically
demanding. Apparently, the protein pocket contributes to the stabilisation of the
binding of either substrate through n-stacking interactions.213
In the present study, two modes of binding for dioxygen were modelled for each of
the copper complexes 120, 128 and 130, i.e. a fJ -1,2 end-on and a fJ-r1:r1 side
on bridging mode since these have been reported in the literature for copper
complexes. 214.215.216
Energy-minimised structures for the ligands, their dicopper complexes and oxygen
bridged derivatives were modelled using MSI Cerius2 software on a Silicon
Graphics 0 2 platform. Solvent molecules can coordinate to copper and, as a result,
the binding of the solvent, acetonitrile, was taken into account during the modelling
of these complexes. Pertinent data for the complexes are summarised in Tables
10 and 11. The ligands so examined (56b, 68b and 76) are depicted below.
Table 10: Cu-Cu separation in the modelled complexes before dioxygen binding.
Ligand Complex Cu-Cu separation (A)
76 120m 6.836
56b 128m 8.451
68b 130m 4.789
a m = monomeric form
Discussion
Table 11: Cu-Cu separation and the potential energy in the modelled complexes after dioxygen binding.
Ligand Complex' Cu-Cu separation (A) Potential Energy (kcalmol-1)
(after 02 binding)
56b 1290s
56b 1290e
68b 1310s
68b 1310e
76 1320s
76 1320e
as = J.l-ti:ti side-on dloxygen bndgmg; oe = J.l-1,2 end-on dioxygen bridging.
4.880
1.756
2.188
4.616
2.117
4.642
-246.9
644.9
-38.2
1030.3
-687.8
48.0
J
93
Discussion
Complexes containing the biphenyl spacer
(a)
(b)
Figure 31: Energy-minimised conformations of the ligand 5Gb (a) before and (b) after complexation with copper.
94
From the models in Figure 31 it can be seen that there is not a drastic change in
conformation when ligand 5Gb coordinates with copper. Upon binding to dioxygen,
the copper atoms are, of course, brought much closer together. The models for the
fJ-rT:rt side-on (complex 1290s) and fJ-1,2-trans bridging (complex 1290e) of
dioxygen are shown in Figure 32 (a) and (b) respectively. The fJ-1,2-trans bridging
mode is expected to be favoured since this is the more stable arrangement for
dioxygen in dinuclear copper complexes.21o Complex 1290e has a Cu-Cu distance
of 1.756 A, but it is less stable than complex 1290s, which has a Cu-Cu distance
of 4.880 A. It is apparent that there is a considerable change in conformation when
dioxygen is bound to the dinuclear complex 128, a.nd that the geometry of the
metal atoms changes from tetrahedral to octahedral in complex 1290s, and to
trigonal bipyramidal in-complex 1290e.
Discussion
(a)
(b)
J
Figure 32: Energy-minimised conformations of the dioxygen-bridged copper complex 128, showing (a) side-on and (b) trans bridging.
95
Discussion 96
(a)
I
Figure 33: The space-filling models of the energy-minimised conformations of the dioxygen-bridged copper complex 128, showing (a) side-on and (b) trans bridging.
In the dioxygenated sysfem, the biphenyl arene rings remain out of the plane of the -
copper atoms and the binding site is seen to be concave. From the space filling
models of complexes 1-2905 and 1290e (Figure 33), it appears that, in both cases,
the active site is readily accessible.
Discussion 97
Reglier has reported a similar model of a complex that also features the flexible
biphenyl spacer (see section 1.3.5 p.32) and displays both phenolase and
catecholase activity when dioxygen is bound in the I-l-oxo form. 103 It has been
shown, by means of molecular mechanics calculations using a BIOGROMOS
program, that this model reflects a Cu-Cu distance of 3.6 A when the deoxy form
exhibits a biphenyl dihedral angle of 60°.217 In the light of these results it is
expected that the complex 128 should also be capable of attaining a Cu-Cu
distance of ca. 3.6 A and that it could also display phenolase and catecholase
activity.
Complexes containing the 1,10-phenanthroline spacer
In the model of the dicopper deoxy complex 130 the tetrahedral geometry of
copper(l) is apparent. Upon oxygenation, the geometry changes to a distorted -
octahedron in the case of the fJ-r/: r/ side-on bridged complex 13105; in the fJ-1 ,2-
trans complex 1310e (Figure 34), however, the tetrahedral geometry changes to
square pyramidal at the one coordination site and trigonal bipyramidal at the other.
The Cu-Cu distance in complex 13105 is 2.188 A, and 4.616 A in cbmplex 131oe. J
From the potential energies it appears that complex 13105 is more stable than
1310e, but in neither case does the oxygenated complex provide an obvious
binding pocket to accommodate the substrate.
Discussion 98
(a)
(b)
I
Figure 34: Energy-minimised conformations of the dioxygen-bridged copper complex 131 oe: (a) a cylinder model and (b) a space-filling model.
Discussion 99
In summary, the biphenyl spacer, due to its flexibility, should allow the oxygenated
complex (12905 or 1290e) to adopt an optimal conformation that permits
coordination of the substrate between the two copper ions. This may, however, be
more difficult in the 1,1 O-phenanthroline complexes 13105 and 1310e because of
the rigidity imposed by the 1,1 O-phenanthroline spacer. In the latter complexes,
the "active site" is peripheral, the dioxygen bridge being situated above the plane
of the complex. The biphenyl analogues (12905 and 1290e), however, exhibit a
concave region about the "active site" which could act as a binding pocket,
providing access to a substrate molecule.
Schiff base complexes
The acyclic Schiff base ligands were expected to form complexes which would be
considerably more conformationally flexible than the biphenyl or 1,10-
phenanthroline analogues. For ligand 76, a change in conformation occurs upon
coordination with copper and tetrahedral geometry is observed for the copper
atoms in the model of the resulting complex 120. This tetrahedral geometry
changes to distorted octahedral in the case of the l1-rf:rf side-on bAdged complex
13205 and, in complex 132oe, where dioxygen is bound in a 11-1 ,2-trans Bridging
mode, the geometry changes to trigonal bipyramidal (Figure 52) . The Cu-Cu
distance is 2.117 A in complex 1320s.and 4.642 A in complex 1320e. Comparison
of the potential energies of these complexes reveal that complex 13205 is more
stable. From the models of the complexes, it can be seen that, in each case, the
active site lies in a concave region constituting a convenient binding site readily
accessible to substrate molecules.
Discussion 100
(a)
(b)
I
Figure 35: Energy-minimised mod~ls of (a) complex 13205; and (b) complex 1320e.
Unfortunately, none of the complexes afforded crystals suitable for single crystal
X-ray analysis, thus precluding direct comparison of actual and computer-modelled
structures. Moreover, in the case of the biphenyl- and 1,1 O-phenanthroline-based
systems, the formation of polymeric complexes was observed.
Discussion 101
2.3.4 Other Transition Metal Complexes
2.3.4.1 Cobalt Complexes
Cobalt may exist in various oxidation states, viz., cobalt(I), cobalt(II), cobalt(lIl) and
cobalt(IV).218 The cobalt(l) ion with its eight d electrons occurs in many complexes
with n -bonded ligands. To make these complexes, in which the metal is trigonal
bipyramidal or tetrahedral, CoCI2 is reduced with Zn or N2H4 in the presence of the
ligand. 219 The reduced form of Vitamin B12 is known to contain Co(l).220 The
cobalt(lI) ion has a d 7 configuration and typically exhibits four-coordinate
tetrahedral or six-coordinate octahedral stereochemistry. A small difference in
stability exists between these arrangements and, therefore, they may occur in
equilibrium.
Cobalt(III), a d 6 low spin, diamagnetic cation, is kinetically inert and displays
octahedral stereochemistry. This is the most common oxidation state for cobalt in
complexes, and cobalt(lI) complexes are readily oxidised to cobalt(III). The
oxidation of cobalt(lI) to cobalt(llI) is attributed to the higher crystal field
stabilisation energy of cobalt(III).221 Both cobalt(lI) and (III) pre\er nitrogen or
oxygen donor ligands. The cobalt(lV) oxidation state is the highest oxidatign state
known for cobalt, but this is not as qommon as the cobalt(lI) and (III) oxidation
states.
Cobalt plays an important role in biological systems such as enzymes. The
enzyme, .glutamic mutase, is involved in the metabolism of amino acids, and
ribonucleotide reductase in the biosynthesis of DNA221 Vitamin B12, which was the
first naturally occurring organometallic compound to be identified, is a cobalt
complex which is involved in alkylation reactions. 218,222,225 In biological systems,
- - iron(ll) (e.g. haemoglobin and myoglobin) or copper(IHhaemocyanin) complexes
serve as reversible oxygeo carriers for the t~ansport and storage of oxygen. 223, 224
Since the discovery that Co(lI) forms simple complexes that react reversibly with
oxygen to give 1: 1 and 2: 1 metal complex-oxygen adducts, 225, 226 cobalt complexes
Discussion 102
have been widely studied as models for biological processes. 15, 227,228 Tetradentate
Schiff base cobalt complexes have been used to study dioxygen activity and, since
they undergo alkylation reactions, they have been used to mimic the reactions of
Vitamin 812.
2.3.4.1.1 Synthesis of cobalt(lI) complexes
Cobaltous chloride hexahydrate (CoCI2.6H20) was used to prepare the cobalt
complexes, following the procedures detailed in the Experimental section (3.3.2).
The microanalysis data for the resulting complexes, given in Table 10, indicate that
four chloride anions are generally present and suggest that the amide, imidazole
and benzimidazole protons are not removed during complexation with cob.alt. The
complexation of the biphenyl and 1,1 O-phenanthroline ligands with cobalt are
outlined in Schemes 22 and 23. The formation of complex 135 (Scheme 22) was
unsuccessful as could be seen from the microanalysis data which are not included
in Table 12.
Table 12: Microanalytical data for the cobalt(ll) complexes followed, in parentheses, by the calculated values.
J
Complex Complex
Stoichiometry
%Carbon %Hydrogen %Nitrogen
----------------------------------------------------------------------------------------
133 Co2(55a)CI4·Hp 46.3 (46.3) 3.7 (4.3) 7.5 (7.7)
134 Co2(55b)CI4·8Hp 41.5 (41.3) 4.0 (4.8) 9.5 (9.0)
136 Co(61a)CI2 57.8 (58.7) 4.5 (4.7) 6.6 (6.5)
137a Co2( 69a )CI4 . 6HzO 39.1 (39.8) 3.3 (4.3) 10.3 (10.0)
137b Co2(69b )CI4. 8H2O 39.7 (40.2) 3.6 (4.4) 12.1 (11.7)
137c Co2(69c )CI4·2H2O 38.1 (38.4) 3.6 (3.5) 14.8 (14.9)
138 Co2(68a)614·8H2O 41.8 (41.3) 3.8 (4.9) 10.1 (103)
Discussion
55a-c
CoCI2. ~~;P / DMF,Me~
MeOH DMF
CoCb.6H;P * MeCN, MeOH
I abc
MeCN
61a
CI CI ,/
/Co'-...,. I
~N ~ I u N
H I
103
H N~
o jN~ ~c/ C( "CI 133
134
135
136 I
Scheme 22: Complexation reactions of the biphenyl ligands with cobalt(II).
Discussion
R
~ p=q DMF Ij ~ Ij ~ a 0 COCI2.6H;P -N N-
Ib
o 0 .. HNtN HN 0 0 NH NH HN r C~-CI CI_\ \
b ) 2 0 I o-R R R
CI \ CI tN 70a-c 137a-c
c
I H~
M-N~ IjN-~ MeCN
COCI2.6Hp
or
68a 138a 138b
or
I
138c
Scheme 23: Complexation reactions of the 1,1 O-phenanthroline ligands with cobalt(II).
104
Discussion 105
2.3.4.1.2 Spectroscopic analysis of the cobalt(lI) complexes
1H and 13C NMR spectra of the cobalt complexes were run to define the oxidation
state of the metal ions. As cobalt can form both paramagnetic [Co(ll)] and
diamagnetic [Co(lll)] complexes, 1H NMR spectroscopy was expected to establish
the oxidation state of cobalt in the complexes. The 1H NMR spectra obtained for
the biphenyl- and 1, 10-phenanthroline complexes reveal broad, poorly resolved
signals, indicating that at least one of the cobalt ions in each complex is
paramagnetic.
IR spectra of the complexes were expected to establish whether the cobalt ions
coordinate through the amide nitrogen or oxygen atoms. Determining whether
coordination occurs through the aromatic. nitrogen donors, however, was not
possible, due to the congestion of bands in the aromatic region (1600-1500 cm-1)
which makes detecting a band shift in this region rather difficult. Spectra were run
in the far-IR region to determine whether the coordinated chlor-ide anions are in a
tetrahedral or octahedral environment. The IR frequencies for selected bands are
shown in Table 13. From the negative IR frequency shifts of the amide carbonyl
(amide I) bands, it is apparent that coordination occurs through the ~mide oxygen
atom in both the biphenyl and 1,1 O-phenanthroline cobalt complexes. Althol!9h the
benzimidazole NH band cannot be ider)tified in the IR spectra of the biphenyl and
1,10-phenanthroline complexes 134 and 137b respectively, it is assumed that
coordination does not involve the secondary benzimidazole nitrogen as the
microanalysis data show the presence of four chloride ions in each case. This is
an indication that no deprotonation occurs on formation of these complexes, and
it is believed that coordination involves the tertiary, benzimidazole nitrogen in both
of these complexes. For the 1, 10-phenanthroline complex 137c, the imidazole NH
bands are shifted, relative to the free ligand, indicating coordination through the
-. -tertiary, imidazole nitrogen.
Discussion
Table 13: Summary of the IR frequencies (v M-C') and the amide frequency shifts (/1 V NH and /1 V c=o) on formation of the amide cobalt complexes.
Cobalt Complex lw NH /cm·1 L1v c=o/cm-1 vM-c,/cm-1
133 - -19 306
134 13 -30 295
137a 18 -7 303
137b -62 -7 311
137c -38 -6 299
106
While the amide NH band cannot be seen in the IR spectrum of the biphenyl
complex 133, due to the presence of a strong, broad water band, the microanalysis
data clearly indicates that formation of the complex does not involve deprotonation.
An amide NH band is, however, observed ~,at 3274 cm-1 in the IR spectrum of the
1,10-phenanthroline complex 137a, thus confirming the microanalysis data
obtained for this complex which, due to the presence of four chloride ions, indicate
that the amide functionality is not deprotonated.
Two Co-CI bands characteristic of tetrahedral geometry are anticipated in the far
IR region (ca. 301 and ca. 324 cm-1).229 These bands are not observed for these
~
amide complexes instead, a very strong, broad band, often with shouldJers, is
observed at ca. 300 cm-1. This may be due to accidental degeneracy of the
symmetric and antisymmetric Co-CI stretches, and it is suggested that the band at
ca. 300 cm-1 indicates a distorted tetrahedral cobalt geometry occurring within
these complexes.
Coordination of the ligand with the tetrahedral cobalt ion in the amine complex 136
was unambiguously established by single crystal X-ray crystallography of this
complex (Figure 36). A far-IR band at 298 cm-1 is consistent with coordination of
_the chloride ion in a tetrahedral arrangement.
Discussion
J
Figure 36: X-ray crystal structure of cobalt(lI) complex 136, showing the crystallographic numbering. "
107
Discussion 108
An IR band at 3398 cm-1 for complex 138 suggests that deprotonation of the
secondary amine does not occur during complexation, while a shift of 98 cm-1 for
this NH band (relative to the free ligand) reflects coordination to the aliphatic
amine nitrogen. In the far-IR region the strong, irregular band at 311 cm-1 suggests
that the chloride ions coordinate to cobalt in a tetrahedral arrangement.
Cobalt ions in tetrahedral or octahedral coordination environments give rise to
characteristic absorption bands in the visible region. Absorption data for the cobalt
complexes and their assigned geometry are summarised in Table 14, while the
electronic spectrum for complex 137a is illustrated in Figure 37.
Table 14: Electronic absorption bands with their assigned transition types and geometries for the cobalt complexes.
Complex Absorption (nm) Assignment Geometry
133 600sh,613,657,678 4A2 ~ 4T1(P) tetrahedral
134 579sh,608,628 4A2 ~ 4T1(P) ~ tetrahedral
136 576,621,638 4A2 ~ 4T 1(P) tetrah ed ral
137a 596sh, 604, 665, 677 4~ ~ 4T1(P) tetrahedral
137b 597sh, 611, 656, 676 4A2 ~ 4T1(P) tetrahedral
137c 580sh, 608, 629, 677sh 4.~ ~ 4T1(P) ~ tetrahedral
138 597sh , 604, 666, 678 4A2 --> 4T1(P) tetrahJd ral
In all cases, absorption spectra were observed corresponding to the 4A2 ---t 4T1(P)
transition, which is characteristic of tetrahedral cobalt coordination. The "fine
structure" evident in Figure 37 is attributed to spin-orbit coupling effects and to
transitions involving doublet states. 230
Discussion 109
"----.-- --------. - -~ - - -----_.--
-- --.. -.---------- ---~
Figure 37: The electronic spectrum of complex 137a in DMF.
,I
Discussion 110
2.3.4.1.3 Computer modelling of the cobalt complexes
These studies were undertaken to explore the possible 3-D structures of the
dinuclear cobalt complexes because crystals suitable for single crystal X-ray
analysis could not be obtained. Experimental IR and UV-Visible spectroscopic data
has been taken into account in developing representative structures of the
complexes detailed in Figure 38. For some of these complexes, isomeric structures
of the product are possible and molecular mechanics calculations were used to
predict the most likely structure. Thus, the symmetrical complex 138c, is
considered more likely than the isomeric systems 138a or 138b.
137b
.1
138c
Figure 38: Cobalt complexes modelled.
The computer modelled structure of the 1,1 O-phenanthroline diamide cobalt
complex 138c is shown in [Figure 39(a)]. In this model, the distorted tetrahedral
geometry of the metal ions can again be clearly seen. For the 1,1 O-phenanthroline
diamide complexes coordination through 'the carbonyl oxygen of the amide
functionality is indicated (see section 2.3.4.1.2). Complex 137b was modelled on
· ,-
Discussion 111
this basis and the resulting structure illustrates the conformation expected to be
typical of the analogous diamide cobalt complexes 137a and 137c. In this model ,
the distorted tetrahedral geometry of the metal ions can be seen [Figure 39(b)] .
(a)
(b)
I
Figure 39: Computer-modelled structures of the 1,1 O-phenanthroline cobalt
complexes: (a) complex 138c and (b) complex 137b for the biphenyl
diamide cobalt complexes. Coloured atoms: carbon: light'blue;
nitrogen: dark blue; oxygen: red; chlorine: green; cobalt light-brown.
112
139
Discussion
-N
~ N N
Ha~ ~aH CaJ \ ( ~a~ HO OH
-N CI N'\ I /
CO N----I ~N
Ha~ CI ~aH CoJ \ ( ~O~
HO OH
112
Figure 40: The dendrimer-based ligand 112 and the proposed structure of its cobalt(lI) complex 139. \
I .
It was also decided to model the dendrimer-based ligand 112 and the proposed
cobalt(lI) complex 139 (Figure 40). From the models shown in Figure 41, the 3-D
arrangement of the dendrimer moieties in the ligand and the compl~x can be
clearly seen. In the cobalt complex (Figure 41 b), the 1,1 O-phenanthroline spacer
is no longer planar, but slightly bent, while the octahedral geometry of the cobalt
cation is also clearly apparent.
'.
Discussion
(a)
(b)
I
Figure 41: Computer modelled structures of: (a) the dendrimer ligand 112; (b) the resulting cobalt(lI) complex 139.
113
Discussion 114
2.3.4.2 Nickel Complexes
Various oxidation states have been observed for nickel ranging from (-I) to (+IV),
but studies of the chemistry of nickel have concentrated on the (+11) oxidation
state. The metal ion in nickel(lI) complexes exhibits considerable variability in
molecular geometry, e.g. four coordinate (tetrahedral or square planar), five
coordinate (square pyramidal or trigonal bipyramidal) and six-coordinate
(octahedral)?31 As a consequence, the chemistry of nickel(lI) is quite complicated.
Tetrahedral complexes are intensely blue in colour and paramagnetic;232 square
planar complexes are diamagnetic and usually red, brown or yellow in colour.232
Thus, tetrahedral complexes may be distinguished from square planar complexes
by their colour and their magnetic properties. Octahedral complexes may also be
blue or purple in colour and paramagnetic,due to the dB ion having two unpaired
electrons. 232 The nickel(llI) oxidation state is rare and very few Ni(lll) complexes
are known; the (+IV) oxidation state, which is the highest for nickel, is also rare.
Nickel plays an important role in biological systems. The first such system to be
discovered was the enzyme, urease, isolated from jack beans233.234 and shown by
UV-Visible spectroscopy and EXAFS studies to contain two octa~edral nickel(lI)
ions in a nitrogen- and oxygen-donor environment. Urease is responsjble for
catalysing the hydrolysis of urea to ar.nmonia and carbonic acid, thus:-
Nickel has subsequently been found in other enzymes, viz., hydrogenases, CO
dehydrogenases and coenzyme F 430. 234 Hydrogenases which occur in many
bacteria, catalyse the oxidation of molecular hydrogen, while CO dehydrogenases
interconvert carbon monoxide and carbon dioxide. It has been found that the
-. - hydrogenases and CO dehydrogenases have nickel(rII) (low spin d 7) and Fe-S
clusters present in their stwctures.234 Coenzy;me F 430, which is a cofactor of methyl
coenzyme M reductase and which contains nickel(lI) in a square planar geometry,
- . -
Discussion 115
is functional in a series of reactions in bacteria that result in the generation of
methane gas.
2.3.4.2.1 Synthesis of nickel complexes
Nickel chloride hexahydrate (NiCI 2.6H20) was used to prepare the nickel
complexes (Schemes 24 and 25), following the procedure detailed in the
Experimental section (3.3.3).
From the microanalysis data summarised in Table 15, it can be seen that:- i) most
of the complexes examined are dinuclear; ii) most of the complexes have four
chloride ions, except the mononuclear complex 143 for which there are two; iii)
complexes 141 and 142, appears to have.. DMF present, possibly as part of an
octahedral coordination sphere; iv) deprotonation of the amide, amine, imidazole
or benzimidazole groups has not occurred during formation of the dinuclear
complexes.
Table 15: Microanalytical data for the nickel(lI) complexes followE(d, in parentheses, by the calculated values
J
Complex Complex
Stoichiometry
% Carbon % Hydrogen % Nitrogen
140 Ni2(55a)CI4·6Hp 40.5 (41.1 ) 4.2 (4.7) 7.0 (6.9)
141 Ni2( 55b )CI4(DMF)4' 9Hp 41.7 (42.6) 5.3 (5.9) 11.7 (113)
142 Ni2( 55e )CI4(DMF)4 3H2O 41.4 (41.8) 5.2 (5.7) 13.2 (135)
143 Ni(61a)CI21H2O 57.1 (56.5) 4.6 (5.0) 6.7 (6.3)
144a Ni2(69a)CI4.2H2O 42.6 (43.6) 4.0 (3.7) 11.3 (10.9)
144b Ni2(69b )CI4(DMFh .8H2O 41.3 (42.1) 4.1 (4.8) 13.4 (12.9)
144e Ni2(6gelfI4· 2Hp 37.6 (38.5) 4.2 (3.5) 14.5 (15.0)
145 Ni2(68a)CI4·3Hp 44.1 (44.2) 4.0 (4.5) 11.0 (11.0) ---------------------------------------------------------------------------------------------------------------------------
55a-c
R
a
b
c
61a
Discussion
NiCb.~~~ ./ Me7"MeoH
DMF
NiC".6H~
MeCN
142
~~
I: N~ ~ CI " CI
116
140
141
I
143
Scheme 24: Complexation reactions of the biphenyl ligands with nickel(II).
NH
S R
0 HN
( R
69a-c
68a
Discussion
a b c
R --.LiN, N~ N~ ~+tN-0~HN
NiCI2.6H:zO or • DMF
144a-c
or MeCN
145
0
CI
Scheme 25: Complexation reactions of the 1 ,1 O-phenanthroline ligands with nickel(ll).
117
I
Discussion 118
2.3.4.2.2 Spectroscopic analysis of the nickel(lI) complexes
The 1 H NMR spectra of the biphenyl and the 1,1 O-phenanthroline nickel(lI)
complexes were expected to permit paramagnetic (tetrahedral and octahedral) and
diamagnetic (square planar) nickel(ll) complexes to be distinguished. However, the
1 H NMR spectra of the 1,1 O-phenanthroline complexes typically reveal a
combination of sharp and broad peaks as illustrated by the spectra of complex
144c and the ligand 69c (Figures 42 and 43). In the 1H NMR spectra of the
biphenyl Ni(lI) complexes, the peaks in the aromatic region (06-8 ppm) were,
typically, better resolved than in the spectra of the 1,1 O-phenanthroline Ni(lI)
complexes. Nevertheless, the signals for the biphenyl complexes are still broader
than the corresponding free rigand signals (cf. Figures 44 and 45). These
observations precluded unambiguous assignment of the metal ion geometries.
IR studies were undertaken to determine whether coordination with nickel
occurred through the oxygen or the nitrogen of the amide group, since it is known
that nickel coordinates with both oxygen and nitrogen donors. Pertinent IR data are
summarised in Table 16.
Table 16: Summary of the IR frequencies (VM_C,) and the amide frequency shifts (.6.VNH and !1Vc=o) on formation of the nickel complexes.
Complex .6.VNH Icm-1 .6.vc=o/cm -1 V M-c,/cm
-1
140 15 -11 276, 325
141 11 -6 387
142 61 13 378
144a -33 2 253, 378
144b -78 23 283,384
144c -~
-61 0 310,373
The 1,1 O-phenanthroline amide complexes 144a and 144b, exhibit negative shifts
of the amide NH band an'd,-positive shifts fo(the amide carbonyl bands indicating
coordination through the amide nitrogen. In the case of complex 144c no shift
Discussion 119
I I
pp. "
Figure 42: The 400 MHz 1 H NMR spectrum of the 1,1 O-phenanthroline complex 144c in DMSO-ds"
o I{N~ HN~i
J
69c
S Jj~ J J
pp. 10 ~ I , t
3
Figure 43: The 400 MHz 1 H NMR spectrum of the 1,1 O-phenanthroline ligand 6ge in DMSO-ds"
Discussion
__ L] ppo 12 10
Figure 44: The 400 MHz 1H NMR spectrum of the biphenyl complex 140 in DMSO-ds"
55a HWI ~N ~ 0 f:I~ ~N 0 ~ N....vv
I ~ H
I
JJ/J 10 8 ~ . " ";' Ii""""""": PPII 12 .q . -
I"'"'' , • I I" • 0
Figure 45: The 400 I'y1ljz 1 H NMR spectrum of the biphenyl ligand 55a in DMSO-ds" <
120
Discussion 121
for the amide carbonyl is observed, but a negative shift of the amide NH band is
an indication of coordination through the amide nitrogen. For the biphenyl amide
complexes 140 and 141 coordination through the amide oxygen is indicated by
positive NH shifts and negative carbonyl shifts; in the case of complex 142,
coordination through the amide nitrogen is suggested by the positive carbonyl
shift, although /). VNH is positive. The presence of the amide NH band in all cases
shows that deprotonation of the amide nitrogen has not occurred, thus supporting
the microanalysis data for these complexes.
A benzimidazole secondary amine NH stretching band was observed in the IR
spectra of complexes 141 and 144b; NH stretching bands for the imidazole
secondary amine were also evident in the IR spectra of complexes 142 and 144c,
further supporting the microanalysis data which, in each case, indicated the
presence of four chloride anions.
In the case of complexes 141 and 142 the strong bands in the 370-390 cm-1 region
are attributed to chloride anions coordinated in a trans geometry in an octahedral
environment. For complex 143, the two relatively strong bands observed at 289
and 329 cm-1 are believed to be due to chloride ions coordinated within a
tetrahedral environment, and the X-ray crystal structure for complex 143 Wigure
46) clearly confirms the tetrahedral geometry. Very weak bands at 276 and 325
cm-1 in the far IR region were observed for 140 and have been tentatively aSSigned
to Ni-CI stretches. The low intensity of these bands suggests that the chloride
anions are not in a tetrahedral environment (in contrast to those observed for
complex 143) and that the geometry of complex 140 is, in fact, square planar. In
the case of complexes 144a-c, the strong bands in the region 370-390 cm-1 are
attributed to trans-coordinated chloride ions in an octahedral environment, while
others at 253,283 and 31 0 cm-\ are indicative of chloride ions coordinated in a
- tetrahedral environment.235 Similar bands for complex 145 (at 278 and 352 cm-1)
are also considered to indiCate trans-coordinated chloride ions in tetrahedral and
octahedral environments respectively.
Discussion 122
J
Figure 46: X-ray crystal structure of complex 143 showing the crystal/ographic numbering.
Discussion 123
Different UV-Vis absorption patterns characterise different geometries in nickel
complexes,231,236,237,238 and the absorption data, proposed transition types and
geometries for some of the nickel complexes synthesised in this study are
summarised in Table 17. The absorption bands for the complexes 144b and 144c
appear to be masked by solvent bands (DMF and DMSO); for complex 145 a
shoulder at 377 nm has been tentatively assigned as the main tetrahedral
absorption band. The proposed geometries apply to at least one, but not
neccessarily both, Ni2+ ions in each dinuclear complex.
Table 17: Electronic absorption bands with their assigned transition types and the proposed geometries for the nickel complexes.
Complex Absorption (n m) Assignment Geometry
140 425 "'io. -- Square planar
141 412 3A29
-. 3T29 Octahedral
590 3A29
--> 3T19
(F)
619 3A29
--> 3T19
(P)
142 410 3A29
-> 3T29 Octahedral
525 3A29
-, 3T,i F)
576 3A29
--> 3T,9
(P)
143 514.555 3T, --> 3T,(P) Tetrahedral
144a 363 3A29
--> 3T29 Octahedral \
582 3A29
--> 3T19
(F)
621 3A29
--> 3T,9
(P)
144b masked -- ---144c masked --- ---
145 377sh 3T, --> 3T,(P) Tetrahedral
I
Discussion 124
2.3.4.2.3 Computer modelling of the nickel complexes
In the absence of X-ray crystal structures, computer modelling was used to explore
the possible 3-D structures of the dinuclear nickel complexes. The microanalytical,
IR and UV-Visible spectroscopic data were again considered in developing
structures for these complexes. In some cases, isomers are possible and
molecular mechanics calculations have been used to predict the most likely
structure. In this section, the discussion will focus on the computer modelling of the
representative dinuclear nickel complexes shown in Figures 47 and 49.
141
142
CI
_ --Ni--- 1 ~ H DMF I DMQy /1 ~ ~ N NH o-~ CI \)o~. 0 ~ h
HN ______ N I ~ "-.1 /' ~-H ~ /Ni"",--
DMF 1 DMF CI
CI DMF // DMF-Ni
/I-N~ N~NH H ~
o I
Figure 47: The representative biphenyl nickel complexes that have been modelled.
In the case of the biphenyl diamide complexes, coordination is presumed to involve
amide oxygen in complex 141 (to give 8-membered chelate rings) and the amide ~~
nitrogen in complex 142 (to give 6-membered chelate rings). The .energy-
minimised models of these complexes are shown in Figure 48. The octahedral,
metal ion geometry and ltfe mutually perpendicular arrangement of the arene rings
is apparent in these complexes.
'.
Discussion
(a)
(b)
I
Figure 48: Energy-minimised models of (a) complex 141 and (b) complex 142. Coloured atoms: Carbon: light-blue; nitrogen: dark-blue; oxygen: red; chlorine: green; nickel: light-green.
125
Discussion
(a)
(b)
, ,-
I
126
Figure 49: Computer-modelled structures of isomeric possibilities for the nickel(lI) complex 144a.
For the 1,1 O-phenanthroline complex 144a two isomeric products are possible [(a)
and (b); Figure 49]. These two complexes were modelled and the potential energy
of each structure was calculated and found to be -89.6 kcalmol-1 for isomer (a) and
40.5 kcalmol-1 for isomer (b) , suggesting that isomer (a) is the favoured _structure.
In each case, one of the nickel(ll) ions is octahedral , the other tetrahedral.
Discussion 127
2.3.4.3 Platinum complexes
Platinum exhibits a very unusual pattern in transition metal chemistry. Although the
other transition metals display a range of oxidation states, platinum is one of the
few that display oxidation states differing by two electrons, viz., 0, II and IV.239
For Pt(IV), low-spin, kinetically inert d 6 octahedral complexes are obtained,240
while Pt(lI) affords low-spin, kinetically inert d 8 square planar, diamagnetic
complexes.239 Although very few complexes of Pt(O) are known, examples do exist
in which platinum is two, three and four coordinate; in this oxidation state, the
ground state can be considered to be d10 or d9s 1 and coordination with arsine,
phosphine and isocyanide ligands has been reported. 239 The less common
oxidation states (I) and (III) have assuf!1ed some importance due to their
intermediacy in substitution reactions. 239
In addition to its widespread use in catalysis, jewelry and electrical applications,
platinum has assumed particular importance in the form of its complex, cisplatin,
the cis isomer of [Pt(NH3h(Clhl Cisplatin is used as an anti-cancer drug for
treating several kinds of malignant tumours.239 It is highly biologically active, while , the trans isomer is ineffective. The discovery of cisplatin as a chemotherapeutic
agent has resulted in the rapid development of bio-platinum chemistry.241
2.3.4.3.1 Synthesis of the Platinum Complexes
The platinum complexes of the biphenyl (Scheme 26) and 1,1 O-phenanthroline
ligands (Scheme 27) were generally prepared by adding a solution of the ligand
in DMF or MeCN, to a solution of K2[PtCI4] in water. The microanalysis results
(Table 18) obtained for these platinum complexes show that they are dinuclear and
_. Jhat four chloride ions are present in all cases except complex 149 in which there
are two, suggesting that the amide group is deprotonated in this complex. The ~ .- ~
expected benzimidazole complexes 147 and 150 did not appear to form, being
Discussion
inconsistent with the structures depicted in Schemes 26 and 27.
55a-c
H N~R
o
-9'1 N (GH
~ N ............... / Pt
/ ........ Cl CI
K2[PtCI4]
* DMF H20
a
146
b c
I
Scheme 26: Complexation of the biphenyl ligands with platinum:
128
149
150
Discussion
K:zIPtCI41 p=q .... o 0
DMF I'ItI HN
Hp ) ( R R
69a-c -x: K'PtCl,j DMF 1 K,PteI,j
H2O DMF H2O
AA i 2'2CI f' f' -N ~- N-
o \. / 0
~ ___ ~It~~~ \
N-Pt-N r ~ I ~ ~ HN CI NH
151
a b c
HN:)-r~N
129
FRs HN I'ItI G8a
d b 1 K,PteI.
MeCN H2O
FB=f2
'
2C' f ~ f ~ -N N-
\. / __ pt __
b CIJ _N-~t-N ~!J I 'I ~ ~ CI _
152
J
Scheme 27: Complexation of the 1,.1 O-phenanthroline ligands with platinum.
Discussion
Table 18: Microanalytical data for the platinum complexes followed, in parentheses, by the calculated values.
130
Complex Complex
stoichiometry
% Carbon % Hydrogen % Nitrogen
---------------------------------------------------------------------------------------------------------
146 Pt2(55a)CI4·3Hp 34.6 (34.4) 3.2 (3.4) 7.0 (7.5)
148 Pt2( 55e )CI4.2Hp 29.7 (28.9) 3.4 (2.8) 7.8 (8.4)
149 Pt2(69a)CI2·3Hp 34.3 (34.6) 2.9 (2.8) 8.5 (B.7)
151 Pt2(6ge )C14 25.0 (25.9) 2.4 (5.1 ) 9.B (10.1 )
152 Pt2(6Ba)CI4·3Hp 31.B (31.1 ) 2.B (3.4) 7.3 (7.B)
2.3.4.3.2 NMR studies of the Platinum Complexes
For both the biphenyl and 1,1 O-phenanthrolme series, more signals are observed
than expected in both the lH and 13C NMR spectra of the resulting Pt(lI)
complexes. It was initially thought that n-stacking242 could be occurring in these
complexes; consequently, lH NMR spectra of the complexes were recorded at
60°C, but no changes in the spectra were observed, suggesting the absence of n
stacking effects. The lH NMR spectrum of complex 149 (Figure 50) illustrates the
multiplicity of signals seen in the spectra of the 1,1 O-phenanthrGlline platinum
complexes - a feature which is particularly prominent in the aromatic region. The
signal multiplicity may reflect either a. certain asymmetry in the structures of the
complexes or, possibly, the presence of isomeric systems in solution.
, I PO'
, ,0 01
7
Discussion
, ~
o
Figure 50: The 400 MHz 1H NMR spectrum of complex 149 in DMSO-d6 o
69a
, ppm
, 12
-U '---- '- l..J. \.L ,
10
Figure 51: The 400 MHz 1 H NMR spectrum of ligand 69a in DMSO-d6 o
J
131
Discussion 132
2.3.4.3.3 IR studies of the platinum complexes
Platinum can coordinate to both nitrogen and oxygen and the IR studies were
expected to reveal which donor atoms in the biphenyl and 1,1 O-phenanthroline
amide complexes were involved in complexation. The IR data for relevant
absorption bands are summarised in Table 19.
Table 19: Summary of the IR frequencies (VM-C,) and the amide frequency shifts (LWNH and t;;vc=ot for the biphenyl and 1,1 O-phenanthroline Pt(lI) complexes.
Complex ~VNH /cm-1 ~Vc=o/cm-1 I -1 VM-cr em
146 -69 4 315,342 (cis)
148 31 - 4 335 (trans)
149 18 8 329 (trans)
151 -39 4 321 (trans)
a Frequency shift on complexation
From the data in Table 19 it appears that complexation does not involve
deprotonation of the amide group since an amide NH band is observed in each
case. It can also be seen that coordination through the amide nitrogeh is preferred
because positive shifts are observed for the amide carbonyl band in eacK case.
These results also indicate, in most cases, that trans coordination of the chloride
anion is favoured over cis coordination; in the case of complex 146, however, the
presence of weak Pt-CI bands at 342 and 315 cm-1 suggest a cis-geometry.243
The imidazole NH band is also present in the IR spectra of the biphenyl complex
148 (3120 cm-1) and the 1,10-phenanthroline complex 151 (3135 cm-1
) - an
observation in agreement with the microanalysis data which indicate four chloride
anions in each complex. For the biphenyl complex 148 the polymeric structure in
Scheme 26 has been tentatively suggested due to the trans coordination of the
chloride anion in this complex.
Discussion 133
The 1, 10-phenanthroline complex 152 exhibits a strong NH band at 3480 cm-1,
suggesting that the secondary amine is not deprotonated upon complexation - a
conclusion which is consistent with the microanalysis data obtained for this
complex.
The geometry of the platinum complexes could not be elucidated by UV-Vis
spectroscopy due to masking of the absorption bands of interest by the solvent,
DMF.
J
Discussion 134
2.3.4.3.4 Computer modelling of the platinum complexes
Since none of the dinuclear platinum complexes afforded crystals suitable for
single crystal X-ray crystallography, computer modelling studies were undertaken
to explore their possible 3-D arrangements. It was also hoped that the results of
these modelling studies might explain the multiplicity of signals observed in the 1H
and 13C NMR spectra of the 1,1 O-phenanthroline platinum complexes. The
specimen complexes which were modelled are shown in Figure 52.
146
149
J
Figure 52: Proposed structures of the biphenyl and 1,1 O-phenanthroline platinum complexes investigated by computer modelling.
The energy-minimised structures for the two specimen systems are shown in
Figure 53. The structure of complex 149 reveals a trans arrangement of the
chlorine ligands in a squ£lre planar environment, while the biphenyl complex 146
exhibits a cis-arrangement of the chlorine ligands -- observations which are
consistent with deductions based on the IR absorption data. The apparent
symmetry in the model of the 1, 10-phenanthroline complex 149, however, is not
consistent with the multiplicity of peaks observed in the aromatic region of the
:.
Discussion 135
(a)
(b)
Figure 53: Computer modelled structures:- (a) complex 149; (b) complex 146. (Colours: Carbon: light-blue; nitrogen: dark-blue; oxygen: red ; chlorine: green; platinum: lilac). J
spectra of the 1,1 D-phenanthroline complexes. It is, of course, possible that the
use of a universal force constant for platinum resulted in structures which reflect
a degree of symmetry not present in the actual complexes.
Discussion 136
2.4 ELECTROCHEMICAL STUDIES: CYCLIC VOL TAMMETRY
Electrochemical techniques can be used to study the redox properties of
organometallic complexes. The synthetic dinuclear complexes were subjected to
a particular electrochemical technique called cyclic voltammetry, to establish the
oxidation state(s) and explore the electronic effects of the ligands. This technique
also reveals the reversibility or irreversibility of a redox process when the redox
potential of a redox couple is measured.
IZOjIA
1" 0.:5 - 0.:5
VOLTS
.1
Figure 54: A cyclic voltammogram for a reversible redox process.
In cyclic voltammetry, the potential is scanned linearly from an initial value Ej to a
second value Ej and then back to Ej, and the current monitored. The peaking in
current occurs at the potential Epc where the species of interest is reduced or
oxidised. For reversible systems, the re-oxidation or re-reduction of the species
in the vicinity of the electrode gives a current peak in the reverse scan, the
- . potential corresponding to this peak is Epa in Figure 54. For irreversible systems,
no return peak is obsefV§d. The separation, between the cathodic and anodic peak
potentials, .1E (Epa -Epc), is equal to 59/n, where n is the number of electrons
Discussion 137
required in the redox process for a reversible system. Disproportionation reactions
cause irregularities in the shape of the curves in a cyclic voltammogram. 244 The
redox potentials are, however, dependent upon various factors such as:
- solvent effects
- the electronic nature of the ligands and their substituents
- the steric demands of the ligand
- the flexibility of the ligand and the size of the chelate rings in the complex245
In the following discussion, an attempt has been made to explain the results of the
cyclic voltammetric studies obtained for the copper, cobalt and nickel complexes
of selected ligands.
2.4.1 Copper Complexes
The analysis of the dinuclear copper complexes by cyclic voltahlmetry is important
as the results may indicate the biomimetic potential of the synthetic models of the
enzyme, tyrosinase. If reversibility is observed in the cyclic voltammogram of a
synthetic model, then biomimetic activity may be expected; if no~ reversibility is
observed, then the catalytic activity is likely to be poor or absent. J
Since it is known that copper(l) is unstable and easily oxidised to copper(ll) it is
important to establish whether the synthetic models can maintain a copper(l)
oxidation state and whether they permit the oxidation to copper(II). Dinuclear
copper(lI) complexes may be reduced in a single two-electron reduction, as
observed for a triketonate complex,246 or in a stepwise manner with a Cu(l)Cu(lI)
species being formed as an intermediate. Generally, it has been found that
synthetic dinuclear copp~er complexes are reduced in a stepwise manner by two -
-. - single-electron steps. "Type III" copper sites in proteins are, however, reduced in
a single two-electron redt:lction at redox potentials that are higher than expected
for their proposed coordination environment. 246 To quantify the redox processes,
Discussion 138
the standard redox potentials are measured and the separation, ~E, between the
consecutive reduction potentials, is determined, i.e.
where ~E is a measure of ~om' the comproportionation constant, which is the
equilibrium constant for the reaction:
CU"CU" + CUICUI -t CUICU"
and ~om is related to ~E by the equation:247
For the dinuclear complexes examined here, the copper ions could, in principle,
both be copper(I), both copper(II), or a combination of copper(l) and copper(II).
The biphenyl and 1~ 10-phenanthroline complexes
From the cyclic votammograms, no reduction to CUD was evident during the 1
analysis of the biphenyl and 1,1 O-phenanthroline copper complexes, except for ,I
complex 116. Peaks that could not be assigned to either the ligand or the copper
oxidation states, may be ascribed to ligand oxidation induced by the presence of
copper. Such ligand oxidations have complicated the assignment of peaks in the
cyclic voltammograms of the copper complexes and have also precluded the
assignment of oxidation states for most of the copper complexes. Moreover, the
polymeric nature of most of the copper complexes has resulted in complicated
cyclic voltammograms. Nevertheless, an attempt has been made to assign some,
but not all, of the peaks observed. The measured potentials of the copper
complexes are summarised in Table 20.
Discussion 139
Table 20: The measured potentials for the biphenyl and 1,1 O-phenanthroline copper complexes.
Complex Potentials measured in cyclic voltammogram (V) vs Ag/AgCI
115 Oxidation side: 0.32 (Ea' Cu2+/Cu3+)
Reduction side: -0.20 (Ea, ligand), -0.46 (Ea, EV2 = -0.51) and -0.55 (Ee, E112 = -0.51, CUIiCUIl
+ 2e- ---> (CUICUI).
116 Reduction side: -0.29 (Ea), -0.55 (Ee) and -0.80 (Ee).
118a Oxidation side: 0.25 (Ea)
Reduction side: -0.46, -0.52 (Ee' ligand), -0.65 (Ee, ligand), -0.97 (Ea, E112 = 1.1), -1.13 (Ee,
E112 = 1.1, CUIiCUIl + 2e- ---> (CUICUI).
118b Oxidation side: 0.85 (Ea)' 0.48 (Ea)'
Reduction side: -0.41 (Ee, ligand), -0.61 (Ee), -1.17 (Ee), -1.67 (Ee' ligand).
118c Oxidation side: 0.86 (Ea) ~
Reduction side: -0.50 (Ee, CUIICUII + 2e----> CUICUI ), -1.57 (Ee, ligand).
119 Oxidation side: 0.75 (Ea, ligand), 0.34 (Ee, CUIiCUIl ---> CUIllCUIll), 0.14 (Ee, ligand).
Reduction side: -0.71 (Ea, E112 = -0.77) and -0.82 (Ee, E112 = -0.77, CUIiCUIl + 2e- ---> CUICUI).
For complex 115, the reduction CUIiCUIl - CUICUI was assigned to the slightly
reversible couple at -0.46 and -0.55 V, and the oxidation peak at 0.32 V to a ~
CU2+/CU3+ oxidation. For complex 116, the sharp peak at -0.29 V has been ,I
assigned to copper deposition at. the electrode [i.e. the formation245,248 of
copper(O)]; the sharp peak is typical for absorbed species. The peak observed at
-0.80 V was assigned to a CUIiCUIl - CUICUI reduction and the one at -0.55 V to a
CUICUI - CuoCuo reduction, which corresponds to a two-step, two-electron
reduction process.
For complex 118a, the peaks at -0.52 and -0.65 V have been ascribed to the
ligand, while the the coufJle at -0.97 and -1.13 V (E1/2 = -1.1 V) has been assigned
- to a CUIiCUIl - CuICu' reduction.138 For complex 118b, it is not certain whether the
peak at -1.67 V is due)o CUll - CUi re9uction or whether it is due to ligand
reduction. It is also not possible to tell whether the peaks at -0.61 V and -1.17 V
are due to Cu" - CUi reduction, but they were not observed for the ligand. The
peaks at 0.85 and 0.48 V are, however, attributed to ligand oxidation. For complex
Discussion 140
118c, the peak at -0.50 V has been tentatively assigned to to a CUll -. CUi
reduction. The peak at -1.57 V cannot be assigned with certainty as a copper
peak, and it may well be due to ligand reduction. For this complex, only one Cu(lI)
oxidation peak (0.86 V) is observed, which suggests that both copper atoms are
in a irreversible Cu(lI) oxidation state.
A peak at 0.34 V in the cyclic voltammogram of complex 119 may be due to a
CUIiCUIl -. CulilCuliioxidation, and the couple at -0.71 and -0.82 V to a single two
electron Cu"cd -. CJCu reduction; the LiE of -0.11 V suggests a quasi-reversible
one-electron system. The peaks observed at 0.75 and 0.14 V may be attributed to
ligand oxidation, by comparison with the ligand cyclic voltammogram.
The Schiff base complexes and the macro cyclic complex
The formation of copper(O) and its adsorption on the electrode is characterised by
a sharp peak in the cyclic voltammogram. 248 The cyclic voltammogram of each of
these copper complexes, but not their respective ligands, displayed this
characteristically sharp peak. The measured potentials for these copper complexes
are shown in Table 21.
Table 21: The measured potentials of the Schiff base and the J
macrocyclic copper complexes.
Complex Potentials measured in cyclic voltammogram (V) vs Ag/AgCI w
120 Reduction side: -0.26 (Ea) , -0.98 (Ee) and -1.40 (Ee), -1.75 (Ee)'
121 Oxidation side: 0.76 (Ea)' *
Reduction side: -0.22 (Ea), -0.59, -0.75 (Ee).
123 Oxidation side: 0.75 (E.). *
Reduction side: -0.13 (Ea), -1.00(Ee)' -1.75 (Ee)' w
124 Reduction side: -0.28 (Ee), -0.61 (Ee)' ..
*Peaks assigned to CUICul• CUD and copper deposition
Several peaks were obseFVed for complex 120. The strong, sharp peak at -0.26 V
has been assigned to copper deposition at the electrode. The peak at -0.98 V is
Discussion 141
attributed to a Cullcdl -t CUICUI reduction and the peak at -1.40 V to a CUICUI
-t CuoCuo reduction, thus representing a two-step, two-electron reduction
process138 to CUD. The peak at -1.75 V is assigned to ligand reduction by
comparison with the ligand cyclic voltammogram. For complex 121, the cyclic
voltammogram also exhibits a strong, sharp peak at -0.22 V, and this is attributed
to copper deposition. The peaks at -0.59 and -0.75 V have been assigned to a
two-step, single-electron reduction process and the peak at 0.76 V to ligand
oxidation. Complex 123 also exhibits similar peaks to those of complexes 120 and
121. The strong, sharp peak at -0.13 V has been assigned to copper deposition,
and the peak at -1.75 V to ligand reduction. Here, however, the two-step, single
electron reduction process was absent since only one peak was observed at -1.00
V, and it is suggested that this peak may be due to a single, two-electron reduction
process. The peak· at 0.75 V has been ascribed to ligand oxidation. The
macrocyclic complex 124 exhibits a strong peak at -0.28 V, which is attributed to
copper deposition, but the peak at -0.61 V could not be assigned with certainty and
it seems from a comparison with the ligand cyclic voltammogram, that this latter
peak is due to ligand reduction.
A general mechanism reported in the literature for the reduction of copper(lI) to , copper(O) has been proposed138 to follow the sequence:-
I
2~r 2e-CUIlCUIl ---t Cu'Cul ---t 2Cuo
In this sequence, the two copper(lI) ions are reduced to copper(l) by a potential of
-0.98 V, followed by a subsequent reduction to copper(O) by a potential of -1.40 V.
In turn, a potential of -0.26 V results in the re-oxidation of copper(O).
Discussion 142
2.4.2 Cobalt Complexes
In the case of the dinuclear cobalt complexes, cyclic voltammetry was used to
establish whether the metal ions were cobalt(lI) or (III) or a mixture of both. The
measured potentials for the cobalt complexes are shown in Table 22. From the
results it is apparent that cobalt(lI) is oxidised to cobalt(lIl) on the cyclic
voltammetric time scale. The observation of a strong peak at ca. 1 V, which was
not observed for the ligand alone, indicates that the oxidation involves the cobalt
ion. Since Co(lIl) cannot be oxidised any further, the results suggest that Co(lI) is
present and is oxidised to Co(lll).
When comparing the oxidation potentials of the biphenyl diamide complexes (133
and 134) with those of the 1,1 O-phenanthroline diamide complexes (137a, 137b
and 137c), it is apparent that the latter complexes have higher oxidation potentials.
It was also observed that the 1,10-phenanthroline diamine complex 138 has a
lower oxidation potential than the diamide complexes, and it is presumed that this
is due to electron-withdrawal by the carbonyl oxygen of the amide group. Thus,
complex 138 is more easily oxidised than the diamide complexes, complex 137a
proving to be the most difficult.
I
The higher oxidation potentials of. the 1,1 O-phenanthroline-based complexes
(compared to the biphenyl analogues) may be attributed to the presence of the
additional, electronegative nitrogen atoms of the 1,1 O-phenanthroline nucleus,
which increase the electron-withdrawing capacity of the ligands, thus increasing
the oxidation potential of the resulting complexes. The rigidity of the 1,10-
phenanthroline system and the smaller, less flexible 5-membered chelate rings
which are formed upon complexation (in contrast to the flexibility of the biphenyl
system and its formation of larger, more flexible 6-membered chelate rings) may
-. - also contribute to the higher oxidation potentials observed for the 1,10-
phenanthroline complexes. Representative examples of the cyclic voltammograms
obtained for the biphenyl and 1,1 O-phenanthroline cobalt complexes are illustrated
Discussion
in Figures 55 and 56.
Table 22: Measured potentials for the biphenyl and 1,1 O-phenanthroline cobalt complexes.
Complex Potentials measured in cyclic voltammogram (V) vs Ag+/AgCI
133 Oxidation side: 0.97 ( CO"CO" --t COII1COII1 )
134 Oxidation side: 0.99 (COIICOII --t Co'IICOIII ).
137a Oxidation side: 1.08 (COIICO" --t COII1COII1 ).
137b Oxidation side: 1.06 (CO"CO"--> Co'IIC011I ).
137c Oxidation side: 1.02 (COIICOII --t C01IIC011I ).
138 Oxidation side: 0.86 (COIICOII --t COIIICO"1).
143
Discussion 144
+30+I~~--~~~~~~~~--~~~~
J l O~ __ -~~ l i
-3°l r
1 ~ ~oJ ~
I ! 1 r
~Oi ~ I I l r
-120 +1 ---r----'I:---'--'-I -----'-----',:--'---'---1 -'---'1--""--'---1 -.-+-1 +1.4 +1.0 +0.6 +0.2 -0.2 -0.6 -1.0 -1.4
Potential ,V
Figure 55: Cyclic voltammogram of biphenyl cobalt complex 134.
+30 I I l ~
1
o~ I I- .I
I I 1 r <{ 1
:::J -30~ ~ ..... J 1 c: L .0)
I 1
L.. I L.. :::J ~ol r ()
~ I I l-
I I -gal r J ~ I
-120 I I , I , , I , , I
+1.4 +1.0 +0.6 +0.2 -0.2 -0.6 -1.0 -1.4
Potential,V
Figure 56: Cyclic voltammogram of 1,1 O-phenanthroline cobalt complex 137c.
Discussion 145
2.4.3 Nickel complexes
Cyclic voltammetry was also used to establish the oxidation state(s) of the metal
ions in the dinuclear nickel complexes. Although the nickel(lI) oxidation state is
the most stable and most prevalent, the possibility of the Ni(III) and Ni(IV) oxidation
states occurring within these complexes had to be considered. The cyclic
voltammetry data for the complexes is summarised in Table 23.
From these results it can be seen that nickel(lI) was oxidised to nickel(lIl) on the
cyclic voltammetric time scale, since only one oxidation peak was observed in
each case. 249 In certain complexes (141, 144a, 144b and 145), ligand reduction
is evidenced by the peaks between -1.13 and -1.25 V, the oxidation peak being
clearly visible in the cyclic voltammogram of complex 142 (Figure 57); the cyclic
voltammogram for the ligand SSc is illustrated in Figure 58.
The 1,1 O-phenanthroline-cobalt complexes exhibit higher oxidation potentials than
their biphenyl counterparts, this trend was not observed for the corresponding
nickel complexes. It is also apparent that, of the biphenyl systems, complex 142
(Figure 57) has the highest oxidation potential and 141 the lowest.
Of the 1,1 O-phenanthroline nickel .systems, complex 144b has the highest
oxidation potential and 144a the lowest. Although the ligand G8a has an oxidation
potential at 0.86 V (see Figure 60) it was expected that the complex 145 would
have a lower oxidation potential and, consequently, the peak at 0.85 V (Figure 59)
has been tentatively assigned to the oxidation of Ni2+.
Discussion 146
Table 23: Cyclic voltammetric data for the nickel complexes.
Complex Potentials measured in cyclic
voltammogram (V) vs Ag+/AgCI
140 oxidation side: 0.83 (Ni2+)
141 oxidation side: 0.80 (Ni2+/Ni3+)
reduction side: -1.25 (ligand reduction)
142 oxidation side: 0.84 (Ni2+/Ni3+)
144a oxidation side: 0.79 (Ni2+/Ni3+)
reduction side: -1.13 (ligand reduction)
144b oxidation side: 0.95 (Ni2+/Ni3+)
reduction side: -1.17 (ligand reduction)
144c oxidation side: 0.82 (Ni2+)
145 oxidation side: 0.85 (Ni2+/Ni3+)
reduction side: -1.13 (ligand reduction)
Discussion 147
+40 i-I -----L--L-------L------"----'-----"---LI -'-I ---1-1 --LI ----'-, --'--, ~I ----'---, --"---+1
l ~~ __ --------~L -40 l
1 ( I f ~ r
~ -120~ I
~ 1 ~ ~ ~oo~ l
l ~ ~OO~ ~
I I l r
-360 I 1 1 I I I'! 1 I I 1 I I I +1.6 +1.2 +0.8 +0.4 0 -0.4 -0.8 -1.2 -1.6
Potential,V
Figure 57: A cyclic voltammogram of biphenyl nickel complex 142.
+15 \ I
I I 1 ~
I
+5~ ~ J
I I 1 I <{
-5~ ~ ~ ..... J l c (]) I I l- I I-~ -151 r ()
~ ~ I I
-25l r
~ ~ -351 I
I I I I I I I
+1.4 +1.:.0 +0.6 +0.2 -0.2 -0.6 -1.0 -1.4
Potential, V - . -
Figure 58: A cyclic voltammogram of ligand 55e.
Discussion 148
+100 i I I I I I I I I
I --:dt l O~ ---I / / !
i
-< 1 / I ::l -100~ / ~ ..... J l c: Q)
I I L. L. I ::l
-2ool I ()
~ ~
-300~ I I I
~ ~ I
-400 I I
! I I I I I I I I
+1.6 +1.2 +0.8 +0.4 0 -0.4 -0.8 -1.2 -1.6
Pote!!tial, V
Figure 59: A cyclic voltammogram of the 1,1 O-phenanthroline nickel complex 145.
+10 I I
I -1 r I
-10~ L I I I
-< 1 I ::l -30~ ~ ..... J l c: Q) I I L. L. I I ::l -SOl I I ()
~ L I N
I I -7°1 r
~ ~ -90 I I
I I I I I I I
+1.4 +1.0 +0.6 +0.2 -0.2 -0.6 -1.0 -1.4
Potential,V
Figure 60: A cyclic voliammogram of the 1 ,1 O-phenanthroline ligand 6Sa that has an oxidation potential at 0.86 V.
Discussion 149
Conclusion
The cyclic voltammetry studies of the copper complexes reveal that the 1,10-
phenanthroline ligands are unstable once they are coordinated to copper, ligand
oxidation being apparent in the cyclic voltammograms of the complexes. In the
case of the biphenyl analogues, complex 115 exhibits a Cu(ll) oxidation state,
while in complex 116 the metal is reduced to Cu(O), resulting in copper deposition
at one of the electrodes. In the Schiff base and macrocyclic complexes the copper
is also reduced to Cu(O) with concomitant electrodeposition of Cu(O). As a result
of the complexity of the cyclic voltammograms and the electrodeposition, it has
been difficult to assess either the redox reversibility or the potential of the copper
complexes as biomimetic catalysts.
In the cobalt complexes Co(lI) is oxidised to Co(llI) on the cyclic voltammetric time
scale, indicating that cobalt is in the Co(lI) oxidation state in the biphenyl- and
1,10-phenanthroline-based cobalt complexes. Similarly, the nickel complexes
exhibit predominant oxidation of the metal to Ni(lIl) confirming the oxidation state
of nickel in the biphenyl- and 1,1 O-phenanthroline-based complexes as Ni(II).
J
- .
Discussion
2.5 EVALUATION OF THE CATALYTIC ACTIVITY OF THE BIOMIMETIC
COPPER COMPLEXES
150
In order to determine whether the copper complexes were suitable models of
tyrosinase, their ability to oxidise a phenol and/or catechol was examined. For a
model to be successful it should display either phenolase or catecholase activity
using molecular oxygen. For this study, the substrate di-t-butylphenol (DTBP) 153
was used to evaluate the phenolase activity, and di-t-butylcatechol (DTBC) 154 the
catecholase activity of these complexes. 15, 250 These substrates were used because
they are activated for electron-donation by their alkyl substituents,208 and their
oxidation products are somewhat resistant to polymerisation. DTBP is oxidised to
DTBC which, in turn, is oxidised to 3,5-di-t-butyl-o-quinone (OTBQ) 155. The 0-
quinone has a characteristic absorption ban(j at 400 nm in the UV-visible spectrum
and can therefore be detected spectroscopically (e = 1830 M-1cm-1). DTBP can
also be oxidised to the coupled product 156.
\ (y0~ ~
153
OH
154
o
155 156
The reactions for evaluating biomimetic activity were conducted in DMF or in
CH2CI2. DMF was chosen because it is a highly polar solvent and was.expected
to dissolve, at least, some of the complex. Reactions were also attempted in
CH2CI2 because of its capacity to dissolve dioxygen, which must be present in non
rate limiting concentrations. Tyrosinase can catalyse the oxidation of a variety of
substrates in an aqueous medium, but the range of substrates is decreased when
an organic medium is used.251 In this study, 1H NMR spectroscopy was ljsed to
detect the product(s) of oxidation reactions catalysed by selected biphenyl and
1,1 O-phenanthroline copper complexes.
Discussion 151
The 1H NMR data for the expected oxidation products DTBC 154 and DTBQ 155
and the coupled product 156 are detailed in Table 24, while the results of the
biomimetic evaluation of the copper complexes are summarised in Table 25. At the
conclusion of each reaction period, the reaction mixture was concentrated to
dryness in vacuo and the residue analysed by 1 H NMR spectroscopy to establish
the substrate: product ratios.
Table 24: 1H NMR data for DTBC 154, DTBQ 155 and the coupled product 156.
Compound OJppm
DTBC 154 1.27, 5, 9H, But
1.41, S, 9H, But
6.76, d, 1 H, H-4
~.89, d, 1 H, H-6
DTBQ 155 1.22, 5, 9H, But
1.26, S, 9H, But
6.21, d, 1 H, H-4
6.90, d, 1H, H-6 -
Coupled product 156 1.31, s, 18H, But
1.41,5, 18H, Bd
7.10, d, 2H, H-4 and H-4'
7.38, d, 2H, H-6 and H-6'
I
. Table 25: Results of the biomimetic evaluation of the copper complexes in
DMF.
Reaction Phenolase % Catecholase % Entry Complex Solvent time/h activity Conversion activity Conversion
product product
* 1 115 DMF 24h none none o-quinone 6.3
2 116 DMF 120 h coupled product 8.8 o-quinone 13.3
* 3 118a DMF 24h coupled product 14.3 o-quinone 7.3
4 118b DMF ~ 120 h coupled product 13.0 o-quinone 38.0
5 118c DMF 120 h none none" o-quinone 54.3
6 119 DMF 120 h none none none none
* Stirred for 24 h without ~tl.J
Discussion 152
The catalytic oxidation reactions were first attempted in CH2CI2, in the absence of
Et3N, but these were unsuccessful. The reactions were then repeated in DMF, but
catalytic activity was only observed for certain complexes. The complexes which
still failed to display any catalytic activity were then reacted, in DMF, in the
presence of EtJi138 Under these conditions, three more complexes exhibited
biomimetic activity (Entries 2, 4 and 5; Table 25). From the tabulated results, it can
be seen that some complexes displayed both phenolase and catecholase activity
(Entries 2,3 and 4), while all the complexes, with the exception of complex 119,
exhibited catecholase activity.
..
Scheme 28: Mechanism for the oxidative phenolic coupling proposed by Kitajima.20
Signals for the coupled product 156, indicating phenolase activity, were thus
observed in reactions with complexes 116, 118a and 118b. The formation of the
coupled product 156 has been observed by Reglier138 and Karlin,253 and other
coupled biphenyl products from reactions of phenol$ and biomimetic -copper
complexes have also been widely reported.254-257 Kitajima has proposed a
mechanism for the phenolic coupling, involving catalytic oxidation (Scheme 28).20
156
I pplfl 7 5
I 7.'
Discussion
, 7.3 7.2
153
/1
H-4 l __ ~~~~~.~
1:1 [::1
7.' 7.0
Figure 61: Partial 1H NMR spectrum, in CDCI3 , of the residue following reaction of complex 118a and DTBP in DMF in the absence of ET3N, showing the formation of the coupled product 156, i.e. phenolase activity.
155 ±~o xUo
. ( ,I \11 I J
H~I H-4 .
II! II I :\ I !~~W t 1 I~~I \
___ ~0J \J~J ~ Iii" I
PPII 10 , 1
Figure 62: The 400 MHz 1 H NMR spectrum, in CDCI3 , of the residue following reaction oJ c;omplex 118c an<~ DTBC in DMF in the presence of Et3N, showing formation of the ortha-quinone 155, i.e. catecholase activity.
Discussion 154
Catecholase activity was confirmed by the 1H NMR signals for the o-quinone at ca.
06.2 and 06.9 ppm observed in the spectra of residues from the reactions with
complexes 115,116, 118a, 118b and 118c) .
It is possible that the lack of phenolase activity exhibited by some of the complexes
may be due to either the polymeric copper complexes being too flexible to bind
DTBP 153, or to coordination being limited to only one copper atom, thus making
a-hydroxylation unlikely. The fact that both phenolase and catecholase activity is
exhibited by some of the complexes suggests that, in these cases at least, the
copper ions are sufficiently close (after binding dioxygen) to allow for the binding
and bridging of DTBP 153 and DTBC 154. While the copper complexes appear to
be polymeric (see Section 2.3.1.1.), the formation of polymer-monomer equilibria
in solution would afford some monomer moiecules capable of acting as biomimetic
catalysts. On the other hand, the macromolecular characteristics of tyrosinase
may also have been simulated, to some extent, by the polymeric structure of the
biomimetic complexes.
I
Discussion 155
2.6 CONCLUSIONS
During the course of this research, several sets of ligands, designed to mimic the
active site in tyrosinase, have been successfully prepared. The diimine ligands
containing the biphenyl spacer have been shown to undergo intramolecular
cyclisation during reduction with sodium borohydride, affording azepine
derivatives; X-ray crystallographic analysis of cobalt and nickel complexes
facilitated identification of the azepine systems, and a mechanism has been
proposed to account for the observed cyclisation. In contrast, neither the 1,10-
phenanthroline nor the Schiff base analogues undergo intramolecular cyclisation.
However, Schiff base ligands, in which the imine functionalities are separated by
one carbon atom, undergo significant tautomerism, forming six-membered H
bonded chelates.
Complexation of the biphenyl- and 1,1 O-phenanthroline-based amide ligands with
copper appears to afford polymeric copper complexes, analysis of which reveals
coordination through both the amide nitrogen and oxygen donor atoms, as well as
through the tertiary and secondary nitrogen donors of the imidazole and
benzimidazole moieties. In the case of the Schiff base copp$r complexes,
unidentate and bidentate coordination of the nitrate anion has complicated
elucidation of the structures.
Tetrahedral geometry appears to be dominant in the dinuclear cobalt complexes
of the biphenyl- and 1,1 O-phenanthroline-based amide I igands. Coordination with
nickel, results in the formation of complexes in which the metal exhibits tetrahedral,
octahedral or square planar geometries, while the biphenyl and 1,10-
phenanthroline platinum(ll) complexes appear to favour a trans arrangement of
the chlorine ligands in a square planar environment.
Unlike the polymeric copper complexes, the cobalt and nickel complexes afforded
uncomplicated cyclic voltammograms, confirming the formation of cobalt(ll) and
Discussion 156
nickel(l/) complexes with the biphenyl- and 1,1 O-phenanthroline-based ligands.
Despite the polymeric nature of the copper complexes, biomimetic activity for both
biphenyl- and 1,1 O-phenanthroline-based polymeric complexes was observed. The
presence of triethylamine appears to enhance the biomimetic activity, and it seems
that the copper atoms in the complexes are close enough for dioxygen bridging
to occur and that substrate binding is possible. Such evidence suggests the
existence of polymer-monomer equilibria in solution, with the monomeric dicopper
complexes capable of acting as biomimetic catalysts.
Future research in this area is expected to involve:-
i) complexation of the biphenyl- and 1,1 O-phenanthroline-based amide ligands
with copper in the presence of base; -
ii) complexation of the Schiff base and macrocyclic ligands with copper(l) to
explore the potential of the resulting complexes as biomimetic catalysts;
iii) an investigation of the potential of the biphenyl- and 1,1 O-phenanthroline
based cobalt(lI) complexes to bind oxygen and thus catalyse the oxidation of
3,5-di-t-butylphenol and 3,5-di-t-butylcatechol; and
iv) exploration of the potential of the nickel(l/) complexes as catal~sts for the
hydrolysis of urea. J
157
3 EXPERIMENTAL
3.1 GENERAL
Infrared spectra were recorded on Perkin Elmer 2000 and Perkin Elmer 180
spectrophotometers; the mid-infrared spectra (4000-300 cm-1) were recorded using
potassium bromide discs and, nujol mulls and hexachlorobutadiene (HCBD). The
far-infrared (500-50 cm-1) spectra were obtained using nujol mulls. NMR spectra
were recorded on a Bruker AMX 400 spectrometer, and chemical shifts are
reported relative to the solvent peaks. Low resolution mass spectra were obtained
on a Hewlett-Packard 5988A mass spectrometer, and high resolution analyses on
a Kratos MS80RF double focussing magnetic sector instrument (Cape Technikon
Mass spectrometry unit); FAB mass spectra~were obtained on a VG Micromass 70-
70E spectrometer (Ion tech B11 N FAB-gun), using Xe as bombarding gas
(University of Potchefstroom). UV-Visible spectra were recorded on a Cary 1 E UV
Visible spectrometer, and the resulting data for the cobalt and nickel complexes
are summarised in Tables 14 and 17 respectively. Microanalysis (combustion
analysis) was conducted at the University of Cape Town, and the data for the
copper, cobalt, nickel and platinum complexes are reported in Tables~8, 12, 15 and
18 respectively. X-ray crystallographic data were collected on a Siemens sMART
CCD diffractometer at the University of the Witwatersrand. Electrochemical data
were recorded with a Bio Analytical Systems (BAS) CV-50 voltammograph. Melting
points were obtained using a Kofler hot-stage microscope and are uncorrected.
Experimental 158
3.2 PROCEDURES FOR LIGAND SYNTHESES
3.2.1 Biphenyl ligands
Biphenyl-2,2'-dicarba/dehyde 48140
A stirred suspension of phenanthrene 47 (2.5 g, 14 mmol) in dry methanol (50 mL)
was cooled to -30°C in an ozonolysis vessel. 0 3 was gently bubbled through the
mixture until all of the substrate had dissolved. KI (8.5 g) and glacial AcOH (7.5
mL) were added to the mixture at O°C. The mixture was then allowed to stand at
room temperature for 1 h, after which, an aqueous solution of Na2S20 3 (10%) was
added. A stream of air was passed through the mixture for 2 h. Cold H20 (O°C; 50
mL) was added, and the solid product was filtered off and recrystallised from Et20-
hexane to give, as a pale yellow solid, biphenyl-2,2'-dicarbaldehyde 48 (2.74 g,
93%), mp 61-62°C [lit. 140 62-63°C]; vmruJKBr/cm-1) 1700 (CO); oH(400MHz; CDCI3)
7.35 (2H, d, ArH) 7.59 (2H, t, ArH), 7.64 (2H, t, ArH), 8.05 (2H, d, ArH) and 9.83
(2H, s, CHO).
Diphenic Acid 49141
Phenanthrene 47 (10 g, 56 mmol) was dissolved in glacial AcOH (113 mL) and the
solution warmed to 85°C on a water bath. An aqueous solution of H20 2 (BO%;39
mL, 0.45 mmol) was added dropwise during a period of 40 minutes after which the
mixture was heated for a further 3-4 h. The volume of the mixture was then
reduced to half by distillation under reduced pressure, and the diphenic acid,
which precipitated out, was filtered off. The filtrate was evaporated almost to
dryness under reduced pressure and then extracted through warming with an
aqueous solution of Na2C03 (10%; 42 mL). This extract was boiled with a little
decolourising carbon and then filtered. To the filtrate, dilute HCI was added until
a pH of 4.5 was reached (using narrow range indicator paper). The solution was
-. - further stirred with a small amount of activated charcoal and the tarry material was
filtered off. The clear solution was then acidified with dilute HCI at O°C. The crude
diphenic acid was collected by filtration, washed with H20, dried at 110°C and then
Experimental 159
recrystallised from glacial AcOH. The total yield of diphenic acid 49 was 9.1 g
(67%), mp 228-229°C [lit.141 230°C]; vmaiKBr/cm-1) 2500-3500 (OH stretch), 1700
(CO); oH(400 MHz; DMSO-d6) 7.18 (2H, d, ArH) 7.43 (2H, t, ArH), 7.53 (2H, t, ArH),
7.93 (2H, d, ArH) and 12.44 (2H, s, C02H).
2-(2-Aminoethy/)benzimidazo/e 52138
A stirred mixture of 1 ,2-diaminobenzene 57 (8.33 g, 77 mmol) and .B-alanine 58
(10.2 g, 115 mmol in HCI (6M; 90 mL) was boiled under reflux for 48 h, and then
allowed to stand for 48 h at room temperature. The completion of the reaction was
confirmed by TLC. The solvent was removed under reduced pressure at 90°C, and
the residual solid was dissolved in H20 (50 mL). EtOH (100 mL) was then added,
and the dihydrochloride salt crystallised out as blue needles on cooling.
Recrystallisation from 95% EtOH gave~c the dihydrochloride (4.0 g, 32%). A
methanolic solution of NaOMe (0.1 M; 171 mL, 17.1 mmol) was then added to the
salt (2.0 g), and the mixture stirred for 1.5 h. The solvent was removed under
reduced pressure before adding CHCI3 (50 mL) to dissolve the amine. The
solution was filtered, and a pale pink product was obtained after removing the
CHCI3 under reduced pressure. Recrystallisation from THF gave 2-(2-amino
ethyl)benzimidazole 52 (1.1 g, 80%), mp 134 -135°C (lit. 138 134 -136°C);
vrnax (KBr/cm-1) 3350 (NH) and 1540 (C=N); oH(400 MHz; 0 20) 2.91 (2H, ,t, CH2),
2.99 (2H, t, CH2), 7.21 (2H, m, ArH),}.49 (2H, m, ArH).
Histamine 53
Histamine dihydrochloride (2.0 g, 11 mmol) was added to a methanolic solution of
NaOMe (0.1 M; 220 mL, 22 mmol) and the resulting mixture stirred for 1.5 h at room
temperature. The solvent was then removed under reduced pressure, and CHCI3
was added to the residue. The flask was warmed to aid the dissolution of the
liberated amine; the solution was filtered, and evaporation of the solvent gave, as
_. - a light yellow oil, histamine 53 (1.20 g, 98%); vrnax(thin film/cm-1) 3481 and 3250
(NH); oH(400MHz; COCht2.72 (2H, t, CH2), 2.99 (2H, t, CH2), 4.5 (2H, br s, NH2)'
6.79 (1H, s, ArH) and 7.53 (1H, s, ArH).
Experimental 160
2, 2'-Bis[4-(2-pyridyl}-2-azabut-1-eny/]bipheny/ 54a 103
2-(2-Aminoethyl)pyridine 51 (1.1 mL, 9.0 mmol) was added to a solution of 1,1 '
biphenyl-2,2'-dicarbaldehyde 48 (1.00 g, 4.76 mmol) in CHCI3 (50 mL) in a 2-
necked flask fitted with a condenser and a modified Dean-Stark apparatus. The
mixture was boiled under reflux for 16 h, and completion of the reaction was
confirmed by IR spectroscopy. The CHCI3 was removed under reduced pressure
to afford, as a pure brown oil, 2,2'-bis[4-(2-pyridyl)-2-azabut-1-enyl]biphenyl 54a
[(1.88 g, 97%); vmax (NaCllcm-1) 1650 (C=N); oH(400 MHz; CDCI3) 3.03 (4H, t,
NCH2CH2), 3.76 (4H, m, NCH2C~), 7.00 (4H, t, ArH), 7.06 (2H, d, ArH), 7.34 (4H,
m, ArH), 7.47 (2H, t, ArH), 7.85 (2H, s, CH=N), 8.04 (2H, d, ArH), 8.40 (2H, d,
ArH)], which was used without further purification.
2, 2'-Bis{[2-(2-pyridy/)ethy/amino]carbonyJ}bipheny/ 55a
~ ~N 0
o ~~ ~ H
Diphenic acid 49 (1.00 g, 4.1 mmol) was dissolved in dry DMF (10 rnL) in a round
bottomed flask fitted with a reflux condenser and drying tube. The soluti'on was
warmed to 40°C, and COl (2.13 g, 13.1 mmol) was added with stirring. The mixture
was stirred for 5 min at 40°C, after which time, gas evolution ceased. After cooling
to room temperature, 2-(2-aminoethyl)pyridine 51 (1.1 mL, 9.0 mmol) was added.
The resulting solution was stirred for 1 h at room temperature, and the reaction
was quenched with H20 (7 mL). Volatiles were removed under reduced pressure,
and aqueous 1 M Na2C03 (50 mL) was added to the residual oil. The mixture was
extracted with EtOAc (2 x 80 mL), and the combined extracts were washed with
H20 (80 mL) and brine (8D mL), and dried (MgS04). The solvent was evaporated
-. - and the residue chromatographed [flash chromatography on silica gel; elution with
CHCI3-hexane-MeOH -(3:3:1)] to afford, as a brown oil, 2,2'-bis{[2-(2-
pyridy/)ethyJamino]carbonyl}bipheny/55a (1.00 g, 54%) (Found: M+, 450.2044.
Experimental 161
C2sH2S02N4 requires, M 450.2054); vmaithin film/cm-1) 3321 (amide NH), 1634
(CO); oH(400 MHz; CDCI3) 2.68 (4H, quintet, NHCH2CH2), 3.42-3.67 (4H, m,
NHCH2CH2), 7.02-7.12 (6H, m, ArH), 7.25-7.35 (4H, m, ArH), 7.48 (2H, m, ArH),
7.52-7.58 (2H, m, ArH), 7.74 (2H, t, NH), 8.45 (2H, d, ArH); oC<100 MHz; CDCI3)
37.1 (NHCH2CH2), 39.1 (NHCH2CH2), 121.7 ,123.6,127.4,128.0, 129.6,129.7,
136.6, 136.8, 139.4, 149.4 and 159.6 (ArC) and 170.1 (CO).
2,2'-Bis{[2-(2-benzimidazo/y/)ethy/amino]carbonyl}bipheny/55b
Following the procedure used for synthesising 2,2'-bis{[2-(2-pyridyl)ethylamino]
carbonyl}biphenyl 55a, a solution of diphenic acid 49 (1.00 g, 4.1 mmol), 2-(2-
aminoethyl)benzimidazole 52 (1.46 g, 9.0 mmol) and COl (2.13 g, 13.1 mmol) in
dry DMF (10 mL) was stirred for 64 h at room temperature. The reaction was
quenched with H20 (7 mL), and the solvent~as removed under reduced pressure.
Addition of aqueous Na2C03 (1 M; 50 mL) to the residual oil precipitated the crude
product, which was recrystallised from DMF-H20 to afford, as a pale pink powder,
2,2'-bis{[2-(2-benzimidazo/y/)ethylamino]carbonyl}bipheny/55b (1.21 g, 56%) mp
> 250°C (Found: M+, 528.2261. C32H2SNs02 requires, M 528.2272; vmax(KBr/cm-1)
3172 (amide NH), 1656 (CO); oH(400 MHz; DMSO-d6) 2.62 (4H, s, NHCH2CH2),
3.43 (4H, s, NHCH2CH2), 6.99 (2H, d, ArH), 7.05-7.16 (4H, m, ArHh7.28-7.37 (4H,
m, ArH), 7.38-7.42 (4H, m, ArH), 7.49 (2H, d, ArH), 8.64 (2H, m, amide NH~, 12.14
(2H, s, NH); oc(100 MHz; DMSO-d6)t 28.2 (NHC~C~), 37.2, (NHC~C~), 110.7,
118.0,120.7,121.4,126.9,127.2,128.9,134.2,136.2, 138.5,143.2 and 152.1
(ArC) and 169.0 (CO).
2,2'-Bis{[2-( 4-imidazolyl)ethylaminojcarbonyljbiphenyl 55e
The procedure described for the synthesis of 2,2'-bis{[2-(2-pyridyl)ethylamino}
carbonyl}biphenyl 55a was followed, using histamine 53 (1.00 g, 9.0 mmol), COl
(2.13 g, 13.1 mmol) anadiphenic acid 49 (1.0 g, 4.1 mmol). After stirring for 94 h -
-. - at room temperature in dry DMF (10 mL), the reaction was quenched with H20 (7
mL) and the volatiles -were removed under reduced pressure. The addition of
t The coincidence of some 13C signals is presumed.
Experimental 162
aqueous 1 M Na2C03 (50 mL) to the residual oil precipitated the crude product,
which was recrystallised from DMF-H20 to afford, as an off-white powder, 2,2'
bis{[2-(4-imidazo/y/)ethy/amino]carbonyl}bipheny/55c (1.44 g, 82%), mp 232-234°C
(from DMF-H20) (Found: M+, 428.1955. C24H2402Ns requires, M 428.1961);
vmax(KBr/cm-1) 3187 (amide NH), 1640 (CO); oH(400 MHz; MeOH-d4) 2.51 (4H, s,
NHCH2CH2), 3.34 (4H, s, NHCH2CH2) , 6.73 (2H, s, ArH), 7.08 (2H, m, ArH), 7.40
(4H, m, ArH), 7.48 (2H, m, ArH), 7.53 (2H, s, ArH); od100 MHz; MeOH-d4) 27.5
(NHCH2CH2),40.5(NHCH2CH2), 117.9, 128.4, 128.9, 130.6, 130.7, 135.7, 136.1,
137.4 and 140.4 (ArC) and 172.5 (CO).
2,2'-Bis{[2-(2-pyridy/)ethy/amino]methy/}bipheny/ 56a
Attempted method 1.
H ~N ~N ~
~
1.9 N H
2,2'-Bis[4-(2-pyridyl)-2-azabut-1-enyl]biphenyl 54a(1.00 g, 2.39 mmol) was added
to methanol (10 mL) in a 2-necked flask fitted with a reflux conpenser. To the
heated mixture, NaBH4 (0.18 g, 4.8 mmol) was added in portions while ,ptirring.
Once the addition was complete, the,reaction mixture was boiled under reflux for
0.5 h and then quenched with ice. The product was extracted with CHCI3 (3 x 40
mL) and the combined extracts were dried over anhydrous MgS04. The CHCI3 was
removed under reduced pressure. A sample of the crude product was purified by
preparative thin layer chromatography [on silica; elution with MeOH-CHCI3-hexane
(1 :4:1)] to afford 1-[2-(2-pyridy/)ethyf]dibenz[c,e]perhydroazepine 61a as a brown
oil; oH(400 MHz; CDCI3) 2.97-3.01 (2H, m, NCH2CH2 ), 3.11-3.14 (2H, m,
NCH2CH2 ), 3.48 (4H, s, 2--x CH2 ), 7.10-7.13 (1 H, m, ArH), 7.23 (1 H, d, ArH), 7.33-
-. - 7.36 (4H, m, ArH), 7.40-7.44 (2H, m, ArH), 7.49 (2H, -d, ArH), 7.60 (1 H, td, ArH),
8.54 (1H, d, ArH); oc(1QO.MHz; CDCI3) 37.~ (NCH2CH2), 55.43 (NCH2CH2), 55.51
(ArCH2N), 121.2,123.2,127.5,127.6,128.0,129.7,134.7,136.3, 141.1, 149.3 and
Experimental 163
160.3 (ArC).
Attempted method 2.
NaBH4 (0.18 g, 4.8 mmol) was added in portions to a stirred solution of 2,2'-bis[4-
(2-pyridyl}-2-azabut-1-enyl]biphenyl 54a (0.46 g, 1.1 mmol) in EtOH (20 mL),
effervescence occurring during the addition of the NaBH4. The solution was stirred
for 67 h, at room temperature, before evaporating the EtOH under reduced
pressure to yield a yellow powder. This residue was dried under high vacuum to
remove remaining EtOH. CHCI3 was added to the residue to dissolve the product,
and the mixture was then filtered to remove unreacted NaBH4. The CHCI3 was
removed under reduced pressure to afford, as a pale brown oil, 1-[2-(2-
pyridyl)ethyl]dibenz[c,e]perhydro-azepine 61a (0.46 g, 100%).
2,2'-Bis{[2-(2-benzimidazolyl)ethylaminojinethy/jbiphenyI 56b
Attempted method 1.
A solution of biphenyl-2,2'-dicarbaldehyde 48 (0.49 g, 2.3 mmol) and 2-(2-amino
ethyl)benzimidazole 52 (0.74 g, 4.6 mmol) in CHCI3 (100 mL) was boiled under
reflux for 59 h. The completion of the reaction was confirmed by TLC. The solvent
was removed under reduced pressure, and the residue recrystalised from MeCN
to afford the diimine 54b as a yellow powder (0.9 g, 80%). NaBH4 (0.27 g, 7.1
mmol) was then added to a solution of the diimine 54b in MeOH (10 mL), and the
mixture was boiled under reflux for 30-40 min. Ice was then added to the reaction
mixture to quench the reaction, precipitating, as a pale yellow powder, 1-[2-(2-
benzimidazolyl)ethyl)dibenz[c,ejperhydroazepine 61b (0.49 g, 65%) (Found: MH+,
340.1814. C23H21N3 requires MH, 340.1814), mp 184-186 °C; vmax(KBr/cm-1) 3174
(NH); 5H (400 MHz; MeOH-d4) 3.10 (2H, m, NHCH2CH2), 3.23 (2H, t, NHCH2CH2),
3.50 (4H, s, CH2NHC~C~), 7.17-7.21 (2H, m, ArH), 7.34-7.41 (4H, m, ArH), 7.44-
-. - 7.48 (2H, m, ArH), 7.49-7.52 (4H, m, ArH); 5d100 MHz; MeOH-d4)t 28.2
(NHCH2CH2), 54.4 (NHGH2CH2), 56.0 (CH2NHCH2CH2), 115.5, 123.4, 128.8,
129.1,129.8,131.2,134.7,139.4,142.5 and 154.7 (ArC).
Experimental 164
Attempted method 2.
Following the procedure described for the attempted preparation of 2,2'-bis{[2-(4-
imidazolyl)ethylamino]methyl}biphenyI55e (method 2), a stirred mixture of 2,2'-bis
{[2-(2-benzimidazolyl)ethylamino]carbonyl}biphenyl 55b (0.50 g, 0.95 mmol) and
LiAIH4 (0.72 g, 19 mmol) was boiled under reflux in dry THF (50 mL) for 55 h under
N2. 1H NMR and IR spectroscopy of the material obtained after work-up indicated
that the desired product had not been obtained.
Attempted method 3.
A mixture of 2,2'-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}biphenyl 55b (1.0
g, 1.9 mmol) and Raney nickel (0.33 g) in absolute EtOH (60 mL) was stirred under
H2 for 48 h at room temperature. The reaction mixture was filtered through a celite
pad to remove the Raney nickel, which was quenched with HCI. The filtrate was
evaporated to dryness under reduced pressure. The residue was vacuum dried,
and analysis by 1 H NMR and IR spectroscopy indicated that this reaction was also
unsuccessful.
Attempted method 4.
A solution of 2,2' -bis{N-[2-(2-benzimidazolyl)ethyl]-N-benzamidol1lethyl}biphenyl
S3 (0.80 g, 1.1 mmol) in HCI (6N; 15 mL) was boiled under reflux for 14 h. The
reaction mixture was washed with Et20, basified with NaOH (10N) and then
extracted with CHCI3. The CHCI3 extracts were combined and then dried with
anhydrous MgS04. The CHCI3 was removed under reduced pressure to yield an
off-white powder, 1H NMR spectroscopy of which, showed that the reaction had
been unsuccessful.
2, 2'-Bis-{[2-( 4-imidazolyl)ethylaminojmethyl}biphenyl 5Se
-. - Attempted method 1.
Biphenyl-2,2'-dicarbaldebyde 48 (0.72 g, ~.4 mmol) was added to a solution of
histamine 53 (0.75 g, 6.8 mmol) in CHCI3 (100 mL), and the resulting solution
Experimental 165
boiled under reflux for 6 h, using a modified Dean-Stark apparatus to remove H20.
The solvent was removed under reduced pressure to yield a glassy yellow solid
shown, by 1H NMR spectroscopy, to be the impure diimine 54e (1.34 g, 99%)
[vmax(KBr/cm-1) 1650 (C=N)}. The crude product (1.00 g, 1.2 mmol) was then
dissoved in methanol (10 mL), and NaBH4 was added in portions. The resulting
mixture was boiled under reflux for 40 min. before adding ice to quench the
reaction. The precipitated product was washed with Et20 to afford, as a white
powder, 1-[2-(4-imidazo/y/)ethyljdibenz[c,ejperhydroazepine 61e (0.32 g, 33%), mp
149-151°C (Found: MH+, 290.165729. C1Ji19N3 requires, MH 290.1657;
vmax(KBr/cm-1) 3413 (NH); OH(400 MHz; MeOH-d4) 2.89 (2H, m, NCH2CH2), 2.95
(2H, m, NCH2CH2), 3.46 (4H, s, 2 x CH2), 6.83-6.87 (1 H, m, ArH), 7.37-7.44 (4H,
m, ArH), 7.45-7.58 (4H, m, ArH),7.59-7.63 (1H, m, ArH); Od100 MHz; MeOH-d4)t
56.08 (2x CH2), 56.35 (NCH2CH2), 128.77-129.0,129.6,131.1,135.2,136.0 and
142.5 (ArC).
Attempted method 2.
2,2'-Bis{[2-(4-imidazolyl)ethylamino]carbonyl}biphenyl 55e (0.80 g, 1.8 mmol) was
added in portions to a suspension of LiAIH4 (0.35 g, 9.2 mmol) in dry THF (40 mL),
and the stirred mixture was boiled under reflux for 8 h under N2 . Aqueous NaOH
(4M, 25 mL) was added to the reaction mixture, which was then stirred oljernight
to ensure quenching of the excess L.:iAIH4. The precipitated solid was filtered off
and washed with THF.1f The filtrate and the washings were combined and
evaporated to dryness under reduced pressure. 1H NMR and IR analysis of the
vacuum-dried residue indicated that the reaction was unsuccessful.
N-[(2-Benzimidazo/y/)ethy/]benzamide 62
A mixture of benzoic acid (1.00 g, 8.19 mmol), COl (2.16 g, 13.3 mmol) and 2-(2-
aminoethyl)benzimidazole (1.32 g, 8.19 mmol) in DMF (20 mL) was stirred for 2.5
_. - d following the procedure used for the preparation of 2,2'-bis{[2-(2-
pyridyl)ethylamino]carbonyl}biphenyl 55a. The pale pink powder, which
Experimental 166
precipitated out, was filtered off and washed with aqueous Na2C03 (1 M; 50 mL) to
give N-[(2-benzimidazo/y/)ethy/]benzamide 62 (1.58 g, 73%), mp >250°C (from
DMF-H20) (Found: MH+, 266.1294. C1sH1SN30 requires, MH 266.1293);
vmaiKBr/cm-1) , 3305 (NH), 3176 (amide NH),1638 (CO); oH(400 MHz; DMSO-d6)
3.09 (2H, t, NHCH2CH2), 3.73 (2H, m, NHCH2C~) ),7.12 (2H, m, ArH), 7.49 (5H,
m, ArH), 7.84 (2H, d, ArH), 8.63 (1H, m, amide NH), 12.50 (1H, s, NH); od100
MHz; DMSO-d6)t 28.7 (NHCH2CH2) , 37.9 (NHCH2CH2 ), 121.0, 127.0, 128.1,
131.0, 134.4 and 152.7 (ArC) and 166.2 (CO).
2, 2'-Bis-{N-[2-(2-benzimidazo/yl)ethyl]benzamidomethyl}biphenyl 63
To a stirred suspension of NaH (50% dispersion in oil, pre-washed with dry DMF
under N2; 0.19 g, 3.2 mmol) in dry DMF (10 mL), was added N-[(2-
benzimidazolyl)ethyl]benzamide 62 (0.78"'9,2.9 mmol), and the resulting mixture
was boiled under reflux for 1.5 h under N2. 2,2'-Bis-(bromomethyl)biphenyl (0.50
g, 1.5 mmol) was then added and stirring was continued at room temperature
under N2 for 2.5 d. The reaction mixture was heated for 2 h before working up. The
DMF was removed under reduced pressure before adding H20 to the residue. The
precipitated solid was filtered off, washed with H20 and recrystallised from DMF
H20 to give, as an off-white solid, 2,2'-bis-{N-[2-(2-benzimidazclyl)ethyl]benz
amidomethyl}biphenyl63 (1.01 g, 97%), mp >250 °C (Found: MH+, 709.329087.
C4sH40Ns02 requires, MH 709.329099); vmax(KBr/cm-1) 1638 (CO); OH(400 MHz;
DMSO-d6) 2.89 (4H, s, CH2C~NC~), 3.64 (4H, m, C~CH2NC~), 5.10-5.24 (4H,
m, CH2CH2NCH2), 6.67 (2H, d, ArH), 7.12 (4H, t, ArH), 7.06-7.17 (4H, m, ArH),
7.20-7.27 (4H, m, ArH), 7.27-7.34 (2H, m, ArH), 7.34-7.43 (6H, m, ArH), 7.45-7.50
(2H, m, ArH), 7.61 (2H, d, ArH) , 7.71 (4H, d, ArH) , 8.59 (2H, s, NH); oc(100 MHz;
DMSO-d6) 26.7 (CH2C~NC~), 37.3 (C~C~NC~), 44.6 (C~C~NC~), 110.0,
118.5,121.3,121.8,126.2,126.9,127.6,128.0, 128.3,129.7,130.9,134.17,134.2,
135.1,138.0,142.2 and 103.1 (ArC) and 166.2 (CO).
Experimental 167
3.2.2 1,1 O-Phenanthroline-based ligands
1, 1 O-Phenanthroline-2, 9-dicarbaldehyde 65145
A mixture of neocuproine 64 (3.0 g, 14 mmol) and Se02 (7.5 g) in dioxan (200 mL)
was boiled under reflux for 2 h, and then filtered through celite while hot. The
filtrate was cooled on ice, and the crude dialdehyde (2.5 g, 73%) separated from
the cold filtrate as a yellow powder. Recrystallisation from THF gave, as yellow
crystals, 1,1 0-phenanthroline-2,9-dicarbaldehyde 65, mp 231-232°C(Iit. 145 231-
232°C); vmax(KBr/cm-1) 1720 (CO); ~ (DMSO-q,) 8.28 (2H, s,Ar-H), 8.31 (2H, d, Ar
H), 8.79 (2H, d, Ar-H), 10.36 (CHO).
1, 10-Phenanthroline-2,9-dicarboxylic acid 66145
A solution of 1,1 0-phenanthroline-2,9-dicarbaldehyde 65 (0.5 g, 2.1 mmol) and
80% HN03 (10mL) was boiled under reflux for 3 h. After cooling, the solution was
poured onto ice and the precipitated solid recrystallised from MeOH to give, as a
yellow solid, 1, 10-phenanthroline-2,9-dicarboxylic acid 66 (0.40-g, 65%), mp 238°C
(lit. 145 238°C); vmaiKBr/cm-1) 1724 (CO), 2800-3700 (COOH).
2,9-Bis{[2-(2-pyridy/)ethyljaminomethyl}-1, 10-phenanthroline 6Sa ,
To a suspension of 1, 10-phenanthroline-2,9-dicarbaldehyde 65 (1.12 g, 4.7'mmol)
in CHC13 (50 mL), was added 2-(2-aminoethyl)pyridine 51 (1.0 mL, 8.2 mmol), and
the resulting mixture boiled under reflux for 2 h. The completion of the reaction was
confirmed by IR spectroscopy. The CHCI3 was removed under reduced pressure
to yield the crude diimine 67a as a dark-brown oil (2.11 g, 95%), which became
semi-solid upon standing at room temperature. 1 H NMR and IR analysis confirmed
that the reaction had been successful. The semi-solid diimine 67a (1.0 9, 2.3
mmol) was dissolved in dry MeOH (10 mL), and NaBH4 (0.17 g, 4.51 mmol) was
added to the solution in portions. The resulting mixture was then reflLJxed for
-. -2.5 h, after which the reaction was quenched with ice. The product was extracted
with CHCI3 (4 x 40 mL) and the combined extracts were dried over anhydrous
MgS04. The CHCI3 was removed under reduced pressure to yield, as a brown oil,
- .
Experimental 168
which became a semi-solid upon standing at room temperature, 2,9-bis{[2-(2-
pyridy/)ethyljaminomethyl}-1,10-phenanthroline 68a (0.71 g, 71%) (Found: M+,
448.2371. C28H2SNe requires M, 448.2375; vmax (thin film/cm-1) 3300 (NH) and 1590
(C=N); oH(400 MHz; CDCI3) 3.08 (4H, t, CH2NHCH2CH2), 3.17 (4H, t,
CH2NHCH2CH~, 4.32 (4H, s, CH2NHCH2CH2), 7.06 (2H, t, ArH), 7.19 (2H, t,
ArH), 7.54 (2H, td, ArH), 7.72 (2H, d, ArH), 8.14 (2H, d, ArH), 8.49 (2H, t,
ArH); oC<100 MHz; CDCI3) 38.5 (CH2CH2NHCH2), 49.3 (CH2CH2NHCH2), 56.0
(CH2CH2NHCH2), 121.2, 122.0, 123.3, 125.8, 127.7, 136.3, 136.5, 145.2, 149.3,
160.3 and 160.8 (ArC).
2, 9-Bis-{[2-(2-benzimidazo/y/)ethyljaminomethyl}-1, 10-phenanthro/ine 68b
N~N H '~h
HN~_'
A solution of 2-(2-aminoethyl)benzimidazole 52 (0.74 g, 4.7 mmol) in MeOH (10
mL) was added dropwise to a ·hot solution of 1,10-phenanthroline-2,9-
dicarbaldehyde 65 (0.54 g, 2.3 mmol) in MeOH (30 mL). The resulting solution was
boiled under reflux for 1.5 h, completion of the reaction being confirmed by IR
spectroscopy. After removing the solvent under reduced pressure, the crude
diimine 67b was obtained as a glassy orange-brown solid. NaBH4 (0.29 g, 7.6
mmol) was then added in portions to a solution of the crude diimine 67b (1.0 g, 1.9
mmol) in MeOH (20 mL). After boiling the mixture under reflux for 45 min., the
reaction was quenched-with ice precipitating, as an orange-yellow powder, 2,9-
- bis{[2-(2-benzimidazo/y/)ethy/aminojmethyl}-1, 10-phenanthroline 68b, (0.40 g,
40%), mp >250°C (Found: MH+, 527.26~2. C32H30NS requires MH, 527.2672);
oH(400 MHz; DMSO-d6) 3.0-3.12 (8H, m, CH2NHCH2CH2), 4.16 (4H, s,
Experimental 169
CH2NHC~C~), 6.9-7.3 (4H, m, ArH), 7.30-7.60 (4H, br s, ArH), 7.87 (2H, d, ArH),
7.91 (2H, s, ArH), 8.41 (2H, d, ArH), 12.31 (2H, br s, NH); 5d100 MHz; OMSO-d6)t
29.3 (CH2NHCH2CH2), 47.2 (CH2NHCH2CH2), 55.0 (CH2NHCH2CH2), 120.9,
121.6, 125.7, 127.3, 136.4,144.4,153.8 and 160.8 (ArC).
Attempted Method
A stirred mixture of 2,9-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}-1, 1 0-
phenanthroline 69b (1.0 g, 1.7 mmol) and LiAIH4 (0.66 g, 17 mmol) in dry THF (40
mL) was boiled under reflux for 8 h under N2, and worked-up following the
procedure described for the attempted preparation of 2,2'-bis{[2-( 4-imidazolyl)
ethylaminojcarbonyl}bipheny/55e (Method 2). 1H NMR and IR analysis of the
isolated material revealed that the reaction had been unsuccessful.
2, 9-Bis{[2-( 4-imidazo/y/)ethy/jaminomethyl}-1, 10-phenanthroline 68c
Attempted Method
To a suspension of LiAIH4 (0.36 g, 9.6 mmol) in THF (20 mL), 2,9-bis{[2-(4-
imidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline 6ge (0.80 g, 1,9 mmol) was
added in portions. The resulting mixture was boiled under reflur for 9 h, and
worked-up following the procedure described for the attempted preparation,of 2,2'
bis{[2-(2-imidazolyl)ethylamino]carbonyl}biphenyl 55e (Method 2). IR and 1 H NMR
spectra of the isolated material indicated that the reaction had not been
successful.
2, 9-Bis{[2-(2-pyridy/)ethy/aminojcarbony/}-1, 10-phenanthro/ine 69a
A solution of 1, 10-phenanthroline-2,9-dicarboxylic acid 66 (0.48 g, 2.05 mmol) in
dry OMF (10 mL) was heated to 40-S0°C. COl (1.07 g, 13.1 mmol) was added in
portions and the resulting-mixture stirred until effervescence ceased. 2-(2-Amino-
-. - ethyl)pyridine 51 (0.S5 mL, 4.S mmol) was then added at room temperature, and
the reaction mixture was stirred for 4.S days.<The reaction was quenched with H20
(7 mL), and the solvents were removed under reduced pressure at 90°C. Aqueous
Experimental 170
Na2C03 (1 M, 50 mL) was added to the residue, and the resulting precipitate was
filtered off to give, as a light-brown powder, 2,9-bis{[2-(2-pyridyl)ethy/amino]
carbony/}-1,10-phenanthroline 69a (0.78 g, 73%), mp 55-57°C (from OMF-H20)
(Found: M+, 476.1960. C2sH24N602 requires M, 476.1961); vmax(KBr/cm-1) 3256
(NH) and 1651 (CO); oH(400 MHz; OMSO-d6) 3.18 (4H, t, NHCH2CH2),3.75-3.85
(4H, m, NHCH2CH2), 7.20 (2H, dd, ArH), 7.35 (2H, d, ArH), 7.69 (2H, t, ArH), 8.18
(2H, s, ArH), 8.44 (2H, d, ArH), 8.49 (2H, d, ArH), 8.73 (2H, d, ArH), 9.56 (2H, br
s, NH); OcC100 MHz; OMSO-ds) 36.9 (NHC~C~), 39.0 (NHCI1 CI1), 120.8, 121.6,
123.0,127.7,130.1,136.7,138.1,143.6,148.8,149.4 and 159.0 (ArC) and 163.7
(CO).
2, 9-Bis{[2-(2-benzimidazo/y/)ethy/amino]carbony/}-1, 10-phenanthroline 69b
A mixture of 2-(2-aminoethyl)benzimidazole 52 (1.46 g, 9.0 mmol), 1,10-
phenanthroline-2,9-dicarboxylic acid 66 (0.96 g, 4.1 mmol) and COl (2.13 g, 13.1
mmol) in dry OMF (20 mL) was stirred for 26 h, using the procedure described for
the synthesis of 2,9-bis-{[2-(2-pyridyl)ethylamino]carbonyl}-1,1 O-phenanthroline
69a. Work-up afforded as a light-brown solid, 2,9-bis{[2-(2-benzimidazo/y/)
ethy/amino]carbony/}-1,10-phenanthro/ine 69b (1.53 g, 61 %), mp >250°C (from
OMF-H20) (Found: M+, 554.2179. ~~~ q requires M, 554.2179)i 'fuax (KBr/cm1 )
3145 and 3323 (NH) and 1630 (CO); oH(400 MHz, OMSO-d6) 3.29/(4H, t,
NHCH2CH2), 3.90 (4H, dd, NHCH2C~), 7.06-712 (4H,m, ArH), 7.41:'7.49 (4H, m,
ArH), 8.15 (2H, s, ArH), 8.45 (2H, d, ArH), 8.71 (2H, d, ArH), 9.71 (2H, br s, amide
NH); oc(100 MHz, OMSO-ds)t28.2 (NHC~C~), 37.8 (NHC~CH2)' 120.8, 121.2,
127.8, 130.1, 138.1, 143.5, 149.4 and 152.8 (ArC) and 163.6 (CO).
2, 9-Bis-{[2-( 4-imidazo/y/)ethy/amino]carbony/}-1, 10-phenanthroline 69c
Following the procedure described for the preparation of 2,9-bis{[2-(2-pyridyl)
ethylamino]carbonyl}-1, 1Q-phenanthroline 69a, a mixture of histamine 53 (1.00 g,
_ . 9.0 mmol), 1, 10-phenanthroline-2,9-dicarboxylic acid-66 (0.96 g, 4.1 mmol) and
COl (2.13 g, 13.1 mmol) in dry OMF (15 mL) was stirred for 55 h. Work-up <
afforded, as a light-brown solid, 2,9-bis{[2-(4-imidazo/y/)ethyJamino]carbonyl}-1, 10-
Experimental 171
phenanthroline 69c (1.18 g, 63%), mp 122-124°C (from DMF-H20) (Found M+,
454.1851. C24~Ns~ requires M, 454.1866); vmax(KBr/cm-1) 3130 and 3297 (NH)
and 1649 (CO); oH(400 MHz, DMSO-d6) 2.93 (4H, t, NHCH2CH2), 3.68 (4H, dd,
NHCH2CH2), 6.91 (2H, s, ArH), 7.57 (2H, s, ArH), 8.17 (2H, s, ArH), 8.45 (2H, d,
ArH), 8.68 (2H, d, ArH), 9.55 (2H, t, amide NH); oc(100 MHz, DMSO-de)t 26.8
(NHCH2CH2), 39.3 (NHCH2CH2), 120.8, 127.7, 130.1, 134.7, 138.0, 143.6 and
149.5 (ArC) and 163.7 (CO).
J
Experimental 172
3.2.3 Schiff base ligands prepared from diketones and 2-(2-aminoethyl)
pyridine
N, N' -Bis[2-(2-pyridyl)/ethyl]pentane-2, 4-diimine 76§
Acetylacetone 70 (0.41 mL, 4.0 mmol) was dissolved in CHCI3 (5 mL). To this
solution, 2-(2-aminoethyl)pyridine 51 (0.95 mL, 7.9 mmol) was added and the
resulting mixture was boiled under reflux for 2 h and then stirred at room
temperature for 48 h. The completion of the reaction was confirmed by TLC. The
solvent was removed under reduced pressure and the residue was purified by
chromatography [flash chromatography on silica; elution with MeOH-benzene
EtOAc (1 :4:4)] to afford, as a brown oil, N,N'-bis[2-(2-pyridy/)ethyl]pentane-2,4-
diimine 76 (0.70 g, 57%) (Found: MH+, 309.2079. C19H24N4 requires MH,
309.2079); oH(400 MHZ; CDCI3) 1.82 (3H,cs, CH3), 1.95 (3H, s, CH3), 3.01 (4H, t,
NHCH2CH2), 3.65 (4H, q, NHCH2CH2), 4.89 (1 H, s, NHC=CH), 7.09-7.14 (2H, m,
ArH), 7.16 (2H, d, ArH), 7.58 (2H, t, ArH), 8.52 (2H, d, ArH), 10.85 (1 H, br s, 0 20
exchangeable, NH); od100 MHz; CDCI3) 18.6 (CH3), 28.7 (CH3), 38.8
(NHCH2CH2), 42.6 (NHCH2CH2), 95.2 (NHC=CH), 121.7, 123.6, 136.5, 149.5,
158.2, 162.8 and 194.7 (ArC, NHC=C and C=N).
3-methyJ-N, N' -bis[(2-(2-pyridyJ)ethyl]pentane-2, 4-diimine 77§
To a solution of 3-methyl-2,4-pentanedione 71 (0.41 mL, 3.5 mmol) in CHCI3 (5
mL), 2-(2-aminoethyl)pyridine 51 (0.87 mL, 7.0 mmol) was added, and the reaction
mixture was boiled under reflux for 2 h and then stirred at room temper~ture for 3
h. Completion of the reaction was confirmed by TLC. The CHCI3 was evaporated
off under reduced pressure. Purification of the residue by chromatography [(flash
chromatography on silica gel; elution with MeOH-benzene-EtOAc (1 :4:4)] yielded,
as a brown oil, 3-methyl-N,N'-bis(2-(2-pyridyl)ethyl]pentane-2,4-diimine 77 (0.48
g, 43%); (Found: MH+, 323.2235. C2oH26N4 requires MH, 323.2236); oH(400 MHz;
-. - CDCls) 1.78 (3H, s, CHs), 1.90 (3H, s, CH3), 2.08 (3H, s, CH3), 3.01 (4H, t,
NHCH2CH2), 3.66 (4H, q, .NHCH2CH2), 7.1 t (2H, m, ArH), 7.18 (2H,d, ArH), 7.58
§ In CDCls• the compound exists as a monoimino tautomer.
Experimental 173
(2H, td, ArH), 8.52 (2H, d, ArH), 12.00 (1H, br s, NH); oeC100 MHz; CDCI3) 14.7
(CH3)' 15.0 (CH3)' 28.4 (CH3), 39.0 (NHCH2CH2), 43.1 (NHCH2CH2), 98.1
(NHC=C), 121.6, 123.6, 136.5, 149.5, 158.5, 161.9 and 194.6 (ArC, NHC=C and
C=N).
3-Ethy/-N,N'-bis[2-(2-pyridy/)ethyljpentane-2,4-diimine 78§
A solution of 2-(2-aminoethyl)pyridine 51 (1.50 mL, 12.5 mmol) and 3-ethyl-2,4-
pentanedione 72 (0.84 mL, 6.2 mmol) in CHCI3 (5 mL) was boiled under reflux for
1 h. The reaction was shown to be complete by TLC. After removal of the solvent
under reduced pressure, the residue was chromatographed [flash chromatography
on silica; elution with MeOH-benzene-EtOAc (1 :4:4)J to give, as a brown oil, 3-
ethy/-N,N'-bis[2-(2-pyridy/)ethyljpentane-2,4-diimine 78 (0.73 g, 35%) (Found: MH+,
337.2392. C21H2SN4 requires MH, 337.2392); oH(400 MHz; CDCI3) 0.94 (3H, t,
CH 2CH3), 1.90 (3H, s, CH3), 2.10 (3H, s, CH3), 2.20 (2H, q, CH2CH3), 3.01 (4H,
NHCH2CH2), 3.65 (4H, q, NHCH2CH2), 7.10 (2H, t, ArH), 7.17 (2H, d, ArH), 7.57
(2H, t, ArH), 8.52 (2H, d, ArH), 12.14 (1H, br s, NH); oeC100 MHz; CDCI3) 14.3
(CH2CH3), 15.5 (CH2CH3) ), 22.0 (CH3)' 27.3 (CH3)' 38.9 (NHCH2CH2), 43.1
(NHCH2CH2), 105.5 (NHC=CH), 121.6, 123.6, 136.5, 149.47 ,149.49, 158.5, 162.2
and 194.6 (ArC, NHC=C and C=N).
3-benzy/-2,4-pentanedione 73
A stirred solution of acetyl acetone 70 (0.82 mL, 8.0 mmol) in methanolic NaOMe
(79.9 mL, 8.0 mmol) was boiled under reflux for 1.5 h. Benzyl bromide (0.95 mL,
8.0 mmol) was then added to the mixture, and stirring continued at room
temperature for 2.5 d. The solvent was evaporated off under reduced pressure and
the residue extracted with EtOAc. This mixture was then gently heated and filtered.
Evaporation of the solvent under reduced pressure gave, as a pale yellow oil, 3-
benzyl-2,4-pentanedione-?3 (0.92 g, 61%) [oc(100 MHZ; CDCI3} 29.7 (CH2), 30.0
-. - (CH3)' 72.1 (CH), 126.0, 128.21, 128.42 , 140.9 (ArC) and 207.8 (CO)], which was
used without further purjfi.cation.
Experimental 174
3-Benzy/-N, N' -bis[2-(2-pyridy/)ethy/]pentane-2, 4-diimine 79§
To a solution of crude 3-benzyl-2,4-pentanedione 73 (0.59 g, 3.1 mmol) in CHCI3
(5 mL) was added 2-(2-aminoethyl)pyridine 51 (0.75 mL, 6.3 mmol), and the
resulting mixture was boiled under reflux for 2.5 h. After removal of the solvent
under reduced pressure, the residue was chromatographed [flash chromatography
on silica; elution with MeOH-EtOAc (1:8)] to give, as a brown oil, 3-benzy/-N,N'
bis[2-(2-pyridy/)ethyl]pentane-2,4-diimine 79 (0.35 g, 25%) (Found: MH+, 399.2548.
C26~N.t requires MH, 399.2549); ~(400 MHz;CDC6) 1.80 (3H, s, C~), 2.03 (3H,
s, CH3), 3.07 (4H, t, NHCH2CH2), 3.63 (2H, s, CH2Ph), 3.71 (4H, q, NHCH2CH2),
7.10 (2H, d, ArH), 7.11-7.18 (2H, m, ArH), 7.19-7.26 (4H, m, Ar-H), 7.61 (2H, td,
ArH), 8.54 (2H, d, ArH), 12.36 1 H, br s, NH); od100 MHz; CDCI3) 15.0 (CH3)'
27.9 (CH3), 34.6 (C~Ph), 39.0 (NHC~CH2)' 43.2 (NHCH2C~), 101.4 (CC~Ph),
121.7,123.8,125.7,127.5,128.4,136.5,141.7,149.6, 158.4, 163.7 and 195.4
(ArC, NHC=C and C=N).
1, 3-Diphenyl-N, N'-bis[2-(2-pyridyl)ethyl]propane-1, 3-diimine 80§
2-(2-Aminoethyl)pyridine 51 (0.85 mL, 7.1 mmol) was added to a solution of
dibenzoylmethane 74 (0.80 g, 3.6 mmol) in CHCI3 (10 mL), and the reaction
mixture was boiled under reflux for 6 d. Completion of the reaction was confirmed
by TLC. After removing the solvent under reduced pressure, the r~sidual material
was chromatographed (flash chromatography on silica gel; elution with BOAc) to
afford, as a yellow-green oil, 1,3-dipnenyl-N,N'-bis[2-(2-pyridy/)ethy/]propane-1,3-
diimine 80 (0.90 9, 58%) (Found: MH+, 433.2392. C29H28N4 requires MH,
433.2392); 0H(400 MHz; CDC~) 3.02 (4H, t, NHC~CH2)' 3.64 (4H, q, NHCH2C~),
5.69 (1H, s, NHC=CH), 7.09-7.17 (4H, m, ArH), 7.26-7.28 (4H, m, ArH), 7.33-7.43
(12H, m, ArH), 7.53-7.60 (2H, m, ArH), 7.30-7.87 (4H, m, ArH), 8.49 (2H, d, ArH),
11.41 (1 H, br s, NH); od100 MHz; CDCI3) 39.4 (NHCH2CH2), 44.4 (NHCH2CH2),
93.6 (NHC=CH),121.6, 123.6, 127.0, 127.6, 128.1, 128.5, 129.4, 130.6, 135.6,
136.4, 140.35, 149.5, 158.2, 166.7 and 188.4 (ArC, ~HC=C and C=N) ...
Experimental 175
1-Pheny/-N,N' -bis[2-(2-pyridy/)ethy/]butane-1, 3-diimine 81 §
To a solution of benzoyl acetone 75 (0.80 g, 4.9 mmol) in CHCI3 (10 mL) was added
2-(2-aminoethyl)pyridine 51 (1.2 mL, 9.9 mmol), and the reaction mixture was
boiled under reflux for 76 h. The reaction was monitored by TLC and completion
was confirmed. The CHCI3 was removed under reduced pressure, and the residue
was chromatographed [flash chromatography on silica; elution with MeOH-CHCI3-
hexane (1 :4: 1)] to afford, as a light-brown oil, 1-pheny/-N,N'-bis[2-(2-pyridy/)
ethyl]butane-1,3-diimine 81 (0.77 g, 43%) (Found: MH+, 371.2235. C24H2SN4
requires MH, 371.2236); oH(400 MHz; CDCI3) 1.97 (3H, s, CH3), 3.09 (4H, t,
NHCH2CH2), 3.76 (4H, q, NHCH2C~), 5.60 (1H, s, NHC=CH), 7.14 (2H, m, ArH),
7.20 (2H, d, ArH), 7.33-7.43 (3H, m, ArH), 7.59 (2H, td, ArH), 7.82 (2H, m, ArH),
8.56 (2H, d, ArH), 11.49 (1 H, br s, NH); od100 MHz; CDCI3) 19.2 (CH3), 38.8
(NHCH2CH2), 42.9 (NHCH2CH2), 92.1 (f\!HC=CH), 121.7, 123.7, 126.8, 128.0,
130.3,136.5,140.4,149.6,158.2,164.7 and 187.7 (ArC, NHC=C and C=N).
N, N' -Bis[2-(2-pyridy/)ethyl]hexane-2, 5-diimine 84
2-(2-Aminoethyl)pyridine 51 (0.84.mL, 7.0 mmol) was added to a solution of
acetonylacetone 82 (0.41 mL, 3.5 mmol) in CHCI3 (5 mL), and the resulting mixture
was boiled under reflux for 2.5 d, completion of the reaction bein~ confirmed by
TLC. The solvent was removed under reduced pressure, and the residual rvaterial
was chromatographed [flash chromatography on silica gel; elution with MeOH
EtOAc(1 :8)] to give, as a brown oil, N,N'-bis[2-(2-pyridy/)ethyl]hexane-2,5-diimine
84 (0.68 g, 60%) (Found: MH+, 323.2236. C2oH2SN4 MH, requires 323.2236);
vmax(NaCllcm-1) 1652 (C=N); ~(400 MHz; 2.13 (6H, s, CI1), 3.06 (4H, t, CIiC~ N),
4.13 (4H, t, CH2CH;N), 5.74 (4H, s, N=CCH2), 6.92 (2H, d, ArH), 7.12-7.18 (2H, m,
ArH), 7.55 (2H, td, ArH), 8.57 (2H, d, ArH); od100 MHz; CDCI3) 12.3 (CH3), 39.6
(CH2C~C=N), 43.4 (CH2CH2C=N), 105.2 (NCH2CH2), 121.7, 123.6, 127.4, 136.5
(ArC), 149.5 and 158.6 (ArC and C=N).
Experimental 176
1, 5-0ipheny/-N, N'-bis[2-(2-pyridy/)ethy/]pentane-1, 5-diim ine 85
Attempted preparation
1 ,3-Dibenzoylpropane 83 (0.8 g, 3 mmol) and 2-(2-aminoethyl)pyridine 51 (0.76
mL, 6.3 mmol) were added to CHCI3 (10 mL), and the resulting mixture was boiled
under reflux for ca. 3.5 d. Completion of the reaction was confirmed by TLC. The
solvent was evaporated under reduced pressure, and the residual material was
chromatographed [flash chromatography on silica gel; elution with MeOH-benzene
hexane (1 :4:1)] to yield a red-brown oil, 1H NMR analysis of which indicated the
absence of the required product.
J
Experimental 177
3.2.4 The Baylis-Hillman approach to ligand synthesis
3-Hydroxy-2-methy/ene-3-(2-pyridy/)propanenitrile 92149
A mixture of pyridine-2-carbaldehyde 91 (2.95 g, 28 mmol), acrylonitrile (1.54 g,
29 mmol) and DABCO (0.15 g, 1.3 mmol) in CHCls (2mL) was allowed to stand at
room temperature for 4d. The solvent was evaporated, and the residue
chromatographed (flash chromatography on silica gel; elution with EtOAc) to
afford, as colourless crystals, 3-hydroxy-2-methylene-3-(2-pyridyl)propanenitrile
92 (4.09 g, 91 %), mp 65-66°C (from hexane) (1it.149 66-6JOC); vmaithin film/cm-1)
3220 (OH) 2227 (CN) and 1600 (C=N); 0H(CDCls) 5.28 (2H, 2 x overlapping s,
CHOH and OH), 5.99 and 6.15 (2H, 2 x s, C=CH2), 7.23 (1 H, m, 5'-H), 7.38 (1 H,
d, 3'-H), 7.71 (1 H, m, 4'-H) and 8.49 (1 H, m, 6'-H).
3-Acetoxy-2-methyJene-3-(2-pyridyJ)propanenitrile 93149
A mixture of A~O (5mL) and 3-hydroxy-2-methylene-3-(2-pyridyl)propanenitrile 92
(1.0 g, 6.2 mmol) was heated at 100°C for 30 min. in a flask fitted with a reflux
condenser and drying tube. After cooling, the mixture was poured on to NaHCOs-
ice and, after stirring for 30 min., extracted with Et20 (2 x 100 mL). The combined
extracts were washed with aqueous NaHCOs (100 mL) and dried over anhydrous ~
MgS04. The solvent was removed under reduced pressure, and the resid,ue was
chromatographed [flash chromatography on silica gel; elution with EtOAc-hexane
(5:5)J to give, as a yellow oil, 3-acetoxy-2-methylene-3-(2-pyridyl)propanenitrile 93
(0.75 g, 60%); vrnax(thin film cm-1) 2226 (CN) and 1748 (CO); oH(400 MHZ; CDCls)
2.21 (3H, s, CH3CO), 6.14 and 6.17 (2H, 2 x s, C=CH2 ), 6.38 (1 H, s, CHOAc), 7.28
(1H, m, 5'-H), 7.48 (1H, d, 3'-H), 7.76 (1H, m, 4'-H), 8.60 (1H, m, 6'-H).
2-[(1-Piperidiny/)methyJ]-3-(2-pyridy/)prop-2-enenitri/e 96
Piperidine (0.64 g, 7.6 ml]]ol) was added to a solution of 3-acetoxy-2-methylene-3-
_. _ (2-pyridyl)propanenitrile 93 (1.5 g, 6.9 mmol) in THF (5mL), and the resulting
mixture was allowed to stand for 4 d at room temperature. Work-up, following the ~ -- .;
procedure described for preparing 3-(2-pyridy/)-1-[1-pyrro/idiny/)methyl]prop-2-
enenitri/e 97, gave, as a brown oil, 2-[(1-piperidiny/)methyl}-3-(2-pyridy/)-prop-2-
Experimental 178
enenitrile 96 (1.08 g, 69%) (Found: MH+, 228.1500. C14H17N3 requires MH,
228.1500); vmax<thin film/cm-1) 2217 (CN); oH(400 MHz; CDCI3) 1.40-1.47 (2H, m,
CH2), 1.55-1.65 (4H, m, 2 x CH2), 2.49 (4H, m, 2 x CH2), 3.29 (2H, d, CH2), 7.23
(1 H, CH=C), 7.28 (1 H, m, ArH), 7.73 (1 H, td, ArH), 7.86 (1 H, d, ArH), 8.65 (1 H, d,
ArH); od400 MHz; CDCI3) 24.1 (CH2), 25.9 (CH2), 54.2 (CH2), 62.9 (CH2), 112.9
(CH=C), 118.2 (CN), 123.5 (ArC), 124.1 (ArC), 136.7 (ArC),144.0 (CH=C), 149.9
(ArC) and 152.1 (ArC).
3-(2-Pyridy/)-2-[1-pyrro/idiny/)methy/]prop-2-enenitrile 97
A mixture of pyrrolidine (0.18 g, 2.5 mmol) and 3-acetoxy-2-methylene-3-(2-
pyridyl)propanenitrile 93 (0.50 g, 2.3 mmol) in THF (2mL) was allowed to stand at
room temperature for 4 d. The solvent was removed under reduced pressure, and
the residue was washed with NaOH (50 mL~ and extracted with CHCI3 (3 x 40 mL).
The combined extracts were dried with anhydrous MgS04, and the solvent was
evaporated under reduced pressure to give, as a brown oil, 3-(2-pyridy/)-2-[1-
pyrro/idiny/)methy/jprop-2-enenitri/e 94 (0.39 g, 80%) (Found: MH+, 214.1344.
C13H1sN3 requires MH, 214.1344); vmax(thin film/cm- 1) 2217 (CN); oH(400 MHz;
CDCI3) 1.81 (4H, s, 2 x CH2), 2.62 (4H, s, 2 x CH2), 3.44 (2H, s, CH2), 7.25-7.40
(2H, m, ArH and CH=C), 7.73 (1H, t, ArH), 7.82 (1H, d, ArH), 8.6~ (1H, d, ArH);
od 400 MHz; CDCI3) 23.7 (CH2), 53.8 (CH2), 59.8 (CH2), 113.4 (CH=C)! 118.2
(CN), 123.5 (ArC), 124.1 (ArC), 136.7 (ArC), 143.6 (CH=C), 149.8 (ArC) and 152.0
(ArC).
2, 10-Dicyano-1, 11-bis(2-pyridy/)-5, 8-diazaundeca-1, 11-diene 98
Attempted preparation
A mixture of 3-acetoxy-2-methy/ene-3-(2-pyridy/)propanenitri/e 93 (0.48 g, 7.3
mmol) and 1 ,3-diaminopropane (0.26 g, 3.7 mmol) in THF (6 mL) was allowed to
-. -stand at room temperature for 4 d. Completion of the reaction was confirmed by
TLC, and the THF was removed under reduced pressure. The residual dark-brown
oil was washed with aqueous NaHC03 (70 mL) and brine (60 mL). 1H NMR
Experimental 179
analysis of the fractions obtained by flash chromatography of the residue failed to
indicate the presence of the required product.
2,9-Bis(2-cyano-1-hydroxy-2-propenyl)-1, 10-phenanthroline 87
Attempted preparations
Method 1
A mixture of 1,10-phenanthroline-2,9-dicarbaldehyde 66 (1.0 g, 4.2 mmol),
acrylonitrile (0.46 g, 8.6 mmol) and DABCO (0.02 g, 0.4 mmol) in CHCI3 (8 mL)
was stirred at room temperature for 10 d. The CHCI3 was removed in vacuo and the
residue analysed by 1H NMR spectroscopy. The characteristic peaks for the
Baylis-Hillman product between 65.0-6.5 ppm were not observed in the spectrum.
Method 2
A mixture of acrylonitrile (0.94 g, 18 mmol), 1,10-phenanthroline-2,9-
dicarbaldehyde 66 (0.5 g, 2 mmol) and DABCO (0.02 g, 0.4 mmol) in CHCI3 (22
mL) was boiled under reflux for 40 min., followed by stirring at room temperature
for 7 d. After evaporating off the CHCI3, the residue was analysed by 1H-NMR
spectroscopy, but the characteristic peaks for the Baylis-Hillman product were not
observed.
Method 3
A mixture of acrylonitrile (0.94 g, 18 mmol), 1,1 0-phenanthr9Iine-2,9-
dicarbaldehyde 66 (0.5 g, 2 mmol) and DABCO (0.02 g, 0.4 mmol) in CHCI3 (22
mL) was stirred at room temperature for 7 d. After evaporating off the CHCI3, the
residue was analysed by 1 H NMR spectroscopy, but the characteristic peaks for
the Baylis-Hillman product were not observed.
-. -Method 4
1,10-Phenanthroline-2,9-diearbaldehyde 66 (~.O g, 4.2 mmol) was dissolved in hot
MeOH (110 mL) to give a clear yellow solution. DABCO (0.45 g, 9 mmol) and
Experimental 180
acrylonitrile (0.94 g, 18 mmol) were added to the hot solution, and the resulting
mixture was boiled under reflux for ca. 3.5 h. The MeOH was evaporated off under
reduced pressure and the residue analysed by 1 H NMR spectroscopy, which
indicated that the reaction had been unsuccessful.
J
Experimental 181
3.2.5 Macrocycle syntheses
The dibenzo macrocycle 99
A stirred mixture of 1,1 0-phenanthroline-2,9-dicarbaldehyde 66 (0.70 g, 3.0 mmol)
and 1 ,2-diaminobenzene (0.35 g, 3.0 mmol) in MeOH (85 mL) was boiled under
reflux for 5 min. The mixture was then stirred at room temperature for 12 h, during
which time, a yellow solid precipitated, which was filtered off to give, as a cream
powder, the dibenzo macrocycle 99 (0.56 g, 30%) mp 239-241°C (Found: MH+
616.2122. C4oH24Na requires MH, 616.2124); vmaiKBr/cm-1) 1619 (C=N).
The macrocycle 100
Attempted preparations
Method 1162
1 ,10-Phenanthroline-2,9-dicarbaldehyde 66 (0.70 g, 3.0 mmol) was dissolved in
MeOH (80 mL) by heating and stirring. The yellow solution was allowed to cool to
room temperature and was then added dropwise, during 40 min., to a solution of
1 ,2-diaminoethane MeOH (50 mL). The mixture was then stirred for 12 h at room
temperature. The MeOH was evaporated off in vacuo to afford a brown powder,
which was insoluble in DMSO, and clearly not the expected product.
Method 2
1,2-Diaminoethane (0.18 g, 3.0 mmol) was added to a hot solution ,af 1,10-
phenanthroline-2,9-dicarbaldehyde 66 (0.7 g, 3.0 mmol) in MeOH (70 ml), and the
resulting mixture was boiled under reflux for 2.5 h. The MeOH was removed under
reduced pressure to yield a brown powder, which was insoluble in DMSO, and was
not the expected product.
Experimental 182
3.2.6 Dendrimer-based ligands
Tris(2-cyanoethyl)nitromethane 102172
Acrylonitrile (3.98 g, 75 mmol) was added dropwise to a stirred solution of
nitromethane 101 (1.52 g, 24.9 mmol) and 40% aqueous Triton B (trimethylbenzyl
ammonium hydroxide) (0.25 g) in dioxan (2.50 g, 62.5 mmol) over a period of ca.
25 min. while maintaining the temperature of the exothermic reaction at 25-30°C
by external cooling. The reaction mixture was then allowed to stand at room
temperature for 18 h. Dilute HCI was used to neutralise (pH 7) the reaction mixture,
which was then extracted with an equal volume of dichloroethane. The extract was
washed with H20 (2.5 mL), and the dichloroethane evaporated off under reduced
pressure. The crystalline product (2.15 g, 39%) was recrystallised from EtOH to
give, as colourless prisms, tris(2-cyanoethyl)nitromethane 102, mp 107-
109°C(lit.172 mp 11~C); oc(100 MHZ; MeOH-d4) 12.7 (CH2CH2CN), 31.4 (CH2CN),
92.3 (CN02) and 119.7 (CN).
4-[2-Carboxyethyl)]-4-nitroheptanedioic acid 103172
Tris(2-cyanoethyl)nitromethane 102 (1.5 g, 6.8 mmol) was dissolved in
concentrated HCI (6.5 mL), and the resulting solution boiled under reflux for 45
min., and then cooled to 5°C. The white solid which precipitated out was ,'filtered
off, washed with cold H20 (4 x 15 mL) and dried in vacuo to yield 4-[2-
carboxyethyl)]-4-nitroheptanedioic acid 103 (1.25 g, 66%), mp 186-18rC (lit. 172 mp
186°C); vrnax(KBr/cm1) 1721 (C=O), 2500-3500 (OH); od100 MHZ; MeOH-d4 ) 29.4
(CH2CH2C02H), 31.5 (CH2C02H), 93.9 (CN02) and 175.6 (C=O).
4-Nitro-4-(3-hydroxypropyl)-1, 7-heptanedio/1 04172
To a stirred solution of the triacid, 4-[2-carboxyethyl)]-4-nitroheptanedioic acid 103
(1.0 g, 3.6 mmol) in dry TRF (50 mL) at O°C, a BH3-THF solution (1.0 M; 11.9 mL,
-. - 11.9 mmol) was added dropwise. The temperature was allowed to rise to 25°C
once the white precipitatetlad formed. AfteFstirring for another 30 min., H20 was
slowly added until the solid had dissolved. Saturated NaHC03 was then added and
Experimental 183
the solvent was removed under reduced pressure. The residual oil was dried in
vacuo, and the resultant solid triturated with hot EtOH (3 x 60 mL), the ethanolic
solution being filtered in each case. The combined extracts were concentrated
under reduced pressure to give 4-nitro-4-(3-hydroxypropyl)-1 ,7 -heptanediol 104
(0.78 g, 93%); vmax(KBr/cm-1) 3040-3575 (OH); Od100 MHz; MeOH-d4) 26.6
(CH2CH20H), 31.7 (CH2CH2CH20H), 60.3 (CH20H) and 94.5 (CN02).
4-Amino-4-(3-h ydroxypropy/)-1, 7 -heptanedio/105172
A mixture of T-1 Raney Ni (ca. 3.0 g), nitro triol 104 (2.5 g, 10.6 mmol) and
absolute EtOH (100 mL) was shaken under H2 in a Parr hydrogenator at 3 atm for
3 d. The catalyst was cautiously removed by filtering the mixture through celite.
The solvent was then removed under reduced pressure, and the residual oil was
dried in vacuo to yield, as a semi-solid, 4-amino-4-(3-hydroxypropyl)-1, 7-
heptanediol105, shown by 1H NMR spectroscopy to be eventually pure, (1.67 g,
77%); OH(400 MHz; DMSO-d6) 1.20-1.26 (6H, m, CH2CH20H), 1.32-1.42 (6H, m,
CH2CH2C~OH), 3.35 (6H, t, CH2 0H), 4.61 (3H, br s, OH); ~(100 MHz; DMSO
d6) 26.7 (CH2CH20H), 36.2 (CH2CH2CH20H), 52.1 (CNH2) and 61.6 (CH20H).
Preparation of the T-1 Raney nickel catalyst173
Raney nickel-aluminium alloy (50%; 20 g) was added in small portions durtng ca.
25 min. to a stirred aqueous NaOH solution (10%, 300 mL). The temperature was
maintained at 90-95°C during the addition. Once the addition was complete, the
mixture was stirred for 1 h, after which the nickel was allowed to settie, and the
supernatant solution was decanted. The residue was washed with water (5 x 100
mL) and then with EtOH (5 x 25 mL). The washing was done in such a way that the
catalyst was always covered with liquid. The catalyst was then kept under EtOH
and stored under refrigeration.
-. - The dendrimer-based ligand 112
To a hot solution of 1,1 0'"phenanthroline-2,9-dicarbaldehyde 66 (0.57 g, 2.4 mmol)
in absolute EtOH (60 mL) was added a solution of 4-amino-4-(3-hydroxypropyl)-
Experimental 184
1 ,7-heptanedioI105 (1.0 g, 4.9 mmol) in EtOH (30 mL), and the resulting mixture
was boiled under reflux for ca. 20 min. The completion of the reaction was
confirmed by IR spectroscopy. The solvent was removed under reduced pressure
to yield, as a brown oil, the dendrimer-based ligand 112 (1.4 g, 96%) (Found:
MNa+, 633.3627. C34HsoN4 Q, requires MNa, 633.3628); vmax (KBr/cm1 ) 1647 (C=N);
5H (400 MHz; DMSO-d6 ) 1.37 (24H, s, CH2CH2CH20H), 1.64 (12H, s, CH20H),
4.44 (6H, br s, OH), 8.09 (2H, s, CH=N), 8.36 (2H, d, ArH), 8.53 (2H, d, ArH) and
8.62 (2H, s, ArH); 5d100 MHz; DMSO-d6 ) 29.1 (CH2CH20H), 33.2
(CH2CH2CH20H), 63.5 (CH20H), 94.5, 119.6 (ArC), 127.3 (ArC), 129.34 (ArC),
137.1 (ArC), 144.8 (ArC) and 154.8 (ArC) and 157.5 (C=N).
2,9-Dimethyl-1, 10-phenanthroline-5,6-dione 109175,176 - attempted synthesis
To a mixture of neocuproine 64 (2.5 g, 12 mmol) and NaBr (2.5 g), was added an
ice cold mixture of H2S04 (30 mL) and HN03 (15 mL). The resulting mixture was
then boiled under reflux for 3 h. The hot solution was added to 400 mL of ice and
neutralised very cautiously with NaOH until neutral or slightly acidic. The resulting
mixture was extracted with CHCI3 and the extract dried with anhydrous MgS04.
The solvent was removed under reduced pressure, and analysis of the residue
revealed that the central ring in neocupoine was still intact.
J
The monoketone 111174 - attempted synthesis
To a boiling solution of neocuproine 64 (2.0 g) and KOH (1.0 g) in H20 (150 mL)
was added, in portions with stirring, a hot solution of KMn04 (5.0 g) in H20 (80
mL). The reaction mixture was then boiled under reflux for 1.5 h and filtered while
hot; the brown cake was washed with H20 (120 mL). The orange filtrate and
washings were extracted with CHCI3 (3 x 60 mL), and the combined extracts dried
with anhydrous MgS04. The CHCI3 was evaporated off under reduced pressure.
The residue was analysed by 1H NMR spectroscopy, which indicated that oxidation
_. _ of the central ring of neocuproine had not occurred. -
Experimental 185
3.3 SYNTHETIC PROCEDURES FOR THE PREPARATION OF COMPLEXES
3.3.1 Copper Complexes;
Preparation of tetrakis(acetonitrile)copper(l) hexafluorophosphate
Copper (I) oxide (4.0 g, 28 mmol) was dissolved in MeCN (80 ml) and stirred under
N2 in a closed flask fitted with a pressure-compensating dropping funnel. An aqueous
solution of HPF6 (60-65%; 10 mL, 113 mL) was added from the funnel, and the
mixture was stirred for at least 5 min. The mixture was then filtered and cooled to
-20°C to precipitate the crude product, which was recrystallised by redissolving in
MeCN (100 mL) and adding Et20 (100 mL), followed by cooling for approximately
6 h. The white crystalline complex [Cu(MeCN)4][PF6J (9,1 g, 44%) was filtered off,
dried under reduced pressure and stored at 4°C under N2 in a sealed container placed
in a desiccator.
Biphenyl and 1~ 10-phenanfhroline complexes
The copper complex 115
A clear, pink solution of 2,2'-bis{[2-(2-benzimidazolyl)ethylamino]tarbonyl}biphenyl I
55b (0.23 g, 0.44 mmol) in hot, dry, degassed DMF (20 mL) was added dropwise to
a stirred solution of [Cu(MeCN)4][PF61 (0.34 g, 0.92 mmol) in dry, degassed MeCN (10
mL). The resulting pale yellow-green solution gradually changed to a clear green
colour as the reaction mixture was stirred under N2 for 3.5 h. The addition of Et20
resulted in the precipitation of the copper complex 115 as a light-green, polymeric
solid (0.30 g), mp 198-202°C; vrnax(HCBD/ClTf1 ) 3237 (amide NH); vmax(nujollcm1) 1651
(CO) and 845 (PFs).
:t: See Table 8 (p.84) for microanalysis data.
Experimental 186
The copper complex 116
A solution of [Cu(MeCN)4][PFsl (0.34 g, 0.92 mmol) in dry, degassed MeCN (10 mL)
was added to a hot solution of 2,2'-bis{[2-(4-imidazolyl)ethylamino]carbonyl}biphenyl
55e (0.19 g, 0.44 mmol) in a mixture of dry, degassed DMF (10 mL) and dry,
degassed MeCN (20 mL). The reaction mixture turned blue and, upon addition of
Et20, the copper complex 116 precipitated out as a light-green solid (0.17g), mp 212-
214°C; vmaiHCBD/cm-1) 3242 (amide NH) and 3156 (imidazole NH); vmax(nujollcm-1
)
1652 (CO) and 846 (PFs).
Attempted preparation of the biphenyl dicopper complex 117
A colourless solution of [Cu(MeCN)4][PFs] (0.34 g, 0.92 mmol) in dry, degassed
MeCN (10 mL) was added to an almost colourless solution of 2,21-bis{[2-(2-
pyridyl)ethylaminojcarbonyl}biphenyf 55a (0.20 g, 0.44 mmol) in dry, degassed MeCN
(4 mL). No colour change was observed when the ligand solution was added
dropwise to the solution of the Cu(l) reagent, but a solid precipitated out of the
reaction mixture during stirring under N2 for 3.5 h. The solid was filtered off and Et20
was added to the filtrate to precipitate out more of the product. The microanalysis
results were not consistent with formation of the expected product. .
The copper complex 118a J
2,9-Bis{[2-(2-pyridyl)ethylamino]carbonyl}-1,1 O-phenanthroline 69a (0.20 g, 0.44
mmol) was dissolved in a mixture of hot, dry, degassed DMF (10 mL) and MeCN (15
mL). Dropwise addition of this solution to a colourless solution of [Cu(MeCN)4][PFsl (0.34 g, 0.92 mmol) in dry, degassed MeCN (10 mL) gave a dark-red mixture, the
colour of which changed to dirty green upon stirring under N2 for 6 h. The precipitated
solid was filtered off and Et20 was added to the filtrate to precipitate out the
remainder of the copper complex 118a, which was filtered off as a green powder
(0.27 g), mp >230°C; vm:(nujollcm-1) 1630 (CO) and 842 (PFs).
Experimental 187
The copper complex 118b
A brown solution of 2,9-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}-1, 1 O-phenan
throline 6gb (0.25 g, 0.44mmol) in hot, dry, degassed DMF (20 mL) was added to a
colourless solution of [Cu(MeCN)4][PFsl (0.34 g, 0.92 mmol) in dry, degassed MeCN
(10 mL). The initially dark-red colour changed to green-brown and later to light-green
during stirring under N2 for 4.5 h. Et20 was added to precipitate the copper complex
118b as a green-brown solid (0.29 g), mp >230°C; vmax(HCBD/cm-1) 3227 (NH);
vmax(nujollcm-1) 1645 (CO) and 846 (PFs)'
The copper complex 118e
A hot, dark-brown solution of 2,9-bis{[2-(4-imidazolyl)ethylamino]carbonyl}-1, 10-
phenanthroline 6ge (0.19 g, 0.44 mmol) in dry, degassed DMF (20 mL) was added
dropwise to a colourless solution of [Cu(MeCN)4][PFs] (0.34 g, 0.92 mmol) in dry,
degassed MeCN (10 ml). The solution became dark red-brown in colour when stirred
under N2 for 5.5 h. Addition of E!:zO precipitated the copper complex 118e as a brown
solid (0.15 g), mp >230°C; vmax(HCBD/cm-1) 3157; vmax(nujollcm-1
) 1651(CO) and 845
(PFs)·
The copper complex 119
A solution of 2,9-bis{[2-(2-pyridylethylamino]methyl}-1,1 0-phenanthroline'68a (0.20
g, 0.44 mmol) in dry, degassed MeCN (50 mL) was added dropwise to a solution of
[Cu(MeCN)4JPFe (0.34 g, 0.44 mmol) in dry, degassed MeCN (10 mL). The reaction
mixture was stirred for 1.5 h under N2 before adding Et20 to precipitate, as a brown
solid, the copper complex 119 (0.38 g, 78%), mp >230°C; vmax(HCBD/cm1) 3273 (NH);
vmax(nujol/cm-1) 842 (PFs).
Experimental 188
Schiff base complexes and the macrocyclic complex
The copper complex 120
To a stirred solution of Cu(II)(N03h3H20 (0.47 g, 1.95 mmol) in MeCN (3.5 mL),
N,N'-bis[2-(2-pyridyl)ethyl]pentane-2,4-diimine 76 (0.30 g, 0.97 mmol) in MeCN (3.5
mL) was added dropwise. The colour of the reaction mixture changed from turquoise
to dark green during the addition. The reaction mixture was stirred for 3 d before Et20
was added and the copper complex 120 separated out as a green, hygroscopic oil
(0.68 g, 87%); vmaiKBr/cm-1) 1638 (C=N) and 1383 (N03).
The copper complex 121
A solution of 3-methyl-N,N'-bis[(2-(2-pyridyl)ethyl]pentane-2,4-diimine 77 (0.20 g,
0.62 mmol) in MeCN (2 mL) was added dropwise to a stirred solution of Cu(II)(N03h
.3H20 (0.30 g, 1.2 mmol) in MeCN (2.5 mL). The reaction mixture changed from
turquoise to dark green in colour during the addition. After stirring for 3 d, Et20 was
added to precipitate the crude complex, which was redissolved in MeCN. Evaporation
of the solvent under reduced pressure yielded, as a green, hygroscopic semi-solid,
the copper complex 121 (0.36 g, 58%); vmax(KBr/cm-1) 1637 (C=N), 1480, 1445, 1315,
1283 and 1013 (N03).
!
The copper complex 122 - attempted· synthesis
A solution of 3-ethyl-N,N'-bis-[2-(2-pyridyl)ethyl]pentane-2,4-diimine 78 (0.30 g, 0.89
mmol) in MeCN (3 mL) was added dropwise to a stirred solution of Cu(II)(N03h.3H20
(0.43 g, 1.78 mmol) in MeCN (2 mL). The colour changed from turquoise to dark blue
and, after 3 d, Et20 was added to affect separation of the copper complex.
Microanalysis of the resulting green hygroscopic semi-solid indicated that the
expected complex had not been obtained.
- .
Experimental 189
The copper complex 123
A solution of 3-benzyl-N,N'-bis[2-(2-pyridyl)ethyl]pentane-2,4-diimine 79 (0.30 g,
0.75 mmol) in MeCN (3 mL) was added dropwise to a stirred solution of
Cu(IJ)(N03h.3H20 (0.36 g, 1.5 mmol) in MeCN (3 mL). The colour of the reaction
mixture changed from turquoise to dark-green, and stirring was continued for 3 d
before Et20 was added to effect separation of the copper complex 123 as a green,
hygroscopic, semi-solid (0.41 g, 58%); vmaiKBr/cm-1) 1638 (C=N), 1483, 1383 and
1288 (N03).
The macrocyclic copper complex 124
A solution of macrocycle 99 (0.35 g, 1.1 mmol) in DMF (8 mL) was added to a stirred
solution of Cu(II)(N03h.3~O (0.52 g, 2.17 mmol) in DMF (4 mL). The colour changed
from turquoise to red-brown and, aftero~ stirring for 2.5 d, Et20 was added to
precipitate, as a dark-brown solid, the macrocyclic copper complex 124 (0.38 g, 35%),
mp >250°C; vmaiKBr/cm-1) 1653 (C=N) and 1383 (N03).
Attempted preparation of the copper complex 125
A solution of 1-phenyl-N,N'-bis[2-(2-pyridyl)ethyl]butane-1 ,3-diimine 81 (0.20 g, 0.54
mmol) in MeCN (3 mL) was added dropwise with stirring to a solution of
Cu(IJ)(N03h.3H20 (0.26 g, 1.1 mmol) in MeCN (2 mL). A colour chdnge from
turquoise to dark-green was observe(j during the addition and, after stirring for 3 d,
Et20 was added to precipitate the crude product which was redissolved in MeCN.
Evaporation of the solvent under reduced pressure gave a green, crystalline material,
microanalysis of which indicated that the desired complex had not been formed.
Attempted preparation of the copper complex 126
A solution of 1 ,3-diphenyl-N,N'-bis[2-(2-pyridyl)ethyl]propane-1 ,3-diimine 80 (0.40 g, ~
0.93 mmol) in MeCN (5 mL), was added dropw~se to a stirred solution of
Cu(lI)(N03h-3H20 (0.45 g, 1.9 mmol) in MeCN (3 mL). The reaction mixture was
Experimental 190
stirred for 1 d before adding Et20 to precipitate out the product, microanalysis of
which indicated that the expected complex had not been formed.
Attempted preparation of the dicoppercomplex 127
A solution of N,N'-bis[2-(2-pyridyl)ethyl]hexane-2,5-diimine 84 (0.30 g, 0.93 mmol) in
MeCN (5 mL) was added dropwise to a stirred solution of Cu(II)(N03)2.3H20 (0.45 g,
1.9 mmol) in MeCN (3 mL). After stirring the reaction mixture for 2 d, Et20 was added
to precipitate out the product, microanalysis of which indicated that the expected
complex had not been formed.
3.3.2 Cobalt Complexes§
The cobalt complex 133
To a stirred solution of CoCI2.6H20 (0.22 g, 0.92 mmol) in MeOH (5 mL), a solution
of 2,2'-bis{[2-(2-pyridyl)ethylamino]carbonyl}biphenyl 56a (0.20 g, 0.44 mmol) in
MeCN (5 mL) was added dropwise, and the resulting mixture was stirred for 48 h.
Et20 was then added to precipitate the cobalt complex 133 as a blue solid (0.21 g,
66%), mp 198-200°C; vmax(KBr/cm-1) 1622 (CO); vmax(nujollcm-1
) 3Q6 (Co-CI).
,I
The cobalt complex 134
A clear, colourless solution of 2,2'-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}
biphenyl 55b (0.23 g, 0.44 mmol) in hot DMF (20 mL) was added to a stirred, blue
solution of CoCI2.6H20 (0.22 g, 0.92 mmol) in MeOH (5 mL) and stirred for 25 h. The
volume of the reaction mixture was reduced to less than half the original volume by
evaporating off the solvents under reduced pressure, and Et20 was added to
precipitate, as a blue solid, the cobalt complex 134 (0.24 g, 59%), mp >230°C;
§ See Table 12 (p.1 02) for microanalysis data.
Experimental 191
vmax(KBr/cm-1) 3185 (amide NH) and 1633 (CO); vmax(nujolfcm-1
) 295 (Co-CI).
The cobalt complex 135 - attempted preparation
A solution of 2,2'-{[2-(4-imidazolyl)ethylamino]carbonyl}biphenyl 55e (0.20 g, 0.46
mmol) in MeOH (10 mL) was added to a stirred solution of CoCI2.6H20 (0.23 g, 0.96
mmol) in MeOH (5 mL). After stirring for 48 h, during which time the colour changed
from light-blue to dark-blue, Et20 was added to precipitate the product. Microanalysis
of the resulting dark-blue hygroscopic semi-solid indicated that the desired complex
had not been obtained.
The cobalt complex 136
A solution of 1-[2-(2-pyridyl)ethyl]dibenzo[c,e]perhydroazepine 61 a (0.19 g, 0.44
mmol) in MeCN (5 mL) was added dropwisQ to a solution of CoCI2.6H20 (0.22 g, 0.92
mmol) in MeCN (10 mL), and the resulting mixture was stirred for 48 h. The MeCN
was allowed to evaporate off at room temperature, during which time, blue crystals
of the cobalt complex 136 precipitated and were filtered off (0.17 g, 89%), mp
>250°C; vmax(nujolfcm-1) 298 (Co-CI).
The cobalt complex 137a
A solution of 2,9-bis{[2-(2-pyridyl)ethylamino]carbonyl}-1, 1 0-phenanthroline169a (0.20
g, 0.44 mmol) in a mixture of hot MeOH (10 mL) and MeCN (5 mL) was added
dropwise to a purple solution of CoCI2.6~O (0.22 g, 0.92 mmoJ) in MeOH (4 mL). The
colour of the reaction mixture changed to dark-green during stirring for 22.5 h. The
reaction mixture was concentrated in vacuo to half the original volume. Et20 was
added to preCipitate, as a green solid, the cobalt complex 137a (0.26 g, 100%), mp
78°C; vmax(KBr/cm-1) 3274 (NH) and 1645 (CO); vmax(nujol/cm-1
) 303 (Co-CJ).
The cobalt complex 137b
-. - A solution of 2,9-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline
Experimental 192
69b (0.23 g, 0.40 mmol) in DMF (10mL) was added dropwise to a solution of
CoCI2.6H20 (0.20 g, 0.84 mmol) in DMF (5mL). The resulting mixture was stirred for
52 h, during which time, the colour changed from purple-blue to dark-green. The
volume of the reaction mixture was reduced to less than half by evaporating off the
solvent under reduced pressure. The subsequent addition of Et20 resulted in the
precipitation of the cobalt complex 137b as a green powder (0.32 g, 57%), mp
>230°C; vmaiKBr/cm1) 3251 (amide NH) and 1651 (CO); vmax(nujol/cm1) 311 (Co-CI).
The cobalt complex 137c
A solution of 2,9-bis{[2-(4-imidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline 69c
(0.19 g, 0.44 mmol) in hot DMF (15 mL) was added to a stirred solution of CoCI2.6H20
(0.22 g, 0.92 mmol) in DMF (10 mL), resulting in a dark-green mixture. After stirring
for 41 h, the volume of the reaction mixture was reduced to less than half by
evaporating off the DMF under reduced pressure. This was followed by the addition
of Et20 which precipitated, as a dark-green solid, the cobalt complex 137c (0.31 g,
94%), mp 206-210°C; vmax{KBr/cm-1) 3259 (amide NH) and 3121 (imidazole NH);
vmax(nujol/cm-1) 299 (Co-CI).
The cobalt complex 138
A solution of 2,9-bis{[2-{2-pyridylethylamino]methyl}-1, 1 0-phenanthroline'68a (0.20
g, 0.44 mmol) in MeCN (10 mL) was added dropwise to a solution of CoCI2.6H20
(0.22 g, 0.92 mmol) in MeCN (10 mL). The colour changed from bright blue to green,
and, after stirring for 18 h the cobalt complex 138, precipitated ou~ as a green
powder (0.19 g, 49%), mp >230°C; vmax(KBr/cm-1) 3398 (NH); vmax(nujol/cm-1) 311
(Co-CI).
Experimental 193
3.3.3 Nickel Complexest ,lI
The nickel complex 140
A solution of 2,2'-bis{[2-(2-pyridyl)ethylamino]carbonyl}biphenyl 55a (0.20 g, 0.44
mmol) in MeOH (5 mL) was added to a stirred solution of NiCI2.6H20 (0.22 g, 0.92
mmol) in MeCN (5 mL). After stirring for 2.5 d, Et20 was added to precipitate, as a
light-green, hygroscopic solid, the nickel complex 140 (0.26 g, 72%), mp 48-49°C;
vrnaAKBr/cm-1) 3336 (amide NH) and 1619 (CO); vmaAnujol/cm-1
) 325 and 276 (Ni-CI).
The nickel complex 141
A hot solution of 2,2'-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}biphenyI 55b (0.23
g, 0.44 mmol) was added dropwise to a stirred solution of NiCI2.6H20 (0.22 g, 0.92
mmol) in DMF (7 mL). The reaction mixture was stirred for 57 h before Et20 was
added to precipitate, as a light-green solid, the nickel complex 141 (0.29 g, 53%), mp
>250°C; Vmax (KBr/cm-1) 3183 (amide NH) and 1650 (CO); vmaAnujol/cm1
) 387 (Ni-CI)
The nickel complex 142
A solution of 2,2'-bis{[2-(4-imidazolyl)ethylamino]carbonyl}biphenyl 55c (0.15 g, 0.35
mmol) in DMF (10 mL) was added dropwise to a stirred soluti6n of NiCI2.6H20
(0.17 g, 0.72 mmol) in MeOH (5 mL). Stirring was continued for 55 h befdre adding
Et20 to precipitate, as a hygroscopic dark blue-green solid, the nickel complex 142,
(0.10 g, 27%), mp 204-205°C; vmax(KBr/cm-1) 3248 (amide NH), 3143 (imidazole NH)
and 1653 (CO); vmax(nujol/cm-1) 378 (Ni-CI).
The nickel complex 143
To a stirred solution of NiCI2.6H20 (0.22 g, 0.92 mmol) in MeOH (4 mL), a solution of
1-[2-(2-pyridyl)ethyl]dibenz[c,e]perhydroazepine 61 a (0.19 g, 0.44 mmol) in MeCN
_ . t While 1H and 13C NMR spectra were obtained for each of these-complexes, the complexity of - their spectra (see Discussion 2.3.4.2.2 p.118) precludes systematic peak assignment. ~ See Table 15 (p.11S) for microanalysis data.
Experimental 194
(10 mL) was added dropwise, and stirring was continued for 19 h. The solvent was
allowed to evaporate off at room temperature, during which time, purple crystals
precipitated from the reaction mixture and were filtered off to give the nickel complex
143 (0.13 g, 65%), mp >250°C; vmax(nujollcm-1) 329 and 289 (Ni-CI).
The nickel complex 144a
To a stirred solution of NiCI2.6~O (0.20 g, 0.92 mmol) in MeOH (5 mL), a solution of
2,9-bis{[2-(2-pyridyl)ethylamino]carbonyl}-1, 1 O-phenanthroline 69a (0.20 g, 0.44
mmol) in DMF (5 mL) was added dropwise. Although no immediate colour change
was observed, a suspension formed during stirring for 48 h. Et20 was then added to
the reaction mixture to precipitate, as a light green solid, the nickel complex 144a
(0.24 g, 71 %), mp 249-252°C; vmax (KBr/cm-1) 3223 (amide NH) and 1653 (CO); vmax
(nujollcm-1) 378 and 253 (Ni-CI).
The nickel complex 144b
A solution of 2,9-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline
69b (0.22 g, 0.44mmol) in DMF (15 mL) was addded dropwise to a solution of
NiCI2.6H20 (0.20 g, 0.92 mmol) in DMF (7 mL). After stirring for 52 h E~O was added
to precipitate, as a brown, hygroscopic solid, the nickel complex 14t1-b (0.31 g, 66%),
mp >250°C; Vmax (KBr/cm-1) 3245 (amide NH) and 1653 (CO); vmax(nujollcm') 384 and
283 (Ni-CI).
The nickel complex 144c
A solution of 2,9-bis{[2-(4-imidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline 69c
(0.20 g, 0.44 mmol) in DMF (6.5 mL) was added dropwise to a stirred solution of
NiCI2.6H20 (0.21 g, 0.88 mmol) in DMF (5 mL). The resulting suspension was stirred
for 20.5 h before adding Et20 to precipitate, as a light-green solid, the nickel complex
144c (0.31 g, 94%), mp >250°C; vmax (KBr/cm-1) 323f? (amide NH) and 1649 (CO);
vmax(nujollcm-1) 373 and 310 (Ni-CI).
Experimental 195
The nickel complex 145
A solution of 2,9-bis{[2-(2-pyridylethylamino]methyl}-1,1 O-phenanthroline 6Sa (0.25
g, 0.56 mmol) in MeOH (5 mL) was added dropwise to a solution of NiCI2.6H20 (0.26
g, 1.11 mmol) in MeOH (5 mL). The colour changed from light-green to dark-green
and, after stirring for 48 h, Et20 was added to precipitate, as a light-green solid, the
nickel complex 145 (0.30 g, 70%), mp 244-246°C; vmaAKBr/cm-1) 3367 (NH);
vmax(nujollcm-1) 352 and 278 (Ni-CI).
3.3.4 Platinum Complexes tt, t
The platinum complex 146
A solution of 2,2'-bis{[2-(2-pyridyl)ethylamino]carbonyl}biphenyl 56a (0.12 g, 0.26
mmol) in MeCN (5 mL) was added dropwise to a stirred solution of K2[PtCI4] (0.24 g,
0.57 mmol) in H20 (3 mL). After stirring for 51 h, the solvents MeCN and H20 were
evaporated, almost to dryness, under reduced pressure, before adding H20 to
precipitate out, as a yellow solid, the platinum complex 146 (0.16 g, 55%), mp 209-
214°C; vmax(HCBD/cm-1) 3252 (amide NH); vmax(nujol/cm-1
) 1634 (CO) and, 342 and
315 (Pt-CI). J
The platinum complex 147 - Attempted synthesis
To a solution of ~[PtCI4] (OAO g, 0.76 mmol) in DMF (84 mL), a solution of 2,2'-bis{[2-
(2-benzimidazolyl)ethylamino]carbonyl}biphenyl 56b (0.20 g, 0.38 mmol) in DMF (6
mL) was added dropwise while stirring. After stirring for 7 d, the volume of DMF was
evaporated to less than half the original volume before adding Et20 to precipitate out
a cream powder, microanalysis of which indicated that the desired complex 147 had
not been obtained.
_. _ tt While the 1H and 13e NMR spectra were obtained for each of these complexes, the complexity of their spectra (see Discussion 2.3.4.2.2 p.130) precludes systematic peak assignment.
t See Table 18 (p.122) for rnifroanalysis data.
- .
Experimental 196
The platinum complex 148
A solution of 2,2'-bis{[2-(4-imidazolyl)ethylamino]carbonyl}biphenyI56c (0.11 g, 0.26
mmol) in DMF (6 mL) was added dropwise to a stirred solution of K2[PtCI4] (0.24 g,
0.57 mmol) in H20 (3 mL). After stirring for 52.5 h, the solvents were evaporated
under reduced pressure to afford, as a light-brown solid, the platinum complex 148
(0.16 g, 62%), mp >230°C; vmax(nujol/cm1) 3218 (amide NH), 3120 (imidazole NH) and
1627 (CO); vmaAnujol!cm-1) 335 (Pt-CI).
The platinum complex 149
The dropwise addition of a solution of 2,9-bis{[2-(2-pyridyl)ethylamino]carbonyl}-1, 10-
phenanthroline 69a (0.11 g, 0.23 mmol) in DMF (4 mL) to a stirred solution of
K2[PtCI4] (0.21 g, 0.50 mmol) in H20 (4 mL) was accompanied by the formation of a
suspension. After stirring for 65 h, the precipitate was filtered off to afford, as an
orange-brown powder, the platinum complex 149 (0.22 g, 100%), mp >230°C;
vmax(nujol!cm-1) 1660 (CO); vmax(nujollcm-1
) 329 (Pt-CI).
The platinum complex 150 - Attempted synthesis
A solution of 2,9-bis{[2-(2-benzimidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline
69b (0.15 g, 0.27 mmol) in DMF (10 mL) was added dropwise to a ~tirred solution of
K2[PtCI4] (0.23 g, 0.54 mmol) in DMF (20 mL) and H2 0 (8 mL). The resultirig mixture
was stirred for 6 d before concentrating the mixture in vacuo to less than half the
original volume. Et20 was then added to precipitate a peach-coloured solid,
microanalysis of which indicated that the expected complex 150 had not been
obtained.
The platinum complex 151
A solution of 2,9-bis{[2-(4..:imidazolyl)ethylamino]carbonyl}-1, 1 O-phenanthroline 69c
(0.20 g, 0.44 mmol) in DMF (5 mL) was added dropwise to a stirred solution of
K2[PtCI2] (0.21 g, 0.50 mmol) in DMF (20 mL) and H20 (9 mL). After stirring for 6 d,
Experimental 197
the mixture was concentrated to less than half the original volume under reduced
pressure. The addition of Et20 resulted in precipitation of the platinum complex 151
as an orange-yellow solid (0.43 g, 100%), mp >250°C); vmax(KBr/cm-1) 3259 (amide
NH), 3135 (imidazole NH) and 1653 (CO); vmax(nujollcm-1) 321 (Pt-CI).
The platinum complex 152
To a solution of ~[PtCI4] (0.21 g, 0.50 mmol) in ~O (3 mL) and HCI (2.5 mL, 2M) was
added dropwise 2,9-bis{[2-(2-pyridylethylamino]methyl}-1, 1 O-phenanthroline S8a
(0.11 g, 0.23 mmol) in a mixture of DMF (4 mL) and MeCN (26 mL). The colour
changed from orange-red to dark-brown and a suspension formed during stirring for
5 d. After this time, the mixture was filtered and the filtrate evaporated, almost to
dryness, under reduced pressure. Addition of H20 to the residue afforded, as a brown
solid, the platinum complex 152 (0.25 g, 100%), mp >230°C; vmax(nujollcm-1) 3480
(NH) and 318 (Pt-CI).
J
Experimental 198
3.4 PROCEDURE FOR COMPUTER MODELLING OF COMPLEXES
Computer modelling was conducted using the MSI Cerius2 version 3.2 modelling
package on a Silicon Graphics 0 2 platform. The sequence followed for the
computer modelling runs for both ligands and complexes is outlined in Figure 63,
and was aimed at establishing the global minimum in each case.
Structure
building
Dynamics run Dynamics anneal cycles • at 300 K --... at 500 K
Minimisation .04-- Dynamics anneal trajectory at 300 K
Figure 63: The procedure followed for the modelling of the ligands and complexes.
This sequence involved starting with structure building followed by a dynamics run
of 5000 steps at 300 K. This was then followed by 250 dynamics anneal cycles
during which the temperature was raised to 500 K followed by a drnamics anneal
trajectory involving cooling to 300 K. The lowest energy structure was then, energy
minimised. Minimisations were consi~ered to converge when the energy gradient
was less than 0.01 kcalmol-1. The ligands were first modelled and then the metals
were inserted and the modelling process repeated for the complex. Dioxygen was
inserted once the minimised model of the complex was obtained, and the
modelling process once again repeated for the copper-dioxygen complex. The
potential energies and the Cu-Cu distances of these minimised models were then
recorded for selected complexes. A universal force field was used for modelling all
the complexes except oepper.
Experimental 199
3.5 ELECTROCHEMICAL STUDIES: CYCLIC VOL TAMMETRY
Electrochemical data were collected with a Bio Analytical Systems (BAS) CV-50
voltammograph. The measurements were carried out under a nitrogen atmosphere
using freshly distilled, dried, degassed solvents. A glass carbon electrode
(diameter = 3.0 mm) was used as the working electrode and a platinum wire as the
counter electrode. A non-aqueous reference electrode was employed. The
electrode solution for the non-aqueous reference electrode was prepared by
dissolving 0.01 M AgN03 in 0.1 M TEAP (tetraethylammonium perchlorate) in
MeCN or DMF, resulting in a Ag/Ag+ (TEAP/MeCN or TEAP/DMF) electrode.
TEAP was employed as an electrolyte. The same reference electrode was used
for both MeCN and DMF.
3.4.1 Copper complexes
The conditions used for the analysis of the copper complexes are summarised in
Table 26. The resulting cyclic voltammograms are illustrated in Figures 65-67.
Cyclic voltammograms were also obtained for the ligands 55b and 6gb (Figure 64).
Table 26: Conditions used to measure the cyclic voltammogram~ of the copper complexes. J
Complex Solvent Scanning Scanning speed
range (mV) (mV.s·1)
115 DMF 1300 to -1300 1000
116 DMF 1550 to -1550 500
118a DMF 1580 to -1580 200
118b DMF 2200 to -2200 1000
118c DMF 2000 to -2050 500 r-
11 9 DMF 1200 to -1200 200
120 MeCN 2200 to -2200 300
121 - - MeCN 22QO to -2200 500
123 MeCN 2250 to -2250 100
127 DMF 1650 to -1650 500
Experimental 200
+16 1 ! ! ! ! ! ! ! ! I I I I
1 +151 I I I I I I I ! I I I
I
J I
1 ....-,L
1 I I I
OJ r +51 L I
~ ~ ~ ~ J I
I
I I 1 I
<C -101 I r <C -51 r ::::> I ::::> I -E I
~ -E 1 t ~ i ~ ::::> I l ::::>
-151 l 0
-321
0
I f I 1 \ 1 I
~ I
-48~ I
-25~ I ~ '-I
I I I I i
~J r 1 r I ! I I I I I I I I I I I I -351 I I I I I I I I I I I I I 1
+1.4 +1.0 +0.0 +0.2 -0.2 -{).6 -1.0 -1.4 +1.4 +1.0 +0.0 +0.2 -{).2 -0.0 -10 -1.4
Potential,V Potential,V
(a) (b)
Figure 64: Cyclic voltammograms of: (a) the biphenyl ligand 55b and (b) the 1,10-phenanthroline ligand 6gb.
+80.00j i ~ +60.00 L
+0000 • ._.//~.~) f +20.00 ~ ./ ~ i .:oO::jl ;i L
<3 -40.00 .~ ,~.~ ~
I' r ~::::j _I! L~ -100.01 I
-120.0 i I I ! + 1.40 .+-1 ,':-C -1-0.50 +C.2~ -C.20 -0.60 -l.CJ -1.4;
Potentiol/V
Figure 65: Cyclic voltammogram of the oiphenyl copper complex 115.
Experimental
:1··········~ 1 r
c ~ ~l :3_ J' "E
~ I I o ~i ~
c :3
-E' ~ ::J
0
'V -40 / ,
+1.6 +1.2
+80 I J I I
+4°1
j
o~ I I 1
-401
i I
-80~
-120 i I
~ I r ~ I
I I I I I I I
+0.8 +0.4 ° -D.4 -D.S -1.2 -1.6
I I
Potential,V
(a)
I ~
I r ~ I r r I , e , I . r , I L I
I r
I I I I I,
+2.0 +1.5 +1.0 +0.5 -D.S -1.0 -1.5 -2.0 -2.5
Potential,V
(C)
c :3
-E' ~ ::.
0
+48
1
~ ,
+32~ I
-1 I
+161
I +1
I ' I o -1
Potential,V
(b)
, ,
o~ -16~
-32/ , , , , +1.2 +0.8 +0.4 a -D.4
Potential,V
(d)
, ,
, -D8
I -2
,
~ I r ~ l
.I I I ~ I r ~ I I ,
-1.2
Figure 66: Cyclic voltammograms of the 1,1 O-phenanthroline complex-es: (a) 118a; (b) 118b; (c) 118c; and (d) 119.
201
Potential ,V
(a)
\ 1 \
, o
Potential,V
(c)
I -1
Experimental
+800+-
J --"--, -1'----'-' -----'---'---'-----L----L-I ~I --tl
I I +4001 r
~ ~ J ~
~ 1 I ~ I r 8 AOOJ l .- I I
i I 1 I
-800~ ~ I I 1 I
-1200 I I I I I I I I ~ ~ 0 ~ ~
Potential,V
(b)
I +45Oj I I I I I ' I I I ' I , I
t ~J t
1 1 ~ ~ <~~ ~ l ~- J l 1 ~ I 1
r <..) -45Oi r ~ ~ ,I ~
Ir ___ I 1 -I~l r
t 1 I I I -1050 I . I . I . I . I . I ' I . I . I I
-2 +1.8 +1.4 +1.0 +0.6 +0.2 -0.2 -0.6 -1.0' -1.4 -1.8
Potential,V
(d)
Figure 67: Cyclic voltammograms obtained for the Schiff base complexes
202
and the macrocycle complex: (a) 120; (b) 121; (c) 123; and (d) 124_
Experimental 203
3.4.2 Cobalt Complexes
The conditions used for the analysis of the cobalt complexes are summarised in
Table 27.
Table 27: Conditions used to measure the cyclic voltammograms of the cobalt complexes.
Complex Solvent Scanning Scanning
range (mV) speed (mV.s·1)
133 DMF 1600 to -1600 500
134 DMF 1250 to -1250 300
137a DMF 1600 to -1600 400
137b DMF 1250 to -1250 300
137c DMF 1300 to -1300 400
138 DMF 1250 to -1250 300
.1
'-
Experimental 204
3.4.3 Nickel Complexes
The conditions used for the analysis of the nickel complexes are summarised in
Table 28.
Table 28: Conditions used to measure the cyclic voltammograms of the nickel complexes.
Complex Solvent Scanning Scanning
range (mV) speed (mV.s-1)
140 DMF 1550 to -1550 300
141 DMF 1550 to -1550 500
142 DMF 1550 to -1550 300
144a DMF ''1550 to -1550 300
144b DMF 1550 to -1550 700
144c DMF 1550 to -1550 500
145 DMF 1550 to -1550 - 500
,I
Experimental 205
3.6 METHOD FOR THE EVALUATION OF THE CATALYTIC ACTIVITY OF
THE COPPER COMPLEXES
The substrates DTBP 153 and DTBC 154 were added to separate suspensions of
the complexes in dry DMF (3 mL) or CH2CI2 (3 mL) in molar ratios of 100: 1
(substrate: complex). The resulting mixtures were aerated by vigorously stirring
at room temperature to provide the oxygen necessary for reaction. Generally the
reactions conducted in CH2CI2 were stirred for ca. 3-4 d, reactions in DMF for ca.
5 d; the reactions with complexes 115 and 118a, however, showed biomimetic
activity after stirring for 24 h. The reactions in DMF, which displayed no catalytic
activity, were repeated in the presence of triethylamine (30 IJL per reaction) to
inhibit decomposition of the complex. 138 After stirring, the reaction mixtures were
concentrated to dryness in vacuo, and tile solid residues analysed by 1H NMR
spectroscopy. The extent of conversion to the products was determined by
comparing the integrals of signals corresponding to the individual products and
unreacted substrate (see Tables 29 and 30).
Table 29: Data for the catalytic oxidation of DTBP 153 to the coupled product 156.
Complex Integral ratio % conversion
116 10.33:1 8.8
118a 6:1 14.3
118b 6.67:1 13.0
Table 30: Data for the catalytic oxidation of DTBC 101 to DTBQ 102.
Complex Integral ratio % conversion
115 15: 1 6.3 ~
116 13:2 13.3
118a 12.7: 1 7.3 - - <
118b 5:3 38.0
118c 1: 1.19 54.3
J
206
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5 APPENDIX
Crystallographic data for cobalt complex 136.
Table 1: Crystal data and structure refinement for cobalt complex 136.
Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume Z Density (calculated) Absorption coefficient F(OOO) Theta range for data collection Limiting indices Reflections collected 1 unique Independent reflections Completeness to theta Absorption correction Refinement method Data 1 restraints / parameters Goodness-of-fit on F2 Final R indices [1>2sigma (I)] R indices (all data) Largest diff. peak and hole
rw6rco m C21 H2o CI2 Co N2 430.24 296(2) K 0.71073 A Monoclinic P(2)/n a = 8.7818 (5) A alpha = 90 deg b = 16.0994 (10) A beta = 91.8600 {"10) deg. c = 13.7265 (8) A gamma = 90 deg. 1939.7 (2) A3
1.892 Mg/m3
1.193 mm-1
1148 1.95 to 28.30 deg. -9<=h<=11, -21<=k<=19, -17<=1<=17 11620 4349 [R (int) = 0.0386] , 28.30, 90.1 % None Full-matrix least-squares on F2 4349/0/315 1.074 R1 = 0.0581, wR2 = 0.1477 .. R1 = 0.0992, wR2 = 0.1730 0.315 and -0.302 e.A3
221
Table 2: Atomic coordinates (x 104) and equivalent isotropic dislacement
parameters (A2 x 103) for cobalt complex 136.a
,b U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x y z U (eq)
Co(l) 2209(1) 1070(1) 2078(1) 46(1) Cl (1) 2963(2) 2060(1) 3119 (1) 83(1) N (1) 4200(3) 583(2) 1632(2) 45 (1) C (1) 5297(5) 1115(3) 1380(3) 52 (1) Cl(2) 833(1) 1373(1) 715 (1) 65(1) N (2) 1283(3) 41(2) 2754(2) 37 (1) C(2) 6622(5) 850(4) 963 (3) 57(1) C (3) 6815(5) 19(3) 796(3) 59(1) C(4) 5724(5) -526(3) 1092(3) 52 (1) C(5) 4408(4) -238(2) 1508(3) 44 (1) C (6) 3153(6) -815(3) 1780(4) 54(1) C (7) 2420(5) -651(3) 2758(3) 48(1) C (8) -154(4) -212c(3) 2214(3) 41 (1) C (9) -1205(4) -794(2) 2725(3) 39 (1) C(10) -1405(5) -1611(3) 2395(3) 48 (1) C(ll) -2489(5) -2118(3) 2793(4) 58 (1) C(12) -3398(5) -1820(3) 3510(3) 59 (1) C(13) -3216(5) -1015(3) 3849(3) 52 (1) C(14) -2131(4) -491(2) 3460 (3) 41(1) C(15) -1936(4) 377(2) 3822(3) 43(1) C(16) -3205(5) 840(3) 4070(3) 56(1) C(17) -3038(6) 1627(3) 4470(3) 62 (1) C (18) -1627(6) 1949(3) 4620(4) 64 (1) C(19) -349(6) 1520(3) 4360(3)~ 54(1) C(20) -480(4) 719(2) 3960(3) 43 (1) C (21) 933(4) 209(3) 3800(3) .I 42 (1)
a For atom labelling see Figure 36.
b Estimated standard deviations in parenthesis.
222
Table 3: Bond lengths [AJ and angles [deg] for cobalt complex 136.
Co (1) -N (1) 2.030(3) Co(1)-N(2) 2.078(3) Co (1) -Cl (1) . 2.2261(14) Co(1)-Cl(2) 2.2481(12) N(l) -C(l) 1.342(5) N(l)-C(5) 1.345(5) C(l)-C(2) 1.381(6) N(2) -C(7) 1.496(5) N(2) -C (8) 1.499(5) N (2) -C (21) 1.502(5) C(2)-C(3) 1.370(7) C(3)-C(4) 1.370(6) C(4)-C(5) 1.386(5) C (5) -C (6) 1.499(6) C(6) -C(7) 1.530(6) C(8) -C(9) 1.505(5) C(9)-C(10) 1.400(5) C(9)-C(14) 1.404(5) C(10)-C(11) ~, 1.379 (6) C(11)-C(12) 1.374 (7) C(12)-C(13) 1.385(6) C(13)-C(14) 1.392 (5) C(14)-C(15) 1.491(5) C(15)-C(16) 1.391(6) C(15)-C(20) 1.399(5) C(16)-C(17) 1.387(6) C(17)-C(18) 1.353(7) C(18)-C(19) 1.375 (7) C(19)-C(20) 1.404(6) C(20)-C(21) 1.510(5)
N(1)-Co(1)-N(2) 100.36(12) .I
N (1) - Co ( 1) - Cl (1) 103.21(10) N(2)-Co(1)-Cl(1) 113.38(9) N(1)-Co(1)-Cl(2) 106.14(9) N(2)-Co(1)-Cl(2) 109.74(9) Cl(1)-Co(1)-Cl(2) 121.30(6) C(1)-N(l)-C(5) 119.5(3) C(l)-N(l)-Co(l) 117.6(3) C (5) - N (1) - Co (1) 122.6(3) N(l) -e(l) -C(2) 122.1(5) C(7) -N(2) -C(8) 110.5(3) C(7) -N(2) -C(21) 106.8(3) C(8) -N(2) -C(21) 109.1(3) C (7) - N (2) - Co (1) 109.0(2) C(8)-N(2)-Co(1) 109.3(2)
- . C(21)-N(2)-Co(1) 112.2(21 -C(3) -C(2) -C(l) 118.7(5) C(2) -C(3) -C(4) 119.0(4) C(3) -C(4) -C(5) c
120.5(4) N(l) -C(5) -C(4) 119.9(4) N(l) -C(5) -C(6) 118.3'( 3)
C(4) -C(5) -C(6) C(5) -C(6) -C(7) N(2) -C(7) -C(6) N(2) -C(8) -C(9) C(10) -C(9) -C(14) C(10) -C(9) -C(8) C(14) -C(9) -C(8) C(ll) -C(10) -C(9) C(12)-C(11)-C(10) C(11)-C(12)-C(13) C(12)-C(13)-C(14) C(13)-C(14)-C(9) C(13) -C(14) -C(15) C(9) -C(14) -C(15) C(16)-C(15)-C(20) C(16)-C(15)-C(14) C(20)-C(15)-C(14) C (17) -C (16) -C (15) C(18)-C(17)-C(16) C(17)-C(18)-C(19) C(18)-C(19)-C(20) C(15)-C(20)-C(19) C(15)-C(20)-C(21) C(19)-C(20)-C(21) N(2) -C(21) -C(20)
121. 6 (4) 116.4(4) 115.1(3) 117.2(3) 119.3(4) 120.5(3) 119.8(3) 120.6(4) 120.1(4) 120.3(4) 120.7(4) 119.0.( 4) 120.8(3) 120.2(3) 119.5(4) 119.9(4) 120.5(3) 120.7(5) 119.7(5) 121.3(5) 120.4(4) 118.5(4) 121.2 (3) 119.9(4) 115.6(3)
223
. Co (1) Cl(l) N (1) C(l) Cl(2) N (2) C(2) C (3) C(4) C(5} C (6) C (7) C(8) C(9) C(10) C(ll) C(12) C(13)
. C (14) C(15) C(16) C(17) C(18) C(19) C (20) C (21)
Table 4: Anisotropic displacement parameters (A2 x 103) for cobalt complex
136. The anisotropic displacement factor exponent takes the form: -2 pi2 [h2 a*2 U11 + ... + 2 h k a* b* U12]
Ull U22 U33 U23 U13
40(1) 34(1) 64(1) 6 (1) 15 (1) 76(1) 53 (1) 122 (1) -30(1) 39 (1) 36(2) 44(2) 54(2) -4(2) 7 (1) 42(2) 59(3) 56(3) - 5 (2) 4 (2) 56 (1) 66 (1) 74 (1) 30(1) 16 (1) 35(2) 36(2) 39(2) 4 (1) 3 (1) 37(2) 84(4) 50 (3) -5 (2) 3 (2) 37(2) 89(4) 50(2) - 8 (2) 1 (2) 48(2) 60(3) 47(2) -4(2) - 6 (2) 42(2} 45(2) 45(2) -2(2) o (2) 56(3) 38(2) 69(3) - 6 (2) 14(2) 50(2) 40(2) 53(2) 14(2) 6 (2) 40(2) 46(2) 36(2) .. ~ 0(2 ) -1 (2) 39(2) 42(2) 36(2) 5 (2) - 3 (2) 52(2) 45(2) 48(2) -1(2) - 3 (2) 65(3) 40(2) 69(3) 2 (2) -7 (2) 58(3) 55(3) 65(3) 12(2) 6 (2) 52(2) 58(3) 48 (2) 4(2) 10(2) 42(2) 44(2) 36(2) 7 (2) 4 (2) 47(2) 45(2) 38 (2) 5 (2) 5 (2) 50(3) 65(3) 54(3) -2(2) 11(2) 75(3) 57 (3) 55(3) -4(2) 22( 2) 91(4) 44(3) 59(3) - 6 (2) 21(3) 70(3) 49(2) 44(2) - 3 (2) 1,8(2) 53(2) 46(2) 30(2) 2 (2) 7 (2) 45(2} 43 (2) 39 (2) 7 (2) -2 (2) .I
224
U12
3 (1) -20 (1)
o (1) -7 (2) 18(1)
1 (1) - 8 (2) 12(2) 19(2} 10(2}
9 (2) 6 (2) 1 (2)
-4 (2) -1 (2)
-10(2) -19(2)
-7 (2) - 5 (2) -5 (2) 1(2)
11 (3) -4 (3)
-13 (2) - 3 (2) -9 (2)
225
Table 5: Hydrogen coordinates ( x 104) and isotropic displacement parameters
(A2 x 103) for cobalt complex 136.
x y z U(eq)
H (1) 5160(50) 1690(30) 1470(30) 63 (13) H(2) 7310(60) 1220(30) 850(40) 79(17) H (3) 7650(60) -220(30) 480(40) 76(15) H (4) 5830(50) -1100(30) 1030(30) 60(13) H(6B) 2310(50) -790(20) 1240(30) 50(11) H (6A) 3510(60) -1270(30) 1780(30) 73(16) H(7B) 2000(50) -1150(30) 3050(30) 48(11) H (7A) 3160(50) -490 (30), 3210(30) 48(11) H(8B) -720(40) 230(20) 2100(30) 37(10) H (8A) 130(40) -470(20) 1530(30) 40 (9) H (10) -860(50) -1790(30) 1900(30) 51(12) H(ll) -2600(50) -2640(30) 2520(30) 57(12) H(12) -4140(60) -2150(30) 3780(40) 87(17) H(13) -3790(50) -790(30) 4390(30) 56(12) H(16) -4190(50) 650(30) 3920(30) 49(11) H(17) -3800(50) 1910(30) 4640(30) 53 (12) H (18) -1480(60) 2420(40) 4850(40) 82(17) H(19) 750(50) 1720(30) 4480(30) 54(12) H{21B) 830(30) -320(20) 4096(20) 22(8) H (21A) 1820(40) 480(20) 4080(30) 41(10)
J
226
Crystallographic data for nickel complex 143.
Table 1: Crystal data and structure refinement for nickel complex 143.
Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume Z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for data collection Limiting indices Reflections collected / unique Independent reflections Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [1>2sigma (I)] R indices (all data) Largest diff. peak and hole
newfin C21 H2o CI2 Co N2 430.00 296(2) K 0.71073 A Monoclinic P(2)/n a = 8.7689 (5) A alpha = 90 deg b = 15.8377 (10) A beta = 91.8760 (10)deg. C = 13.7979 (8) A gamma = 90 deg. 1915.2 (2) A3
1'.491 Mg/m3
1.299 mm-1
888 0.20 x 0.20 x 0.10 mm 1.96 to 28.28 deg. --11=h<=10, -20<=k<=20, -17<=1<=16 11748 4317 [R (int) = 0.0328] Full-matrix least-squares on F2 4317 / 0 / 31 5 ~ 1.087 J
R1 = 0.0494, wR2 = 0.0979 R1 = 0.0714, wR2 = 0.1072 0.367 and -0.339 e.A3
227
Table 2: Atomic coordinates ( x 104) and equivalent isotropic dislacement
parameters (A2 x 103) for nickel complex 143.a
,b U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x y z U(eq)
Ni (1) 2197(1) 1086 (1) 2108(1) 41 (1) Cl(l) 3094(1) 1985(1) 3225(1) 68 (1) N (1) 4142(3) 589(2) 1657(2) 39 (1) C (1) 5243(4) 1134(2) 1417(3) 46 (1) Cl(2) 861(1) 1315(1) 718(1) 56 (1) C(2) 6558(4) 879(3) 991(3) 51 (1) N (2) 1270(3) 46(2) 2744(2) 33 (1) C(3) 6770(4) 38(3) 816(2) 50 (1) C(4) 5679(4) -526(2) 1082(2) 46 (1) C(5) 4344(4) -239(2) 1499(2) 40 (1) C (6) 3092(4) -831(2) 1754(3) 48 (1) C(7) 2390(4) -671(2) 2734(2) 42 (1) C (8) -192(3) -18~(2) 2207(2) 35 (1) C(9) -1226(3) -791(2) 2711(2) 34 (1) C(10) -1432(4) -1611(2) 2366(2) 42 (1) C (11) -2527(4) -2130(2) 2755(3) 51 (1) C(12) -3421(4) -1840(2) 3487(3) 53 (1) C(13) -3223(4) -1030(2) 3839(3) 47(1) C(14) -2125(3) -493(2) 3459(2) 36 (1) C(15) -1930(3) 380(2) 3839(2) 37 (1) C (16) -3192(4) 858(2) 4095(3) 48 (1) C(17) -3015(5) 1644(2) 4514(3) 55 (1) C(18) -1582(5) 1973(2) 4668(3) 55 (1) C(19) -317(4) 1528(2) 4391(2), 47(1) C (20) -465(4) 728(2) 3968(2) 38 (1) C (21) 932(4) 202(2) 3792(2) .I 37 (1)
a For atom labelling see Figure 46. b Estimated standard deviations in parenthesis.
228
Table 3: Bond lengths [A] and angles [deg] for nickel complex 143.
Ni(l)-N(l) 1.997(2) Ni(1)-N(2) 2.047(2) Ni(l)-Cl(l) 2.2229(11) Ni(1)-Cl(2) 2.2447(10) N(l) -C(5) 1.342(4) N (1) -C (1) 1.344(4) C(1)-C(2) 1.372 (5) C(2)-C(3) 1.368(5) N(2)-C(7) 1.501(4) N(2)-C(8) 1.505(4) N(2) -C(21) 1.506(4) C(3)-C(4) 1.368(5) C(4)-C(5) 1.397(4) C(5)-C(6) 1.495 (5) C(6)-C(7) 1.525 (5) C(8)-C(9) 1.506 (4) C(9)-C(10) 1.393(4) C(9)-C(14) 1.401(4) C(10)-C(11) 1.386(5) C(11)-C(12) 1.377 (5) C(12)-C(13) 1.381(5) C(13)-C(14) 1.399(4) C (14) -C (15) 1.487 (4) C(15)-C(16) 1. 395 (4) C(15)-C(20) 1.403(4) C(16)-C(17) 1.380(5) C(17)-C(18) 1.3~0(6) C(18)-C(19) 1.379(5) C(19)-C(20) 1.400(5) C(20)-C(21) 1.508(4)
,I N(1)-Ni(1)-N(2) 99.87(10) N(l)-Ni(l)-Cl(l) 100.49(8) N(2)-Ni(1)-Cl(1) 110.81(7) N(1)-Ni(1)-Cl(2) 102.97(8) N(2)-Ni(1)-Cl(2) 107.03(7) Cl(1)-Ni(1)-Cl(2) 130.68(4) C(5) -N(l) -C(l) 119.2(3) C(5)-N(1)-Ni(1) 123.7(2) C(l) -N(l) -Ni (1) 116.8(2) N(1)-C(1)-C(2) 122.5(3) C(3)-C(2)-C(1) 118.9(4) C(7) -N(2) -C(8) 111.1(2) C(7) -N(2) -C(21) 106.4(2) C(8) -N(2) -C(21)-- 108.8'( 2) C(7)-N(2)-Ni(1) 109.6(2)
- C(8) -N(2) -Ni (1) 109.2(2-) -C(21) -N(2) -Ni (1) 111.8 (2) C(4) -C(3) -C(2) ~119.2(3)
C(3) -C(4) -C(5) 120.0(3) N(l) -C(5) -C(4) 120.1(3) N(l) -C(5) -C(6) 118.3(3)
C(4)-C(S)-C(6) C(S) -C(6) -C(7) N(2) -C(7) -C(6) N(2)-C(8)-C(9) C(10)-C(9)-C(14) C(10)-C(9)-C(8) C(14)-C(9)-C(8) C(ll) -C(10) -C(9) C(12) -C(ll) -C(10) C(ll) -C(12) -C(13) C(12) -C(13) -C(14) C(13) -C(14) -C(9) C(13)-C(14)-C(lS) C(9) -C(14) -C(1S) C (16) -C (IS) -C (20) C (16) -C (1S) -C (14) C(20)-C(lS)-C(14) C(17) -C(16) -C(lS) C(18) -C(17) -C(16) C(17)-C(18)-C(19) C(18) -C(19) -C(20) C(19) -C(20) -C(lS) C (19) -C (20) -C (21) C(lS)-C(20)-C(21) N(2) -C(21) -C(20)
121.6(3) 11S.1(3) 114.6(3) 116.3(2) 119.7(3) 120.6(3) 119.2(3) 120.3(3) 120.3(3) 120.0(3) 120.9'(3) 118.8(3) 120.4(3) 120.8(3) 119.0(3) 120.7(3) 120.2(3) 121.1 (4) 119.9(4) 120.3(4) 120.9(3) 118. 7 (3) 120,2(3) 120.6(3) 11S.6(2)
229
Ni (1) Cl (1) N (1) C(l) Cl(2) C(2) N (2) C(3) C(4) C(5) C (6) C(7) C (8) C (9) C(10) C(ll) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19)
. C (20) C (21)
Table 4: Anisotropic displacement parameters (A2 x 103) for nickel complex
143. The anisotropic displacement factor exponent takes the form: -2 pj2 [h2 a*2 U11 + ... + 2 h k a* b* U12]
U11 U22 U33 U23 U13
36 (1) 31 (1) 56(1) 4 (1) 13 (1) 62(1) 50 (1) 92(1) -23 (1) 25 (1) 32 (1) 38 (1) 47(2) -2 (1) 7 (1) 36(2) 46(2) 55 (2) -7 (2) 4 (1) 51(1) 55(1) 62 (1) 22 (1) 14(1) 34(2) 72 (3) 47(2) -4 (2) 6 (2) 32(1) 35(1) 33 (1) 3 (1) 2 (1) 30(2) 82 (3) 38(2) - 8 (2) -1 (1) 43(2) 52 (2) 42 (2) - 8 (2) - 5 (1) 37(2) 44(2) 39(2) -2 (1) 2 (1) 51(2) 34(2) 61(2) - 2 (2) 12(2) 42(2) 36(2) 47(2) 10(1) 5 (2) 37(2) 39(2) 29(2) 2 (1) 2 (1) 33 (2) 36(2) 32 (2) 4 (1) -2 (1) 42(2) 38(2) 44(2) 0(1) 1 (1) 58(2) 32 (2) 62 (2) 2 (2) -7(2) 51(2) 50(2) 60(2) 11(2) 9(2) 45(2) 52 (2) 45(2) 3 (2) 10 (2) 35(2) 40(2) 34(2) 5 (1) 2 (1) 43 (2) 41(2) 29 (2) 5 (1) 5 (1) 45(2) 50(2) 48(2) 2 (2) 10(2) 67(3) 46(2) 53 (2) - 3 (2) 18(2) 80 (3) 39(2) 45(2) - 3 (2) 17(2) 58(2) 45(2) 37(2) o (1) ~ (2) 49(2) 40(2) 25(2) 5 (1) 6 (1) 38(2) 42(2) 32(2) 4 (1) -1(1) .I
230
U12
3 (1) -16(1)
o (1) - 2 (2) 12 (1) - 8 (2) o (1)
11(2) 16(2)
9 (1) 5 (2) 4 (1)
-3 (1) - 2 (1)
1 (1) - 8 (2)
-14(2) - 8 (2) -2 (1) -1 (1)
1 (2) 10(2) -1(2)
-10(2) - 2 (1) - 6 (1)
231
Table 5: Hydrogen coordinates ( x 104) and isotropic displacement parameters
(A2 x 103) for nickel complex 143.
x y z U (eq)
H (1) 5067(34) 1716(21) 1556(22) 38(8) H (2) 7228(40) 1250(22) 840(24) 46 (10) H (3) 7615(48) -155(25) 492(29) 72(12) H(4) 5757(38) -1088(21) 961(24) 46(10) H (6B) 2299 (41) -781(21) 1220(26) 49(10) H (6A) 3475(41) -1345(25) 1782(26) 57(11) H(7A) 1880(38) -1144 (21) . 2941(24) 43 (9) H (7A) 3203(39) -542(22) 3250(25) 49 (9) H (8B) 92 (31) -405(18) 1625(22) 29 (7) H (8A) -734(35) 327(20) 2108(21) 36 (8) H (10) -834(36) -1791(20) 1828(24) 43(9) H (11) -2682(38) -2642(22) 2524(25) 47(9) H(12) -4129(41) -2184(23) 3753(27) 58(11) H(13) -3802(41) -847(21) 4340(26) 52 (10) H (16) -4145(42) 616(23) 3961(25) 54(10) H (17) -3742(48) 1943(26) 4670(30) 71(13) H (18) -:1.465(43) 2458(26) 4976(27) 62(11) H (19) 639(42) 1756(24) 4493(27) 60(11) H (21A) :1.849(36) 465(20) 4107(22) 41 (8) H (21B) 859(34) -362(20) 4102(22) 38(8)
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