Introduction

1

1.0 General Introduction:

The lanthanide ions have no known biological use, and only trace

amounts are found in whole body analysis. However, they show

biological activity. For instance, they may act as enzyme activation or

deactivation and in in-vivo studies, as nerve impulse stimulators (1). The

unique similarities in terms of coordination and binding characteristics

between the paramagnetic lanthanides with calcium makes the

lanthanides to act as an ―absorption probes‖ in understanding the

biochemical reactions and for structural studies of biomolecule

compounds and functions involving the isomorphous substitution of

Ca(II) by Ln(III) (2-6).

1.1 Chemical reactivity

One property of the Lanthanides that affect how, they will react with

other elements is called the basicity. Basicity is a measure of the ease

at which an atom will lose electrons. In another words, it would be the

lack of attraction that a cation has for electrons or anions. In simple

terms, basicity refers to have much of a base a species is. For the

Lanthanides, the basicity series is in the following order:

La(III) > Ce(III) > Pr(III) > Nd(III) > Pm(III) > Sm(III) > Eu(III) >

Gd(III) > Tb(III) > Dy(III) > Ho(III) > Er(III) > Tm(III) > Yb(III) >

Lu(III)

In other words, the basicity decreases as the atomic number

increases. Basicity differences are shown in the solubility of the salts

and the formation of the complex species. Another property of the

Lanthanides is their magnetic characteristics. The major magnetic

properties of any chemical species are a result of the fact that each

moving electron is a micro-magnet. The species are either

diamagnetic, meaning they do not have unpaired electrons, or

paramagnetic, meaning that they do have some unpaired electrons (7-

10).

Introduction

2

For Mendeleyev, each discovery of a new rare-earth element meant a

new puzzle, because each of them showed very similar chemical

behaviour that made it difficult to assign positions in his periodic

table. This unique chemical similarity is due to the shielding of 4f

valence electrons by the completely filled 5p6 and 6s2 orbitals. The

beauty of this family of elements is that, although the members are

very similar from a chemical point of view, each of them has its own

very specific physical properties--including colour, luminescent

behaviour, and nuclear magnetic properties (11-12).

1.2 Characteristics of the lanthanides

The lanthanides exhibit a number of features in their chemistry that

differentiate them from the d-block metals. The reactivity of the

elements is greater than that of the transition metals to the Group II

metals:

1. A very wide range of coordination numbers (generally 6–12 but

numbers of 8 or 9 are known).

2. Coordination geometries are determined by ligand steric factors

rather than crystal field effects.

3. They form labile ‗ionic‘ complexes that undergo facile exchange

of ligand.

4. The 4f orbital in the Ln(III) ion do not participate directly in

bonding, being well shielded by the 5p6 and 6s2 orbital. Their

spectroscopic and magnetic properties are thus, largely

uninfluenced by the ligand environment.

5. Small crystal-field splitting and very sharp electronic spectra in

comparison with the d-block metals.

6. They prefer anionic ligands with donor atoms of rather high

electro negativity (e.g. O, F).

7. They readily form hydrated complexes (on account of the high

hydration energy of the small Ln(III) ion) and this can cause

uncertainty in assigning coordination numbers.

Introduction

3

8. Insoluble hydroxides precipitate at neutral pH unless

complexing agents are present.

9. The chemistry is largely that of one (+3) oxidation state

(certainly in aqueous solution).

10. They do not form Ln=O or Ln≡N type of multiple bonds, which is

known for many transition metals and certain actinides.

11. Unlike the transition metals, they do not form stable carbonyls

and have (virtually) no chemistry in the zero oxidation elemental

state (13-16).

12. Using above information, the comparisons between d-block and

f-block elements are given in the following Table 1.1.

Features 4f 3d Group I

Electron configurations

of ions Variable Variable Noble gas

Stable oxidation states Usually +3 Variable 1

Coordination numbers

in complexes

Commonly 8–

10 Usually 6 Often 4–6

Coordination polyhedral

in complexes

Minimize

repulsion Directional

Minimize

repulsion

Trends in coordination

numbers

Often constant

in block

Often constant

in block

Increase down

group

Donor atoms in

complexes

‗Hard‘

preferred

‗Hard‘ and

‗soft‘

‗Hard‘

preferred

Hydration energy High Usually

moderate Low

Ligand exchange

reactions Usually fast Fast and slow Fast

Magnetic properties of

ions

Independent of

Environment

Depends on

environment

and ligand

field

None

Table 1.1 The characteristic features of the s-block metals (use group 1 as typical) and the d-block transition metals.

Introduction

4

Electronic spectra of

ions Sharp lines Broad lines None

Crystal field effects in

complexes Weak Strong None

Organometallic

compounds

Usually ionic,

some with

covalent

character

Covalently

bonded

Ionically

bonded

Organometallic in low

oxidation states Few Common None

Multiply bonded atoms

in complexes None Common None

1.3 Coordination chemistry of trivalent lanthanides

As a result of the different degrees of stabilization experienced by the

4f, 5d, and 6s orbitals occurring upon ionization of the neutral metal,

the lanthanides ((La-Lu, Z = 57-71) exist almost exclusively in their

trivalent state Ln(III) ([Xe]4fn, n = 0-14) in coordination complexes (17-

18).

Ln(III) complexes with their poor stereochemical preferences and high

coordination numbers provide ample scope for designing PDT active

species using photoactive organic ligands to achieve efficient oxidative

DNA cleavage activity and photocytotoxicity. Ln(III) complexes are also

expected to be non-toxic in dark owing to the redox stability of the

Ln(III) ions thus, making them suitable for cellular applications in the

presence of reducing cellular glutathione (19).

The physico-chemical properties of the resulting assembly are

determined by the nature of the ion-to-ligand chemical bonds and by

the geometrical arrangement of the ligands around the metal ion. One

shall concentrate on the applications since, they have been the main

thrust for the fast development of Ln(III) coordination chemistry

during the last two decades (20-21).

Coordination of fluoride as a neutral donor has relatively little

precedent in lanthanide chemistry. Early investigations of the

Introduction

5

reactions between fluorinated compounds and organolanthanide- (II)

compounds resulted in reductive C-F bond cleavage and the isolation

of Ln(III) products with F- ligands (22-27).

The coordination number, which is the number of metal-to-ligand

bonds, usually ranges between 4 and 6 and it was long thought by

analogy that Ln(III) ions have also coordination number 6 (28-31).

Investigation on molecular coordination complexes of lanthanide ions

has been attracted significant attention, owing to their fluorescent

broad applications in biochemistry, material chemistry, medicine and

so forth (32-33).

The coordination number of lanthanide though found to vary in the

range of 3 to 12, however, coordination number 8 and 9 are most

stable, contrary to this calcium shows presence for coordination

number 7 or 8. This tendency of lanthanide having larger number of

donor atoms in their primary coordination sphere is crucial in

isomorphous substitution of Ca(II) by Ln(III) ions. The Ln(III) generally

interacts with the binding site of soluble carrier ligands and this

complexed metal ion move from the site of inoculation to the other

parts very effectively. The formation of insoluble precipitate of Ln(III)

hydroxide, carbonates or phosphate or other form of complexes

species leads to concentration of Ln(III) at the site. The interference of

Ln(III) in normal metabolism involves the specific biochemical

interaction resulting in the production of toxic and pharmacological

sequel of different categories. The lanthanide interference in which

many toxic and pharmacological materials are released actually

induces complication in body system.

Site selectivity for coordination of lanthanide

Being hard acceptor, Ln(III) ions have strong affinity towards hard

donor like oxygen and its derivatives. This is because that these

binding sites are strong enough or compete with water molecules,

Introduction

6

which form the immediate coordination environment around Ln(III)

ions.

Lanthanide size and geometry of binding site

The size of lanthanides vary in the series, so the lower

lanthanide with larger size yield nona coordinated species, while

smaller Ln(III) go for octa coordination. In general, the Ln(III),

which can opt either octa or nona coordinated species, strong

preference is displayed for either site symmetry or geometry.

Binding strength

The binding of Ln(III) with ligand is much weaker than that

observed for transition metal ion but at the same time it is

considerably stronger than that of alkaline earth ions and very

much stronger than that of alkali metal ions. Ln(III) ions exhibit

a strong propensity for oxygen donor atoms. Nitrogen can also

coordinate but the interaction will be weaker and bond can

easily be disrupted by the presence of oxygen donor ligands or

even by water molecules.

1.4 Similarity of Ln(III) ions and Ca(II) ions

The unique similarity between the lanthanides and calcium in terms

of size and the coordination preference for higher coordination

numbers, the former has been used as probes in biochemical

reactions and for structural studies of biomolecular compounds

involving Ca(II) (34-35).

Lettiven and co-workers (36) drew attention towards the unique

similarities between Ca(II) and Ln(III) and suggested that lanthanides

might be used in studying the interaction of Ca(II) with nerves. This

prediction proved correct in later years as the effect of lanthanide ions on

celluar metabolism and physiology was studied (37).

Introduction

7

The similarity between trivalent lanthanides and divalent calcium in

terms of ionic radius and oxophilicity may enable direct substitution into

calcium-binding proteins, providing a valuable spectroscopic handle for

structural and dynamic studies (38-42).

Lanthanide metal ions, sharing many similar chemical properties with

calcium ions, have been observed to exchange with calcium ions in

bone tissue. Lanthanide metals have been proven to functionally,

Lanthanide-containing Pharmaceuticals 5 imitate calcium, as they

possess analogous ionic radii (0.86 – 1.22 Å vs. 1.14 Å, respectively),

donor atom preferences (O > N > S), and coordination numbers (CN =

6-9) (43). These similarities allow Ln(III) ion to exchange with Ca(II)

ion in bone, during which the bone remodeling cycle is altered so that,

the pro life ration of osteoblasts (cells that regenerate bone) is

stimulated. The differentiation of osteoclasts (cells that break down

bone) is impeded (43-47). Scientists (48) found different lanthanides

showing different behaviour and this was ascribed to the similarity of

Ln(III) predominantly with Ca(II) or the similarity of Ln(III) with Mg(II),

the two most abundant metal ions in our body system.

For years, many biological effects of lanthanides were considered to be

related with calcium. It is well known that, due to the similarity

between Ca(II) and Ln(III) ions in coordination chemistry, lanthanides

can compete with and/or substitute Ca(II) from calcium binding

proteins and also have some influences on intracellular Ca(II)

homeostasis (49-51).

It is true that Ln(III) is very similar to Ca(II) in many aspects such as

low covalence tendency and negligible redox properties. Ca(II) ion was

found to destabilize microtubules, contrary to Mg(II). The lower

lanthanides behaved more like Ca(II), because of their larger size and

hence the propensity of exhibiting relatively higher coordination

number. Heavier lanthanide like Tb(III), Dy(III) and Ho(III), being

Introduction

8

smaller in size, behave more like Mg(II), having a greater potential for

strengthening the microtubules (52).

Lanthanide salts were first investigated in clinical trials for

antimicrobial, anticoagulant and other pharmacogical properties in

the early part of this century (53-57). Water is essential component of

all biological fluids and nearly all biochemical reactions involved water

as the medium, participant or catalyst. At the same time, water has

high affinity for lanthanides ion as a ligand.

The ionic radii of lanthanides range from 0.0848 nm (Lu) to 0.1034

nm (Ce), the values being relatively higher than those in other

elements with the same oxidation. The ionic radii of cerium,

praseodymium, neodymium and gadolinium are similar to that of

calcium (0.104 nm), the element that plays an essential role in many

metabolic processes. This similarity determines physiologic effects of

soluble lanthanide salts (58).

The difficulty that competing ligands experience in their attempt to

extracts water molecules from the strong coordination shell around

the lanthanide restricts the number of these ligands, which can

interact with the lanthanide ion in aqueous medium. Williams (59)

showed in early 1970s that the similarity between calcium and

lanthanides is not restricted to ionic radii but included important

aspects of coordination. It is logical to assume that biological activities

of lanthanide ions as well as their activity for calcium substitution

reactions include coordination phenomenon, which is controlled by

similarities in size, nature of bonding, coordination number, binding

site preference, hydration number, complex stability, coordination

geometry and virtually no ligand field stabilization energy. Each of

these properties is related to the coordination characteristics of both

Ca(III) and Ln(III) ions. This coordination characteristic of Ln(III) not

only are responsible for controlling Ca(II) activity but sometimes

allows Ln(III) to participate in several biochemical reactions involving

Introduction

9

Mg(II), Iron and Manganese also (60-65). Some unique similarity in

the coordination properties of lanthanide and calcium are shown in

Table 1.2. Moreover, the following three points make Ln(III) ions

unique in substitution for Ca(II): (66)

(a) Ln(III) ions serving at the Ca(II) sites and activating biological

activities.

(b) Ln(III) ions acting as competing inhibitors of Ca(II) functions.

(c) Ln(III) ions introduction causing no effect on the biological

activities of biomolecules in the metabolism.

1.5 Ln(III) ions as a probe

Ln(III) ions as an indirect probe to investigate the interaction of

biomolecules with Ca(II), the most abundant metal ion in our body

system can be investigated by an electrochemical, luminescence,

NMR, X-ray diffraction and absorption spectral technique.

Ln(III) ions are normally present in living systems in a very trace

amount (67-68). But the most important utility of these Ln(III) ions

are due to their ability to serve as an informative spectroscopic probe

Property Ca(II) Ln(III)

Coordination number 6-12 reported 6-12 reported

Coordination geometry 6 or 7 favoured 8 or 9 favoured

Donor atom preference 0 >> N >> S 0 >> N >> S

Ionic radius (Ao) 1.00 – 1.18(CN 6-9) 0.86 – 1.22 (CN 6-9)

Type of bonding Ionic Ionic

Hydration number 6 8 or 9

Water exchange rate constant (s-1)

-5 × 108 -5 × 107

Diffusion coefficient (cm2 /s × 105)

1.34 1.30

Crystal field stabilization None Negligible

Table 1.2 Salient features of lanthanide and calcium

Introduction

10

and are also useful in enzyme assay, electron microscopy and in

number of other types of biochemical investigations.

1.5.1 Ln(III) as a NMR- probe

Paramagnetic Ln(III) ions have been used successfully as

spectroscopic probes for the study of chemical, physical and

physiological properties of many Ca(II) dependent biological systems in

the past several years. Some paramagnetic Ln(III) (e.g. Pr(III), Eu(III),

and Yb(III)) possessing very short electronic relaxation times are able

to exhibit relatively sharp isotropically shifted 1H NMR features

attributable to the protons in the close proximity of the metal (69-72).

Thus, the use of such Ln(III) ions as substitutes for Ca(II) in proteins

raises the possibility of detailed NMR study of the Ca(II) binding

environment in proteins (73). These paramagnetic Ln(III) ions have

also been used as NMR probes for the study of the structural and

functional roles of several metal-dependent antibiotics, such as the

anthracyclines (74-76).

1.5.2 Ln(III) as a MRI probe

The introduction of paramagnetic Ln(III) increases the difference in

proton spin lattice, spin-spin relaxation time and thus, enhancing the

contrast obtained during NMR imaging. The resulting images are thus,

affected by the degree to which Ln(III) are concentrated in the target

tissue i.e., two adjourning structures having different concentration of

Ln(III) ions. In this class, Gd-DTPA has extensively been used in

producing good image enhancement in animal studies. The high

effectivity of Ln(III) is well documented as MARKER for studying

efficiency of many reactions in human and animals (77-80).

1.5.3 Ln(III) as a Laser YAG probe

It has been more than 30 years since the first lanthanide lasers were

reported. Lanthanide-doped yttrium aluminium garnet (YAG) lasers

Introduction

11

are extensively used in research laboratories and in industry as a

laser source, while different physical properties and microscopic

processes and their effects on the laser performance continue to be

under study. Nd-YAG laser probe is very well known and well

recognized as boon in neurosurgical investigations.

1.5.4 Ln(III) as an absorption spectral probe

The unique similarities in the coordination characteristics between

Ca(II) and Ln(III) lead to isomorphous substitution of Ca(II) by Ln(III),

because Ca(II) is diamagnetic hence, spectroscopically inactive

whereas Ln(III) ions are paramagnetic, which provide number of

spectroscopic signals. Therefore, Ln(III) (Pr(III) and Nd(III) ions) can be

used as an absorption spectral probe, to investigate many biochemical

reactions in which Ca(II) is involved.

4f - 4f transition in Ln(III) ions

The 14 elements from Lanthanum to lutetium with access to their 4f

shell are known as the lanthanides. They are hard acceptor,

electropositive metals and the nature of their 4f shells imparts some

unique properties to the lanthanides (81). The electronic shielding of

the f electrons is quite weak and hence, as one proceeds from La to Lu

the increasing atomic number or nuclear charge causes a decrease in

the radiation of the atoms, which is known as the lanthanide

contraction. The lanthanides are easily oxidized and favour the +3

oxidation state with few exceptions. Since, the f orbital are buried

within the atom they interact only very weakly with ligand orbital. As

a result the f-f transitions, which occur in the visible region of the

spectrum, give rise to very narrow bands and the lifetimes of their

excited states are quite long lived (s–ms) (82).

The valence 4f electrons of trivalent lanthanides ion [Ln(III)] are well

shielded from the environment by the outer core 5p and 6s electrons

and are minimally involved in bonding. Because of this shielding, the

Introduction

12

atomic properties of these ions are typically retained after

complexation.

As a result of the small Laporte-forbidden (LF) splitting for the Ln(III)

complexes, radiation less decay processes are relatively inefficient and

emission from these complexes is common. The absorption and

emission spectra of Ln(III) ions consist of sharp, narrow bands

corresponding to the f-f transitions of the metal ion (83-85).

The number of bands depends on the particular lanthanide ion and its

arrangement of electronic states. Upon complexation with ligands no

significant change is observed in the electronic absorption spectra

only small displacements in the peak positions, usually toward longer

wavelengths and changes in the relative intensities of spectra are two

common features (86).

Extensive measurements of energy levels of the 4fn configurations of

lanthanide in various host lattices were carried out in the 1950s and

1960s. Much of this work was carried out by Dieke and co-workers

and the data summarized in his well known book published in 1968

(87). The energy-level diagram for trivalent lanthanide ions presented

in that book is commonly referred to as a ―Dieke diagram‖, which

shown in the Fig. 1.1.

Introduction

13

Although Ln(III) ions have weak absorption and emission intensities,

due to the fact that the intra-configurational f –f transitions are

Laporte forbidden, this disadvantage can be overcome by indirect

sensitization through the absorption bands (indirect excitation) of the

ligand molecules coordinated to the Ln(III) ions using UV light.

The information obtained is of direct chemical interest in relation to

the coordination number, immediate coordination environment

involvement of metal 4f orbital, structure and geometry of the complex

species in solution (88-89). The use of lanthanides as an absorption

spectral probe in several biochemical reaction involving Ca(II) and

Mg(II) has opened up a new dimensions in the fast developing field of

optical spectroscopy for biochemistry of Ln(III) ions (90-93). The

development of this research requires information on composition and

Fig. 1.1 The energy-level diagram for trivalent lanthanide ions (Dieke diagram)

Introduction

14

structure of such species exiting in system under investigation, their

spectra, thermodynamic and kinetic parameters.

The 4f electron of lanthanide yield three types of transitions

Internal 4f-4f transition, which give rise to sharp, narrow bands

of comparatively weak intensity, which are laporte forbidden

(94-95).

Allowed 4f n- 4f n-1 (n-1), which is relatively broad and intense.

Broad often intense 4f n- λ-1f n+1 electron transfer bands

generally occurring in ultraviolet region (represents a hole in the

orbital) concentrated mainly on ligands (96-98).

1.5.5 Ln(III) as an electrochemical Probe

As mentioned earlier that Ca(II) can isomorphously substituted by

using Ln(III) ions because of their certain properties and

electrochemical study of Ca(II) is very difficult, as it requires drastic

conditions. Eu(III) can be used as an electrochemical probe, as it

resembles very closely to Ca(II) in its unique di-positive state due to

half field 4f orbital.

Electrochemistry of Ln (III)

Kolthoff and Lingane (99) have discussed the electrochemical features

of lanthanide metal ions in its +3 oxidation state. The reduction of

these metal ions seems to be an interesting problem because of their

typical electronic structure. Only three lanthanide metal ions [Eu(III),

Yb(III) and Sm(III)] have stable divalent ions (100) therefore, the

reduction step is accessible for electrochemical investigation (101).

However, the cyclic voltammograms of Eu(III) recorded in perchloric

acid, sodium chloride and potassium chloride show that the reduction

of Eu(III) is found quasi reversible at Hanging Mercury Drop

Electrode(HMDE) (102). The authors have narrated that the cathodic

Introduction

15

peak is sharp but anodic peak is rounded and diffusive. The reduction

of Eu(III) at Dropping Mercury Electrode(DME) in the presence of

different base electrolytes are also reported as totally irreversible

(103).

Thus, the electrochemistry of Eu(III)/Eu(II) coupled at DME/HMDE/Pt

and other electrodes have been the subject of a large number of

investigations. Comprehensive studies are also reported by Misumi

and Ide (104), Vleck (105), Gierst and Cornelissen (106) and by

Macero et.al. (107). The main interest in this system is due to the fact

that the Eu(III) is the only one of the three lanthanides that has a

stable +2 state in aqueous solutions. The standard redox potentials

(E), of that system is very close to the point of zero charge at the

mercury when there is no specific adsorption is observed.

It has been found that the reduction of Eu(III) at the DME is

polarographically irreversible in most supporting electrolytes except in

thiocyanate (108). An unstable Eu(II) intermediate of different

electronic configuration from the reduced solutions has been

postulated and the activation over potential associated with the

electrochemical reaction has been attributed to a shielding effect

caused by the 5p and 6s electrons. The utility of Kalouske (K-I and K-

II) polarography in the investigation of the Eu(III)/Eu(II) system using

variable electrode kinetics was studied by Kindrd and Philipir (109)

and suggested the reversibility of Eu(III)/Eu(II) reaction as evidenced

by K-I/K-II curves increases in order of supporting electrolytes as

ClO4 < Cl < NO3

< Br < I and < SCN. The double anodic wave

observed by Kinard (109) at low ionic strength in perchlorate is

explained as the double layer effect rather than in an intermediate in

the reduction. An electrochemical behaviour of Eu(III) in presence of

halide and sulfate is assumed as;

Introduction

16

M3 + X (MX) 2

(MX) 2+ + X (MX2)+

The reversible reduction of Eu(III) at DME in the presence of EDTA

and in format buffer has also been reported (110). The electrode

mechanism of Eu(III)/Eu(II) coupled reaction is also shown by

Sluyters et.al. (111).

The reduction of rare earth ions at DME has been investigated in a

number of nonaqueous solvents like DMF and DMSO (112).

Sm(III), Eu(III) and Yb(III) show two steps reduction, while the other

rare earth ions exhibit only one. The detailed mechanism of

M(III)/M(II) redox process for Sm(III) and Eu(III) cannot be regarded as

established in non aqueous solvents and the electron transfer process

seems rather slow in all solvents studied. Galus et.al. (112) have

studied the kinetics of Eu(III)/Eu(II) system at mercury electrode in

aqueous, CH3CN, DMF, DMSO and HMPA solvents and established

order of the formal potential as CH3CN< H2O < DMF < DMSO < HMPA

with the increase in salvation ability.

Eu(III) is found to be an excellent ideal system for elaborate studies,

which behave from totally reversible to irreversible depending on the

supporting electrolyte and/or the ligands present in the solution

(113). Further, comprehensive studies on the Eu(III)/Eu(II) coupled

system at the DME have been reported by many workers (113-122).

The influence of water and the effect of [H+] ion on Eu(III) electrode

reduction in aetonitrile explained as

Eu3+ + e Eu2+

Eu2+ + H+ Eu3+ + 1/2 H2

Eu3+ (H2O)x (CH3CN)y Eu3+ (OH) (H2O)x-1 (CH3CN)y+ H+

Introduction

17

The replacement of water molecules by CH3CN within the coordination

sphere of Eu(III) is a fast reaction, while its behaviour in DMF (112) as

given bellow.

M2+ + H2O M3+ + OH +1/2 H2

(DMF)n Sm3+ (H2O) (DMF)n Sm3+ (OH+ H+

M (DMF)83+ + (n-8) DMF +e M(DMF) 2n

The importance of lanthanides in understanding the behaviour of

many biomolecules and particularly the electrochemical behaviour of

Eu(III) ion has tempted us for investigation in depth.

1.5.6 Ln(III) as a luminescence probe

Trivalent lanthanide ions show intense luminescence in the visible

and near-infrared regions with many favourable properties like narrow

emission bands, long decay times and a large stokes‘ shift. Thus,

lanthanide compounds have gained widespread attention as potential

materials for light-emitting diodes, medical and biological applications

(123-131).

The lanthanides (Ce–Lu) are unique among the elements, barring the

actinides, in resembling each other so markedly in their chemical

properties, particularly oxidation states (132-133). This is readily

explained by the electronic configuration of the atoms and their

derived ions, which essentially exist in their trivalent state Ln(III)

([Xe]4fn, n=0–14) (134) in aqueous solutions, in view of the various

degrees of stabilization experienced by the 4f, 5d and 6s orbital upon

ionization. The shielding of the 4f orbital by the filled 5p6 6s2 sub-

shells results in special spectroscopic properties with parity-forbidden

4f–4f absorptions having very low molar absorption coefficients and

characteristic narrow-line emission, mostly in the visible and near

infrared ranges. Luminescence has been instrumental in the discovery

Introduction

18

of several lanthanide elements (cf. the work of Crookes (135) and

Urbain). In turn, these elements have always played a prominent role

in lighting and light conversion technologies and more recently in both

cathode-ray (136) and plasma (137) displays.

Presently, attention has been given to several potential applications of

luminescent lanthanide ions: (138)

(i) Their continuing use in the lighting industry for the engineering

of lamp phosphors (139),

(ii) Their ability to provide electroluminescent materials for organic

light emitting diodes and optical fibers for telecommunications

and

(iii) Their capacity to yield functional complexes for biological

assays and medical imaging purposes (140-142).

Eu(III), Gd(III) and Tb(III) are the best ions, with ∆E = 12,300 (5D0 →

7F6), 32,200 (6P7/2 → 8S7/2) and 14,800 (5D4 → 7F0) cm-1, respectively.

However, Gd(III) emits in the UV, and it is not very useful as

luminescent probe for bio-analyses because its luminescence

interferes with either emission or absorption processes in the organic

part of the complex molecules. On the other hand, it can efficiently

transfer energy onto Eu(III) upon vacuum-UV excitation, resulting in

the emission of two red photons (the so-called quantum cutting or

down-conversion effect) (143).

Gd(III) is therefore, a potential phosphor component for mercury-free

fluorescent lamps. The sizeable energy gap displayed by Eu(III) and

Tb(III), explains why luminescent probes containing these ions have

been so popular during the last decades. Nevertheless, development of

dual luminescent time-resolved immunoassays has also stirred

interest for Sm(III) (∆E =7400, 4G5/2 → 6F11/2) or Dy(III) (7850 cm-1,

4F9/2 → 6F3/2) (144-149). The other ions have very low quantum yield

Introduction

19

in aqueous solutions and appear to be less useful with respect to

similar applications. Pr(III) emits both in visible and NIR ranges and is

often a component of solid state optical materials, in view of its ability

of generating up-conversion that is blue emission from 3P0 upon two

or three photon pumping of the 1G4 or 1D2 states (150). Thulium is a

blue emitter from its 3P0, 1D2 and 1G4 levels and is used as such in

electroluminescent devices; it is the first Ln(III) ion for which up-

conversion has been demonstrated (150); several other ions [Nd(III),

Dy(III), Ho(III) and Er(III)] present up-conversion processes as well. In

addition, Nd(III), Ho(III), Er(III) and Yb(III) have special interest in that

they emit in the NIR spectral range and are very useful in the design

of lasers (especially Nd(III) with its line at 1.06 mm) and of

telecommunication devices (151). The partial energy level diagram for

various Ln(III) ions is depicted in the Fig. 1.2

Introduction

20

Most of the electronic transitions of the trivalent Ln(III) ions involve a

redistribution of electrons within the 4f sub-shell. Electric dipole

selection rules forbid such transitions but these rules are relaxed by

several mechanisms. An important one is the coupling with

vibrational states, where a molecular vibration temporarily changes

the geometric arrangement around the metal ion and therefore, its

symmetry. Other mechanisms, which cause a breakdown of the

selection rules are the J-mixing and the mixing with opposite-parity

wave functions such as 5d orbital, ligand orbital or charge transfer

states. The coupling between these vibrational and electronic states

and the 4f wave functions depends on the strength of the interaction

between the 4f orbital and the surrounding ligands; in view of the

shielding of the 4f orbital, the degree of mixing remains small, and so

Fig. 1.2 Partial energy diagrams for the lanthanide aqua ions. The main luminescent levels are drawn in red, while the fundamental level is indicated in blue.

Introduction

21

are the oscillator strengths of the f–f transitions. As a consequence,

even if many lanthanide containing compounds display a good

quantum yield, direct excitation of the Ln(III) ions rarely yields highly

luminescent materials. Indirect excitation (called sensitization or

antenna effect) (152-153)has to be used and is proceeds in three

steps (154-156), as shown in following Fig 1.3

First, light is absorbed by the immediate environment of the Ln(III) ion

through the attached organic ligands (chromophores). Energy is then

transferred onto one or several excited states of the metal ion and

finally, the metal ion emits light as shown in Fig 1.4. Sensitization of

trivalent lanthanide ions is an exceedingly complex process involving

numerous rate constants (157-160).

Fig. 1.4 Simplified diagram showing the main energy flow paths during sensitization of

Lanthanide luminescence via its surroundings (ligands).

Fig. 1.3 Antenna effect of Ln 3+

Introduction

22

In aqueous solution, interaction with water (both in the inner and

outer coordination sphere of the Ln(III) ion) lead to a severe quenching

of the metal luminescence via O–H vibrations (161). Although

disadvantageous to the design of highly luminescent edifices, this

phenomenon can be used to assess the number of water molecules (q)

interacting in the inner coordination sphere. Several approximate

phenomenological equations have been proposed based on the

assumptions that O–D oscillators do not contribute to de-activation

and that all the other de-activation paths are the same in water and in

deuterated water and can henceforth be assessed by measuring the

lifetime in the deuterated solvent (162-164).

The emission from lanthanides has proven useful as a sensitive

detection method in biological systems and has facilitated their

understanding. The changes in the intensity of the Eu(III)

luminescence upon binding to proteins and enzymes have been

utilized to examine the ligation sphere within the active site, whereas

distance and conformational information under physiological

conditions has been obtained from energy transfer studies either

between two lanthanide ions or from the protein‘s residues to Eu(III)

or Tb(III) bound to the active site (165-166). Luminescence

enhancement of a given probe in the presence of nucleic acids can in

principle yield such detection, with marked safety and environmental

advantages over radioactive labelling. Owing to the emissive properties

of Tb(III) and Eu(III), including their luminescence enhancement

through energy transfer and their ability to bind single stranded

regions of proteins.

One initial landmark was the discovery in year 1942 of what is known

today as the antenna effect by Weissman (20), who demonstrated that

energy transfer occurs from the bound ligands to the metal ion

providing an excellent way for the sensitization of the Ln(III) ion

luminescence.

Introduction

23

The use of lanthanide f-ions such as Eu(III), Tb(III), Sm(III), Yb(III),

Nd(III), etc. in such luminescent supramolecular systems, has become

a very active area of research (167-174). From the view of developing

luminescent chemical sensors, changes in various photo-physical

properties such as wavelength, lifetimes and quantum yield (the

outputs) can all be modulated as a result of external perturbation.

This phenomenon can also be employed to investigate the formation

and physical properties of complexes of supramolecular structures

and self-assemblies (175-178).

1.6 Applications of Lanthanide ions

1.6.1 Therapeutic application

Lanthanide complexes are of considerable interests for their

therapeutic utility providing strong impetus to explore their biological

activities (179-181). There is fast moving research on lanthanides and

their interrelations with bio-systems to understand their functional

roles in biology and medicine (182-184).

The coordinating chemistry of lanthanides, relevant to the biological,

biochemical and medical aspects, makes a significant contribution to

understanding the basis of application of lanthanides, particularly in

biological and medical systems. The importance of the applications of

lanthanides, as an excellent diagnostic and prognostic probe in

clinical diagnostics, and an anticancer material, is remarkably

increasing. Lanthanide complexes based X-ray contrast imaging and

lanthanide chelates based contrast enhancing agents for magnetic

resonance imaging (MRI) are being excessively used in radiological

analysis in our body systems. Conjugation of antibodies and other

tissue specific molecules to lanthanide chelates has led to a new type

of specific MRI contrast agents and their conjugated MRI contrast

agents with improved relaxivity, functioning in the body similar to

drugs (185).

Introduction

24

In 1931, Maxwell and coworkers used an aqueous solution of

lanthanum chloride for treating cancer by administering LaCI3

solution intraperitoneally. However, it was only the work of Anghileri

and coworkers, which could successfully demonstrate the strong

inhibitory effects of LaCl3 and other lanthanide compounds on the

growth of sarcoma tumors in rats. Excellent work has come out of

Anghileri‘s laboratory, on lanthanide compounds and complexes in

cancer research as a diagnostic and prognostic probe. These workers

used Ln(III) as an adjunct to the distraction of tumors by using a

combination of the complexes of two different lanthanides specially

derived form hydroxy carboxylic acids for treating animals and in

some cases involving humans suffering from Yoshida Sarcoma. The

results were found astounding. The complexes of lanthanides are

getting more and more applications in cancer therapy and the most

important of these are those derived from poly (aminocarboxylic)

acids. These days‘ diagnostic imaging procedures are a routine part of

modern medicine and are useful in performing the initial diagnosis,

the planning of the treatment and post treatment evaluation (185-

195).

Lanthanide ions are trivalent and similar in their chemical and

biological properties to the alkaline earth elements. In the past, some

lanthanide compounds were used in the treatment of tuberculosis, as

anticoagulant agents for prevention of thrombosis, and as anti nausea

agents during early pregnancy. More recently, lanthanides have been

used in dentistry for cancer treatment as anti-inflammatory agents,

and as antivirus agents (196).

Alpha- and flaviviruses contain class II fusion proteins, which form

ion-permeable pores in the target membrane during virus entry. The

pores generated during entry of the alphavirus Semliki Forest virus

have been shown previously to be blocked by lanthanide ions. Here,

analyses of the influence of rare earth ions on the entry of the flavi

viruses, West Nile virus and Uganda S virus revealed an unexpected

Introduction

25

effect of lanthanide ions. The results showed that a 30 s treatment of

cells with an appropriate lanthanide ion changed the cellular

chemistry into a state in which the cells no longer supported the

multiplication of flaviviruses. This change occurred in cells treated

before during or after infection, did not inhibit multiplication of

Semliki Forest virus and did not interfere with host-cell multiplication.

The change was generated in vertebrate and insect cells, and was

elicited in the presence of actinomycin D. In vertebrate cells,

specifically La(III), Ce(III), Pr(III) and Nd(III) elicited the change. In

insect cells, additional lanthanide ions had this activity. Further

analyses showed that lanthanide ion treatment blocked the ability of

the host cell to support the replication of flavivirus RNA. These results

open two areas of research: the study of molecular alterations induced

by lanthanide ion treatment in uninfected cells and the analysis of the

resulting modifications of the flavivirus RNA replicase complex. The

findings possibly open the way for the development of a general

chemotherapy against flavivirus diseases such as Dengue fever,

Japanese encephalitis, West Nile fever and yellow fever (197).

Lanthanum and the fourteen elements following it (together, called the

lanthanide series) are used in medical image visualisation. At a

certain concentration, the cerium compounds could be possibly

involved in the control of cell proliferation and inhibiting the growth of

cancer cells (198-199).

A big stimulus arose in the mid 1980‘s when a small Finnish

company, Wallac Oy from Turku, marketed bioassays based on

timeresolved luminescence of Eu(III) (200).

In the literature, very few Yb(III) complexes have been reported to display

promising anti-cancer activities without photoactivation or conjugation

to cytotoxic counterparts/radionuclides (201).

The La(III), Eu(III) and Yb(III) complexes 1La, 1Eu and 1Yb,

respectively, from cyclen by incorporating four amino esters

(the‗pseudo‘ dipeptide GlyAla) as pendant arms into cyclen. From an

Introduction

26

applications point of view, such lanthanide ion based ribonuclease

mimics are highly desirable as therapeutics in gene therapy, as

antisense agents, and as tools in molecular biology and genetics (202-

203).

Several years ago, however, the remarkable catalytic activity of the

lanthanide ions was discovered, and both DNA and RNA were for the

first time hydrolysed at reasonable rates under physiological

conditions. The Ce(IV) ion is the most active for DNA hydrolysis,

whereas Tm(III), Yb(III) and Lu(III) (the last three lanthanide ions) are

quite effective for RNA hydrolysis (204-206). Lanthanide have been

used as biochemical probes to study calcium transport in

mitochondria and other organelles (207). Lanthanide complexes have

an increasingly important role in medicine, where they are employed

as diagnostic as well as therapeutic agents (208). The peculiar

electronic properties of lanthanide ions, in fact, are exploited for the

development of powerful NMR probes for medical application (209);

Gd(III) complexes are in current clinical use for magnetic resonance

imaging (210-211) and lutetium compounds have shown a great

potential as radio sensitizer for the treatment of certain types of

cancers (212). The study of the remarkable catalytic activity of the

rare earth metals for the hydrolysis of nucleic acids is another active

field of research, mainly because it is essential for further

developments in biotechnology, molecular biology, therapy and related

fields (213-216). The biological properties of the Ln(III) ions, primarily

based on their similarity to calcium, have been the basis for research

into potential therapeutic applications of Lns since the early part of

the twentieth century (217-219).

However, lanthanides might be clinically valuable for blocking gene-

specific transcription for antibiotics or chemotherapeutic applications

or for customized targeting of oncogenic mutations (220). The

gadolinium concentration in the new biomaterial is relatively high;

this flux is becoming to be close to the necessary therapeutic values.

Introduction

27

This means that the new biomaterial opens an opportunity to carry

out the effective irradiation by thermal neutrons using smaller and

safer machines with a smaller flux and to reduce harmful effects of

the irradiation (221).

Rare earth elements (REEs) are widely used in industry and medicine.

As an example, radioactive REEs can be used in the diagnosis and

treatment of cancer. This therapeutic aspect attracts increasing

interest and inspires many researchers to investigate REE effects on

tumour development and growth. There is substantial evidence

showing that REEs inhibit proliferation and induce apoptosis in

certain cancer cell lines (222-228).

1.7 Biochemistry of Ln(III) ion

Lanthanides are known to form complexes with many functional

groups found in biological molecules, especially with donor groups

that posses a lone pair of electrons, such as oxygen atoms in the

carboxylic groups of amino acids. Lanthanides can bind at the active

sites of biomolecules, replacing various ions that include Ca(II), Zn(II),

Mg(II), Mn(II), Fe(II) and Fe(III).

The ability of lanthanide ions to luminescence at room temperature

and their specific spectroscopic characteristics made them a versatile

probe for the study of the biochemical processes that take place in

metal binding proteins and metalloenzymes.

The effect of coordination compounds of lanthanides with DTPA on the

phase behavior of DPPC liposomes is smaller than that of their

chlorides. La(III), Gd(III), and Yb(III), can displace Ca(II) binding on

DPPC liposomes, but there coordination compounds of DTPA can

hardly displace Ca(III) (229).

Information regarding the composition and structure of the metal

binding site can be obtained from the emission and excitation spectra

of Tb(III) and Eu(III)-protein complexes. Furthermore, binding

Introduction

28

constants of metal ions such as Ca(II) and Zn(II) to proteins can also

be calculated using Eu(III)-metal competition titration method (230).

The binding constant of Eu(III) is first determined using the titration

curve of the intensity of the 5D0 → 7F0 (λem = 579nm) emission as a

function of total equivalents of Eu(III) added to the protein. The

intensity of the Eu(III) luminescence decreases as a known quantity of

the competing metal ion is added, which is proportional to the amount

of replaced Eu(III), making the relative binding constant measurement

possible (230-232).

The hydration number (the number of water molecules) in the inner

coordination sphere of the metal can also be determined by measuring

the differences of emission lifetime of Tb(III) and Eu(III) in H2O and

D2O. As discussed earlier, the excited state lifetime of Eu(III) is very

sensitive to the number of water molecules coordinated to the ion

thus, replacing H2O by D2O can cause lifetimes to increase

dramatically (by a factor of ~9). For example, two water molecules

were found at the Ca(II) binding site in the satellite tobacco necrosis

virus (233-236) and four waters were found to coordinate at the

catalytic Mg(II) site in the ATP dependent enzyme glutamine syntheses

(237). Knowledge of the number of water molecules leads to the direct

estimation of the total number of coordinating atoms supplied by the

protein, since, Ln(III) ions usually possess total coordination numbers

of 7 to 9.

Laser-excited Ln(III) ion has been widely used to identify the metal

binding site in a variety of proteins and metalloenzymes (238).

Analysis of the 5D0 → 7F0 band in the excitation spectrum and

luminescence titration of Eu(III) in a complex with bovin α-

lactalbumin, at least two different calcium binding sites and three

kinds of ligands have been determined (239).

Lanthanide Luminescent Bioprobes (LLBs) are amongst the most

sensitive luminescent probes because their excited states are long-

Introduction

29

Fig. 1.5 Lanthanide Luminescent Bioprobes (LLBs)

lived, which allows Time Resolved Detection (TRD) of their

luminescence. Applications of LLBs to immunoassays, DNA analysis,

ligand binding assays, analytes sensing, and cellular imaging has

been reviewed (240-245). Route mechanism of LLBs is represented in

the Fig. 1.5.

1.8 Aim & significance of the work

The main aim of this Ph.D. programme is to focus on application of

Ln(III) in mimicking the biochemical reaction, that involved Ca(II), one

of the most abundant metal ions in our body system.

To achieve the aim following objects are selected:

i) Study of the Ln(III) ions like Nd(III) and Pr(III) ions inleution with

biomolecules in conditions similar to physiological conditions,

using 4f-4f transitions.

ii) Study of the Ln(III) ions and their interaction with

Lysozyme/GSSG using electroanalytical tools.

iii) Study of the Eu(III) ion and their interaction with

Lysozyme/GSSG using Luminescence method.

Introduction

30

iv) Study the divalent states of Europium, Samarium,

Praseodymium, Neodymium and ytterbium in non-aqueous

medium.

v) Ultra sonic sound technique will be used for various acoustical

properties of Eu(III) and Eu(III) + Lysozyme in ternary system.

Adopted methodology in our lab, we have spectro fluorometer (1501

RF) from Shimadzu, UV-1800 from Shimadzu and One electro

chemical substation with US. UV-1800 will be used for study of 4f-

4f transition of Pr(III) and Nd(III). Spectro-Florometer 1501 RF will

be used for Luminescence study of Eu(III) and its in taking with

Lysozyme/GSSG. Electrochemical substation (CH 660B) will be

used for study of divalent states of Eu/Sm/Pr/Nd/Yb and their

interaction with Lysozyme/GSSG.

Introduction

31

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