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FARMACIA, 2008, Vol.LVI, 3

THE LANTHANIDES: PHYSICO–CHEMICAL PROPERTIESRELEVANT FOR THEIR BIOMEDICAL APPLICATIONS

CARMEN MARIA STURZA1*, RICA BOSCENCU2, VERONICA NACEA2

1”Arsmedica” 150 Aurel Vlaicu str, Bucharest

2University of Medicine and Pharmacy “Carol Davila”

Departament of Inorganic Chemistry, 6 Traian Vuia str, Bucharest

*corresponding author:

Abstract

Over the past ten years a resurgence of interest in the lanthanides chemistry has been noticed, especially in the biomedical applications of these elements. In this review we try to demonstrate that for the biomedical applications of lanthanides their spectral, magnetic and coordinative properties are essential.

The lanthanides represent the largest naturally occurring group of elements in the periodic table. They are highly electropositive and reactive metals. Spectral and magnetic properties of lanthanide ions are remarkable. Their coordination chemistry is complicated, especially in solutions having not well defined stereochemistry and uncertain coordination numbers. However, the complexes of lanthanides and even the lanthanide salts are getting more and more applications in biology, biochemistry and medicine.

The chelates of lanthanide ions are used as labels in fluorescent immunoassays. The paramagnetic and luminescent Tb+3- phosphatidylcholine-complexes are unique evidence for the cation phospholipid interaction. Water-soluble La+3 and Eu+3 complexes are effective in detecting sugars neutral environment and glycolipids and phospholipids as well. Furthermore, literature data show that some simple lanthanide salts and complexes exhibit an antitumoral activity.

All above reveal the actuality of the subject.

Rezumat

În ultimii 10 ani a existat o revenire a interesului pentru chimia lantanidelor, în special pentru aplicaţiile biomedicale ale acestor elemente. În acest referat încercăm să demonstrăm că proprietăţile spectroscopice, magnetice şi coordinative ale lantanidelor sunt esenţiale pentru aplicaţiile lor biomedicale.

Lantanidele reprezintă cea mai largă grupăde elemente naturale din sistemul periodic. Sunt metale foarte electropozitive şi reactive.

Proprietăţile spectroscopice şi magnetice ale ionilor lantanidelor sunt remarcabile. Chimia lor coordonativă este complicată, în special în soluţie, de o stereochimie dificilăşi de numere de coordinare incerte. Cu toate acestea, complecşi ai lantanidelor şi chiar unele săruri au din ce în ce mai multe aplicaţii în biologie, biochimie şi medicină.Chelaţi ai lantanidelor sunt utilizaţi ca markeri în imunoteste bazate pe fluorescenţă.Complecşii paramagnetici şi luminiscenţi Tb+3-fosfatidilcholina oferă dovada interacţiei cationi metalici-fosfolipide.

Complecşii solubili în apă ai La+3şi Eu+3 permit identificarea glucidelor în mediu neutru ca şi a unor glicolipide şi fosfolipide.

Mai mult, date din literatură confirmă activitatea antitumorală a unor săruri simple şi chiar combinaţii complexe ale lantanidelor.

Toate acestea relevă actualitatea subiectului.

  • lanthanides
  • physico-chemical properties

INTRODUCTION

One of the confusions associated with the group of lanthanides is connected to the terminology. The term “rare earth” was originally used to describe almost any naturally occurring but unfamiliar oxide and until about 1920 generally included also compounds as ThO2 and ZrO2. By that time the term began to be applied to the elements themselves rather than to their oxides, and also was restricted to that group of elements which could only be separated from each other with great difficulty [1, 2].

The lanthanides comprise the largest naturally-occurring group in the periodic table. They are belonging to 6-th period.

The first element of the 6-th period, Cs (Z=55), has the electronic configuration of Xe for 54 of its electrons and the last electron is placed in the P shell. Similarly, the next element, Ba (Z=56) has two electrons in the P shell. The first member of the 5d transition series, 57La, now appears with the expansion of penultimate shell. However, a new phenomenon appears with the expansion of the O shell in successive stages from 18 electrons to 32 electrons. The fourteen new elements, between Z= 58 and 72 are called lanthanons, lanthanides or rare earth. They are very similar to one another.

This is a transition series within another transition series are so called inner transition series.

Their properties are so similar, that from 1794, when J.Gadolin isolated “yttria” which he thought it was the oxide of a single new element, until 1907, when lutetium was discovered, nearly a hundred claims were made for the discovery of elements belonging to this group.

GENERAL PROPERTIES

The metals are silvery in appearance (except for Eu and Yb, which are pale yellow) and are rather soft, but become harder across the series. Most of them exist in more than one crystallographic form.

The electronic configurations of the free atoms are determined only with difficulty because of the complexity of their atomic spectra, but it is generally agreed that they are nearly all [Xe] 4fn5d06s2. The exceptions are:

1. Cerium, for which the sudden contraction and reduction in energy of the 4f orbitals immediately after La is not yet sufficient to avoid occupancy of the 5d orbital;

  1. Gadolinium, which reflects the stability of the half-filled 4f shell, 4f7;
  2. Lutetium, at which point the shell has been filled, 4f14.

However, only in the case of cerium this has any marked effect on the chemistry in aqueous solution, which is otherwise dominated by the +3 oxidation state, for which the configuration varies regularly from 4f1 (CeIII) to 4f14 (LuIII). It is notable that a regular variation is found for any property for which this 4fn configuration is maintained across the series, whereas the variation in those properties for which this configuration is not maintained can be highly irregular. This is illustrated dramatically in size variations between 1,02Å for CeIII and 0,861 Å for LuIII. The radii of LnIII ions decrease regularly from LaIII (included for completeness) to LuIII. This “lanthanide contraction” occurs because, although each increase in nuclear charge is exactly balanced by a simultaneous increase in electronic charge, the directional characteristics of the 4f orbitals cause the 4fn electrons to shield themselves and other electron from nuclear charge only imperfectly[3].

Thus, each unit increase in nuclear charge produces a net increase in attraction for the whole extranuclear electron charge cloud and each ion shrinks slightly in comparison with its predecessor.

On the other hand, a similar overall reduction is seen in the metal radii, but irregular.

A contraction resulting from the filling of the 4f electron shell is not exceptional. Similar contractions occur in each row of the periodic table and, in the d block for instance, the ionic radii decrease from ScIII to CuIII, and from YIII to AgIII. The importance of the lanthanide contraction arises from its consequences:

1. the reduction in size from one LuIII to the next could make their separation possible, but the smallness and regularity of the reduction makes the separation difficult;

2. by the time Ho is reached the LuIII radius, it has been sufficiently reduced to be almost identical to that of YIII; that is why this much lighter element is invariably associated with the heavier lanthanides;

3. the total lanthanide contraction is of a similar magnitude to the expansion found in passing from the first to the second transition series, and which might therefore have been expected to occur also in passing from second to third. The interpolation of the lanthanides in fact almost exactly cancels this anticipated increase with the result that in each group of transition elements the second and third members have very similar sizes and properties. Redox processes, which of necesity entail a change in the occupancy of the 4f shell, vary in very irregular manner across the series. The use of thermodinamic data (4) offers the ionization energies. The sudden falls of the third ionization energy at Gd and Lu reflect the ease with which these elements form Gd3+ (f7)and Lu3+ (f14).

CHEMICAL REACTIVITY

The lanthanides are highly electropositive and reactive metals. With the exception of Yb, their reactivity apparently depends on their size, so that Eu, which has the largest metal radius, is the most reactive [2, 5].

Treatment with water yields hydrous oxides, and the metals dissolve rapidly in dilute acids, even in the cold, to give aqueous solutions of LnIII salts. The great bulk of lanthanide chemistry is of the +3 oxidation state, where, because of the large sizes of the LnIII ions, the bonding is predominantly ionic and the cations are the typical calss-a acids.

A number of trends connected with the ionic radii are noticeable across the series; salts become somewhat less ionic as the LnIII radius decreases; reduced ionic character in the hydroxide implies a reduction in alkaline properties and, at the end of the series, Yb(OH)3 and Lu(OH)3, though undoubtedly mainly alkaline, can with difficulty be solved in hot concentrated NaOH. Paralleling this change, the [Ln(H2O)x]3+ ions are subject to an increasing tendency to hydrolyse, and hydrolysis can only be prevented by using increasingly acidic solutions.

However, solubility cannot be simply related to the cation radius. No consistent trends are apparent in aqueous, or for that matter nonaqueous, solutions, but an empirical distinction can often be made between the lighter “cerium” lanthanides and the heavier “yttrium” lanthanides. Thus oxalates, double sulfates and double nitrates of the former, are rather less soluble and basic nitrates more soluble than those of the latter. The differences are by no means sharp, but classical separation procedures depended on them.

Although lanthanide chemistry is dominated by the +3 oxidation state, and a number of binary compounds which ostensibly involve LnII are actually better formulated as involving LnIII with an electron in a delocalized conduction band, genuine oxidation states of +2 and +4 can be obtained. CeIV and EuII are stable in water and are strongly oxidizing and strongly reducing respectively. TbIV presumably owes its existence to the stability of the 4f7 configuration.

The stabilizing effects of half and completely filled shells can be similarly invoked to explain the occurrence of the divalent state in EuII (4f7) and YbII (4f14).

SPECTRAL PROPERTIES

The electronic configurations of the lanthanides are described by using the Russell-Saunders coupling scheme. Values of the quantum numbers S and L corresponding to the lowest energy are obtained in the conventional manner [3, 5, 6].

Because of lanthanides 4f electrons, ions are largely burried in the inner core, they are effectively shielded from their chemical environment. As a result, the spin-orbit coupling is much larger than the crystal field (2000 cm-1 compared to 100 cm-1) and must be considered first. Note that this is precisely the reverse of the situation in the d-block elements, where the d electrons are exposed directly to the influence of neighbouring groups and the crystal field is therefore much greater than the spin-orbit coupling.

Electronic absorption spectra are produced when electromagnetic radiation promotes the ions from their ground state to excited states. For the lanthanides the most common of such transition involve the excited states which are either components of the ground term or else belong to excited states, which arise from the same 4fn configuration as the ground term. In either case, the transitions therefore involve only a redistribution of electrons within the 4f orbitals (i.e. f→f transitions) and so are orbitally forbidden, just like d→d transitions. In the case of the latter, the rule is partially relaxed by a mechanism which depends on the effect of the crystal field in distorting the symmetry of the metal ion. However, it has already been pointed out that crystal field effects are very much smaller in the case of LnIII ions and they cannot therefore produce the same relaxation of the selection rule. Consequently, the colours of LnIII compounds are usually less intense.

A further consequence of the relatively small effect of the crystal field is that the energies of the electronic states are only slightly affected by the nature of the ligands or by thermal vibrations, and so the absorption bands are very much sharper than those for d→d transitions. Because of this, they provide an useful means of characterizing, and quantitatively estimating, LnIII ions. [7, 8].

Nevertheless, crystal fields cannot be completely ignored. The intensities of a number of bands (“hypersensitive” bands) show a distinct dependence on the actual coordinated ligands. Also, in the same way that crystal fields lift some of the orbital degeneracy (2L + 1) of the terms of dn ions, so they lift some of the 2J + 1 degeneracy of the states of fn ions, though in this case only by the order of 100cm-1. This produces a fine structure in some bands of LnIII spectra.

CeIIIand TbIII are exceptional in providing (in the ultraviolet) bands of appreciably higher intensity than usual. The reason is that the particular transitions involved are of the type 4fn→4fn-15d1, and so are not orbitally forbidden. These 2 ions have 1 electron more than an empty f shell and 1 electron more than a half-full f shell, respectively, and the promotion of this extra electron is thereby easier than for other ions.

Sm, Dy but more specifically Eu and Tb have excited states which are only slightly lower in energy than the excited states of typical ligands. If the electrons on the ligand are excited, the possibility therefore exists that, instead of falling back to the ground state of the ligand, they might pass first to the excited state of the LnIII and then fall to the metal ground state, emitting radiation of characteristic frequency in doing so (fluorescence or, more generally, luminescence). Excitation by UV light produces luminescence spectra, which gives information about the donor atoms and co-ordination symmetry [8].

MAGNETIC PROPERTIES

The lanthanides are transition metals.

The magnetic moments of the transition metals ions are assumed to be due to electron spin only; as the orbitals occupied by unpaired electrons are near the peripheries of the ions, it is generally supposed that the orbital angular momenta are quenched by external fields [3, 5].

From the very high values of the magnetic moments for Tb+3, Dy3+, Ho3+ and Er+3, it is clear that at least for these ions the orbital contributions must be taken into account. Since the 4f quantum shells are well shielded from outside fields by the electrons of the n=5 and n=6 quantum shells, this is a reasonable conclusion.

It is also clear that there is a minimum value for the magnetic moment of trivalent ions such as Pb3+, Sm3+ and Eu3+. Agreement between observed and calculated values is good, except for Sm+3 and Eu3+.

The magnitude of the separation between the adjacent states of a term indicates the strength of the spin-orbit coupling, and in all cases, except Sm+3 and Eu3+, it is sufficient to render the first excited state of the Ln+3 thermally inaccessible, and so the magnetic properties are determined only by their ground state.

Table I

Magnetic properties and colours of LnIII ions in hydrated salts

Ln / Unpaired
electrons / Ground
state / Colour / µe / BM
g√J(J + 1) / µe / BM
Observed
Ce / 1(4f1) / 2F5/2 / Colourless / 2.54 / 2.3-2.5
Pr / 2(4f2) / 3H4 / Green / 3.58 / 3.4-3.6
Nd / 3(4f3) / 4I9/2 / Lilac / 3.62 / 3.5-3.6
Pm / 4(4f4) / 5I4 / Pink / 2.68 / -
Sm / 5(4f5) / 6H5/2 / Yellow / 0.85 / 1.4-1.7(*)
Eu / 6(4f6) / 7F0 / Very pale pink / 0 / 3.3-3.5(*)
Gd / 7(4f7) / 8S7/2 / Colourless / 7.94 / 7.9-8.0
Tb / 6(4f8) / 7F6 / Very pale pink / 9.72 / 9.5-9.8
Dy / 5(4f9) / 6H15/2 / Yellow / 10.65 / 10.4-10.6
Ho / 4(4f10) / 5I8 / Yellow / 10.60 / 10.4-10.7
Er / 3(4f11) / 4I15/2 / Rose-pink / 9.58 / 9.4-9.6
Tm / 2(4f12) / 3H6 / Pale green / 7.56 / 7.1-7.5
Yb / 1(4f13) / 2F7/2 / Colourless / 4.54 / 4.3-4.9
Lu / 0(4f14) / 1S0 / Colourless / 0 / 0

* These are the values of µe at room temperature. The values fall when the temperature is reduced.

The high-spin paramagnetism and long electronic relaxation time of Gd3+ have made it pre-eminent among contrast agents for magnetic resonance imaging [9, 10].

In addition, paramagnetic properties of lanthanide complexes are of great importance.

COORDINATION CAPACITY

Over the past years there has been a great interest in the chemistry of lanthanide complexes in solution in general and in aqueous solution in particular.

Coordonation chemistry of lanthanides is quite different from that of the d-transition metals [12, 7].

Coordination number is generally high and stereochemistries, being determined largely by the requirements of the ligands and lacking the directional contraints of covalency, isfrequently not well defined and the complexes are labile.

Thus, in spite of widespread opportunities for isomerism, there appears to be no confirmed example of a lanthanide complex existing in more than one molecular arrangement. Furthermore, only strongly complexing (i.e. usually chelating) ligands lead to products which can be isolated from aqueous solution, and the comparative tenacity of the small H2O molecule commonly leads to its inclusion, often with consequent uncertainty to the coordination number involved. This is not to say that other types of complex cannot be obtained, but complexes with uncharged monodentate ligands, or ligands with donor atoms other than O, must usually be prepared in the absence of water.

Lanthanides, both in crystalline complexes as well as in solutions, show variable coordination number (6….12), in which C.N. 9 is the most predominant.

Coordination numbers below 6 are found only with very bulky ligands and even the coordination number of 6 itself is unusual, 7, 8 and 9 being more characteristic.

Coordination numbers of 10 and over require chelating ligands with small “bites”, such as NO3- or SO42-, and are confined to compounds of the larger, lighter lanthanides.

The stereochemistries quoted, especially for high coordination numbers, are idealized and in most cases appreciable distortions are in fact found.

DISCUSSIONS

The most interesting revelation of the importance of the chemical lanthanides ions properties (ionic radius, redox properties, coordination capacity) is offering by the cancer domain (13)

Lanthanides are consuming Reactive Oxygen Species (ROS), which are mainly oxygen derived free radicals and peroxides, being the mediators of a number of degenerative diseases. The “antioxidants” are excellent substrances used as drugs for the treatment of degenerative diseases.

Tocopherol, ascorbates and a number of other organic compounds are considered as components of such drugs due to their property shown towards ROS induced degenerative diseases. Lanthanides are considered of high potential because of their inherent antioxidant properties[12] Liu et. al. [14] found LaCl3 effective in inhibiting silica induced lipid peroxidation of lung macrophagus and smaller of some other lanthanide chlorides inhibited lipid peroxidation in rat lung.

In fact, it was found that almost all lanthanides compounds, especially chlorides, are quite effective in inhibiting H2O2 mediated peroxidation of liposomes [15].

Table II

Ionic radius of lanthanide (III) ions