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From 1970s, the study of macrocyclic compounds have attracted a great interests in such different research areas, such as coordination chemistry, metal complexation, molecular recognition, biological systems and pharmaceutical development. [1-4]
In the chemical literatures, the definition of macrocycle is more narrow as just a cyclic compound. A molecule has at least nine atoms and in which three or more of them are donor atoms and can coordinate to a metal centre, this is generally defined as a macrocycle by coordination chemists (Fig. 1.1).  The cyclic compounds below are all not macrocycles.
Figure 1.1. Four cyclic molecules which are not macrocycles
Macrocycle can be divided into six basic types according to its different donor atoms and composed functions (Fig. 1.2.). Structure 1.5 is called polyamine macrocycle, in which nitrogen play as the donor atoms. Structure 1.6 is a crown ether compound; it contains oxygen donors and conformed by cyclic ether which composes a crown shaped macrocycle. Sturcture 1.7 is a mixed donor-atom macrocycles. Sturcture 1.8 is a macrocyclic compound which is based on the porphyrin ring system. Structure 1.9 is a cryptand compound, it is related to open-chain ligand to expand the structure into the third dimension to give which more capable of coordinating a metal ion. Sturcture 1.10 is named as linked macrocyclic ligand, this compound is modified to chelate two or more metal ions. 
Figure 1.2. Six ligands which are considered as macrocycles
1.1.2 Synthesis of Macrocycles
In the early 1960s, Charles J. Pedersen discovered a very first macrocyclic ligand which was later named as dibenzo-18-crown-6 (Fig. 1.3.). This compound was isolated in only 0.4% yield in a "brownish goo" while he was attempting to prepare another completely different compound.[7-8]
Figure 1.3. Dibenzo-18-crown-6
There are many various procedures to synthesize macrocyclic compounds. Consequently, the published reactions can be divided into two major ways. The first method belongs to a conventional organic cyclization reaction, which produces free ligand directly. The other preparation procedure is to generate a macrocyclic compound in the presence of a metal ion, this also called coordination template reaction.[9-10]
18.104.22.168 Free ligand preparation
The directly ring-formation reaction is to produce macrocylic compound without any other effects, but there is a problem involved in this method. Yield for carbocycles are the largest for common rings with 5-7 carbons, large ring has very low strain effect. It is more likely that the compound is reacting with a second functionalized molecule rather than reacting with itself "head to tail"(Fig. 1.4.), which tends to polymerization.
Figure 1.4. Cyclization at different concentration
However, ring formation still can be carried out when the reactant at very low concentration, ring closure is favoured rather than polymerization because the molecules are isolated and therefore more time is available for intramolecular reaction.
Macrocyclic compound contains very conventional donor atoms, such as nitregen, oxygen and sulfur, which can act as nucleophiles. Referring to this, macrocyclic compound can also be synthesized by nucleophile-electrophile reactions. Here is an example of how to synthesize 1,4,7,10-tetraazacyclododecane, cyclen (Fig.1.5.). It is also the fundamental macrocyclic compound which developed in this project.
Figure 1.5. Preparation route of cyclen
The tosylate group, 4-CH3C6H4SO2, plays a very important role which pushes forward every step in this entire reaction. Tosyl chloride can protect the secondary amine, the tertiary amine and the alcohol groups, prepared by combining them in a basic solvent, such as pyridine and 4-methyl morpholine, by which activate the reaction. Secondary, it provides -OTs as a very good leaving group to develop the cyclization reaction.
22.214.171.124 Metal template reaction
Another type of proceed to obtain macrocyclic systems is use of metal template reaction, which started from 1960 when Curtis discovered a template reaction for obtaining an isomeric pair of Ni(II) macrocyclic complexes. The template synthesis of these complexes opened the beginning of renewed interest in macrocyclic ligand chemistry which continues to the present day. Moreover, template synthesis is divided into two different effects, kinetic coordination template effect and thermodynamic template effect.
For the kinetic coordination template effect, metal ion coordinates with reactants, promoting a series of controlled steps, providing the product which is not formed in the absence of the metal.
One of this template reaction is presented below (Fig. 1.6.):
Figure 1.6. Kinetic coordination template effect
When the bifunctional reagent Î±,Î±'-Dibromo-o-xylene is employed to a Ni(II) complex precursor, a new chelate ring is formed, and the product of the reaction is a high yielded macrocyclic system. But as a free ligand of the reactant, it has both nucleophilic thiol groups and electrophilic imine groups, which increases the probability to occur intramolecular reaction (Fig. 1.7.) as below:
Figure 1.7. Intramolecular reaction occurs in the absence of metal
In contrast, the thermodynamic template effect in macrocycle synthesis is a process by which the presence of a metal ion is to stabilize the ligand or remove one particular cyclic compound from equilibrium mixture. One of the most significant case of it is the formation of the tetrazamacrocycles discovered by Neil Curtis. These two ligands (Fig. 1.8.) can be isolated in the presence of such metal ions as nickel and copper, leads to the removal of a selected macrocycles by the metal ions because of the super efficacy of macrocycle as a ligand.
Figure 1.8. Thermodynamic template effect
1.1.3 Macrocyclic effect
The macrocyclic effect was discovered in 1969 by Cabbines and Margerum. Coordination chemists found that macrocycles with three or more potential donor atoms in a ring of greater than nine atoms have strong binding abilities with metals. The macrocyclic effect is developed on the base of chelate effect, in which when a monodentate ligand methylamine CH3-NH2 is replaced by a bidentate ligand ethylenediamine NH2-CH2-CH2-NH2, the formation constant K increases by four orders of magnitude.
The macrocyclic effect is apparently expressed by comparison between zinc(II) complex of the macrocyclic ligand (I) and open-chain analogues (II): (Fig. 1.9.)
Figure 1.9. zinc(II) complex of the macrocyclic ligand (left)
and open-chain analogue complex (right)
The stability constant of zinc(II) complex of macrocyclic ligand was discovered to be approximately 10000 times higher than the zinc(II) complex of the open-chain ligand.
zinc(II) complex, ligand (I)
zinc(II) complex, ligand (II)
Tab.1.1. Thermodynamic parameters for zinc(II) complex of ligand (I) and (II)
The extra stability was observed of macrocyclic effect is referred to enthalpy term and entropy term, corresponding to the Gibbs free energy (â-³G0):
â-³G0 = â-³H - Tâ-³S
Whereâ-³H is the standard enthalpy change of the reaction and â-³S is the standard entropy change. T is the temperature in kelvins.[18,21]
The enhanced stability of macrocyclic ligand is almost entirely due to more favorable â-³H. The enthalpic differences are respected to the decreased ligand solvation of the macrocycle which has less hydrogen-bonded water to be displaced in complex formation. According to the equation shown below, even though the same number of moles and reactants involved the reaction, the entropic term also drives it to the right side because that macrocyclic ligand offers more fixed position for coordinated metal.
[M(open-chain)]n+ + macrocycle â†’ [M(macrocycle)]n+ + open-chain (Equation.1.1)
Thus, complexes of macrocyclic ligands are more stable than those with linear polydentate ligands of similar strength or similar donor atoms.
Macrocyclic > Chelate > Monodentate
1.1.4 Macrocyclic cavity
The relationship between the size of the metal ion and the hole in the middle of the ring clearly should be match properly. So another factor which contributes to the stability of macrocyclic complexes is macrocyclic cavity size. A general method for specifying the hole sizes of macrocyclic ligands was developed by Dr Tasker and Herick of Polytechnic of North London in 1982.
To measure out the hole size RA, the first step is to find out the mean distance of donor atoms in a macrocycle from their centroid, RH, by using X-ray crystal structural data. To obtain the hole size, it is necessary also to subtract the covalent radius of donor atom, RD. (Fig. 1.10.) RA = RH - RD
Figure 1.10. Macrocyle hole size measurement
Finally, another parameter, the "goodness of fit" is considered to indicate how well a metal ion matches the given ligand cavity. It is defined as the ratio of the bonding cavity hole size RA to the Pauling covalent radius RP for the metal. Thus, when RA : RP = 1, then a perfect selectivity of metal and ligand is suggested.
Tab. 1.2. Ideal Metal-Nitrogen bond lengths of the tetraza macrocyclic ligands
Average ideal lengths of metal-nitrogen
From the table above, the selectivity between metals and macrocyclic ligands becomes more mathematically in practical.
1.2.1 Introduction of Lanthanide
In the last decades, interest of lanthanide (Ln) and its complexes increases due to their potential applications in luminescent assays for biochemistry, electroluminescence and molecular devices.
Lanthanide was first discovered in Scandinavia in 1794 by Johann Gadolin, an oxidised metal from a black mineral was obtained and subsequently known as yttrium. The next 15 rare earth elements were discovered between 1803 (Ce) and 1907 (Lu) while the last one, artificial Pm synthesized until 1947. According to the International Union of Pure and Applied Chemistry ( IUPAC ) recommendations (1968), lanthanides include elements 58 (Ce) to 71 (Lu), while the whole series from La (57) to Lu (71) should be called lanthanoids; when Sc (21) and Y (39) are added to the latter, then the resulting 17 elements should be termed rare earths.
The lanthanide series can be found in the Periodic Table under group IIIB, as shown below.
Figure 1.11. Lanthanides in the Periodic Table
1.2.2 Electronic configuration
The lanthanide elements La to Lu were combined by the efforts of Moseley and Bohr whilst the latter concluded that the fourth quantum shell composes 32 electrons and that the lanthanides were associated with placing electrons into the 4f orbitals. The most common oxidation state of lanthanides are Ln(III), so both their atomic electronic configuration, oxidised electronic configuration are shown below.
Electron Configurations of Atom
Electron Configurations of Ln3+
Tab. 1.2. Electron Configurations and radius of lanthanide atoms and ions
1.2.3 Lanthanide contraction
The electronic configuration of lanthanide involves the progressive filling of the 4f electron shell. The 4f electrons are inside the 5s and 5p electrons, so the 5s and 5p orbitals are not shielded by the partial filled 4f orbital from increasing nuclear charge. Hence of this, the increasing effective nuclear charge contracts the outer shell electrons as the atomic number increases. As a direct effect of lanthanide contraction, the atomic radius of Lutetium is slightly smaller than the atomic radius of Yttrium. And also it continuous affects the size and property of the elements beyond Lutetium in the same period.[31,32]
All of the trivalent lanthanide ions share a number of common coordination properties, so they exhibit little variability across the lanthanide series. All the lanthanide ions are classified as a type of hard acid by Pearson's fules. Therefore, it is expected that these cations form more stable complexes with highly electronegative hard bases, in the order O>N>S.[34,35]
1.2.4 Coordination chemistry of lanthanide
Coupled with this is the fact that f-orbitals are inner orbitals, sheiled by the outer s- and d- orbitals, therefore there is little or no directionally interactions between lanthanide cations and ligand. So that the coordination numbers and complex geometries are determined almost by ligands characteristics, such as donor groups, conformational properties, size. Coordination numbers between six to twelve37 are known in lanthanide complexes. Analysis of the coordination numbers for lanthanides in recent 20 years indicated that coordination numbers ranging from nine (La-Eu) to eight (Dy-Lu) are believed most common. Here is a structure of nonaaqualanthanide ion which is assigned tricapped trigonal prismatic shape.
Figure 1.12 tricapped trigonal prismatic shape of nonaaqualanthanide
1.2.5 Spectrospic features
Because of the sharp f-f transitions, involve a rearrangement of the electrons in the 4f sub-shell and are therefore polarity forbidden. Because the 4f shell is well shielded from its environment by the closed 5s and 5p shells, the trivalent lanthanide ions are almost not affected by surroundings. This shielding is responsible for the specific properties of lanthanide luminescence, more particularly for the narrow band emission, which is easily to recognize from other luminescent materials. A lanthanide complex also has an extraordinarily long luminescence lifetime for milliseconds, in contrast to a typical organic compound, which stays at excited state for only nanosecond. Taking advantage of this feature, the influence of short-lived background fluorescence and scattered light can be reduced to a negligible level by the method termed time-resolved luminescence measurement. (Fig. 1.13)
Figure 1.13 Luminescence spectrums of erbium complex and organic dye
Due to the attractive luminescence properties of lanthanide, the compounds of which have been studied by researchers for decades. Most lanthanide ions are luminescent, but some are more emissive than others. The emissive ability of a lanthanide ion depends on how much excited energy can be populated and the deactivation decay minimized. The overall quantum yield of a lanthanide-containing molecule is used to meet this requirement, which is given by Q. It is essentially governed by the energy gap between the lowest excited state of the metal ion and the highest level of its ground state. The smaller this gap, the easier its luminescent emission quenched through non-radiative process by particular high energy vibrations, such as O-H bound in solvent molecules. From displayed energy diagram, it is obviously that Eu (III) and Tb (III) are the best luminescent ions, with â-³E = 12300 (5D0 â†’ 7F6) and 14800 (5D4 â†’ 7F0) cm-1 respectively(Fig. 1.14). This explains why most popular luminescent probes contain Eu (III) and Tb (III), which emits red and green respectively. However, Gd (III) emits at the wavelength which interferes with either absorbance or emission of other organic compounds.
Figure 1.14 Energy diagrams of lanthanides
With respect to the lanthanide ions properties, the research based on optical emissive probes have been investigated recently.[50,51] The employments of lanthanides as part of sensitive tracer technologies have been applied in the past few years, such as ions recognization, bioanalytical assays, optical fibres, medical imaging purposes.
1.2.6 Applications of lanthanides
However, lanthanide ion itself is toxic, some evidence have been discovered. While free ions can easily form colloid in blood, and the colloidal material is taken up by phagocytic cells of the liver and spleen Inhalational or intratracheal. Lanthanide ions act as Ca2+ antagonists in vitro, which causes Ca2+ displacement from cells, binds to Ca2+ binding sites of the intestinal brush-border membrane and surfaces of platelets and vascular smooth muscle.[56,57] Therefore, free lanthanide ions must be complexed whilst being used in any areas. On the other hand, because of f-f transition forbidden because of Laporte selection rules, with excitation coefficient of less than 4 M-1 cm-1, all lanthanide ions suffer from weak light absorption abilities. Hence, lanthanide was complexed by macrocyclic compound and the energy was transferred indirectly through an organic chromophore.
1.3 Lanthanide - macrocycle Complex:
1.3.1 Designer of lanthanide complexes
Since 1980's, lanthanide complexes have been of great help in the analysis of environmental and biological samples. Presently, the attention of Tb3+ and Eu3+ complexes focus on several applications, such as industrial lighting phosphors, organic light-emitting diodes for telecommunication, biological assays techniques and medical imaging purposes.
In order to overcome the drawbacks of free lanthanide ions, a macrocycle-antenna lanthanide effect (Fig. 1.15) has been investigated.
Figure 1.15 Macrocycle-antenna lanthanide effect
Weissman discovered that intense metal-centered luminescence can be observed for lanthanide complexes with organic ligands upon excitation in an absorption band of the organic ligand. The commonly acceptable mechanism of energy transfer in this process is concluded by Crosby and Whan (Fig. 1.16).
Figure 1.16 Energy transfer from absorption to emission
An electron is promoted to excited singlet state S1 of a ligand, the photon drops back to the lowest excited singlet level through internal conversion process. Then this photon can radiatively return to the ground state (S0, ligand fluorescence) or under non-radiative intersystem crossing from the excited singlet state to excited triplet state T1. At this time, it may either return to the ground state (S0, ligand phosphorescence) or alternatively undergo energy transfer from excited triplet state of ligand to an excited state of a lanthanide ion. After this energy transfer, the lanthanide ion may undergo a luminescence emission to the ground state or deactivated by non-radiative processes. But this is not the final step, lanthanide luminescence still could be quenched through non-radiative transition, espically -OH oscillator in aqueous solution.[63,64]
To design an efficiency luminescence, antenna mainly affects the complex. The two most commonly used ions are Tb and Eu, which process the luminescence at the excited energy of 20400 cm-1 and 17200 cm-1 respectively, so the triplet excited level of the ligand needs to be above 22000 cm-1. On the other hand, if the energy gap less than 1500 cm-1, back energy transfer could happen. To sum up, the ideal excitation region of ligand is between 300 to 400 nm.
1.3.2 Lanthanide complex as a molecular switch
With combined these entire designing effects, many bright lanthanide complexes have been discovered over the past decades in different potential applied areas, such as biological or chemical sensors, probes for presence of particular cations or anions. The most remarkable application of lanthanide complexes also can be called molecular devices, or more appropriately, optical molecular switches.
Molecular switch is an optical device on molecular levels, its luminescent signals displays significant difference between their 'off' (no emissive) and 'on' (emissive) states (Fig. 1.17).[68,69]
Figure 1.17 Molecular switch of a lanthanide complex
These output properties change dramatically in response to input environmental conditions, the operating mechanism of these molecular switches are based on acid/base reactions.
1.3.3 Applications of lanthanide complexes
Here are some considerable applications in using lanthanide complexes as probes for the presence of particular cations and anions, these complexes were all with obvious potential in chemical or biological research areas:
Eu.1, Eu.2, Eu.3 and Tb.1, Tb.2 are all pH dependent molecular switches, the intensities increase with pH goes higher from 3 to 10 in aqueous solutions. The excitation wavelengths of these complexes are at 270 nm, 340 nm, 385 nm, 270 nm and 330 nm respectively. The highest luminescent emissions are located at 614 nm for Eu complexes and 544 nm for Tb complexes. As molecular switches, they are 'off' at very acid contagion and 'on' when pH higher than 8.
Lanthanide complex can also act as a molecular device for concentration of potassium ions. Tb.3 is a K+ concentration sensor which is excited at 332 nm, emission at 544 nm in aqueous solution. The more potassium ions exist in the solution, the more intensive signal emits in the luminescent spectroscopy.
1.3.4 Optical quenching mechanism of molecular switches
As a molecular switch, the most interesting part of a complex is its antenna/receptor part moiety; this causes two different luminescent states, 'off' and 'on'. Usually, a receptor is combined with a chromophore together, consists of a completed antenna system. It has been demonstrated that the 'off' status, also called quenching of a lanthanide complex occurs due to intramolecular photo induced electron transfer (Fig. 1.18) from receptor to chromophore.
Figure 1.18 Photo induce electron transfer quenching
When an incoming photon is absorbed, one electron on a chromophore ground state is promoted to the excited state. Photo induced energy transfer occurs if the receptor has a high HOMO level, one electron is driven from receptor to chromophore, quenching the energy transfer to lanthanide ions, luminescence switched off. In contrast, strong luminescence emits because the excitation energy is transfer to the lanthanide ions directly.
1.3.5 Phthalimide as an antenna moiety
The antenna/receptor is a key part which composes of a luminescent lanthanide complex as a molecular switch. In this project, phthalimide function is chosen to be this important component. The major product, N-alkeny-phthalimide has been demonstrated to exhibit low toxicity, its energy transfer process is rapid and quantum efficient. Consequently, excited phthalimide itself participated in photo induced inter- or intramolecular electron transfer.
Figure 1.19 photo induced intramolecular reaction of phthalimide
Phthalimide is believed to be an efficient sensitizer for both Eu (III) and Tb (III) emissions and remarkable a desirable function which can act as ideal antenna, it transfers energy from ligand to metal quickly. UV-Vis spectroscopy has shown that phthalimides suffer from blue shift under different pH, this is because amide could be hydrolysed when pH is higher than 10.
Although phthalimide hasn't been applied in lanthanide complex systems, recently, its analogues were investigated very often. Naphthalimide has been used as a luminescent signal in macromolecular structures and for sensing purposes for several decades in such potential applications, as biological sensors, laser active medias, fluorescent marker, light emitting diodes. Naphthalimide is used as a pH dependent fluorescence sensor, which is based on photo induced electron transfer process. So phthalimide is such a function which provides opportunities to design novel luminescent sensors.
Here is a successful example, in which the complex composed of phthalimide analogues with Eu (III) or Tb (III) ions. The complexes indicate efficient ligand to lanthanide energy transfer. The quantum yield and lifetime of its Tb (III) complex is 0.56 and 2.63 ms respectively in aqueous solution.
To sum up, macrocyclic compound has been proved a remarkable ligand because of its kinetic and thermodynamic stabilities with a metal. Lanthanide based macrocyclic complex has a bright future of many applications; with respect to the antenna effect, phthalimide function can enhance the emission intensity and make a responsible molecular switch.