Chemical Literatures And Definition Of Macrocycle Biology Essay

From 1970s, the survey of macrocyclic compounds have attracted a great involvements in such different research countries, such as coordination chemical science, metal complexation, molecular acknowledgment, biological systems and pharmaceutical development. [ 1-4 ]

In the chemical literatures, the definition of macrocycle is more narrow as merely a cyclic compound. A molecule has at least nine atoms and in which three or more of them are donor atoms and can organize to a metal Centre, this is by and large defined as a macrocycle by coordination chemists ( Fig. 1.1 ) . [ 5 ] The cyclic compounds below are all non macrocycles.

Figure 1.1. Four cyclic molecules which are non macrocycles

Macrocycle can be divided into six basic types harmonizing to its different giver atoms and composed maps ( Fig. 1.2. ) . Structure 1.5 is called polyamine macrocycle, in which nitrogen drama as the giver atoms. Structure 1.6 is a crown quintessence compound ; it contains oxygen givers and conformed by cyclic quintessence which composes a Crown molded macrocycle. Sturcture 1.7 is a assorted 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 acyclic ligand to spread out the construction into the 3rd dimension to give which more capable of organizing a metal ion. Sturcture 1.10 is named as linked macrocyclic ligand, this compound is modified to chelate two or more metal ions. [ 6 ]

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 really first macrocyclic ligand which was subsequently named as dibenzo-18-crown-6 ( Fig. 1.3. ) . This compound was isolated in merely 0.4 % output in a “ chocolate-brown sludge ” while he was trying to fix another wholly different compound. [ 7-8 ]

Figure 1.3. Dibenzo-18-crown-6

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There are many assorted processs to synthesise 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 straight. The other readying process is to bring forth a macrocyclic compound in the presence of a metal ion, this besides called coordination templet reaction. [ 9-10 ] Free ligand readying

The straight ring-formation reaction is to bring forth macrocylic compound without any other effects, but there is a job involved in this method. Output for carbocycles are the largest for common rings with 5-7 Cs, big ring has really low strain consequence. It is more likely that the compound is responding with a 2nd functionalized molecule instead than responding with itself “ caput to chase ” ( Fig. 1.4. ) , which tends to polymerisation. [ 11 ]

Figure 1.4. Cyclization at different concentration

However, pealing formation still can be carried out when the reactant at really low concentration, pealing closing is favoured instead than polymerisation because the molecules are isolated and hence more clip is available for intramolecular reaction. [ 11 ]

Macrocyclic compound contains really conventional giver atoms, such as nitregen, O and S, which can move as nucleophiles. Mentioning to this, macrocyclic compound can besides be synthesized by nucleophile-electrophile reactions. [ 12 ] Here is an illustration of how to synthesise 1,4,7,10-tetraazacyclododecane, cyclen ( Fig.1.5. ) . It is besides the cardinal macrocyclic compound which developed in this undertaking.

Figure 1.5. Preparation path of cyclen

The tosylate group, 4-CH3C6H4SO2, plays a really of import function which pushes frontward every measure in this full reaction. Tosyl chloride can protect the secondary aminoalkane, the third aminoalkane and the intoxicant groups, prepared by uniting them in a basic dissolver, such as pyridine and 4-methyl morpholine, by which activate the reaction. Secondary, it provides -OTs as a really good go forthing group to develop the cyclization reaction. [ 13 ] Metal templet reaction

Another type of proceed to obtain macrocyclic systems is usage of metal templet reaction, which started from 1960 when Curtis discovered a template reaction for obtaining an isomeric brace of Ni ( II ) macrocyclic composites. The template synthesis of these composites opened the beginning of renewed involvement in macrocyclic ligand chemical science which continues to the present twenty-four hours. [ 14 ] Furthermore, template synthesis is divided into two different effects, kinetic coordination templet consequence and thermodynamic templet consequence.

For the kinetic coordination templet consequence, metal ion coordinates with reactants, advancing a series of controlled stairss, supplying the merchandise which is non formed in the absence of the metal. [ 15 ]

One of this template reaction is presented below ( Fig. 1.6. ) :

Figure 1.6. Kinetic coordination templet consequence

When the bifunctional reagent I± , I±’-Dibromo-o-xylene is employed to a Ni ( II ) composite precursor, a new chelate ring is formed, and the merchandise 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 chance to happen intramolecular reaction ( Fig. 1.7. ) as below:

Figure 1.7. Intramolecular reaction occurs in the absence of metal

In contrast, the thermodynamic templet consequence in macrocycle synthesis is a procedure by which the presence of a metal ion is to stabilise the ligand or take one peculiar cyclic compound from equilibrium mixture. [ 16 ] One of the most important instance 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 Ni and Cu, leads to the remotion of a selected macrocycles by the metal ions because of the ace efficaciousness of macrocycle as a ligand. [ 17 ]

Figure 1.8. Thermodynamic templet consequence

1.1.3 Macrocyclic consequence

The macrocyclic consequence was discovered in 1969 by Cabbines and Margerum. Coordination chemists found that macrocycles with three or more possible giver atoms in a ring of greater than nine atoms have strong binding abilities with metals. [ 18 ] The macrocyclic consequence is developed on the base of chelate consequence, in which when a monodentate ligand methylamine CH3-NH2 is replaced by a bidentate ligand ethylenediamine NH2-CH2-CH2-NH2, the formation changeless K additions by four orders of magnitude. [ 19 ]

The macrocyclic consequence is seemingly expressed by comparing between Zn ( II ) composite of the macrocyclic ligand ( I ) and acyclic parallels ( II ) : ( Fig. 1.9. )

Figure 1.9. Zn ( II ) composite of the macrocyclic ligand ( left )

and acyclic parallel composite ( right )

The stableness invariable of Zn ( II ) composite of macrocyclic ligand was discovered to be about 10000 times higher than the Zn ( II ) composite of the acyclic ligand. [ 20 ]

Zn ( II ) composite, ligand ( I )

Zn ( II ) composite, ligand ( II )










Tab.1.1. Thermodynamic parametric quantities for Zn ( II ) composite of ligand ( I ) and ( II )

The excess stableness was observed of macrocyclic consequence is referred to enthalpy term and entropy term, matching to the Gibbs free energy ( a-?G0 ) :

a-?G0 = a-?H – Ta-?S

Wherea-?H is the standard heat content alteration of the reaction and a-?S is the standard information alteration. T is the temperature in Ks. [ 18,21 ]

The enhanced stableness of macrocyclic ligand is about wholly due to more favourable a-?H. The enthalpic differences are respected to the decreased ligand solvation of the macrocycle which has less hydrogen-bonded H2O to be displaced in complex formation. [ 22 ] Harmonizing to the equation shown below, even though the same figure of moles and reactants involved the reaction, the entropic term besides drives it to the right side because that macrocyclic ligand offers more fixed place for co-ordinated metal. [ 23 ]

[ M ( open-chain ) ] n+ + macrocycle a†’ [ M ( macrocycle ) ] n+ + open-chain ( Equation.1.1 )

Therefore, composites of macrocyclic ligands are more stable than those with additive polydentate ligands of similar strength or similar giver atoms. [ 24 ]

Macrocyclic & gt ; Chelate & gt ; Monodentate

1.1.4 Macrocyclic pit

The relationship between the size of the metal ion and the hole in the center of the pealing clearly should be match decently. So another factor which contributes to the stableness of macrocyclic composites is macrocyclic pit size. A general method for stipulating the hole sizes of macrocyclic ligands was developed by Dr Tasker and Herick of Polytechnic of North London in 1982. [ 25 ]

To mensurate out the hole size RA, the first measure is to happen out the average distance of giver atoms in a macrocycle from their centroid, RH, by utilizing X-ray crystal structural informations. To obtain the hole size, it is necessary besides to deduct the covalent radius of giver atom, RD. ( Fig. 1.10. ) RA = RH – RD

Figure 1.10. Macrocyle hole size measuring

Finally, another parametric quantity, the “ goodness of tantrum ” is considered to bespeak how good a metal ion matches the given ligand pit. It is defined as the ratio of the bonding pit hole size RA to the Pauling covalent radius RP for the metal. Therefore, when RA: RP = 1, so a perfect selectivity of metal and ligand is suggested. [ 26 ]

Tab. 1.2. Ideal Metal-Nitrogen bond lengths of the tetraza macrocyclic ligands [ 27 ]

Ringing size

Average ideal lengths of metal-nitrogen











From the tabular array above, the selectivity between metals and macrocyclic ligands becomes more mathematically in practical.

Rare earth

1.2.1 Introduction of Lanthanide

In the last decennaries, involvement of rare earth ( Ln ) and its composite additions due to their possible applications in luminescent checks for biochemistry, electroluminescence and molecular devices. [ 28 ]

Lanthanide was foremost discovered in Scandinavia in 1794 by Johann Gadolin, an oxidized metal from a black mineral was obtained and later known as Y. The following 15 rare Earth elements were discovered between 1803 ( Ce ) and 1907 ( Lu ) while the last one, unreal Pm synthesized until 1947. Harmonizing 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 rare earths ; when Sc ( 21 ) and Y ( 39 ) are added to the latter, so the ensuing 17 elements should be termed rare Earths. [ 29 ]

The lanthanide series can be found in the Periodic Table under group IIIB, as shown below.

Figure 1.11. Rare earths in the Periodic Table

1.2.2 Electronic constellation

The lanthanide elements La to Lu were combined by the attempts of Moseley and Bohr whilst the latter concluded that the 4th quantum shell composes 32 negatrons and that the rare earths were associated with puting negatrons into the 4f orbitals. [ 30 ] The most common oxidization province of rare earths are Ln ( III ) , so both their atomic electronic constellation, oxidised electronic constellation are shown below.

Electron Configurations of Atom

Electron Configurations of Ln3+

Atomic Radius

( autopsy )

Ionic Radius

( autopsy )


[ Xe ] 5d16s2

[ Xe ] 4f0




[ Xe ] 4f15d16s2

[ Xe ] 4f1




[ Xe ] 4f36s2

[ Xe ] 4f2




[ Xe ] 4f46s2

[ Xe ] 4f3




[ Xe ] 4f56s2

[ Xe ] 4f4




[ Xe ] 4f66s2

[ Xe ] 4f5




[ Xe ] 4f76s2

[ Xe ] 4f6




[ Xe ] 4f75d16s2

[ Xe ] 4f7




[ Xe ] 4f96s2

[ Xe ] 4f8




[ Xe ] 4f106s2

[ Xe ] 4f9




[ Xe ] 4f116s2

[ Xe ] 4f10




[ Xe ] 4f126s2

[ Xe ] 4f11




[ Xe ] 4f136s2

[ Xe ] 4f12




[ Xe ] 4f146s2

[ Xe ] 4f13




[ Xe ] 4f145d16s2

[ Xe ] 4f14



Tab. 1.2. Electron Configurations and radius of rare earth atoms and ions

1.2.3 Lanthanide contraction

The electronic constellation of lanthanide involves the progressive filling of the 4f negatron shell. The 4f negatrons are inside the 5s and 5p negatrons, so the 5s and 5p orbitals are non shielded by the partial filled 4f orbital from increasing atomic charge. Hence of this, the increasing effectual atomic charge contracts the outer shell negatrons as the atomic figure additions. As a direct consequence of lanthanide contraction, the atomic radius of Lutetium is somewhat smaller than the atomic radius of Yttrium. And besides it uninterrupted affects the size and belongings of the elements beyond Lutetium in the same period. [ 31,32 ]

All of the trivalent rare earth ions portion a figure of common coordination belongingss, so they exhibit small variableness across the lanthanide series. All the lanthanide ions are classified as a type of difficult acid by Pearson ‘s fules. [ 33 ] Therefore, it is expected that these cations form more stable composites with extremely negatively charged difficult bases, in the order O & gt ; N & gt ; S. [ 34,35 ]

1.2.4 Coordination chemical science of rare earth

Coupled with this is the fact that f-orbitals are interior orbitals, sheiled by the outer s- and d- orbitals, hence there is small or no directionally interactions between lanthanide cations and ligand. So that the coordination Numberss and complex geometries are determined about by ligands features, such as giver groups, conformational belongingss, size. [ 36 ] Coordination Numberss between six to twelve37 are known in rare earth composites. Analysis of the coordination Numberss for rare earths in recent 20 old ages indicated that coordination Numberss runing from nine ( La-Eu ) to eight ( Dy-Lu ) are believed most common. Here is a construction of nonaaqualanthanide ion which is assigned tricapped rhombohedral prismatic form. [ 38 ]

Figure 1.12 tricapped rhombohedral prismatic form of nonaaqualanthanide

1.2.5 Spectrospic characteristics

Because of the crisp f-f passages, involve a rearrangement of the negatrons in the 4f sub-shell and are hence polarity forbidden. [ 39 ] Because the 4f shell is good shielded from its environment by the closed 5s and 5p shells, the trivalent rare earth ions are about non affected by milieus. This shielding is responsible for the specific belongingss of lanthanide luminescence, more peculiarly for the narrow set emanation, which is easy to acknowledge from other luminescent stuffs. [ 40 ] A rare earth composite besides has an inordinately long luminescence life-time for msecs, in contrast to a typical organic compound, which stays at aroused province for merely nanosecond. [ 41 ] Taking advantage of this characteristic, the influence of ephemeral background fluorescence and scattered visible radiation can be reduced to a negligible degree by the method termed time-resolved luminescence measuring. [ 42 ] ( Fig. 1.13 )

Figure 1.13 Luminescence spectrums of Er composite and organic dye

Due to the attractive luminescence belongingss of rare earth, the compounds of which have been studied by research workers for decennaries. [ 43 ] 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 inactivation decay minimized. The overall quantum output of a lanthanide-containing molecule is used to run into this demand, which is given by Q. [ 44 ] It is basically governed by the energy spread between the lowest aroused province of the metal ion and the highest degree of its land province. The smaller this spread, the easier its luminescent emanation quenched through non-radiative procedure by peculiar high energy quivers, such as O-H edge in solvent molecules. [ 45 ] From displayed energy diagram, [ 46 ] it is evidently that Eu ( III ) and Tb ( III ) are the best luminescent ions, with a-?E = 12300 ( 5D0 a†’ 7F6 ) and 14800 ( 5D4 a†’ 7F0 ) cm-1 severally ( Fig. 1.14 ) . This explains why most popular luminescent investigations contain Eu ( III ) and Tb ( III ) , which emits ruddy and green severally. [ 47 ] However, Gd ( III ) emits at the wavelength which interferes with either optical density or emanation of other organic compounds. [ 48 ]

[ 49 ]

Figure 1.14 Energy diagrams of rare earths

With regard to the lanthanide ions belongingss, the research based on optical emissive investigations have been investigated late. [ 50,51 ] The employments of rare earths as portion of sensitive tracer engineerings [ 52 ] have been applied in the past few old ages, such as ions recognization, bioanalytical checks, optical fibers, medical imagination intents. [ 53 ]

1.2.6 Applications of rare earths

However, lanthanide ion itself is toxic, some grounds have been discovered. [ 54 ] While free ions can easy organize colloid in blood, and the colloidal stuff is taken up by phagocytic cells of the liver and spleen Inhalational or intratracheal. [ 55 ] Lanthanide ions act as Ca2+ antagonists in vitro, which causes Ca2+ supplanting from cells, binds to Ca2+ adhering sites of the enteric brush-border membrane and surfaces of thrombocytes and vascular smooth musculus. [ 56,57 ] Therefore, free rare earth ions must be complexed whilst being used in any countries. On the other manus, because of f-f passage forbidden because of Laporte choice regulations, with excitation coefficient of less than 4 M-1 cm-1, all lanthanide ions suffer from weak light soaking up abilities. [ 58 ] Hence, rare earth 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 rare earth composites

Since 1980 ‘s, rare earth composites have been of great aid in the analysis of environmental and biological samples. [ 59 ] Presently, the attending of Tb3+ and Eu3+ composites focus on several applications, such as industrial lighting phosphors, organic light-emitting rectifying tubes for telecommunication, biological checks techniques and medical imagination intents. [ 60 ]

In order to get the better of the drawbacks of free rare earth ions, a macrocycle-antenna rare earth consequence ( Fig. 1.15 ) has been investigated.

Figure 1.15 Macrocycle-antenna rare earth consequence

Weissman discovered that intense metal-centered luminescence can be observed for rare earth composites with organic ligands upon excitement in an soaking up set of the organic ligand. [ 61 ] The normally acceptable mechanism of energy transportation in this procedure is concluded by Crosby and Whan ( Fig. 1.16 ) . [ 62 ]

Figure 1.16 Energy transportation from soaking up to emanation

An negatron is promoted to aroused vest province S1 of a ligand, the photon drops back to the lowest aroused vest degree through internal transition procedure. Then this photon can radiatively return to the land province ( S0, ligand fluorescence ) or under non-radiative intersystem traversing from the aroused vest province to aroused three province T1. At this clip, it may either return to the land province ( S0, ligand phosphorescence ) or instead undergo energy transportation from aroused three province of ligand to an aroused province of a lanthanide ion. After this energy transportation, the lanthanide ion may undergo a luminescence emanation to the land province or deactivated by non-radiative procedures. But this is non the concluding measure, lanthanide luminescence still could be quenched through non-radiative passage, espically -OH oscillator in aqueous solution. [ 63,64 ]

To plan an efficiency luminescence, antenna chiefly affects the composite. The two most normally used ions are Tb and Eu, which process the luminescence at the aroused energy of 20400 cm-1 and 17200 cm-1 severally, so the three excited degree of the ligand needs to be above 22000 cm-1. On the other manus, if the energy spread less than 1500 cm-1, back energy transportation could go on. [ 65 ] To sum up, the ideal excitement part of ligand is between 300 to 400 nanometers.

1.3.2 Lanthanide composite as a molecular switch

With combined these full designing effects, many bright rare earth composites have been discovered over the past decennaries in different possible applied countries, such as biological or chemical detectors, investigations for presence of peculiar cations or anions. [ 66 ] The most singular application of rare earth composites besides can be called molecular devices, or more suitably, optical molecular switches. [ 67 ]

Molecular switch is an optical device on molecular degrees, its luminescent signals shows important difference between their ‘off ‘ ( no emissive ) and ‘on ‘ ( emissive ) provinces ( Fig. 1.17 ) . [ 68,69 ]

Figure 1.17 Molecular switch of a rare earth composite

These end product belongingss change dramatically in response to input environmental conditions, the operating mechanism of these molecular switches are based on acid/base reactions. [ 70 ]

1.3.3 Applications of rare earth composites

Here are some considerable applications in utilizing lanthanide composites as investigations for the presence of peculiar cations and anions, these composites were all with obvious potency in chemical or biological research countries:






Eu.1, [ 71 ] Eu.2, [ 72 ] Eu.3 [ 73 ] and Tb.1, [ 74 ] Tb.2 [ 75 ] are all pH dependent molecular switches, the strengths addition with pH goes higher from 3 to 10 in aqueous solutions. The excitement wavelengths of these composites are at 270 nanometers, 340 nanometer, 385 nanometer, 270 nanometer and 330 nanometer severally. The highest luminescent emanations are located at 614 nanometer for Eu composites and 544 nanometer for Tb composites. As molecular switches, they are ‘off ‘ at really acerb contagious disease and ‘on ‘ when pH higher than 8.

Lanthanide composite can besides move as a molecular device for concentration of K ions. Tb.3 is a K+ concentration detector which is excited at 332 nanometers, emanation at 544 nanometers in aqueous solution. [ 76 ] The more potassium ions exist in the solution, the more intensive signal emits in the luminescent spectrometry.


1.3.4 Optical slaking mechanism of molecular switches

As a molecular switch, the most interesting portion of a composite is its antenna/receptor portion mediety ; this causes two different luminescent provinces, ‘off ‘ and ‘on ‘ . [ 77 ] Usually, a receptor is combined with a chromophore together, consists of a completed aerial system. It has been demonstrated that the ‘off ‘ position, besides called extinction of a rare earth complex occurs due to intramolecular exposure induced negatron transportation ( Fig. 1.18 ) from receptor to chromophore. [ 78 ]

Figure 1.18 Photo induce negatron transportation slaking

When an entrance photon is absorbed, one negatron on a chromophore land province is promoted to the aroused province. Photograph induced energy transportation occurs if the receptor has a high HOMO degree, one negatron is driven from receptor to chromophore, slaking the energy transportation to lanthanide ions, luminescence switched off. In contrast, strong luminescence emits because the excitement energy is transfer to the lanthanide ions straight.

1.3.5 Phthalimide as an aerial mediety

The antenna/receptor is a cardinal portion which composes of a luminescent rare earth composite as a molecular switch. In this undertaking, phthalimide map is chosen to be this of import constituent. The major merchandise, N-alkeny-phthalimide has been demonstrated to exhibit low toxicity, its energy transportation procedure is rapid and quantum efficient. [ 79 ] Consequently, excited phthalimide itself participated in exposure induced inter- or intramolecular negatron transportation. [ 80 ]

Figure 1.19 exposure induced intramolecular reaction of phthalimide

Phthalimide is believed to be an efficient sensitiser for both Eu ( III ) and Tb ( III ) emanations and remarkable a desirable map which can move as ideal aerial, it transfers energy from ligand to metal rapidly. [ 81 ] UV-Vis spectrometry has shown that phthalimides suffer from bluish displacement under different pH, this is because amide could be hydrolysed when pH is higher than 10. [ 82 ]

Although phthalimide has n’t been applied in lanthanide complex systems, late, its parallels were investigated really frequently. Naphthalimide has been used as a luminescent signal in macromolecular constructions and for feeling intents for several decennaries in such possible applications, as biological detectors, laser active medias, fluorescent marker, light breathing rectifying tubes. [ 83 ] Naphthalimide is used as a pH dependent fluorescence detector, which is based on exposure induced negatron transportation procedure. So phthalimide is such a map which provides chances to plan fresh luminescent detectors.

Here is a successful illustration, in which the composite composed of phthalimide parallels with Eu ( III ) or Tb ( III ) ions. The complexes indicate efficient ligand to lanthanide energy transportation. The quantum output and life-time of its Tb ( III ) composite is 0.56 and 2.63 MS severally in aqueous solution. [ 84 ]

[ 84 ]

To sum up, macrocyclic compound has been proved a singular ligand because of its kinetic and thermodynamic stablenesss with a metal. Lanthanide based macrocyclic composite has a bright hereafter of many applications ; with regard to the aerial consequence, phthalimide map can heighten the emanation strength and do a responsible molecular switch.


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