A Mini Review on Mixed Chelation Parameters

Removal of oversupply of toxic metals has been accomplished medically by the addition of metal chelators. Metal chelators, while useful, have many disadvantages, one of which is the undesired complexation and removal of other essential metals. In the reverse sense, metals are capable of ligand scavenging or mixed complex formation. The degrees to which metal ions can chelate greatly depend on the various chemical factors like stability, solvent nature, ionic strength and statistical ratio etc. In this review, we provide update covering above-said factors, biological importance and recent methods leading chelation (Figure 1).


Introduction
In addition to the diverse applications of chelation in catalysis, material synthesis and photochemistry, chelation displayed in biological systems enables metals to attach with or to move away from the susceptible target owing to to ease or hampering those intracellular connections which might finally lead to cancer [1]. In biological system metal ions usually, form ternary complexes which mainly involve the interaction of the metal ion with two or more different ligands [2]. Recently there has been considerable interest in the mixed chelation because it occurs commonly in biological fluids, which contain millions of potential ligands which are likely to compete for metal ions, found in vivo [3]. It is well known that the ternary coordination complexes play an important role in biological processes as exemplified in many instances by which enzymes are known to be activated by metal ions 4. Ternary complexes containing an amino acid as a secondary ligand have significance as they are potential models for enzyme metal ion substrate complexes Ternary complexes have also been implicated in the storage and transport of active substances through membranes and these phenomena are strongly dependent on the formation of these species and the electronic configuration of metal ion concerned [4].

Biological Importance
The essential metal ions like Cu (II), Co (II), Ni (II), Zn (II), have a significant role in complexation with amino acid and peptides in a living system which acts as a model for many complexes metals-amino acid equilibria occurring in the enzymatic process [5]. Metal chelates having vacant orbitals appear to combine with Sulphur bridge coating of the virus, leaving the DNA and later destruction of protein. All this involves ternary complex formation [6]. The role of cobalt in biological systems is widely investigated in series of coenzyme and vitamin B12. The complexes of cobalt with methionine, lysine and serine play a significant role in bacteriostatic and inhibition of virus replication [7]. Nickel is one of the most important trace elements plays numerous roles in the biology of microorganisms, animals and plants [7]. Zinc plays either a predominantly catalytic role or a solely structural role to maintain the protein configuration. It is a versatile ion as it can bind to different combinations of ligand types resulting in a broad range of stability, reactivity and functions [8]. The chelates formation occurs in biological fluids through transition metals with one or more than one coordination site of ligands of different functional group has a significant role in detoxification and remediation of metal pollutants [9].

Study of Mixed Ligand Metal Complexes
The study of mixed ligand complexes having one synthesized ligand attached to metal ion has received great importance in recent years because of their wide applications in various fields and because of their presence in biological systems [10]. The stability of the mixed ligand complex is measured by the overall formation constant i.e. According to the equilibrium, Where M is the metal ion, L and B are either neutral or anionic or cationic ligands. If n i j N = + ≤ . Where n cannot exceed the coordination number N, a total of N-n coordination sites will be occupied by solvent molecules and n is the level coordination number when ligands are monodentate [11]. The equilibrium constant for the system involving the formation of a metal complex from the aqua metal ion and the most basic form of the ligand, can also be specific reasons such as conjugation effects, stabilization of one of the parent complexes or chelate formation [12].
According to Theory of mixed ligand complexes, the formation of the mixed ligand complexes depends on the nature of the metalligand bond whether σ -or π -, σ -bond affects the mixed-ligand formation because the destabilization caused by ligand repulsion (electrostatic) is of smaller magnitude in mixed-ligand complexes, compared to that in binary complexes [13]. Ternary complexes those are more stable than the binary in contrast to the statistical considerations.

2.
Ternary complexes those are less stable than the binary complexes, as expected from statistical consideration [14].
The statistical aspect is that the tendency of the metal ion to be bound with the ligands decrease with an increase in the number of bound ligands. However, the values of the formation constant of mixed ligand complexes are observed to be higher or lower than those expected from statistical considerations. This has been attributed to several factors, including that of the electrostatic effect and higher stabilities of the ternary complex, which also result by a direct charge transfer between the two bound ligands with proper orientation. Electron withdrawing substituents lower the stability, whereas electron donating groups increase the stability of the ternary complex [15]. Another explanation quoted in terms of HSAB principle is that, because of back donation of electrons from the d-orbitals of metals to bi-py, the metal ions becomes a harder acid favouring coordination with oxygen donor ligands. John Teller effect has also been considered as an additional factor [16]. ∆logK is the difference between the stability constant of 1:1:1 ternary complex and corresponding 1:1 binary complex i.e

Following Qualitative Observations Have Been Made About
log K ∆ For Ternary or Mixed Ligand Complexes:

1.
The log K ∆ has a negative value when the coordination of the second ligand is through two nitrogen atoms (aliphatic amino acids).

2.
The log K ∆ value is less negative than the previous case when the secondary ligand coordinates through oxygen and a nitrogen atom (amino acids)

3.
The log K ∆ value is zero or positive when the secondary ligand coordinates through two oxygen atoms.
Bjerrum has given the classification of factors affecting the stability of mix ligand formation. According to which the factors controlling the stability of mixed ligand complexes are two-fold "statistical" and "ligand effects". The ligand effect depends upon the electrostatic nature of the M-L bond. The stability constant and complexation behavior of Co (II), Zn (II) and Cu (II) complexes with various ligand has been studied extensively.

Statistical Effects
It has been proposed that the mixed ligand complexes involve the consideration of a statistical effect. According to this, if the ligand L and R have equal concentrations, the probability that the first bond ligand L is one half. The probability of the formation of ML 3 is, therefore, 1/2 x 1/2 x 1/2 = 1/8. The same probably holds for

Effect of Ligand
The evaluation of "ligand effect" expressed as stabilization constant is done by the application of polarized model ion concept.
This model treats the complex as a system of the polarized sphere in contact, held together by purely electrostatic forces.
In 1977 the "ligand effect" was calculated by neglecting the polarizability of these spheres, thus, predicting the stabilization of the ternary complex [19]. To account for the stabilization of mixed ligand complexes in some cases, Shelki and Jaghirdar introduced the polarization effect on the calculation of ligand effect by means of point dipoles assumed at the centers of the spheres [18].

Effect of Solvent
The effect of solvent on the formation and stability of mixed ligand complexes has been reported, in several cases, especially in systems where binary and ternary complexes differ in charges.
The neutral, mixed -ligand complex formed by the neutralization of charges on the central metal ion and ligands is more stable than the one whose formation does not involve neutralization of charges [19].

The Mutual Interaction of The Ligands
It is observed that bond formation between the twocoordination group L and R have also to be considered in the stabilization of mixed species MLR. The ligand interaction may also give a stereoselective effect. The necessary condition for the formation of the MLR is that the two ligands must combine with the metal ion in different pH ranges. The formation of ML should be complete in the lower pH and MLR should be in the higher pH range where the combination of R starts with ML.

Ionic Strength
The stabilization of mixed ligand complexes is considerably affected by the variation in the ionic strength and this fact is of great importance in biological fluids where parameters such as ionic strength and dielectric constants are extremely variable. If the binary and ternary complexes carry equal charges, the stability increases with ionic strength [21].

Redox Potential of The Central Metal Ion
The overall stability of the mixed complex was found to increase with increase in redox potential of the central ion and decrease in the potential of ligand if metal-ligand bond is a predominantly covalent in character. If the bond is ionic, the stability increases with increase in the ligand potential.

General methods for the study of mixed ligand complexes
The equilibrium process can generally describe the formation of mixed ligand complexes. Various modern techniques are used to determine the stability constant of simple as well as mixed ligand compounds.

Potentiometric Method
The principle of the method is that a solution of known concentration of the base (or acid) to be studied is titrated with a strong acid (or strong base) and the reaction is carried out potentiometrically [22]. The method can be used for studying the protonation equilibria of ligands which in the protonated and non-protonated form is sufficiently soluble to form at least 10-3M solutions and which do not decompose during the titration.

Polarographic Method
The polarographic method is used to determine the stability

Conductance Measurement Method
Werner and others to study metal complexes extensively used this method. In the case of a series of complexes of Co (III) and Pt (IV), Werner assigned the correct formulae based on their molar conductance values measured in freshly prepared dilute solutions.
In some cases, the conductance of the solution increased with time due to a chemical change, for example: The rise in conductance, in this case, was accompanied by a sharp colour change of the solution from deep green to red.

Spectrophotometric Method
At specific pH, the ratio of the two species (the base and its protonated product) in a solution is determined by spectrophotometry and the protonation constant is calculated by using the basic equation. for metal ions, found in vivo. It is well known that the ternary coordination complexes play an important role in biological processes as exemplified by many instances in which enzymes are known to be activated by metal ions [24]. Ternary complexes have also been implicated in the storage and transport of active substances through membranes [25] and these phenomena are strongly dependent on the formation of these species and the electronic configuration of metal ion concerned. The stability constant and complexation behavior of Co (II), Zn (II) and Cu (II) complexes with various ligand has been studied extensively [26,28].