Chemistry of Chelating Ligands by Crystal Cunningham In 1920 the word chelate was first used by Sir Gilbert T.

Morgan and H.D.K. Drew. Chelate is derived from the Greek word chela meaning great claw (1). The reason for this name, proposed by Morgan, is that chelate describes the groups that are capable of behaving like two associating units. Chelates do this by attaching themselves to a central metal atom to produce rings, analogous to a lobster claw. The process of chelation involves coordination of more than one sigma-electron pair donor group from the same ligand to a single central atom. The term polydentate is used to describe the number of ligand groups on a single chelating ligand (2).

Figure 1 bidentate chelation with ethylenediamine

Figure 2 tridentate chelation with diethylenetriammine

Complexes of chelating agents are of interest to many disciplines such as physical chemists, organic chemists, biochemists, and pharmacologists. The emphasis of this paper is to show the diverse and unique characteristics of chelates. To give a full description of the properties and mechanisms of all chelates would be exhaustive. Whole books have been written about a single chelating agent! Instead, emphasis will be placed upon chiral chelate history, the synthesis of a historic chelate complex, chelate thermodynamics, and chelation therapy (CT). Prior to 1914, it was thought that six coordinate metal ions were trigonal prismatic rather than octahedral. It was between the years 1893 and 1914 that Alfred Werner established that six-

coordinate metal complexes were indeed octahedral. To accomplish this, Werner utilized the properties of ethylenediamine-metal chelate rings. Werner observed that replacement of the six ammonia ligands in haxaamminecobalt(III) with three of the ethylenediamine-metal chelate rings resulted in a pair of optical isomers. The trigonal prismatic coordination, previously thought to be the correct coordination, would Fogure 3 Enantiomers of ethylenediamine chelate rings have given rise to achiral geometric isomers. Since this discovery, metals with chelate ligands have been

instrumental in the development of stereoselective reactions involving metals (3). Since the time of Werners contributions, large leaps have occurred in chemical synthesis. Today compounds that were ounce thought to be exotic are readily made in the laboratory. For example the triphenylphosphine is now a common metal ligand. Current research in organic synthesis depends heavily on the formation of the proper enantiomer. In order to ensure that one enantiomer is favored over another, chelates are often called upon to play the role of the catalyst (4). When C-H and C-C bonds are desired, a transition metal with a chelating diphospine ligand is used as the catalyst. The backbone of the chelate provides the chirality and the phosphorus substituents provide a way in which the reactants can bind to the catalytic metal (4). The reactant Werner worked with, Ethylenediammine (en), is one of the most renown chelating agents. Transition metal ions can form complexes with en through the stepwise displacement of water (2): [M(H2O) 6]2+ + en > [M(H2O)4 en]2+ + H 2 O [M(H2O)4 en]2+ + en > [M(H2O)2(en)2]2+ + 2H 2 O K= 2.8 K= 5.0

[M(H2O)2(en)2]2+ + en > [M(en)3]2+ + H 2 O

K= 8.0

Each of the above reactions with en have an equilibrium or stability constant. This constant measures the tendency for the addition of the next en molecule. The Irving-Williams order tells us that the values of the stability constants for the ions Mn2+ to Zn2+ uniformly increases from left to right (2). The [Cu(en)3]2+ complex does not follow this trend and it is very unstable. This complex was even thought to be non-existent until it was prepared in 1958. Gilbert Gordon and Ralph Birdwhistel provided evidence of the existence of hexacoordinate copper (II) in the trisethylenediaminecopper(II) sulfate complex (5). The trisethylenediaminecopper(II) Sulfate was prepared by using a 1:6 mole ratio of the reactants and mixing with enough water to make an approximate 1M solution. Ethanol was then added to the 1M solution and a precipitate formed. The experimenters first attempted to wash the precipitate with ethanol but that resulted in the conversion of trisethylenediaminecopper(II) Sulfate to the deep- purple bisethylenediaminecopper(II) Sulfate . The infrared spectrum of the trisethylenediaminecopper(II) Sulfate showed the -NH2 band to be located at 3230 and 1620 cm-1. Both of these are shifted from the spectra of the free base ethylenediamine and the shift is interpreted as the result of coordination of the amino groups. The sharpness of the peaks suggest that all of the groups are alike and are coordinated (5). The peak shift to a region of higher wavelength due to the addition of the high field en ligand. Although the infrared spectrum gave very strong evidence that coordination occurred, it did not determine if the structure was trigonal bipyramid or octahedral. Since an asymmetrical center could be present in either molecule, optical activity did not help to determine the structure. Instead, absorption studies of the tris complex were carried out. The studies had to be performed

in a high concentration of ethylenediamine to prevent dissociation of the tris complex in solution. The absorption maxima that occurred was at wavelength 647 nm, a value that was first reported by Gordon and Birdwhistel (5). Before the studies of Gordon and Birdwhistel, there was not much evidence to support octahedral formation. The shift of the absorption maximum to blue as one moves from the bisethylenediaminecopper(II) to the trisethylenediaminecopper(II) complex was in agreement with previous shifts for the hexammine complex. This was enough evidence for the authors to conclude that trisethylenediaminecopper(II) is octahedral in both the solid state and in the aqueous state provided the aqueous solutions are sufficiently concentrated in ethylenediamine (5). The instability of the tris complex is due to the tendency for a six-coordinate d9 ion to distort. Distortion by either elongation or compression stabililizes the copper(II) complexes, this is known as the Jahn-Teller effect. The trisethylenediaminecopper(II) complex cannot distort tetragonally without straining at least two of the chelate rings (2). Since, the chelate ring system prevents distortion, trisethylenediaminecopper(II) lacks the stabilization of the Jahn-Teller effect. In general, chelated rings prevent complexes from distorting from the octahedron complex. This occurs from the way the coordinating atoms grab the metal atoms. This property of chelates helps to stabilize metal complex. Although trisethylenediaminecopper is a relatively unstable molecule, complexes containing chelate rings are usually quite stable. This extra stability is due to the chelate effect (2). The reactions of a chelating ligand and a metal ion with a reaction involving monodentate ligands can be compared to observe the chelate effect. If one compares thermodynamic data, the complex resulting from coordination with the chelating ligand is much more thermodynamically

stable. This is illustrated in table 1 (6).

Table 1. Reaction of pyridine and 2,2"-bipyridine with Ni 2+ # of ligands 2 py(1bipy) 4 py(2bipy) 6 py(3bipy) G kJmol-1 -20 -32 -56

The increase in stability is obvious from the fact that the free energy lowers as bidentate ligands are added. Recall that the free energy is affected by two terms, an enthalpy term and a negative entropy term. The chelate effect occurs due to a large increase in the entropy term. One way to explain the increasing entropy is to consider the difference between the number of molecules before and after the reaction. The reaction proceeds to the right with an increase in the number of particles, favoring entropy. The increase in the number of molecules in solution is directly proportional to the entropy increase. A reaction with nickel (II) demonstrates the increase in entropy (2). [Ni(NH3)6]2+ + 3en > [Ni(en)3]2+ + 6NH3 The number of molecules in the reactants is four while the number of molecules in the products is seven. The second factor that can contribute to the stability of chelates is the fact that they can posess resonance stability. For example acetylacetone can have the delocalization of electrons between the ligand-metal pi bonding (2).

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Figure 4 Stabilization by pi bonding The third stabilization factor is the fact that if one end of the ligand were to dissociate, in a polydentate ligand, the dissociated end can be drawn back to the metal by the end that remained attached. Aside from the unique thermodynamic properties of chelating agents, they also play a role in biology. Ethylenediaminetetraacetic acid (EDTA) was first developed to be used in the dye industry (7). Today, its sodium salt is used for the treatment of oisoning by metals. EDTA has received approval by the FDA to be used as a treatment for lead poisoning. Chelation therapy (CT) is accomplished through intravenously inserting EDTA into the bloodstream. The affinity of EDTA for metals allows it to bind tightly to the lead. After binding, the complex can be secreted from the body. Chelation therapy has been promoted as an alternative to bypass surgery. It was thought to pull calcium our of plaque filled arteries causing them to shrink (7). There are serious hazards involved such as kidney failure and hypocalcemic tetany (too much loss of calcium). There have been both successes as declared by bumper stickers reading Im elated, Ive been chelated! (2) and several opponents to chelation therapy. Chelates have a rich history in both inorganic and organic synthesis. The use of these

complexes to provide a desired isomer and to use as catalysts has become increasingly popular since Werners early twentieth century discovery. The stability and thermodynamic properties of chelates have made them interesting objects of research to many scientists. Their biological relevencay adds to the interesting properties of chelates. In a variety of ways chelate complexes have been shown to posses very unique chemical character.

1. Morgan, Gilbert, and Drew, H.D.K., J. Chem Soc., 1920, 117, 1456.

2. Hueey James, Inorganic Chemistry 4th ed., Harper Collins 1993.

3. Annual Report- Inorganic Stereochemistry and Asymmetric Synthesis. (November 2000). Pathfinder-Neoplanet[online]. Available: http:// rsc.anu.edu.au/RSC/ChemResearch/AnnualReport/Current/AH-report.html

4. John M. Brown. (November 2000). Pathfinder-Neoplanet[online]. Available: http://www.chem.ox.ac.uk/dp/jmbrown.html

5. Gordon G., Birdwhistell R.K., Hexacoordinate Copper(II) in Trisethylenediaminecopper(II) Sulfate, J. Amer Chem Soc., 1959, 81, 3567.

6. Stability, chelation, and the chelate effect. (November 2000). Pathfinder-Neoplanet[online]. Available:http://wwwchem.uwimona.edu.jm:1104/courses/chelate.html

7. National Council For Reliable Health Information. (November 2000). PathfinderNeoplanet[online]. Available: Http://www.ncrhi.org/Mis/resources/chelate.htm