A chelate results from a chemical combination of an inorganic ion with at least two electron rich functional groups in a single organic molecule. This reaction results in the formation of a ring usually containing five or six atoms. The term chelate is derived from the Greek chele meaning "the crab's claw." The inorganic component of biological interest commonly involved is one of the transition elements, the same elements usually associated with enzymes. They have a coordination number of 4 or 6.
The organic moiety of the chelate, often called a ligand, has the coordinating functional groups separated by two or three atoms, usually carbon, so that the final ring, including the inorganic ion, contains five or six members. Normally, chelating agents have any combination of F, O, N, S, As (or P as a phos phine), appearing in functional groups as C = O, C - OH, C - NH2, C = N, and C - SH. Open chain or heterocyclic ethers may also be involved. The common chelating agents usually contain intramolecular H bonds. The major exception is probably the class of mercaptans. The S-H group does not form an H-bond. A well-known illustration of this is the very low boiling point of hydrogen sulfide, H2S, a gas, as compared with water, H2O, a liquid.
The use of dimethylglyoxime for the precipitation of nickel, the formation of a copper complex by 8-hydroxyquinoline are classical examples of chelation used by the analytical chemists for years. Amino acids, too, precipitate with copper; the formation of copper glycinate (VIII) is an illustration of a chelate using a biologically important ligand, glycine. The chelate may be pictured geometrically as a square coplanar molecule (VIIIA). The well known ethylenediaminetetraacetic acid, EDTA (IX), can be considered as a modified glycine. For industrial and medicinal purposes, it is often advantageous that the final chelate formed from EDTA is water soluble.
* A complete discussion of the phenomenon of chelation is beyond the scope of this review. Excellent discussions can be found in references 100, 182, 366, 367, 513. Applications of chelation to pharmacology are described in references 5, 7, 40, 170, 488, 528, 593. For the biologist, references 103, 489 are especially useful. Many references to the quantitative aspect of chelation are also available.
It should be noted that chelation need not involve ionic bonding by the organic ligand; for example, consider the octahedral coordination of ferric iron by 2,2'-bipyridyl (X) to form the iron bipyridyl complex (XI).
The number of groups in a ligand which can coordinate with a metal ion by ionic, covalent, or coordinate covalent bonds is indicated by the terms unidentate, bidentate, etc. The minimum requirement for chelation is a bidentate ligand, for a unidentate molecule cannot form a ring. Glycine and 2,2'-bipyridyl (X) are examples of bidentate ligands. The EDTA calcium complex (XII) is an example of a quadridentate structure.
The relative avidity with which the trace elements combine with many of the chelating agents seems to be almost independent of the nature of the organic compound. The empirical order of affinity of some bivalent metals for various ligands is Mg2+<Mn2+<Fe2+<Co2+<Ni2+<Cu2+>Zn2+ (288, 599, 600, 601) as shown by a plot of log stability constant (log KN) for complexes of almost all ligands of the bivalent transition series cations against their atomic numbers.
The shape and size of the chelate ring (including the inorganic ion) also determine the stability of the chelate. Potential ligands with side chains that would result in steric hindrance to ring formation either will not form chelates or will form unstable ones. Three membered rings are not stable, and four membered rings are strained. Stability is greater for saturated ligands containing five membered chelate rings; for unsaturated ligands, six membered rings are considered more stable. For ligands with one double bond, equal stability is found for both five- and six membered rings. The most stable chelates are those in which fused rings have been formed; thus, EDTA (IX) and penicillamine (XIII) chelates have a larger stability constant than would be expected if a comparison was made with a bidentate ligand.
Isomers, especially cis trans, are possible with chelates as well as with complex ions; optical isomers would not be expected when two of the coordinating organic ligands are the same.
In this paper the symbol M will signify a cation which is in the chelate form. The unsubstituted neutral organic molecule will be shown without its hydrogen atoms. The arrow (→) will be used to designate the coordinate covalent bonds, and solid lines, the ionic chelate bonds (as well as ordinary covalent bonds). As a rule, the second or third molecule of the chelating agent will not be drawn, and only representative bonds will be given. Thus, an example of a tridentate chelating agent com plexed with a metallic ion M is the result of treating metal M with penicillamine, as shown in (XIV).