# Chelation

(Redirected from Chelating agent)

Chelation (pronounced /kiːˈleɪʃən/) is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central atom.[1][2] Usually these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.

Chelation is useful in applications such as providing nutritional supplements, in chelation therapy to remove toxic metals from the body, as contrast agents in MRI scanning, in manufacturing using homogeneous catalysts, and in fertilizers.

## Chelate effect

Ethylenediamine ligand chelating to a metal with two bonds.
Cu2+ complexes with nonchelating methylamine (left) and chelating ethylenediamine (right) ligands.

The chelate effect is the enhanced affinity of chelating ligands for a metal ion compared to the affinity of a collection of similar nonchelating (monodentate) ligands for the same metal.

Consider the two equilibria, in aqueous solution, between the copper(II) ion, Cu2+ and ethylenediamine (en) on the one hand and methylamine, MeNH2 on the other.

Cu2+ + en ⇌ [Cu(en)]2+

(1)

Cu2+ + 2 MeNH2 ⇌ [Cu(MeNH2)2]2+

(2)

In (1) the bidentate ligand ethylenediamine forms a chelate complex with the copper ion. Chelation results in the formation of a five-membered CuC2N2 ring. In (2) the bidentate ligand is replaced by two monodentate methylamine ligands of approximately the same donor power, meaning that the enthalpy of formation of Cu—N bonds is approximately the same in the two reactions.

The thermodynamic approach to describing the chelate effect considers the equilibrium constant for the reaction: the larger the equilibrium constant, the higher the concentration of the complex.

[Cu(en)] = β11[Cu][en]

(3)

[Cu(MeNH2)2] = β12[Cu][MeNH2]2

(4)

Electrical charges have been omitted for simplicity of notation. The square brackets indicate concentration, and the subscripts to the stability constants, β, indicate the stoichiometry of the complex. When the analytical concentration of methylamine is twice that of ethylenediamine and the concentration of copper is the same in both reactions, the concentration [Cu(en)] is much higher than the concentration [Cu(MeNH2)2] because β11 >> β12.

An equilibrium constant, K, is related to the standard Gibbs free energy, ${\displaystyle \Delta G^{\ominus }}$ by

${\displaystyle \Delta G^{\ominus }=-RT\ln K=\Delta H^{\ominus }-T\Delta S^{\ominus }}$

where R is the gas constant and T is the temperature in Kelvin. ${\displaystyle \Delta H^{\ominus }}$ is the standard enthalpy change of the reaction and ${\displaystyle \Delta S^{\ominus }}$ is the standard entropy change.

Since the enthalpy should be approximately the same for the two reactions, the difference between the two stability constants is due to the effects of entropy. In equation (1) there are two particles on the left and one on the right, whereas in equation (2) there are three particles on the left and one on the right. This difference means that less entropy of disorder is lost when the chelate complex is formed than when the complex with monodentate ligands is formed. This is one of the factors contributing to the entropy difference. Other factors include solvation changes and ring formation. Some experimental data to illustrate the effect are shown in the following table.[3]

Equilibrium log β ${\displaystyle \Delta G^{\ominus }}$ ${\displaystyle \Delta H^{\ominus }\mathrm {/kJ\ mol^{-1}} }$ ${\displaystyle -T\Delta S^{\ominus }\mathrm {/kJ\ mol^{-1}} }$
Cu2+ + 4 MeNH2 ⇌ Cu(MeNH2)42+ 6.55 -37.4 -57.3 19.9
Cu2+ + 2 en ⇌ Cu(en)22+ 10.62 -60.67 -56.48 -4.19

These data confirm that the enthalpy changes are approximately equal for the two reactions and that the main reason for the greater stability of the chelate complex is the entropy term, which is much less unfavourable. In general it is difficult to account precisely for thermodynamic values in terms of changes in solution at the molecular level, but it is clear that the chelate effect is predominantly an effect of entropy.

Other explanations, including that of Schwarzenbach,[4] are discussed in Greenwood and Earnshaw (loc.cit).

## In nature

Numerous biomolecules exhibit the ability to dissolve certain metal cations. Thus, proteins, polysaccharides, and polynucleic acids are excellent polydentate ligands for many metal ions. Organic compounds such as the amino acids glutamic acid and histidine, organic diacids such as malate, and polypeptides such as phytochelatin are also typical chelators. In addition to these adventitious chelators, several biomolecules are specifically produced to bind certain metals (see next section).[5][6][7][8]

### In biochemistry and microbiology

Virtually all metalloenzymes feature metals that are chelated, usually to peptides or cofactors and prosthetic groups.[8] Such chelating agents include the porphyrin rings in hemoglobin and chlorophyll. Many microbial species produce water-soluble pigments that serve as chelating agents, termed siderophores. For example, species of Pseudomonas are known to secrete pyochelin and pyoverdine that bind iron. Enterobactin, produced by E. coli, is the strongest chelating agent known. The marine mussels use metal chelation esp. Fe3+ chelation with the Dopa residues in mussel foot protein-1 to improve the strength of the threads that it uses to secure itself to surfaces.[9][10][11]

### In geology

In earth science, hot chemical weathering is attributed to organic chelating agents (e.g., peptides and sugars) that extract metal ions from minerals and rocks.[12] Some metal complexes in the environment and in nature are not found in some form of chelate ring (e.g., with a humic acid or a protein). Thus, metal chelates are relevant to the mobilization of metals in the soil, the uptake and the accumulation of metals into plants and microorganisms. Selective chelation of heavy metals is relevant to bioremediation (e.g., removal of 137Cs from radioactive waste).[13]

## Medical applications

### Nutritional supplements

In the 1960s, scientists developed the concept of chelating a metal ion prior to feeding the element to the animal. They believed that this would create a neutral compound, protecting the mineral from being complexed with insoluble salts within the stomach, which would render the metal unavailable for absorption. Amino acids, being effective metal binders, were chosen as the prospective ligands, and research was conducted on the metal-amino acid combinations. The research supported that the metal-amino acid chelates were able to enhance mineral absorption.

During this period, synthetic chelates such as ethylenediaminetetraacetic acid (EDTA) were being developed. These applied the same concept of chelation and did create chelated compounds; but these synthetics were too stable and not nutritionally viable. If the mineral was taken from the EDTA ligand, the ligand could not be used by the body and would be expelled. During the expulsion process the EDTA ligand randomly chelated and stripped another mineral from the body.[14]

According to the Association of American Feed Control Officials (AAFCO), a metal amino acid chelate is defined as the product resulting from the reaction of a metal ion from a soluble metal salt with a mole ratio of one to three (preferably two) moles of amino acids. The average weight of the hydrolyzed amino acids must be approximately 150 and the resulting molecular weight of the chelate must not exceed 800 Da.[citation needed]

Since the early development of these compounds, much more research has been conducted, and has been applied to human nutrition products in a similar manner to the animal nutrition experiments that pioneered the technology. Ferrous bis-glycinate is an example of one of these compounds that has been developed for human nutrition.[15]

### Heavy-metal detoxification

Main article: Chelation therapy

Chelation therapy is the use of chelating agents to detoxify a patient's body of poisonous metal agents, such as mercury, arsenic, and lead, by converting them to a chemically inert form that can be excreted without further interaction with the body. Chelation using calcium disodium EDTA has been approved by the U.S. Food and Drug Administration (FDA), but only for serious cases of lead poisoning. It is not approved for treating "heavy metal toxicity".[16]

Although they can be beneficial in cases of serious lead poisoning, use of unapproved chelating agents is dangerous. Use of disodium EDTA (edetate disodium) instead of calcium disodium EDTA has resulted in fatalities due to hypocalcemia.[17] Disodium EDTA is not approved by the FDA for any use,[16] and all FDA-approved chelation therapy products require a prescription.[18]

### Pharmaceuticals

Chelate complexes of gadolinium are often used as contrast agents in MRI scans. Auranofin, a chelate complex of gold, is used in the treatment of rheumatoid arthritis.

### Other medical applications

Chelation in the intestinal tract is a cause of numerous interactions between drugs and metal ions (also known as "minerals" in nutrition). As examples, antibiotic drugs of the tetracycline and quinolone families are chelators of Fe2+, Ca2+ and Mg2+ ions.[19][20]

EDTA, which binds to and sequesters calcium, is used to alleviate the hypercalcimia that often results from band keratopathy. The calcium may then be scraped from the cornea with a spatula-shaped instrument, allowing for some increase in clarity of vision for the patient. This procedure requires the use of numbing drops, as the acid, though weak from a pH standpoint, would cause acute ocular discomfiture. Patients normally wear an eye shield following such procedures and are advised against swimming for some weeks afterwards. This is normally an outpatient procedure, requiring no general anesthetics to be employed prior to performing the procedure.[citation needed]

### Alternative medicine

Although the practice has been discredited [21][22] and even condemned by organizations such as the U.S. National Institutes of Health, the Journal of the American Medical Association, and The New England Journal of Medicine, chelation was used as a treatment for autism. This practice has largely ended due to the absence of scientific plausibility, its potentially deadly side-effects, and the lack of approval by the U.S. Food and Drug Administration[23]

## Industrial and agricultural applications

### Catalysis

Homogeneous catalysts are often chelated complexes. A typical example is the ruthenium(II) chloride chelated with BINAP (a bidentate phosphine) used in e.g. Noyori asymmetric hydrogenation and asymmetric isomerization. The latter has the practical use of manufacture of synthetic (–)-menthol.Uses of Chelates.

### Water softening

Citric acid is used to soften water in soaps and laundry detergents. A common synthetic chelator is EDTA. Phosphonates are also well-known chelating agents. Chelators are used in water treatment programs and specifically in steam engineering, e.g., boiler water treatment system: Chelant Water Treatment system.

### Fertilizers

Metal chelate compounds are common components of fertilizers to provide micronutrients. These micronutrients (manganese, iron, zinc, copper) are required for the health of the plants. Most fertilizers contain phosphate salts that, in the absence of chelating agents, typically convert these metal ions into insoluble solids that are of no nutritional value to the plants. EDTA is the typical chelating agent that keeps these metal ions in a soluble form.[24]

## Etymology

The ligand forms a chelate complex with the substrate. Chelate complexes are contrasted with coordination complexes composed of monodentate ligands, which form only one bond with the central atom. The word chelation is derived from Greek χηλή, chēlē, meaning "claw"; the ligands lie around the central atom like the claws of a lobster. The term chelate was first applied in 1920 by Sir Gilbert T. Morgan and H. D. K. Drew, who stated: "The adjective chelate, derived from the great claw or chele (Greek) of the lobster or other crustaceans, is suggested for the caliperlike groups which function as two associating units and fasten to the central atom so as to produce heterocyclic rings."[25]

## References

1. ^ IUPAC definition of chelation.
2. ^ Latin chela, from Greek, denotes a claw.
3. ^ Greenwood, Norman N.; Earnshaw, Alan (1997). Chemistry of the Elements (2nd ed.). Butterworth-Heinemann. p. 910. ISBN 0-08-037941-9.
4. ^ Schwarzenbach, G. (1952). "Der Chelateffekt". Helvetica Chimica Acta. 35 (7): 2344–59. doi:10.1002/hlca.19520350721.
5. ^ Krämer, Ute; Cotter-Howells, Janet D.; Charnock, John M.; Baker, Alan J. M.; Smith, J. Andrew C. (1996). "Free histidine as a metal chelator in plants that accumulate nickel". Nature. 379 (6566): 635–8. Bibcode:1996Natur.379..635K. doi:10.1038/379635a0.
6. ^ Magalhaes, J. V. (2006). "Aluminum tolerance genes are conserved between monocots and dicots". Proceedings of the National Academy of Sciences of the United States of America. 103 (26): 9749–50. Bibcode:2006PNAS..103.9749M. doi:10.1073/pnas.0603957103. PMC 1502523. PMID 16785425.
7. ^ Ha, Suk-Bong; Smith, Aaron P.; Howden, Ross; Dietrich, Wendy M.; Bugg, Sarah; O'Connell, Matthew J.; Goldsbrough, Peter B.; Cobbett, Christopher S. (1999). "Phytochelatin Synthase Genes from Arabidopsis and the Yeast Schizosaccharomyces pombe". The Plant Cell. 11 (6): 1153–64. doi:10.1105/tpc.11.6.1153. PMC 144235. PMID 10368185.
8. ^ a b S. J. Lippard, J. M. Berg "Principles of Bioinorganic Chemistry" University Science Books: Mill Valley, CA; 1994. ISBN 0-935702-73-3.[page needed]
9. ^ Das, Saurabh; Miller, Dusty R.; Kaufman, Yair; Martinez Rodriguez, Nadine R.; Pallaoro, Alessia; Harrington, Matthew J.; Gylys, Maryte; Israelachvili, Jacob N.; Waite, J. Herbert (2015). "Tough Coating Proteins: Subtle Sequence Variation Modulates Cohesion". Biomacromolecules. 16 (3): 1002–8. doi:10.1021/bm501893y. PMC 4514026. PMID 25692318.
10. ^ Harrington, M. J.; Masic, A.; Holten-Andersen, N.; Waite, J. H.; Fratzl, P. (2010). "Iron-Clad Fibers: A Metal-Based Biological Strategy for Hard Flexible Coatings". Science. 328 (5975): 216–20. Bibcode:2010Sci...328..216H. doi:10.1126/science.1181044. PMC 3087814. PMID 20203014.
11. ^ Das, Saurabh; Rodriguez, Nadine R. Martinez; Wei, Wei; Waite, J. Herbert; Israelachvili, Jacob N. (2015). "Peptide Length and Dopa Determine Iron-Mediated Cohesion of Mussel Foot Proteins". Advanced Functional Materials. 25 (36): 5840–7. doi:10.1002/adfm.201502256.
12. ^ Dr. Michael Pidwirny, University of British Columbia Okanagan, http://www.physicalgeography.net/fundamentals/10r.html
13. ^ Prasad (ed). Metals in the Environment. University of Hyderabad. Dekker, New York, 2001[page needed]
14. ^ Ashmead, H. DeWayne (1993). The Roles of Amino Acid Chelates in Animal Nutrition. Westwood: Noyes Publications.[page needed]
15. ^ Albion Laboratories, Inc. "Albion Ferrochel Website". Retrieved July 12, 2011.
16. ^ a b "FDA Issues Chelation Therapy Warning". September 26, 2008. Retrieved May 14, 2016.
17. ^ Centers for Disease Control Prevention (CDC) (2006). "Deaths associated with hypocalcemia from chelation therapy--Texas, Pennsylvania, and Oregon, 2003-2005". Morbidity and Mortality Weekly Report. 55 (8): 204–7. PMID 16511441.
18. ^ "Questions and Answers on Unapproved Chelation Products". FDA. February 2, 2016. Retrieved May 14, 2016.
19. ^ Campbell, NR; Hasinoff, BB (1991). "Iron supplements: a common cause of drug interactions". British Journal of Clinical Pharmacology. 31 (3): 251–5. doi:10.1111/j.1365-2125.1991.tb05525.x. PMC 1368348. PMID 2054263.
20. ^ Lomaestro BM, Bailie GR (1995). "Absorption interactions with fluoroquinolones. 1995 update". Drug Safety. 12 (5): 314–33. doi:10.2165/00002018-199512050-00004. PMID 7669261.
21. ^ Willingham, Emily (2012). "No Evidence Supporting Chelation As Autism Treatment". Forbes. Retrieved October 4, 2014.
22. ^ Brownstein, Joseph (2010). "Father Sues Doctors Over 'Fraudulent' Autism Therapy". ABC News. Retrieved October 4, 2014.
23. ^ Doja, Asif; Roberts, Wendy (2006). "Immunizations and Autism: A Review of the Literature". The Canadian Journal of Neurological Sciences. 33 (4): 341–6. doi:10.1017/S031716710000528X. PMID 17168158.
24. ^ Hart, J. Roger (2011). "Ethylenediaminetetraacetic Acid and Related Chelating Agents". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a10_095.pub2.
25. ^ Morgan, Gilbert T.; Drew, Harry Dugald Keith (1920). "CLXII.—Researches on residual affinity and co-ordination. Part II. Acetylacetones of selenium and tellurium". Journal of the Chemical Society, Transactions. 117: 1456–65. doi:10.1039/ct9201701456.