Hydroxamic acid

A hydroxamic acid is a class of organic compounds bearing the functional group RC(O)N(OH)R', with R and R' as organic residues and CO as a carbonyl group. They are amides (RC(O)NHR') wherein the NH center has an OH substitution. They are often used as metal chelators.

The general structure of a hydroxamic acid

Synthesis and reactions

Hydroxamic acids are usually prepared from either esters or acid chlorides by a reaction with hydroxylamine salts. For the synthesis of benzohydroxamic acid, the overall equation is:[1]

C₆H₅CO₂Me + NH₂OH → C₆H₅C(O)NHOH + MeOH

Hydroxamic acids can also be synthesized from aldehydes via the Angeli-Rimini reaction.

A well-known hydroxamic acid reaction is the Lossen rearrangement.

Coordination chemistry and biochemistry

• Sample gallery
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  Ferrichrome
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  Deferoxamine
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  Rhodotorulic acid
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  Fe(III) complex of triacetylfusarinine[2]

In the area of coordination chemistry, hydroxamates are excellent ligands.[3] They form by deprotonation of hydroxamic acids, Hydroxamates bind to metals ions as bidentate ligands, forming five-membered MO₂CN rings. Nature has evolved families of hydroxamic acids to function as iron-binding compounds (siderophores) in bacteria. They extract iron(III) from otherwise insoluble sources (rust, minerals, etc.). The resulting complexes are transported into the cell, where the iron is extracted and utilized metabolically.[4]

Ligands derived from hydroxamic acid and thiohydroxamic acid also form strong complexes with lead(II).[5]

Other uses and occurrences

Hydroxamic acids are used extensively in flotation of rare earth minerals during the concentration and extraction of ores to be subjected to further processing.

Some hydroxamic acids (e.g. vorinostat, belinostat, panobinostat, and trichostatin A) are HDAC inhibitors with anti-cancer properties. Fosmidomycin is a natural hydroxamic acid inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXP reductoisomerase). Hydroxamic acids have also been investigated for reprocessing of irradiated fuel.

References

1. C. R. Hauser and W. B. Renfrow, Jr. (1939). "Benzohydroxamic Acid". Org. Synth. 19: 15. doi:10.15227/orgsyn.019.0015.CS1 maint: uses authors parameter (link)
2. Hossain, M. B.; Eng-Wilmot, D. L.; Loghry, R. A.; an der Helm, D. (1980). "Circular Dichroism, Crystal Structure, and Absolute Configuration of the Siderophore Ferric N,N',N"-Triacetylfusarinine, FeC₃₉H₅₇N₆O₁₅". Journal of the American Chemical Society. 102 (18): 5766–5773. doi:10.1021/ja00538a012.
3. Agrawal, Y K (1979). "Hydroxamic Acids and Their Metal Complexes". Russian Chemical Reviews. 48 (10): 948–963. Bibcode:1979RuCRv..48..948A. doi:10.1070/RC1979v048n10ABEH002422.
4. Miller, Marvin J. (November 1989). "Syntheses and Therapeutic Potential of Hydroxamic Acid Based Siderophores and Analogues". Chemical Reviews. 89 (7): 1563–1579. doi:10.1021/cr00097a011.
5. Farkas, Etelka; Buglyó, Péter (2017). "Chapter 8. Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest". In Astrid, S.; Helmut, S.; Sigel, R. K. O. (eds.). Lead: Its Effects on Environment and Health. Metal Ions in Life Sciences. 17. de Gruyter. pp. 201–240. doi:10.1515/9783110434330-008. ISBN 9783110434330. PMID 28731301.

Further reading

• Fouché, K. F.; H. J. le Roux; F. Phillips (June 1970). "Complex formation of Zr(IV) and Hf(IV) with hydroxamic acids in acidic solutions". Journal of Inorganic and Nuclear Chemistry. 32 (6): 1949–1962. doi:10.1016/0022-1902(70)80604-2. ISSN 0022-1902. Archived from the original on 2013-01-04. Retrieved 2009-04-24.
• Barocas, A.; F. Baroncelli; G. B. Biondi; G. Grossi (December 1966). "The complexing power of hydroxamic acids and its effect on behaviour of organic extractants in the reprocessing of irradiated fuels--II : The complexes between benzohydroxamic acid and thorium, uranium (IV) and plutonium (IV)". Journal of Inorganic and Nuclear Chemistry. 28 (12): 2961–2967. doi:10.1016/0022-1902(66)80023-4. ISSN 0022-1902. Archived from the original on 2013-01-04. Retrieved 2009-04-24.
• Baroncelli, F.; G. Grossi (May 1965). "The complexing power of hydroxamic acids and its effect on the behaviour of organic extractants in the reprocessing of irradiated fuels--I the complexes between benzohydroxamic acid and zirconium, iron (III) and uranium (VI)". Journal of Inorganic and Nuclear Chemistry. 27 (5): 1085–1092. doi:10.1016/0022-1902(65)80420-1. ISSN 0022-1902. Archived from the original on 2013-01-04. Retrieved 2009-04-24.
• Al-Jarrah, R. H.; A. R. Al-Karaghouli; S. A. Al-Assaf; N. H. Shamon (1981). "Solvent extraction of uranium and some other metal ions with 2-N-butyl-2-ethyl octanohydroxamic acid". Journal of Inorganic and Nuclear Chemistry. 43 (11): 2971–2973. doi:10.1016/0022-1902(81)80652-5. ISSN 0022-1902. Archived from the original on 2013-01-04. Retrieved 2009-04-24.
• Gopalan, Aravamudan S.; Vincent J. Huber; Orhan Zincircioglu; Paul H. Smith (1992). "Novel tetrahydroxamate chelators for actinide complexation: synthesis and binding studies". Journal of the Chemical Society, Chemical Communications (17): 1266–1268. doi:10.1039/C39920001266.
• Koshti, Nirmal; Vincent Huber; Paul Smith; Aravamudan S. Gopalan (1994-02-28). "Design and synthesis of actinide specific chelators: Synthesis of new cyclam tetrahydroxamate (CYTROX) and cyclam tetraacetonylacetone (CYTAC) chelators". Tetrahedron. 50 (9): 2657–2664. doi:10.1016/S0040-4020(01)86981-7. ISSN 0040-4020.