# Hydroxamic acid
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{{Short description|1=Organic compounds of the form –C(=O)N(OH)–}}
thumb|right|150px|The general structure of a hydroxamic acid
In [organic chemistry](/source/organic_chemistry), '''hydroxamic acids''' are a class of [organic compound](/source/organic_compound)s having a general formula {{chem2|R\s[C(\dO)](/source/Carbonyl_group)\sN(\sOH)\sR'}} bearing the [functional group](/source/functional_group) {{chem2|\sC(\dO)\sN(\sOH)\s|auto=1}}, where R and R' are typically [organyl group](/source/organyl_group)s (e.g., [alkyl](/source/alkyl) or [aryl](/source/aryl)) or [hydrogen](/source/hydrogen). They are [amide](/source/amide)s ({{chem2|R\sC(\dO)\sNH\sR'}}) wherein the [nitrogen](/source/nitrogen) atom has a [hydroxyl](/source/hydroxyl) ({{chem2|\sOH}}) [substituent](/source/substituent). They are often used as [metal](/source/metal) [chelator](/source/chelation)s.[{{cite book |doi=10.1002/9780470772508.ch15|chapter=Hydroxamic acids |series=PATAI'S Chemistry of Functional Groups |year=1992 |last1=Munson |first1=James W. |pages=849–873 |isbn=9780470772508|editor=S. Patai|title=Acid Derivatives (1992), Volume 2}}]
Common example of hydroxamic acid is aceto-''N''-methylhydroxamic acid ({{chem2|H3C\sC(\dO)\sN(\sOH)\sCH3}}). Some uncommon examples of hydroxamic acids are formo-''N''-chlorohydroxamic acid ({{chem2|H\sC(\dO)\sN(\sOH)\sCl}}) and chloroformo-''N''-methylhydroxamic acid ({{chem2|Cl\sC(\dO)\sN(\sOH)\sCH3}}).
==Synthesis and reactions==
Hydroxamic acids are usually prepared from either [esters](/source/esters) or [acid chloride](/source/acid_chloride)s by a reaction with [hydroxylamine](/source/hydroxylamine) salts. For the synthesis of benzohydroxamic acid ({{chem2|C6H5\sC(\dO)\sNH\sOH}} or {{chem2|Ph\sC(\dO)\sNH\sOH}}, where Ph is [phenyl group](/source/phenyl_group)), the overall equation is:[{{cite journal|author1=C. R. Hauser |author2=W. B. Renfrow Jr |title=Benzohydroxamic Acid|journal=Org. Synth.|year=1939|volume=19|page=15|doi=10.15227/orgsyn.019.0015}}]
:{{chem2|[C6H5\sC(\dO)\sO\sCH3](/source/Methyl_benzoate) + [NH2OH](/source/Hydroxylamine) → C6H5\sC(\dO)\sNH\sOH + [CH3OH](/source/Methanol)}}
Hydroxamic acids can also be synthesized from [aldehyde](/source/aldehyde)s and ''N''-sulfonylhydroxylamine via the [Angeli-Rimini reaction](/source/Angeli-Rimini_reaction),[{{cite book |last1=Li |first1=Jie Jack |title=Name Reactions: A Collection of Detailed Reaction Mechanisms |date=2003 |publisher=Springer |location=Berlin, Heidelberg, New York |isbn=978-3-662-05338-6 |page=9 |edition=2nd}}] Alternatively, [ferric](/source/ferric) ions convert aldehydic [nitrone](/source/nitrone)s (or their [hydroxylamine](/source/hydroxylamines) precursors) to hydroxamic acids, although care must be taken not to over-oxidize via a hydroxy[imide](/source/imide) intermediate to [nitrous oxide](/source/nitrous_oxide) and the corresponding deaminated [diacid](/source/carboxylic_acid).[{{Cite thesis|url=https://open.uct.ac.za/server/api/core/bitstreams/8572acbb-760b-413f-a3eb-50669a33c5c0/content|pp=54–60|title=Cyclic Nitrones: Oxidation studies and the synthesis of a heterocyclic nitrone|first=J. F.|last=Elsworth|type=PhD|institution=[University of Cape Town](/source/University_of_Cape_Town)|date=September 1967}}]
Much like the conversion of [ketone](/source/ketone)s to [acyloin](/source/acyloin)s, [molybdenum oxide diperoxide](/source/molybdenum_oxide_diperoxide) oxidizes [trimethylsilated](/source/trimethylsilyl) [amide](/source/amide)s to hydroxamic acids, although yields are only about 50%.[{{cite journal|year=1979|pages=2481–2487|title=The oxidation of trimethylsilylated amides to hydroxamic acids|first1=Stephen A.|last1=Matlin|first2=Peter G.|last2=Sammes|first3=Roger M.|last3=Upton|journal=Journal of the Chemical Society, Perkin Transactions|doi=10.1039/p19790002481 }}]
In a variation on the [Nef reaction](/source/Nef_reaction), [primary](/source/Primary_carbon) [nitro compounds](/source/nitro_compounds) kept in an acidic solution (to minimize the [nitronate](/source/nitronate) [tautomer](/source/tautomer)) hydrolyze to a hydroxamic acid.[Smith (2020), ''March's Organic Chemistry'', rxn. 16-3.] In base, the reaction requires photoexcitation to the [triplet state](/source/triplet_state), and for secondary nitro compounds, the photoreaction proceeds with a [Beckmann-like](/source/Beckmann_rearrangement) ring expansion.[{{Cite journal|doi=10.1021/cr00004a002|pp=478–479|journal=Chemical Reviews|year=1991|volume=91|title=Photochemistry of hydroxamic acids and derivatives|first=Ewa|last=Lipzcynska-Kochany|orig-date=March 22, 1991}}]
A well-known reaction of hydroxamic acid esters is the [Lossen rearrangement](/source/Lossen_rearrangement).[{{cite book |last1=Wang |first1=Zerong |title=Comprehensive organic name reactions and reagents |date=2010 |publisher=John Wiley & Sons, Inc. |isbn=9780471704508 |pages=1772–1776}}]
==Coordination chemistry and biochemistry==
File:Ferrichrome.svg| [Ferrichrome](/source/Ferrichrome)
File:Deferoxamine-2D-skeletal.png |[Deferoxamine](/source/Deferoxamine)
File:Rhodotorulic acid.svg|[Rhodotorulic acid](/source/Rhodotorulic_acid)
File:Fe(hydroxamate)3.svg|Fe(III) complex of triacetylfusarinine[{{cite journal|last1=Hossain|first1=M. B.|last2=Eng-Wilmot|first2=D. L.|last3=Loghry|first3=R. A.|last4=an der Helm|first4=D.|title=Circular Dichroism, Crystal Structure, and Absolute Configuration of the Siderophore Ferric N,N',N"-Triacetylfusarinine, FeC39H57N6O15|journal=Journal of the American Chemical Society|year=1980|volume=102|issue=18|pages=5766–5773|doi=10.1021/ja00538a012}}]
The conjugate base of hydroxamic acids forms is called a '''hydroxamate'''. [Deprotonation](/source/Deprotonation) occurs at the {{chem2|\sN(\sOH)\s}} group, with the [hydrogen](/source/hydrogen) atom being removed, resulting in a hydroxamate [anion](/source/anion) {{chem2|R\sC(\dO)\sN(\sO−)\sR'}}. The resulting conjugate base presents the metal with an anionic, conjugated ''O'',''O'' [chelating ligand](/source/chelating_ligand). Many hydroxamic acids and many [iron](/source/iron) hydroxamates have been isolated from natural sources.[{{cite book|chapter=Natural and Biomimetic Hydroxamic Acid based Siderophores|author=Abraham Shanzer, Clifford E. Felder, Yaniv Barda|
editor = Zvi Rappoport, Joel F. Liebman|year= 2008|doi=10.1002/9780470741962.ch16|series=PATAI'S Chemistry of Functional Groups|title=The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids|pages=751–815 |isbn=9780470512616}}]
They function as [ligands](/source/ligands), usually for iron.[{{Cite journal
| doi = 10.1070/RC1979v048n10ABEH002422
| issue = 10
| pages = 948–963
| last = Agrawal
| first = Y K
| title = Hydroxamic Acids and Their Metal Complexes
| journal = Russian Chemical Reviews
| year = 1979
| volume = 48
| bibcode = 1979RuCRv..48..948A
| s2cid = 250857281
}}] Nature has evolved families of hydroxamic acids to function as iron-binding compounds ([siderophore](/source/siderophore)s) in [bacteria](/source/bacteria). They extract iron(III) from otherwise insoluble sources ([rust](/source/rust), [minerals](/source/minerals), etc.). The resulting complexes are transported into the cell, where the iron is extracted and utilized metabolically.[{{cite journal |last=Miller |first=Marvin J. |title=Syntheses and Therapeutic Potential of Hydroxamic Acid Based Siderophores and Analogues |journal=[Chemical Reviews](/source/Chemical_Reviews) |date=November 1989 |volume=89 |issue=7 |pages=1563–1579 |doi=10.1021/cr00097a011}}]
Ligands derived from hydroxamic acid and thiohydroxamic acid (a hydroxamic acid where one or both [oxygen](/source/oxygen)s in the {{chem2|\sC(\dO)\sN(\sOH)\s}} functional group are replaced by [sulfur](/source/sulfur)) also form strong [complexes](/source/Coordination_complex) with [lead](/source/lead)(II).[{{cite book|last1=Farkas|first1= Etelka|last2=Buglyó|first2=Péter|chapter= Chapter 8. Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest|pages= 201–240
|publisher= de Gruyter|date= 2017|series= Metal Ions in Life Sciences|volume=17|title=Lead: Its Effects on Environment and Health|editor1-last=Astrid|editor1-first= S.|editor2-last=Helmut|editor2-first=S.|editor3-last=Sigel |editor3-first= R. K. O.|doi=10.1515/9783110434330-008|pmid= 28731301|isbn= 9783110434330}}]
==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.[{{cite journal |last1=Marion |first1=Christopher |last2=Jordens |first2=Adam |last3=Li |first3=Ronghao |last4=Rudolph |first4=Martin |last5=Waters |first5=Kristian E. |title=An evaluation of hydroxamate collectors for malachite flotation |journal=Separation and Purification Technology |date=August 2017 |volume=183 |pages=258–269 |doi=10.1016/j.seppur.2017.02.056}}][{{cite journal |last1=Jordens |first1=Adam |last2=Cheng |first2=Ying Ping |last3=Waters |first3=Kristian E. |title=A review of the beneficiation of rare earth element bearing minerals |journal=Minerals Engineering |date=February 2013 |volume=41 |pages=97–114 |doi=10.1016/j.mineng.2012.10.017|bibcode=2013MiEng..41...97J}}]
Some hydroxamic acids (e.g. [vorinostat](/source/vorinostat), [belinostat](/source/belinostat), [panobinostat](/source/panobinostat), and [trichostatin A](/source/trichostatin_A)) are [HDAC inhibitor](/source/HDAC_inhibitor)s with anti-cancer properties. The hydroxamic acid functionality has been proposed to directly bind a zinc atom in the acetyl lysine binding pocket. [Fosmidomycin](/source/Fosmidomycin) is a natural hydroxamic acid inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase ([DXP reductoisomerase](/source/DXP_reductoisomerase)). Hydroxamic acids have also been investigated for reprocessing of irradiated fuel.{{citation needed|date=July 2022}}
== References ==
{{reflist|30em}}
==Further reading==
*{{Cite journal
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|volume=32
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|pages=1949–1962
|last=Fouché
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|author2=H. J. le Roux
|author3=F. Phillips
|title=Complex formation of Zr(IV) and Hf(IV) with hydroxamic acids in acidic solutions
|journal=Journal of Inorganic and Nuclear Chemistry
|access-date=2009-04-24
|date=June 1970
|url=http://www.science-direct.com/science/article/B758S-48M3JS8-NH/2/906cec1e859eacb47bf1f0efcd27e5cc
|archive-url=https://archive.today/20130104204633/http://www.science-direct.com/science/article/B758S-48M3JS8-NH/2/906cec1e859eacb47bf1f0efcd27e5cc
|url-status=dead
|archive-date=2013-01-04
|url-access=subscription
}}
*{{Cite journal
|doi=10.1016/0022-1902(66)80023-4
|issn=0022-1902
|volume=28
|issue=12
|pages=2961–2967
|last=Barocas
|first=A.
|author2=F. Baroncelli
|author3=G. B. Biondi
|author4=G. Grossi
|title=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=Journal of Inorganic and Nuclear Chemistry
|access-date=2009-04-24
|date=December 1966
|url=http://www.science-direct.com/science/article/B758S-48GWMMM-8P/2/0e24f83e069f7473d7b0663eea4f8302
|archive-url=https://archive.today/20130104153552/http://www.science-direct.com/science/article/B758S-48GWMMM-8P/2/0e24f83e069f7473d7b0663eea4f8302
|url-status=dead
|archive-date=2013-01-04
|url-access=subscription
}}
*{{Cite journal
|doi=10.1016/0022-1902(65)80420-1
|issn=0022-1902
|volume=27
|issue=5
|pages=1085–1092
|last=Baroncelli
|first=F.
|author2=G. Grossi
|title=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=Journal of Inorganic and Nuclear Chemistry
|access-date=2009-04-24
|date=May 1965
|url=http://www.science-direct.com/science/article/B758S-48N50RN-2W/2/fc4a67c10211cd748add5daa51bb55ff
|archive-url=https://archive.today/20130104213629/http://www.science-direct.com/science/article/B758S-48N50RN-2W/2/fc4a67c10211cd748add5daa51bb55ff
|url-status=dead
|archive-date=2013-01-04
|url-access=subscription
}}
*{{Cite journal
|doi=10.1016/0022-1902(81)80652-5
|issn=0022-1902
|volume=43
|issue=11
|pages=2971–2973
|last=Al-Jarrah
|first=R. H.
|author2=A. R. Al-Karaghouli
|author3=S. A. Al-Assaf
|author4=N. H. Shamon
|title=Solvent extraction of uranium and some other metal ions with 2-N-butyl-2-ethyl octanohydroxamic acid
|journal=Journal of Inorganic and Nuclear Chemistry
|access-date=2009-04-24
|year=1981
|url=http://www.science-direct.com/science/article/B758S-48M3SCR-152/2/723dc6c17d83f6266314116734ae71e8
|archive-url=https://archive.today/20130104171746/http://www.science-direct.com/science/article/B758S-48M3SCR-152/2/723dc6c17d83f6266314116734ae71e8
|url-status=dead
|archive-date=2013-01-04
|url-access=subscription
}}
*{{Cite journal
| issue = 17
| pages = 1266–1268
| last = Gopalan
| first = Aravamudan S.
|author2=Vincent J. Huber |author3=Orhan Zincircioglu |author4=Paul H. Smith
| title = Novel tetrahydroxamate chelators for actinide complexation: synthesis and binding studies
| journal = Journal of the Chemical Society, Chemical Communications
| year = 1992
| doi = 10.1039/C39920001266
|url=https://zenodo.org/record/1230022}}
*{{Cite journal
| doi = 10.1016/S0040-4020(01)86981-7 | issn = 0040-4020
| volume = 50 | issue = 9 | pages = 2657–2664
| last = Koshti | first = Nirmal |author2=Vincent Huber |author3=Paul Smith |author4=Aravamudan S. Gopalan
| title = Design and synthesis of actinide specific chelators: Synthesis of new cyclam tetrahydroxamate (CYTROX) and cyclam tetraacetonylacetone (CYTAC) chelators
| journal = Tetrahedron
| date = 1994-02-28
| url = https://zenodo.org/record/1259713
}}
{{Authority control}}
Category:Hydroxamic acids
Category:Functional groups
---
Adapted from the Wikipedia article [Hydroxamic acid](https://en.wikipedia.org/wiki/Hydroxamic_acid) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Hydroxamic_acid?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.