hydroxylamine

Hydroxylamine was first prepared as hydroxylammonium chloride in 1865 by the German chemist Wilhelm Clemens Lossen (1838-1906); he reacted tin and hydrochloric acid in the presence of ethyl nitrate.W. C. Lossen (1865) [https://books.google.com/books?id=6CfyAAAAMAAJ&pg=PA551 "Ueber das Hydroxylamine"] (On hydroxylamine), Zeitschrift für Chemie, 8 : 551-553. From p. 551: "Ich schlage vor, dieselbe Hydroxylamin oder Oxyammoniak zu nennen." (I propose to call it hydroxylamine or oxyammonia.) It was first prepared in pure form in 1891 by the Dutch chemist Lobry de Bruyn and by the French chemist Léon Maurice Crismer (1858-1944).C. A. Lobry de Bruyn (1891) [https://books.google.com/books?id=dGASAAAAYAAJ&pg=PA100 "Sur l'hydroxylamine libre"] (On free hydroxylamine), Recueil des travaux chimiques des Pays-Bas, 10 : 100-112.L. Crismer (1891) [https://books.google.com/books?id=bSvOAAAAMAAJ&pg=PA793 "Préparation de l'hydroxylamine cristallisée"] (Preparation of crystalized hydroxylamine), Bulletin de la Société chimique de Paris, series 3, 6 : 793-795. The coordination complex {{chem2|ZnCl2(NH2OH)2}} (zinc dichloride di(hydroxylamine)), known as Crismer's salt, releases hydroxylamine upon heating.{{cite book|doi=10.1002/9780470132401.ch2|chapter=Dichlorobis(hydroxylamine)zinc(II) (Crismer's Salt)|year=1967|volume=9|last1=Walker|first1=John E.|last2=Howell|first2=David M.|title=Inorganic Syntheses|pages=2–3|isbn=9780470132401}}

Hydroxylamine and its N-substituted derivatives are pyramidal at nitrogen, with bond angles very similar to those of amines. The conformation of hydroxylamine places the NOH anti to the lone pair on nitrogen, seeming to minimize lone pair-lone pair interactions. {{cite book |doi=10.1002/9780470741962.ch2 |chapter=Structural Analysis of Hydroxylamines, Oximes and Hydroxamic Acids: Trends and Patterns |title=The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids |series=PATAI's Chemistry of Functional Groups |date=2008 |last1=Politzer |first1=Peter |last2=Murray |first2=Jane S. |pages=29–51 |isbn=978-0-470-51261-6 }}

Hydroxylamine or its salts (salts containing hydroxylammonium cations {{chem2|[NH3OH]+}}) can be produced via several routes but only two are commercially viable. It is also produced naturally as discussed in a section on biochemistry.

{{chem2|NH2OH}} is mainly produced as its sulfuric acid salt, hydroxylammonium sulfate ({{chem2|[NH3OH][SO4]}}), by the hydrogenation of nitric oxide over platinum catalysts in the presence of sulfuric acid.{{Ullmann |doi=10.1002/14356007.a13_527|title=Hydroxylamine|year=2000|last1=Ritz|first1=Josef|last2=Fuchs|first2=Hugo|last3=Perryman|first3=Howard G.|isbn=3527306730}}

:{{chem2|2 NO + 3 H2 + H2SO4 → [NH3OH]2[SO4]}}

Another route to {{chem2|NH2OH}} is the Raschig process: aqueous ammonium nitrite is reduced by Bisulfite and Sulfur dioxide at 0 °C to yield a hydroxylamido-N,N-disulfonate anion:

:{{chem2|[NH4]+[NO2]− + 2 SO2 + NH3 + H2O → [NH4]2[HON(SO3)2]}}

This ammonium hydroxylamine disulfonate anion is then hydrolyzed to give hydroxylammonium sulfate:

:{{chem2|[NH4]2[HON(SO3)2] + 2 H2O → [HONH3]2SO4}}

Julius Tafel discovered that hydroxylamine hydrochloride or sulfate salts can be produced by electrolytic reduction of nitric acid with HCl or Sulfuric acid respectively:{{cite book|last1=James Hale|first1=Arthur|title=The Manufacture of Chemicals by Electrolysis|date=1919|publisher=D. Van Nostrand Co.|location=New York|page=[https://archive.org/details/manufacturechem00halegoog/page/n48 32]|edition=1st|url=https://archive.org/details/manufacturechem00halegoog|quote=manufacture of chemicals by electrolysis hydroxylamine 32.|access-date=5 June 2014}}{{cite book|author1=Osswald, Philipp |author2=Geisler, Walter|title=Process of preparing hydroxylamine hydrochloride (US2242477)|year=1941|publisher=U.S. Patent Office|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US2242477.pdf}}

:{{chem2|HNO3 + 3 H2 → NH2OH + 2 H2O}}

Hydroxylamine can also be produced by the reduction of nitrous acid or potassium nitrite with bisulfite:

:{{chem2|HNO2 + 2 HSO3− → N(OH)(OSO2−)2 + H2O → NH(OH)(OSO2−) + HSO4−}}

:{{chem2|NH(OH)(OSO2−) + [H3O]+ → [NH3OH]+ + HSO4−}} (100 °C, 1 h)

Hydrochloric acid disproportionates nitromethane to hydroxylamine hydrochloride and carbon monoxide via the hydroxamic acid.{{cn|date=March 2024}}

A direct lab synthesis of hydroxylamine from molecular nitrogen in water plasma was demonstrated in 2024.{{cite journal |journal=Nature Communications |volume = 15 |issue = 1 |article-number = 1535 |doi=10.1038/s41467-024-45832-9 |title=Efficient catalyst-free N₂ fixation by water radical cations under ambient conditions |year=2024 |first1=Xiaoping|last1=Zhang|first2=Rui|last2=Su|first3=Jingling|last3=Li|first4=Liping|last4=Huang|first5=Wenwen|last5=Yang|first6=Konstantin|last6=Chingin|first7=Roman|last7=Balabin|first8=Jingjing|last8=Wang|first9=Xinglei|last9=Zhang|first10=Weifeng|last10=Zhu|first11=Keke|last11=Huang|first12=Shouhua|last12=Feng|first13=Huanwen|last13=Chen|page = 1535 |pmid=38378822|pmc=10879522}}

Solid {{chem2|NH2OH}} can be collected by treatment with liquid ammonia. Ammonium sulfate, {{chem2|[NH4]2SO4}}, a side-product insoluble in liquid ammonia, is removed by filtration; the liquid ammonia is evaporated to give the desired product.

The net reaction is:

:{{chem2|2 NO2- + 4 SO2 + 6 H2O + 6 NH3 → 4 SO4(2-) + 6 [NH4]+ + 2 NH2OH}}

Base, such as sodium butoxide, can be used to free the hydroxylamine from hydroxylammonium chloride:

:{{chem2|[NH3OH]Cl + NaO(CH2)3CH3 → NH2OH + NaCl + CH3(CH2)3OH}}

Hydroxylamine is a base with a pKa of 6.03:

:{{chem2| NH3OH+ <->NH2OH + H+}}

Hydroxylamine reacts with alkylating agents usually at the nitrogen atom:

:{{chem2|R\sX + NH2OH → R\sNH\sOH + HX}}

The reaction of {{chem2|NH2OH}} with an aldehyde or ketone produces an oxime.

:{{chem2|R2C\dO + NH2OH → R2C\dN\sOH + H2O}}

This reaction can be useful in the purification of ketones and aldehydes: if hydroxylamine is added to an aldehyde or ketone in solution, an oxime forms, which generally precipitates from solution; heating the precipitate with aqueous acid then restores the original aldehyde or ketone.Ralph Lloyd Shriner, Reynold C. Fuson, and Daniel Y. Curtin, The Systematic Identification of Organic Compounds: A Laboratory Manual, 5th ed. (New York: Wiley, 1964), chapter 6.

{{chem2|NH2OH}} reacts with chlorosulfonic acid to give hydroxylamine-O-sulfonic acid:{{cite book|first1 = Egon|last1 = Wiberg|first2 = Nils|last2 = Wiberg|title = Inorganic Chemistry|url=https://books.google.com/books?id=Mtth5g59dEIC&pg=PA676|year = 2001|publisher = Academic Press|isbn = 978-0-12-352651-9|pages = 675–677}}

:{{chem2|HO\sS(\dO)2\sCl + NH2OH → NH2\sO\sS(\dO)2\sOH + HCl}}

It isomerizes to the amine oxide {{chem2|H3N+\sO−}}.{{cite journal| title=Ammonia oxide makes up some 20% of an aqueous solution of hydroxylamine. |journal=Chemical Communications |date=28 February 2010 |pmid=20449284 |doi=10.1039/b923742a |volume=46 |issue=8 |pages=1302–4 | last1 = Kirby | first1 = AJ | last2 = Davies | first2 = JE | last3 = Fox | first3 = DJ | last4 = Hodgson | first4 = DR | last5 = Goeta | first5 = AE | last6 = Lima | first6 = MF | last7 = Priebe | first7 = JP | last8 = Santaballa | first8 = JA | last9 = Nome | first9 = F}}

{{See also|Hydroxamic acid}}

File:Hydroxylamine-group-2D.png

Hydroxylamine derivatives substituted in place of the hydroxyl or amine hydrogen are (respectively) called O- or N{{nbh}}hydroxyl­amines. In general N{{nbh}}hydroxyl­amines are more common. Examples are N{{nbh}}tert{{nbh}}butyl­hydroxyl­amine or the glycosidic bond in calicheamicin. N,O{{nbh}}Dimethyl­hydroxylamine is a precursor to Weinreb amides.

Similarly to amines, one can distinguish hydroxylamines by their degree of substitution: primary, secondary and tertiary. When stored exposed to air for weeks, secondary hydroxylamines degrade to nitrones.{{cite journal|doi=10.1021/cr60230a006|first1=Jan|last1=Hamer|first2=Anthony|last2=Macaluso|title=Nitrones|orig-date=29 Feb 1964|page=476|journal=Chemical Reviews|date=1964 |volume=64 |issue=4 }}

N{{nbh}}organyl­hydroxyl­amines, {{chem2|R\sNH\sOH}}, where R is an organyl group, can be reduced to amines {{chem2|R\sNH2}}:Smith, Michael and Jerry March. March's advanced organic chemistry : reactions, mechanisms, and structure. New York. Wiley. p. 1554. 2001.

:{{chem2|R\sNH\sOH (Zn, HCl) → R\sNH2 + ZnO}}

Oximes such as dimethylglyoxime are also employed as ligands.

The hydrolysis of N-substituted oximes, hydroxamic acids, and nitrones easily provides hydroxylamines.

Alkylating of hydroxylamine or N-alkylhydroxylamines proceeds usually at nitrogen. One challenge is dialkylation when only monoalkylation is desired.

:{{chem2|RNHOH + R'X -> RR'NOH + HX}}

For O-alkylation of hydroxylamines, strong base such as sodium hydride is required to first deprotonate the OH group:{{cite book |doi=10.1002/9780470741962.ch5 |chapter=Synthesis of Hydroxylamines |title=The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids |series=PATAI's Chemistry of Functional Groups |date=2008 |last1=Melman |first1=Artem |pages=117–161 |isbn=978-0-470-51261-6 }}

:{{chem2|RNHOH + NaH -> RNHONa + H2}}

:{{chem2|RNHONa + R'X -> RNHOR' + NaX}}

Amine oxidation with benzoyl peroxide is a common method to synthesize hydroxylamines. Care must be taken to prevent over-oxidation to a nitrone. Other methods include:

• Hydrogenation of an oxime
• Amine oxide pyrolysis (the Cope reaction)

:Image:Beckmann-rearangement (cropped).png.]]

Approximately 95% of hydroxylamine is used in the synthesis of cyclohexanone oxime, a precursor to Nylon 6. The treatment of this oxime with acid induces the Beckmann rearrangement to give caprolactam.{{cite book |last1=Clayden |first1=Jonathan |last2=Greeves |first2=Nick |last3=Warren |first3=Stuart |title=Organic chemistry |date=2012 |publisher=Oxford University Press |isbn=978-0-19-927029-3 |page=958 |edition=2nd}} The latter can then undergo a ring-opening polymerization to yield Nylon 6.{{cite journal |last1=Nuyken |first1=Oskar |last2=Pask |first2=Stephen |title=Ring-Opening Polymerization—An Introductory Review |journal=Polymers |date=25 April 2013 |volume=5 |issue=2 |pages=361–403 |doi=10.3390/polym5020361|doi-access=free}}

Hydroxylamine and its salts are commonly used as reducing agents in myriad organic and inorganic reactions. They can also act as antioxidants for fatty acids.

High concentrations of hydroxylamine are used by biologists to introduce mutations by acting as a DNA nucleobase amine-hydroxylating agent.{{cite journal | last1=Waugh | first1=Robbie | last2=Leader | first2=David J. | last3=McCallum | first3=Nicola | last4=Caldwell | first4=David | title=Harvesting the potential of induced biological diversity | journal=Trends in Plant Science | publisher=Elsevier BV | volume=11 | issue=2 | year=2006 | issn=1360-1385 | doi=10.1016/j.tplants.2005.12.007 | pages=71–79| pmid=16406304}} In is thought to mainly act via hydroxylation of cytidine to hydroxyaminocytidine, which is misread as thymidine, thereby inducing C:G to T:A transition mutations.{{cite journal | last1=Busby | first1=Stephen | last2=Irani | first2=Meher | last3=de Crombrugghe | first3=Benoít | title=Isolation of mutant promoters in the Escherichia coli galactose operon using local mutagenesis on cloned DNA fragments | journal=Journal of Molecular Biology | publisher=Elsevier BV | volume=154 | issue=2 | year=1982 | issn=0022-2836 | doi=10.1016/0022-2836(82)90060-2 | pages=197–209| pmid=7042980}} But high concentrations or over-reaction of hydroxylamine in vitro are seemingly able to modify other regions of the DNA & lead to other types of mutations. This may be due to the ability of hydroxylamine to undergo uncontrolled free radical chemistry in the presence of trace metals and oxygen, in fact in the absence of its free radical affects Ernst Freese noted hydroxylamine was unable to induce reversion mutations of its C:G to T:A transition effect and even considered hydroxylamine to be the most specific mutagen known.{{cite book | last=Hollaender | first=Alexander | title=Chemical Mutagens : Principles and Methods for Their Detection Volume 1 | publisher=Springer US | publication-place=Boston, MA | year=1971 | isbn=978-1-4615-8968-6 | oclc=851813793 | page=41}} Practically, it has been largely surpassed by more potent mutagens such as EMS, ENU, or nitrosoguanidine, but being a very small mutagenic compound with high specificity, it found some specialized uses such as mutation of DNA packed within bacteriophage capsids,{{cite journal | last1=Hong | first1=J.-S. | last2=Ames | first2=B. N. | title=Localized Mutagenesis of Any Specific Small Region of the Bacterial Chromosome | journal=Proceedings of the National Academy of Sciences | volume=68 | issue=12 | date=1971-12-01 | issn=0027-8424 | doi=10.1073/pnas.68.12.3158 | pages=3158–3162| pmid=4943557 | pmc=389612 | bibcode=1971PNAS...68.3158H | doi-access=free}} and mutation of purified DNA in vitro.{{cite web |last1=Forsberg |first1=Susan |title=Hydroxylamine Mutagenesis of plasmid DNA |url=http://dornsife.usc.edu/pombenet/hydroxylamine-mutagenesis/ |website=PombeNet |publisher=University of Southern California |access-date=9 December 2021}}

:File:Celanese synthesis of paracetamol.svg

An alternative industrial synthesis of paracetamol developed by Hoechst–Celanese involves the conversion of ketone to a ketoxime with hydroxylamine.

Some non-chemical uses include removal of hair from animal hides and photographic developing solutions. In the semiconductor industry, hydroxylamine is often a component in the "resist stripper", which removes photoresist after lithography.

Hydroxylamine can also be used to better characterize the nature of a post-translational modification onto proteins. For example, poly(ADP-Ribose) chains are sensitive to hydroxylamine when attached to glutamic or aspartic acids but not sensitive when attached to serines.{{Cite journal |last1=Langelier |first1=Marie-France |last2=Billur |first2=Ramya |last3=Sverzhinsky |first3=Aleksandr |last4=Black |first4=Ben E. |last5=Pascal |first5=John M. |date=2021-11-18 |title=HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications |journal=Nature Communications |language=en |volume=12 |issue=1 |pages=6675 |doi=10.1038/s41467-021-27043-8 |issn=2041-1723 |pmc=8602370 |pmid=34795260|bibcode=2021NatCo..12.6675L}} Similarly, Ubiquitin molecules bound to serines or threonines residues are sensitive to hydroxylamine, but those bound to lysine (isopeptide bond) are resistant.{{Cite journal |last1=Kelsall |first1=Ian R. |last2=Zhang |first2=Jiazhen |last3=Knebel |first3=Axel |last4=Arthur |first4=J. Simon C. |last5=Cohen |first5=Philip |date=2019-07-02 |title=The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells |journal=Proceedings of the National Academy of Sciences |language=en |volume=116 |issue=27 |pages=13293–13298 |doi=10.1073/pnas.1905873116 |issn=0027-8424 |pmc=6613137 |pmid=31209050 |bibcode=2019PNAS..11613293K |doi-access=free}}

In biological nitrification, the oxidation of {{chem2|NH3}} to hydroxylamine is mediated by the ammonia monooxygenase (AMO). Hydroxylamine oxidoreductase (HAO) further oxidizes hydroxylamine to nitrite.{{cite journal|last1=Arciero|first1=David M.|last2=Hooper|first2=Alan B.|last3=Cai|first3=Mengli|last4=Timkovich|first4=Russell|date=1993-09-01|title=Evidence for the structure of the active site heme P460 in hydroxylamine oxidoreductase of Nitrosomonas|journal=Biochemistry|volume=32|issue=36|pages=9370–9378|doi=10.1021/bi00087a016|pmid=8369308|issn=0006-2960}}

Cytochrome P460, an enzyme found in the ammonia-oxidizing bacteria Nitrosomonas europea, can convert hydroxylamine to nitrous oxide, a potent greenhouse gas.{{cite journal|last1=Caranto|first1=Jonathan D.|last2=Vilbert|first2=Avery C.|last3=Lancaster|first3=Kyle M.|date=2016-12-20|title=Nitrosomonas europaea cytochrome P460 is a direct link between nitrification and nitrous oxide emission|journal=Proceedings of the National Academy of Sciences|language=en|volume=113|issue=51|pages=14704–14709|doi=10.1073/pnas.1611051113|issn=0027-8424|pmc=5187719|pmid=27856762|bibcode=2016PNAS..11314704C |doi-access=free}}

Hydroxylamine can also be used to highly selectively cleave asparaginyl-glycine peptide bonds in peptides and proteins.{{cite book|title=Enzyme Structure Part E

|author1=Bornstein, Paul |author2=Balian, Gary|chapter=Cleavage at AsnGly bonds with hydroxylamine |series=Methods in Enzymology|year=1977|volume=47(Enzyme Struct., Part E)|pages=132–45|doi=10.1016/0076-6879(77)47016-2 |pmid=927171|isbn=978-0-12-181947-7 }} It also bonds to and permanently disables (poisons) heme-containing enzymes. It is used as an irreversible inhibitor of the oxygen-evolving complex of photosynthesis on account of its similar structure to water.

Hydroxylamine is a skin irritant but is of low toxicity.

A detonator can easily explode aqueous solutions concentrated above 80% by weight, and even 50% solution might prove detonable if tested in bulk.{{Cite journal |last1=Iwata |first1=Yusaku |last2=Koseki |first2=Hiroshi |last3=Hosoya |first3=Fumio |date=2003-01-01 |title=Study on decomposition of hydroxylamine/water solution |url=https://www.sciencedirect.com/science/article/pii/S0950423002000724 |journal=Journal of Loss Prevention in the Process Industries |volume=16 |issue=1 |pages=41–53 |doi=10.1016/S0950-4230(02)00072-4 |issn=0950-4230|url-access=subscription }}{{Cite book |title=Bretherick's Handbook of Reactive Chemical Hazards |url=https://www.sciencedirect.com/book/9780081009710/brethericks-handbook-of-reactive-chemical-hazards |access-date=2023-08-28 |isbn=9780081009710 |language=en}} In air, the combustion is rapid and complete:

:{{chem2|4 NH2OH + O2 → 2 N2 + 6 H2O}}

Absent air, pure hydroxylamine requires stronger heating and the detonation does not complete combustion:

:{{Chem2|3 NH2OH → N2 + NH3 + 3 H2O}}

At least two factories dealing in hydroxylamine have been destroyed since 1999 with loss of life.[http://shippai.jst.go.jp/en/Detail?fn=0&id=CC1000050& Japan Science and Technology Agency Failure Knowledge Database] {{webarchive|url=https://web.archive.org/web/20071220020505/http://shippai.jst.go.jp/en/Detail?fn=0&id=CC1000050& |date=2007-12-20}}. It is known, however, that ferrous and ferric iron salts accelerate the decomposition of 50% {{chem2|NH2OH}} solutions.{{cite journal |last1=Cisneros |first1=L. O. |last2=Rogers |first2=W. J. |last3=Mannan |first3=M. S. |last4=Li |first4=X. |last5=Koseki |first5=H. |title=Effect of Iron Ion in the Thermal Decomposition of 50 mass% Hydroxylamine/Water Solutions |journal=J. Chem. Eng. Data |volume=48 |issue=5 |year=2003 |pages=1164–1169 |doi=10.1021/je030121p}} Hydroxylamine and its derivatives are more safely handled in the form of salts.

It is an irritant to the respiratory tract, skin, eyes, and other mucous membranes. It may be absorbed through the skin, is harmful if swallowed, and is a possible mutagen.[https://www.sigmaaldrich.com/US/en/sds/mm/8.14441 MSDS] Sigma-Aldrich

• Amine
• Amino acid

{{Reflist}}

• [http://www.mrw.interscience.wiley.com/eros/articles/rh057/sect0-fs.html Hydroxylamine]{{Dead link|date=December 2022 |bot=InternetArchiveBot |fix-attempted=yes}}
• Walters, Michael A. and Andrew B. Hoem. "Hydroxylamine." e-Encyclopedia of Reagents for Organic Synthesis. 2001.
• [http://www.colby.edu/chemistry/webmo/hydroxylamine.html Schupf Computational Chemistry Lab]
• M. W. Rathke A. A. Millard "Boranes in Functionalization of Olefins to Amines: 3-Pinanamine" Organic Syntheses, Coll. Vol. 6, p. 943; Vol. 58, p. 32. (preparation of hydroxylamine-O-sulfonic acid).

• [http://psc.tamu.edu/research/reactive-chemical-research Calorimetric studies of hydroxylamine decomposition]
• [http://www.basf.de/en/produkte/chemikalien/anorganika/hydroxyl/hydroxyl_fb/hafb_sucess.htm?id=FcjY57aR-bsf2_l Chemical company BASF info]
• [http://www.basf.de/en/produkte/chemikalien/anorganika/hydroxyl/hydroxyl_fb/pinfo.htm?id=FcjY57aR-bsf2_l MSDS]
• [http://www.wsws.org/articles/1999/feb1999/penn-f24.shtml Deadly detonation of hydroxylamine at Concept Sciences facility]

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