# Hydroxylamine

Hydroxylamine (also known as hydroxyammonia) is an inorganic compound with the chemical formula NH$_2$OH. The compound exists as hygroscopic colorless crystals. Hydroxylamine is almost always provided and used as an aqueous solution or more often as one of its salts such as hydroxylammonium sulfate, a water-soluble solid.
Hydroxylamine and its salts are consumed almost exclusively to produce Nylon-6. The oxidation of NH$_3$ to hydroxylamine is a step in biological nitrification.

## History

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. 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). The coordination complex ZnCl$_2$(NH$_2$OH)$_2$ (zinc dichloride di(hydroxylamine)), known as Crismer's salt, releases hydroxylamine upon heating.

## Structure

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.

## Production

Hydroxylamine or its salts (salts containing hydroxylammonium cations [NH$_3$OH]$^+$) can be produced via several routes but only two are commercially viable. It is also produced naturally as discussed in a section on biochemistry.

### From nitric oxide

NH$_2$OH is mainly produced as its sulfuric acid salt, hydroxylammonium sulfate ([NH$_3$OH][SO$_4$]), by the hydrogenation of nitric oxide over platinum catalysts in the presence of sulfuric acid.
    2 NO + 3 H$_2$ + H$_2$SO$_4$ → [NH$_3$OH]$_2$[SO$_4$]

### Raschig process

Another route to NH$_2$OH is the Raschig process: aqueous ammonium nitrite is reduced by HSO−3 and SO$_2$ at 0 °C to yield a hydroxylamido-N,N-disulfonate anion:
    [NH$_4$]$^+$[NO$_2$]$^−$ + 2 SO$_2$ + NH$_3$ + H$_2$O → [NH$_4$]$_2$[HON(SO$_3$)$_2$]
This ammonium hydroxylamine disulfonate anion is then hydrolyzed to give hydroxylammonium sulfate:
    [NH$_4$]$_2$[HON(SO$_3$)$_2$] + 2 H$_2$O → [HONH$_3$]$_2$SO$_4$

### Other methods

Julius Tafel discovered that hydroxylamine hydrochloride or sulfate salts can be produced by electrolytic reduction of nitric acid with HCl or H$_2$SO$_4$ respectively:
    HNO$_3$ + 3 H$_2$ → NH$_2$OH + 2 H$_2$O
Hydroxylamine can also be produced by the reduction of nitrous acid or potassium nitrite with bisulfite:
    HNO$_2$ + 2 HSO−3 → N(OH)(OSO−2)$_2$ + H$_2$O → NH(OH)(OSO−2) + HSO−4
    NH(OH)(OSO−2) + [H$_3$O]$^+$ → [NH$_3$OH]$^+$ + HSO−4 (100 °C, 1 h)
Hydrochloric acid disproportionates nitromethane to hydroxylamine hydrochloride and carbon monoxide via the hydroxamic acid.
A direct lab synthesis of hydroxylamine from molecular nitrogen in water plasma was demonstrated in 2024.

### Isolation of hydroxylamine

Solid NH$_2$OH can be collected by treatment with liquid ammonia. Ammonium sulfate, [NH$_4$]$_2$SO$_4$, 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:
    2 NO−2 + 4 SO$_2$ + 6 H$_2$O + 6 NH$_3$ → 4 SO2−4 + 6 [NH$_4$]$^+$ + 2 NH$_2$OH
Base, such as sodium butoxide, can be used to free the hydroxylamine from hydroxylammonium chloride:
    [NH$_3$OH]Cl + NaO(CH$_2$)$_3$CH$_3$ → NH$_2$OH + NaCl + CH$_3$(CH$_2$)$_3$OH

## Reactions

Hydroxylamine is a base with a pKa of 6.03:
    NH$_3$OH$^+$ ⇌ NH$_2$OH + H$^+$
Hydroxylamine reacts with alkylating agents usually at the nitrogen atom:
    R−X + NH$_2$OH → R−NH−OH + HX
The reaction of NH$_2$OH with an aldehyde or ketone produces an oxime.
    R$_2$C=O + NH$_2$OH → R$_2$C=N−OH + H$_2$O
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.
NH$_2$OH reacts with chlorosulfonic acid to give hydroxylamine-O-sulfonic acid:
    HO−S(=O)$_2$−Cl + NH$_2$OH → NH$_2$−O−S(=O)$_2$−OH + HCl
It isomerizes to the amine oxide H$_3$N$^+$−O$^−$.

## Functional group

Hydroxylamine derivatives substituted in place of the hydroxyl or amine hydrogen are (respectively) called O- or N‑hydroxyl­amines. In general N‑hydroxyl­amines are more common. Examples are N‑tert‑butyl­hydroxyl­amine or the glycosidic bond in calicheamicin. N,O‑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.
N‑organyl­hydroxyl­amines, R−NH−OH, where R is an organyl group, can be reduced to amines R−NH$_2$:
    R−NH−OH (Zn, HCl) → R−NH$_2$ + ZnO
Oximes such as dimethylglyoxime are also employed as ligands.

### Synthesis

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.
    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:
    RNHOH + NaH → RNHONa + H$_2$
    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)

## Uses

    Conversion of cyclohexanone to caprolactam involving the Beckmann rearrangement.
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. The latter can then undergo a ring-opening polymerization to yield Nylon 6.

## Laboratory uses

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. 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. 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. 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, and mutation of purified DNA in vitro.
    This route also involves the Beckmann Rearrangement, like the conversion from cyclohexanone to caprolactam.
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. Similarly, Ubiquitin molecules bound to serines or threonines residues are sensitive to hydroxylamine, but those bound to lysine (isopeptide bond) are resistant.

## Biochemistry

In biological nitrification, the oxidation of NH$_3$ to hydroxylamine is mediated by the ammonia monooxygenase (AMO). Hydroxylamine oxidoreductase (HAO) further oxidizes hydroxylamine to nitrite.
Cytochrome P460, an enzyme found in the ammonia-oxidizing bacteria Nitrosomonas europea, can convert hydroxylamine to nitrous oxide, a potent greenhouse gas.
Hydroxylamine can also be used to highly selectively cleave asparaginyl-glycine peptide bonds in peptides and proteins. 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.

## Safety and environmental concerns

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. In air, the combustion is rapid and complete:
    4 NH$_2$OH + O$_2$ → 2 N$_2$ + 6 H$_2$O
Absent air, pure hydroxylamine requires stronger heating and the detonation does not complete combustion:
    3 NH$_2$OH → N$_2$ + NH$_3$ + 3 H$_2$O
At least two factories dealing in hydroxylamine have been destroyed since 1999 with loss of life. It is known, however, that ferrous and ferric iron salts accelerate the decomposition of 50% NH$_2$OH solutions. 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.