Hydroxylamine

Structure

The crystal structure of hydroxylamine was first determined in 1955 under the direction of Nobel laureate William Lipscomb, although the positions of the hydrogen atoms were not localized at that time due to methodological limitations. In 2026 a high-precision crystal structure of hydroxylamine with unambiguous anisotropic refinement of hydrogen atoms was successfully obtained.

Hydroxylamine and its N-substituted derivatives are pyramidal at nitrogen, with bond angles very similar to those of amines. The most stable conformation of hydroxylamine has the NOH at the anti-relation to the nitrogen lone pair, seeming to minimize the repulsion between the nitrogen and oxygen lone pairs.

Production

Hydroxylamine or its salts (salts containing hydroxylammonium cations [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.

From nitric oxide

NH₂OH is mainly produced as its sulfuric acid salt, hydroxylammonium sulfate ([NH₃OH]₂[SO₄]), by the hydrogenation of nitric oxide over platinum catalysts in the presence of sulfuric acid.

2 NO + 3 H₂ + H₂SO₄ → [NH₃OH]₂[SO₄]

Raschig process

Another route to NH₂OH is the Raschig process: aqueous ammonium nitrite is reduced by HSO−3 and SO₂ at 0 °C to yield a hydroxylamido-N,N-disulfonate anion:

[NH₄]⁺[NO₂]⁻ + 2 SO₂ + NH₃ + H₂O → [NH₄]₂[HON(SO₃)₂]

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

[NH₄]₂[HON(SO₃)₂] + 2 H₂O → [HONH₃]₂SO₄

Other methods

Julius Tafel discovered that hydroxylamine hydrochloride or sulfate salts can be produced by electrolytic reduction of nitric acid with HCl or H₂SO₄ respectively:

HNO₃ + 3 H₂ → NH₂OH + 2 H₂O

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

HNO₂ + 2 HSO−3 → N(OH)(OSO−2)₂ + H₂O → NH(OH)(OSO−2) + HSO−4

NH(OH)(OSO−2) + [H₃O]⁺ → [NH₃OH]⁺ + 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 NH₂OH can be collected by treatment with liquid ammonia. Ammonium sulfate, [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:

2 NO−2 + 4 SO₂ + 6 H₂O + 6 NH₃ → 4 SO2−4 + 6 [NH₄]⁺ + 2 NH₂OH

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

[NH₃OH]Cl + NaO(CH₂)₃CH₃ → NH₂OH + NaCl + CH₃(CH₂)₃OH

Reactions

Hydroxylamine is a base with a pKa of 6.03:

NH₃OH⁺ ⇌ NH₂OH + H⁺

Hydroxylamine reacts with alkylating agents usually at the nitrogen atom:

R−X + NH₂OH → R−NH−OH + HX

The reaction of NH₂OH with an aldehyde or ketone produces an oxime.

R₂C=O + NH₂OH → R₂C=N−OH + 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.

NH₂OH reacts with chlorosulfonic acid to give hydroxylamine-O-sulfonic acid:

HO−S(=O)₂−Cl + NH₂OH → NH₂−O−S(=O)₂−OH + HCl

In aqueous solution, hydroxylamine is predicted to coexist with a zwitterionic tautomer, the amine oxide H₃N⁺−O⁻ (ammonia oxide, azane oxide) The solvated ammonia oxide form has variously been estimated to be less stable by 0.9–3.5 kcal·mol⁻¹. It is absent from the gas phase, where the predicted stability gap is 27.6 kcal·mol⁻¹.

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−NH₂:

R−NH−OH (Zn, HCl) → R−NH₂ + 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 + H₂

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) or rearrangement

Uses

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.

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.

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 effects 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.

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 NH₃ 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 NH₂OH + O₂ → 2 N₂ + 6 H₂O

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

3 NH₂OH → N₂ + NH₃ + 3 H₂O

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% NH₂OH 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.