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.[6] 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).[7][8] The coordination complex ZnCl₂(NH₂OH)₂, known as Crismer's salt, releases hydroxylamine upon heating.[9]

Hydroxylamine or its salts can be produced via several routes but only two are commercially viable. It is also produced naturally as discussed in a section on biochemistry.

Hydroxylamine reacts with electrophiles, such as alkylating agents, which can attach to either the oxygen or the nitrogen atoms:

R−X + NH₂OH → R−ONH₂ + HX

R−X + NH₂OH → R−NHOH + HX

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

R₂C=O + NH₂OH·HCl → R₂C=NOH + NaCl + H₂O (in NaOH solution)

This reaction is 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 an inorganic acid then restores the original aldehyde or ketone.[13]

Oximes such as dimethylglyoxime are also employed as ligands.

NH₂OH reacts with chlorosulfonic acid to give hydroxylamine-O-sulfonic acid, a useful reagent for the synthesis of caprolactam.

HOSO₂Cl + NH₂OH → NH₂OSO₂OH + HCl

The hydroxylamine-O-sulfonic acid, which should be stored at 0 °C to prevent decomposition, can be checked by iodometric titration.

NH₂OH and N-organylhydroxylamines (R–NHOH), can be reduced to ammonia NH₃ and amines R−NH₂, respectively, where R is an organyl group.[14]

NH₂OH (Zn, HCl) → NH₃

R−NHOH (Zn, HCl) → R−NH₂

Hydroxylamine free base explodes when heated in air:

4 NH₂OH + O₂ → 2 N₂ + 6 H₂O

The high reactivity comes in part from the partial isomerisation of the NH₂OH to ammonia oxide (also known as azane oxide), with zwitterionic structure NH+3−O⁻.[15]

Hydroxylamine water solutions above 80% by weight can be easily detonated by a detonator, and even 50% solution might prove detonable if tested in bulk.[16][17]

In absence of air the detonation of pure hydroxylamine proceeds mainly according to this equation:

3NH₂OH → N₂ + NH₃ + 3H₂O

N‑hydroxyl­amine funct­ional group

Substituted derivatives of hydroxylamine are known. If the hydroxyl hydrogen is substituted, this is called an O-hydroxylamine, if one of the amine hydrogens is substituted, this is called an N-hydroxylamine. In general N-hydroxylamines are the more common. Similarly to ordinary amines, one can distinguish primary, secondary and tertiary hydroxylamines, the latter two referring to compounds where two or three hydrogens are substituted, respectively. Examples of compounds containing a hydroxylamine functional group are N-tert-butyl-hydroxylamine or the glycosidic bond in calicheamicin. N,O-Dimethylhydroxylamine is a coupling agent, used to synthesize Weinreb amides.

Synthesis

The most common method for the synthesis of substituted hydroxylamines is the oxidation of an amine with benzoyl peroxide. Some care must be taken to prevent over-oxidation to a nitrone. Other methods include:

• Hydrogenation of an oxime
• Alkylation of hydroxylamine
• The thermal degradation of amine oxides via the Cope reaction

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.[10] The treatment of this oxime with acid induces the Beckmann rearrangement to give caprolactam (3).[18] The latter can then undergo a ring-opening polymerization to yield Nylon 6.[19]

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.[20] 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.[21] 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.[21] 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 & even considered hydroxylamine to be the most specific mutagen known.[22] Practically, it has been largely surpassed by more potent mutagents 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,[23] & mutation of purified DNA in vitro.[24]

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.[2] 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.[25] Similarly, Ubiquitin molecules bound to serines or threonines residues are sensitive to hydroxylamine, but those bound to lysine (isopeptide bond) are resistant.[26]

In biological nitrification, the oxidation of NH₃ to hydroxylamine is mediated by the ammonia monooxygenase (AMO).[5] Hydroxylamine oxidoreductase (HAO) further oxidizes hydroxylamine to nitrite.[27]

Cytochrome P460, an enzyme found in the ammonia-oxidizing bacteria Nitrosomonas europea, can convert hydroxylamine to nitrous oxide, a potent greenhouse gas.[28]

Hydroxylamine can also be used to highly selectively cleave asparaginyl-glycine peptide bonds in peptides and proteins.[29] 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.

With a theoretical decomposition energy of about 5 kJ/g, hydroxylamine is an explosive, and aqueous solutions above 80% can be easily detonated by detonator or strong heating under confinement.[16] [17] At least two factories dealing in hydroxylamine have been destroyed since 1999 with loss of life.[30] It is known, however, that ferrous and ferric iron salts accelerate the decomposition of 50% NH₂OH solutions.[31] 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.[32]

• Amine
• Amino acid

• Hydroxylamine
• Walters, Michael A. and Andrew B. Hoem. "Hydroxylamine." e-Encyclopedia of Reagents for Organic Synthesis. 2001.
• 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).

• Calorimetric studies of hydroxylamine decomposition
• Chemical company BASF info
• MSDS
• Deadly detonation of hydroxylamine at Concept Sciences facility