Nitrosation and nitrosylation

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Nitrosylation results in a molecule "R" adducted with the group N=O Nitroso-compound-2D.svg
Nitrosylation results in a molecule "R" adducted with the group N=O

Nitrosation and nitrosylation are two names for the process of converting organic compounds or metal complexes [1] into nitroso derivatives, i.e., compounds containing the R−NO functionality. The synonymy arises because the R-NO functionality can be interpreted two different ways, depending on the physico-chemical environment:

Contents

There are multiple chemical mechanisms by which this can be achieved, including enzymes and chemical synthesis.

In biochemistry

The biological functions of nitric oxide include S-nitrosylation, the conjugation of NO to cysteine thiols in proteins, which is an important part of cell signalling. [2]

Organic synthesis

Nitrosation is typically performed with nitrous acid, formed from acidification of a sodium nitrite solution. Nitrous acid is unstable, and high yields require a rapid reaction rate; NO+ synthon transfer is catalyzed by a strong nucleophile, such as (in increasing order of efficacy) chloride, bromide, thiocyanate, or thiourea. Indeed, (meta)stable nitrosation products (alkyl nitrites or nitrosamines) can also nitrosate under such conditions; and the equilibria can be driven in any desired direction. Absent a driving force, thionitrosos form out of nitrosamines, which form out of nitrite esters, which form out of nitrous acid. [3]

Some form of Lewis acid also enhances the electrophilicity of NO+ carriers, but the acid need not be Brønsted: nitroprusside, for example, nitrosates best in neutral-to-basic conditions. Roussin's salts may react similarly, but it is unclear if they release NO+ or NO•. [4]

In general, nitric oxide is a poor nitrosant, Traube-type reactions notwithstanding. But atmospheric oxygen can oxidize nitric oxide to nitrogen dioxide, which does nitrosate. Alternatively cupric ions catalyze disproportionation into NO+ and NO−. [5]

On the carbon skeleton

Nitroso compounds, such as nitrosobenzene, are typically prepared by oxidation of hydroxylamines:

RNHOH + [O] → RNO + H2O

In principle, NO+ can substitute directly onto an aromatic ring, but the ring must be substantially activated, because NO+ is about 14 bel less electrophilic than NO+
2. [6] Unusually for electrophilic aromatic substitution, proton release to the solvent is typically rate-limiting, and the reaction can be suppressed in superacidic conditions. [7]

Excess NO+ typically oxidizes the initially-nitroso product to a nitro compound or diazonium salt. [8]

Of chalcogen heteroatoms

S-nitrosothiols are typically prepared by condensation of a thiol and nitrous acid: [9]

RSH + HONO → RSNO + H2O

They are liable to disproportionate to the disulfide and nitrogen oxides. [10]

Although such cations have not been isolated, nitrosating reagents likely coordinate to sulfides with no hydrogen substituent. [11]

Sulfinates and sulfinic acids add twice to nitrous acid, so that the initial nitroso product (from the first addition) is reduced to a disulfonyl hydroxylamine. A variant on this process with bisulfite is Raschig's hydroxyl­amine production technique. [12]

O-Nitroso compounds are similar to S-nitroso compounds, but are less reactive because the oxygen atom is less nucleophilic than the sulfur atom. The formation of an alkyl nitrite from an alcohol and nitrous acid is a common example: [13]

ROH + HONO → RONO + H2O

Of amines

Nitrosation of aniline Formation N-Phenyl-nitrosamine.svg
Nitrosation of aniline

N-Nitrosamines arise from the reaction of nitrite sources with amino compounds. Typically, this reaction occurs when the nucleophilic nitrogen of a secondary amine attacks the nitrogen of the electrophilic nitrosonium ion: [14]

NO2− + 2 H+ → NO+ + H2O
R2NH + NO+ → R2N-NO + H+

If the amine is secondary, then the product is stable, but primary amines decompose in acid to the corresponding diazonium cation, and then attack any nearby nucleophile. Nitrosation of a primary amine is thus sometimes referred to as deamination. [15]

The stable secondary nitrosamines are carcinogens in rodents. The compounds are believed to nitrosate primary amines during the acid environment of the stomach, and the resulting diazonium ions alkylate DNA, leading to cancer.

Related Research Articles

<span class="mw-page-title-main">Amine</span> Chemical compounds and groups containing nitrogen with a lone pair (:N)

In chemistry, amines are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Formally, amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines, trimethylamine, and aniline. Inorganic derivatives of ammonia are also called amines, such as monochloramine.

<span class="mw-page-title-main">Hydroxylamine</span> Inorganic compound

Hydroxylamine is an inorganic compound with the chemical formula NH2OH. The compound is in a form of a white hygroscopic crystals. Hydroxylamine is almost always provided and used as an aqueous solution. It is consumed almost exclusively to produce Nylon-6. The oxidation of NH3 to hydroxylamine is a step in biological nitrification.

<span class="mw-page-title-main">Nitrous acid</span> Chemical compound

Nitrous acid is a weak and monoprotic acid known only in solution, in the gas phase, and in the form of nitrite salts. It was discovered by Carl Wilhelm Scheele, who called it "phlogisticated acid of niter". Nitrous acid is used to make diazonium salts from amines. The resulting diazonium salts are reagents in azo coupling reactions to give azo dyes.

The nitrite ion has the chemical formula NO−
2. Nitrite is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also refers to organic compounds having the –ONO group, which are esters of nitrous acid.

<span class="mw-page-title-main">Nitro compound</span> Organic compound containing an −NO₂ group

In organic chemistry, nitro compounds are organic compounds that contain one or more nitro functional groups. The nitro group is one of the most common explosophores used globally. The nitro group is also strongly electron-withdrawing. Because of this property, C−H bonds alpha (adjacent) to the nitro group can be acidic. For similar reasons, the presence of nitro groups in aromatic compounds retards electrophilic aromatic substitution but facilitates nucleophilic aromatic substitution. Nitro groups are rarely found in nature. They are almost invariably produced by nitration reactions starting with nitric acid.

<span class="mw-page-title-main">Nitrosamine</span> Organic compounds of the form >N–N=O

In organic chemistry, nitrosamines are organic compounds with the chemical structure R2N−N=O, where R is usually an alkyl group. They feature a nitroso group bonded to a deprotonated amine. Most nitrosamines are carcinogenic in nonhuman animals. A 2006 systematic review supports a "positive association between nitrite and nitrosamine intake and gastric cancer, between meat and processed meat intake and gastric cancer and oesophageal cancer, and between preserved fish, vegetable and smoked food intake and gastric cancer, but is not conclusive".

In organic chemistry, the diazo group is an organic moiety consisting of two linked nitrogen atoms at the terminal position. Overall charge-neutral organic compounds containing the diazo group bound to a carbon atom are called diazo compounds or diazoalkanes and are described by the general structural formula R2C=N+=N−. The simplest example of a diazo compound is diazomethane, CH2N2. Diazo compounds should not be confused with azo compounds or with diazonium compounds.

<span class="mw-page-title-main">Diazonium compound</span> Group of organonitrogen compounds

Diazonium compounds or diazonium salts are a group of organic compounds sharing a common functional group [R−N+≡N]X− where R can be any organic group, such as an alkyl or an aryl, and X is an inorganic or organic anion, such as a halide. The parent compound where R is hydrogen, is diazenylium.

The nitrosonium ion is NO+, in which the nitrogen atom is bonded to an oxygen atom with a bond order of 3, and the overall diatomic species bears a positive charge. It can be viewed as nitric oxide with one electron removed. This ion is usually obtained as the following salts: NOClO4, NOSO4H (nitrosylsulfuric acid, more descriptively written ONSO3OH) and NOBF4. The ClO−4 and BF−4 salts are slightly soluble in acetonitrile CH3CN. NOBF4 can be purified by sublimation at 200–250 °C and 0.01 mmHg (1.3 Pa).

<span class="mw-page-title-main">Nitroso</span> Class of functional groups with a –N=O group attached

In organic chemistry, nitroso refers to a functional group in which the nitric oxide group is attached to an organic moiety. As such, various nitroso groups can be categorized as C-nitroso compounds, S-nitroso compounds, N-nitroso compounds, and O-nitroso compounds.

<span class="mw-page-title-main">Alkyl nitrite</span> Organic compounds of the form R–O–N=O

In organic chemistry, alkyl nitrites are a group of organic compounds based upon the molecular structure R−O−N=O, where R represents an alkyl group. Formally they are alkyl esters of nitrous acid. They are distinct from nitro compounds.

<span class="mw-page-title-main">Fischer–Hepp rearrangement</span> Organic reaction applied to aromatic nitroso and nitrosamine compounds

In organic chemistry, the Fischer–Hepp rearrangement is a rearrangement reaction in which an aromatic N-nitroso or secondary nitrosamine converts to a carbon nitroso compound:

The chemical element nitrogen is one of the most abundant elements in the universe and can form many compounds. It can take several oxidation states; but the most common oxidation states are -3 and +3. Nitrogen can form nitride and nitrate ions. It also forms a part of nitric acid and nitrate salts. Nitrogen compounds also have an important role in organic chemistry, as nitrogen is part of proteins, amino acids and adenosine triphosphate.

<span class="mw-page-title-main">Nitrosyl chloride</span> Chemical compound

Nitrosyl chloride is the chemical compound with the formula NOCl. It is a yellow gas that is commonly encountered as a component of aqua regia, a mixture of 3 parts concentrated hydrochloric acid and 1 part of concentrated nitric acid. It is a strong electrophile and oxidizing agent. It is sometimes called Tilden's reagent, after William A. Tilden, who was the first to produce it as a pure compound.

In organic chemistry, the Baudisch reaction is a process for the synthesis of nitrosophenols using metal ions. Although the products are of limited value, the reaction is of historical interest as an example of metal-promoted functionalization of aromatic substrates.

The Stieglitz rearrangement is a rearrangement reaction in organic chemistry which is named after the American chemist Julius Stieglitz (1867–1937) and was first investigated by him and Paul Nicholas Leech in 1913. It describes the 1,2-rearrangement of trityl amine derivatives to triaryl imines. It is comparable to a Beckmann rearrangement which also involves a substitution at a nitrogen atom through a carbon to nitrogen shift. As an example, triaryl hydroxylamines can undergo a Stieglitz rearrangement by dehydration and the shift of a phenyl group after activation with phosphorus pentachloride to yield the respective triaryl imine, a Schiff base.

<i>S</i>-Nitrosothiol Organic compounds or groups of the form –S–N=O

In organic chemistry, S-nitrosothiols, also known as thionitrites, are organic compounds or functional groups containing a nitroso group attached to the sulfur atom of a thiol. S-Nitrosothiols have the general formula R−S−N=O, where R denotes an organic group.

<span class="mw-page-title-main">Dinitrogen trioxide</span> Chemical compound

Dinitrogen trioxide is the inorganic compound with the formula N2O3. It is a nitrogen oxide. It forms upon mixing equal parts of nitric oxide and nitrogen dioxide and cooling the mixture below −21 °C (−6 °F):

Electrophilic amination is a chemical process involving the formation of a carbon–nitrogen bond through the reaction of a nucleophilic carbanion with an electrophilic source of nitrogen.

<i>N</i>-Nitrosamides

Nitrosamides are chemical compounds that contain of the chemical structure R1C(=X)N(–R2)–N=O, that is, a nitroso group bonded to the nitrogen of an amide or similar functional group. Specific classes include the N-nitrosamides, N-nitrosoureas, N-nitrosoguanidines, and N-nitrosocarbamates. Nitrosamides are usually chemically reactive, metabolically unstable, and often carcinogenic; however, in contrast to the N-nitrosamines, N-nitrosamides are not generally contaminants found in food.

References

  1. ↑ Hayton, T. W.; Legzdins, P.; Sharp, W. B. (2002). "Coordination and Organometallic Chemistry of Metal-NO Complexes". Chem. Rev. 102 (1): 935–991. doi:10.1021/cr000074t. PMID   11942784.
  2. ↑ Mannick, Joan B.; Schonhoff, Christopher M. (7 July 2009). "Review: NO Means No and Yes: Regulation of Cell Signaling by Protein Nitrosylation". Free Radical Research. 38 (1): 1–7. doi:10.1080/10715760310001629065. PMID   15061648. S2CID   21787778.
  3. ↑ Williams 1988.
  4. ↑ Williams 1988, pp. 202, 206–207.
  5. ↑ Williams 1988, pp. 27–28, 209. Williams refers to Traube products as "Drago complexes"; note the typo on p. 27, which should refer to "2:1 complexes".
  6. ↑ Smith, Michael B. (2020). March's Organic Chemistry (8th ed.). Wiley. p. 634.
  7. ↑ Williams 1988, pp. 63–70.
  8. ↑ Williams, D. L. H. (1988). Nitrosation . Cambridge, UK: Cambridge University. pp. 59, 61. ISBN   0-521-26796-X.
  9. ↑ Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, A. J. (2002). "Nitric Oxide Donors: Chemical Activities and Biological Applications". Chemical Reviews. 102 (4): 1091–1134. doi:10.1021/cr000040l. PMID   11942788.
  10. ↑ Williams 1988, pp. 174–175.
  11. ↑ Williams 1988, pp. 182–183.
  12. ↑ Williams 1988, pp. 186, 191–2.
  13. ↑ Williams 1988, pp. 150–151, 177.
  14. ↑ López-Rodríguez, Rocío; McManus, James A.; Murphy, Natasha S.; Ott, Martin A.; Burns, Michael J. (2020-09-18). "Pathways for N -Nitroso Compound Formation: Secondary Amines and Beyond". Organic Process Research & Development. 24 (9): 1558–1585. doi:10.1021/acs.oprd.0c00323. ISSN   1083-6160. S2CID   225483602.
  15. ↑ Williams 1988, pp. 81–83.
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