In
organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
, a nitrile is any
organic compound
Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...
that has a
functional group
In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
. The name of the compound is composed of a base, which includes the carbon of the , suffixed with "nitrile", so for example is called "
propionitrile
Propionitrile, also known as ethyl cyanide and propanenitrile, is an organic compound with the formula CH3CH2CN. It is a simple aliphatic nitrile. The compound is a colourless, water-soluble liquid. It is used as a solvent and a precursor to oth ...
" (or propanenitrile). The prefix ''
cyano
In chemistry, cyanide () is an inorganic chemical compound that contains a functional group. This group, known as the cyano group, consists of a carbon atom triple-bonded to a nitrogen atom.
Ionic cyanides contain the cyanide anion . This a ...
-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including
methyl cyanoacrylate, used in
super glue
Cyanoacrylates are a family of strong fast-acting adhesives with industrial, medical, and household uses. They are derived from ethyl cyanoacrylate and related esters. The cyanoacrylate group in the monomer rapidly polymerizes in the presence ...
, and
nitrile rubber
Nitrile rubber, also known as nitrile butadiene rubber, NBR, Buna-N, and acrylonitrile butadiene rubber, is a synthetic rubber derived from acrylonitrile (ACN) and butadiene. Trade names include Perbunan, Nipol, Krynac and Europrene. This rubber is ...
, a nitrile-containing
polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
used in
latex-free laboratory and
medical gloves
Medical gloves are disposable gloves used during medical examinations and procedures to help prevent cross-contamination between caregivers and patients. Medical gloves are made of different polymers including latex, nitrile rubber, polyvinyl ch ...
. Nitrile rubber is also widely used as automotive and other seals since it is resistant to fuels and oils. Organic compounds containing multiple nitrile groups are known as
cyanocarbons.
Inorganic compound
An inorganic compound is typically a chemical compound that lacks carbon–hydrogen bondsthat is, a compound that is not an organic compound. The study of inorganic compounds is a subfield of chemistry known as ''inorganic chemistry''.
Inorgan ...
s containing the group are not called nitriles, but
cyanide
In chemistry, cyanide () is an inorganic chemical compound that contains a functional group. This group, known as the cyano group, consists of a carbon atom triple-bonded to a nitrogen atom.
Ionic cyanides contain the cyanide anion . This a ...
s instead. Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic.
Structure and basic properties
The N−C−C geometry is linear in nitriles, reflecting the sp hybridization of the triply bonded carbon. The C−N distance is short at 1.16
Å, consistent with a
triple bond
A triple bond in chemistry is a chemical bond between two atoms involving six Electron pair bond, bonding electrons instead of the usual two in a covalent bond, covalent single bond. Triple bonds are stronger than the equivalent covalent bond, sin ...
. Nitriles are polar, as indicated by high dipole moments. As liquids, they have high
relative permittivities, often in the 30s.
History
The first compound of the homolog row of nitriles, the nitrile of
formic acid
Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid. It has the chemical formula HCOOH and structure . This acid is an important intermediate in chemical synthesis and occurs naturally, most notably in some an ...
,
hydrogen cyanide
Hydrogen cyanide (formerly known as prussic acid) is a chemical compound with the chemical formula, formula HCN and structural formula . It is a highly toxic and flammable liquid that boiling, boils slightly above room temperature, at . HCN is ...
was first synthesized by
C. W. Scheele in 1782.
In 1811
J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid.
Around 1832
benzonitrile
Benzonitrile is the chemical compound with the formula , abbreviated PhCN. This aromatic organic compound is a colorless liquid with a cherry or almond like odour. It is mainly used industrially to produce the melamine resin precursor benzoguanam ...
, the nitrile of
benzoic acid
Benzoic acid () is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. The benzoyl group is often abbreviated "Bz" (not to be confused with "Bn," which ...
, was prepared by
Friedrich Wöhler
Friedrich Wöhler Royal Society of London, FRS(For) HonFRSE (; 31 July 180023 September 1882) was a German chemist known for his work in both organic chemistry, organic and inorganic chemistry, being the first to isolate the chemical elements be ...
and
Justus von Liebig
Justus ''Freiherr'' von Liebig (12 May 1803 – 18 April 1873) was a Germans, German scientist who made major contributions to the theory, practice, and pedagogy of chemistry, as well as to agricultural and biology, biological chemistry; he is ...
, but due to minimal yield of the synthesis neither physical nor chemical properties were determined nor a structure suggested. In 1834
Théophile-Jules Pelouze
Théophile-Jules Pelouze (also known as Jules Pelouze), ; 26 February 180731 May 1867) was a French chemist.
Life
He was born at Valognes, and died in Paris.
His father, Edmond Pelouze, was an industrial chemist and the author of several tech ...
synthesized
propionitrile
Propionitrile, also known as ethyl cyanide and propanenitrile, is an organic compound with the formula CH3CH2CN. It is a simple aliphatic nitrile. The compound is a colourless, water-soluble liquid. It is used as a solvent and a precursor to oth ...
, suggesting it to be an ether of propionic alcohol and hydrocyanic acid.
The synthesis of benzonitrile by
Hermann Fehling in 1844 by heating ammonium benzoate was the first method yielding enough of the substance for chemical research.
Fehling determined the structure by comparing his results to the already known synthesis of hydrogen cyanide by heating ammonium
formate
Formate (IUPAC name: methanoate) is the conjugate base of formic acid. Formate is an anion () or its derivatives such as ester of formic acid. The salts and esters are generally colorless.
Fundamentals
When dissolved in water, formic acid co ...
. He coined the name "nitrile" for the newfound substance, which became the name for this group of compounds.
Synthesis
Industrially, the main methods for producing nitriles are
ammoxidation
In organic chemistry, ammoxidation is a process for the production of nitriles () using ammonia () and oxygen (). It is sometimes called the SOHIO process, acknowledging that ammoxidation was developed at Standard Oil of Ohio. The usual substrate ...
and
hydrocyanation. Both routes are
green
Green is the color between cyan and yellow on the visible spectrum. It is evoked by light which has a dominant wavelength of roughly 495570 nm. In subtractive color systems, used in painting and color printing, it is created by a com ...
in the sense that they do not generate stoichiometric amounts of salts.
Ammoxidation
In
ammoxidation
In organic chemistry, ammoxidation is a process for the production of nitriles () using ammonia () and oxygen (). It is sometimes called the SOHIO process, acknowledging that ammoxidation was developed at Standard Oil of Ohio. The usual substrate ...
, a
hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and Hydrophobe, hydrophobic; their odor is usually fain ...
is partially
oxidized
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
in the presence of
ammonia
Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...
. This conversion is practiced on a large scale for
acrylonitrile
Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid. It has a pungent odor of garlic or onions. Its molecular structure consists of a vinyl group () linked to a nitrile (). It is an im ...
:
:
CH3CH=CH2 + 3/2 O2 + NH3 -> N#CCH=CH2 + 3 H2O
In the production of acrylonitrile, a side product is
acetonitrile
Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not class ...
. On an industrial scale, several derivatives of
benzonitrile
Benzonitrile is the chemical compound with the formula , abbreviated PhCN. This aromatic organic compound is a colorless liquid with a cherry or almond like odour. It is mainly used industrially to produce the melamine resin precursor benzoguanam ...
,
phthalonitrile, as well as Isobutyronitrile are prepared by ammoxidation. The process is catalysed by
metal oxide
An oxide () is a chemical compound containing at least one oxygen atom and one other element in its chemical formula. "Oxide" itself is the dianion (anion bearing a net charge of −2) of oxygen, an O2− ion with oxygen in the oxidation state o ...
s and is assumed to proceed via the imine.
Hydrocyanation
Hydrocyanation is an industrial method for producing nitriles from hydrogen cyanide and alkenes. The process requires
homogeneous catalysts. An example of hydrocyanation is the production of
adiponitrile
Adiponitrile is an organic compound with the chemical formula (CH2)4(CN)2. This viscous, colourless dinitrile is an important precursor to the polymer nylon 66. In 2005, about one million tonnes of adiponitrile were produced.M. T. Musser, "Adipi ...
, a precursor to
nylon-6,6 from
1,3-butadiene
1,3-Butadiene () is the organic compound with the formula CH2=CH-CH=CH2. It is a colorless gas that is easily condensed to a liquid. It is important industrially as a precursor to synthetic rubber. The molecule can be viewed as the union of two ...
:
:
From organic halides and cyanide salts
Two
salt metathesis reaction
A salt metathesis reaction (also called a double displacement reaction, double replacement reaction, or double decomposition) is a type of chemical reaction in which two ionic compounds in aqueous solution exchange their component ions to form two ...
s are popular for laboratory scale reactions. In the
Kolbe nitrile synthesis
The Kolbe nitrile synthesis is a method for the preparation of alkyl nitriles by reaction of the corresponding organohalide, alkyl halide with a metal cyanide. A side product for this reaction is the formation of an isonitrile because the cyanide i ...
,
alkyl halide
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents of hydrogen atom. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalka ...
s undergo
nucleophilic aliphatic substitution
In chemistry, a nucleophilic substitution (SN) is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). ...
with alkali metal
cyanide
In chemistry, cyanide () is an inorganic chemical compound that contains a functional group. This group, known as the cyano group, consists of a carbon atom triple-bonded to a nitrogen atom.
Ionic cyanides contain the cyanide anion . This a ...
s. Aryl nitriles are prepared in the
Rosenmund-von Braun synthesis.
In general, metal cyanides combine with alkyl halides to give a mixture of the nitrile and the
isonitrile, although appropriate choice of
counterion
160px, cation-exchange_resin.html" ;"title="Polystyrene sulfonate, a cation-exchange resin">Polystyrene sulfonate, a cation-exchange resin, is typically supplied with as the counterion.
In chemistry, a counterion (sometimes written as "counter ...
and
temperature
Temperature is a physical quantity that quantitatively expresses the attribute of hotness or coldness. Temperature is measurement, measured with a thermometer. It reflects the average kinetic energy of the vibrating and colliding atoms making ...
can minimize the latter. An
alkyl sulfate obviates the problem entirely, particularly in nonaqueous conditions (the
Pelouze synthesis).
[
]
Cyanohydrins
The cyanohydrin
In organic chemistry, a cyanohydrin or hydroxynitrile is a functional group found in organic compounds in which a cyano and a hydroxy group are attached to the same carbon atom. The general formula is , where R is H, alkyl, or aryl. Cyanohyd ...
s are a special class of nitriles. Classically they result from the addition of alkali metal cyanides to aldehydes in the cyanohydrin reaction. Because of the polarity of the organic carbonyl, this reaction requires no catalyst, unlike the hydrocyanation of alkenes. O-Silyl cyanohydrins are generated by the addition trimethylsilyl cyanide
Trimethylsilyl cyanide is the chemical compound with the chemical formula, formula . This volatile liquid consists of a cyanide group, that is CN, attached to a trimethylsilyl group. The molecule is used in organic synthesis as the equivalent of h ...
in the presence of a catalyst (silylcyanation). Cyanohydrins are also prepared by transcyanohydrin reactions starting, for example, with acetone cyanohydrin
Acetone cyanohydrin (ACH) is an organic compound used in the production of methyl methacrylate, the monomer of the transparent plastic polymethyl methacrylate (PMMA), also known as acrylic. It liberates hydrogen cyanide easily, so it is used as a ...
as a source of HCN.
Dehydration of amides
Nitriles can be prepared by the dehydration
In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
of primary amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s. Common reagents for this include phosphorus pentoxide
Phosphorus pentoxide is a chemical compound with molecular formula Phosphorus, P4Oxygen, O10 (with its common name derived from its empirical formula, P2O5). This white crystalline solid is the anhydride of phosphoric acid. It is a powerful desic ...
() and thionyl chloride
Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...
(). In a related dehydration, secondary amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s give nitriles by the von Braun amide degradation. In this case, one C-N bond is cleaved.
:
Oxidation of primary amines
Numerous traditional methods exist for nitrile preparation by amine
In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
oxidation. Common methods include the use of potassium persulfate
Potassium persulfate is the inorganic compound with the formula K2 S2O8. Also known as potassium peroxydisulfate, it is a white solid that is sparingly soluble in cold water, but dissolves better in warm water. This salt is a powerful oxidant, co ...
, Trichloroisocyanuric acid, or anodic
An anode usually is an electrode of a polarized electrical device through which conventional current enters the device. This contrasts with a cathode, which is usually an electrode of the device through which conventional current leaves the devi ...
electrosynthesis. In addition, several selective methods have been developed in the last decades for electrochemical
Electrochemistry is the branch of physical chemistry concerned with the relationship between electrical potential difference and identifiable chemical change. These reactions involve electrons moving via an electronically conducting phase (typi ...
processes.
From aldehydes and oximes
The conversion of aldehydes
In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
to nitriles via aldoxime
In organic chemistry, an oxime is an organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R' may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted ...
s is a popular laboratory route. Aldehydes react readily with hydroxylamine
Hydroxylamine (also known as hydroxyammonia) is an inorganic compound with the chemical formula . The compound exists as hygroscopic colorless crystals.Greenwood and Earnshaw. ''Chemistry of the Elements.'' 2nd Edition. Reed Educational and Prof ...
salts, sometimes at temperatures as low as ambient, to give aldoximes. These can be dehydrated to nitriles by simple heating, although a wide range of reagents may assist with this, including triethylamine
Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. Like triethanolamine and the tetraethylammonium ion, it is often abbreviated TEA. It is a colourless volatile liquid with a strong fishy odor remini ...
/sulfur dioxide
Sulfur dioxide (IUPAC-recommended spelling) or sulphur dioxide (traditional Commonwealth English) is the chemical compound with the formula . It is a colorless gas with a pungent smell that is responsible for the odor of burnt matches. It is r ...
, zeolite
Zeolites are a group of several microporous, crystalline aluminosilicate minerals commonly used as commercial adsorbents and catalysts. They mainly consist of silicon, aluminium, oxygen, and have the general formula ・y where is either a meta ...
s, or sulfuryl chloride
Sulfuryl chloride is an inorganic compound with the formula SO2Cl2. At room temperature, it is a colorless liquid with a pungent odor. Sulfuryl chloride is not found in nature.
Sulfuryl chloride is commonly confused with thionyl chloride, SOC ...
. The related hydroxylamine-O-sulfonic acid
Hydroxylamine-''O''-sulfonic acid (HOSA) or aminosulfuric acid is the inorganic compound with molecular formula H3NO4S that is formed by the sulfonation of hydroxylamine with oleum. It is a white, water-soluble and hygroscopic, solid, commonly r ...
reacts similarly.
:
In specialised cases the Van Leusen reaction can be used. Biocatalysts such as aliphatic aldoxime dehydratase are also effective.
Sandmeyer reaction
Aromatic nitriles are often prepared in the laboratory from the aniline via diazonium compounds. This is the Sandmeyer reaction. It requires transition metal cyanides.
:
Other methods
*A commercial source for the cyanide group is diethylaluminum cyanide which can be prepared from triethylaluminium
Triethylaluminium is one of the simplest examples of an organoaluminium compound. Despite its name the compound has the formula Al2( C2H5)6 (abbreviated as Al2Et6 or TEA). This colorless liquid is pyrophoric. It is an industrially important comp ...
and HCN. It has been used in nucleophilic addition
In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...
to ketone
In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
s. For an example of its use see: Kuwajima Taxol total synthesis
* Cyanide ions facilitate the coupling of dibromides. Reaction of α,α′-dibromoadipic acid
Adipic acid or hexanedioic acid is the organic compound with the formula C6H10O4. It a white crystalline powder at standard temperature and pressure. From an industrial perspective, it is the most important dicarboxylic acid at about 2.5 billion ...
with sodium cyanide
Sodium cyanide is a compound with the formula Na C N and the structure . It is a white, water-soluble solid. Cyanide has a high affinity for metals, which leads to the high toxicity of this salt. Its main application, in gold mining, also expl ...
in ethanol
Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
yields the cyano cyclobutane
Cyclobutane is a cycloalkane and organic compound with the formula (CH2)4. Cyclobutane is a colourless gas and is commercially available as a liquefied gas. Derivatives of cyclobutane are called cyclobutanes. Cyclobutane itself is of no commerc ...
:
* Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines () in the Houben-Fischer synthesis
* α-Amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s form nitriles and carbon dioxide
Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...
via various means of oxidative decarboxylation. Henry Drysdale Dakin
Henry Drysdale Dakin Fellow of the Royal Society, FRS (12 March 188010 February 1952) was an England, English chemist.
He was born in London as the youngest of 8 children to a family of steel merchants from Leeds. As a school boy, he conducted ...
discovered this oxidation in 1916.
* From aryl carboxylic acids ( Letts nitrile synthesis)
Reactions
Nitrile groups in organic compounds can undergo a variety of reactions depending on the reactants or conditions. A nitrile group can be hydrolyzed, reduced, or ejected from a molecule as a cyanide ion.
Hydrolysis
The hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of nitriles RCN proceeds in the distinct steps under acid or base treatment to first give carboxamides and then carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
s . The hydrolysis of nitriles to carboxylic acids is efficient. In acid or base, the balanced equations are as follows:
:
:
Strictly speaking, these reactions are mediated (as opposed to ''catalyzed'') by acid or base, since one equivalent of the acid or base is consumed to form the ammonium or carboxylate salt, respectively.
Kinetic studies show that the second-order rate constant for hydroxide-ion catalyzed hydrolysis of acetonitrile
Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not class ...
to acetamide
Acetamide (systematic name: ethanamide) is an organic compound with the formula CH3CONH2. It is an amide derived from ammonia and acetic acid. It finds some use as a plasticizer and as an industrial solvent. The related compound ''N'',''N''-dime ...
is 1.6 M−1 s−1, which is slower than the hydrolysis of the amide to the carboxylate (7.4 M−1 s−1). Thus, the base hydrolysis route will afford the carboxylate (or the amide contaminated with the carboxylate). On the other hand, the acid catalyzed reactions requires a careful control of the temperature and of the ratio of reagents in order to avoid the formation of polymers, which is promoted by the exothermic character of the hydrolysis. The classical procedure to convert a nitrile to the corresponding primary amide calls for adding the nitrile to cold concentrated sulfuric acid
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid (English in the Commonwealth of Nations, Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen, ...
. The further conversion to the carboxylic acid is disfavored by the low temperature and low concentration of water.
:
Two families of enzymes catalyze the hydrolysis of nitriles. Nitrilases hydrolyze nitriles to carboxylic acids:
:
Nitrile hydratases are metalloenzyme
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...
s that hydrolyze nitriles to amides.
:
These enzymes are used commercially to produce acrylamide
Acrylamide (or acrylic amide) is an organic compound with the chemical formula CH2=CHC(O)NH2. It is a white odorless solid, soluble in water and several organic solvents. From the chemistry perspective, acrylamide is a vinyl-substituted primary ...
.
The "anhydrous hydration" of nitriles to amides has been demonstrated using an oxime as water source:
:
Reduction
Nitriles are susceptible to hydrogenation
Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or Saturated ...
over diverse metal catalysts. The reaction can afford either the primary amine () or the tertiary amine (), depending on conditions. In conventional organic reduction
Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions, because many reactions car ...
s, nitrile is reduced by treatment with lithium aluminium hydride
Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula or . It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthe ...
to the amine. Reduction to the imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
followed by hydrolysis to the aldehyde takes place in the Stephen aldehyde synthesis, which uses stannous chloride in acid.
Deprotonation
Alkyl nitriles are sufficiently acidic to undergo deprotonation of the C-H bond adjacent to the group. Strong bases are required, such as lithium diisopropylamide
Lithium diisopropylamide (commonly abbreviated LDA) is a chemical compound with the molecular formula . It is used as a strong base and has been widely utilized due to its good solubility in non-polar organic solvents and non-nucleophilic nature ...
and butyl lithium Butyllithium may refer to one of 5 isomeric organolithium reagents of which 3 are commonly used in chemical synthesis:
* ''n''-Butyllithium, abbreviated BuLi or nBuLi
* ''sec''-Butyllithium, abbreviated ''sec''-BuLi or sBuLi, has 2 stereoisomers, ...
. The product is referred to as a nitrile anion. These carbanions alkylate a wide variety of electrophiles. Key to the exceptional nucleophilicity is the small steric demand of the unit combined with its inductive stabilization. These features make nitriles ideal for creating new carbon-carbon bonds in sterically demanding environments.
Nucleophiles
The carbon center of a nitrile is electrophilic
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carr ...
, hence it is susceptible to nucleophilic addition
In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...
reactions:
* with an organozinc compound
Organozinc chemistry is the study of the physical properties, synthesis, and reactions of organozinc compounds, which are organometallic compounds that contain carbon (C) to zinc (Zn) chemical bonds.The Chemistry of Organozinc Compounds' (Patai S ...
in the Blaise reaction
The Blaise reaction is an organic reaction that forms a β-ketoester from the reaction of zinc metal with an α-bromoester and a nitrile. The reaction was first reported by Edmond Blaise (1872–1939) in 1901. The final intermediate is a metaloimi ...
* with alcohols in the Pinner reaction.
* with amines, e.g. the reaction of the amine
In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
sarcosine
Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a amino acid with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
with cyanamide
Cyanamide is an organic compound with the formula C N2 H2. This white solid is widely used in agriculture and the production of pharmaceuticals and other organic compounds. It is also used as an alcohol-deterrent drug. The molecule features a ...
yields creatine
Creatine ( or ) is an organic compound with the nominal formula . It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates, where it facilitates recycling of ...
* with arenes to form ketones in the Houben–Hoesch reaction via an imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
intermediate.
* with Grignard reagent
Grignard reagents or Grignard compounds are chemical compounds with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromi ...
s to form primary ketimines in the Moureau-Mignonac ketimine synthesis. While not a classical Grignard reaction
The Grignard reaction () is an organometallic chemical reaction in which, according to the classical definition, carbon alkyl, allyl, vinyl, or aryl magnesium halides (Grignard reagent) are added to the carbonyl groups of either an aldehyde or ...
, it may be considered one under broader modern definitions.
Miscellaneous methods and compounds
* In reductive decyanation the nitrile group is replaced by a proton.[''The reductive decyanation reaction: chemical methods and synthetic applications'' Jean-Marc Mattalia, Caroline Marchi-Delapierre, Hassan Hazimeh, and Michel Chanon ]Arkivoc
''Arkivoc'' (''Archive for Organic Chemistry'') is a peer-reviewed open access scientific journal covering all aspects of organic chemistry. It is published by the non-profit organization Arkat USA, which was established in 2000 through a personal ...
(AL-1755FR) pp. 90–118 200
Article
/ref> Decyanations can be accomplished by dissolving metal reduction (e.g. HMPA and potassium
Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
metal in ''tert''-butanol) or by fusion of a nitrile in KOH. Similarly, α-aminonitriles can be decyanated with other reducing agents
In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ).
Examples of substances that are common reducing agents include hydrogen, carbon ...
such as lithium aluminium hydride
Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula or . It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthe ...
.
* In the so-called Franchimont Reaction (developed by the Belgian doctoral student Antoine Paul Nicolas Franchimont (1844-1919) in 1872), an α-cyanocarboxylic acid heated in acid hydrolyzes and decarboxylates to a dimer.
* Nitriles self-react in presence of base in the Thorpe reaction in a nucleophilic addition
In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...
* In organometallic chemistry
Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and so ...
nitriles are known to add to alkyne
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Acetylene
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Propyne
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1-Butyne
In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...
s in carbocyanation:
:
Complexation
Nitriles are precursors to transition metal nitrile complexes, which are reagents and catalysts. Examples include tetrakis(acetonitrile)copper(I) hexafluorophosphate
Tetrakis(acetonitrile)copper(I) hexafluorophosphate is a salt with the formula u(CH3CN)4F6. It is a colourless solid that is used in the synthesis of other copper complexes. The cation u(CH3CN)4sup>+ is a well-known example of a transition meta ...
() and bis(benzonitrile)palladium dichloride
Bis(benzonitrile)palladium dichloride is the coordination complex with the formula PdCl2(NCC6H5)2. It is the adduct of two benzonitrile (PhCN) ligands with palladium(II) chloride. It is a yellow-brown solid that is soluble in organic solvents. ...
().
Nitrile derivatives
Organic cyanamides
Cyanamides are ''N''-cyano compounds with general structure and related to the parent cyanamide
Cyanamide is an organic compound with the formula C N2 H2. This white solid is widely used in agriculture and the production of pharmaceuticals and other organic compounds. It is also used as an alcohol-deterrent drug. The molecule features a ...
.
Nitrile oxides
Nitrile oxides have the chemical formula
A chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, such as pare ...
. Their general structure is . The R stands for any group (typically organyl
In organic and organometallic chemistry, an organyl group (commonly denoted by the letter " R") is an organic substituent with one (sometimes more) free valence electron(s) at a carbon atom.. The term is often used in chemical patent literatur ...
, e.g., acetonitrile oxide , hydrogen
Hydrogen is a chemical element; it has chemical symbol, symbol H and atomic number 1. It is the lightest and abundance of the chemical elements, most abundant chemical element in the universe, constituting about 75% of all baryon, normal matter ...
in the case of fulminic acid
Fulminic acid is an acid with the formula HCNO, more specifically . It is an isomer of isocyanic acid () and of its elusive tautomer, cyanic acid (), and also of isofulminic acid ().
Fulminate is the anion of any of its salts. For historic ...
, or halogen
The halogens () are a group in the periodic table consisting of six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and tennessine (Ts), though some authors would ...
(e.g., chlorine fulminate ).[
Nitrile oxides are quite different from nitriles: they are highly reactive 1,3-dipoles, and cannot be synthesized from the direct oxidation of nitriles. Instead, they can be synthesised by nitroalkane dehydration, ]oxime
In organic chemistry, an oxime is an organic compound belonging to the imines, with the general Chemical formula, formula , where R is an organic Side chain, side-chain and R' may be hydrogen, forming an aldoxime, or another organic functional g ...
dehydrogenation, or halooxime elimination in base. They are used in 1,3-dipolar cycloadditions, such as to isoxazole
Isoxazole is an electron-rich azole with an oxygen atom next to the nitrogen. It is also the class of compounds containing this ring. Isoxazolyl is the Valence (chemistry), univalent functional group derived from isoxazole.
Occurrence
Isoxazole ri ...
s. They undergo type 1 dyotropic rearrangement to isocyanate
In organic chemistry, isocyanate is the functional group with the formula . Organic compounds that contain an isocyanate group are referred to as isocyanates. An organic compound with two isocyanate groups is known as a diisocyanate. Diisocyan ...
s.
The heavier nitrile sulfides are extremely reactive and rare, but temporarily form during the thermolysis
Thermal decomposition, or thermolysis, is a chemical decomposition of a substance caused by heat. The decomposition temperature of a substance is the temperature at which the substance chemically decomposes. The reaction is usually endothermic ...
of oxathiazolones. They react similarly to nitrile oxides.
Occurrence and applications
Nitriles occur naturally in a diverse set of plant and animal sources. Over 120 naturally occurring nitriles have been isolated from terrestrial and marine sources. Nitriles are commonly encountered in fruit pits, especially almonds, and during cooking of ''Brassica'' crops (such as cabbage, Brussels sprouts, and cauliflower), which release nitriles through hydrolysis. Mandelonitrile, a cyanohydrin
In organic chemistry, a cyanohydrin or hydroxynitrile is a functional group found in organic compounds in which a cyano and a hydroxy group are attached to the same carbon atom. The general formula is , where R is H, alkyl, or aryl. Cyanohyd ...
produced by ingesting almonds or some fruit pits, releases hydrogen cyanide and is responsible for the toxicity of cyanogenic glycosides.
Over 30 nitrile-containing pharmaceuticals are currently marketed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. The types of pharmaceuticals containing nitriles are diverse, from vildagliptin, an antidiabetic drug, to anastrozole
Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used t ...
, which is the gold standard in treating breast cancer. In many instances the nitrile mimics functionality present in substrates for enzymes, whereas in other cases the nitrile increases water solubility or decreases susceptibility to oxidative metabolism in the liver. The nitrile functional group is found in several drugs.
File:Periciazine.svg, Structure of periciazine
Periciazine ( INN), also known as pericyazine ( BAN) or propericiazine, is a drug that belongs to the phenothiazine class of typical antipsychotics.
Periciazine is not approved for sale in the United States. It is commonly sold in Canada, Ital ...
, an antipsychotic
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
studied in the treatment of opiate
An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term ''opioid'' in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain ( ...
dependence
File:Citalopram structure.svg, Structure of citalopram
Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...
, an antidepressant
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
drug of the selective serotonin reuptake inhibitor
A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...
(SSRI) class
File:Cyamemazine.svg, Structure of cyamemazine, an antipsychotic
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
drug
File:Fadrozole.png, Structure of fadrozole, an aromatase inhibitor
Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exo ...
for the treatment of breast cancer
File:Letrozole.svg, Structure of letrozole
Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer for post-menopausal women.
It was patented in 1986 and approved for medical use in 1996. In 2021, ...
, an oral nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents.
List of nonsteroidal steroid receptor mo ...
aromatase inhibitor
Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exo ...
for the treatment of certain breast cancers
See also
* Protonated nitriles: Nitrilium
* Deprotonated nitriles: Nitrile anion
* Cyanocarbon
* Nitrile ylide
References
External links
*
*
{{Nitrogen compounds
Functional groups