View source for Nitrile

{{Short description|Organic compound with a −C≡N functional group}}
{{about|the class of organic compounds|the synthetic rubber product|Nitrile rubber}}
{{distinguish|Cyanide}}
{{Use dmy dates|date=January 2023}}
[[Image:Nitrile Structural Formulae V.1.png|thumb|class=skin-invert-image|The structure of a nitrile: the functional group is highlighted <span style="color:blue;">blue</span>]]

In [[organic chemistry]], a '''nitrile''' is any [[organic compound]] that has a {{chem2|\s[[C]]\t[[N]]}} [[functional group]]. The name of the compound is composed of a base, which includes the carbon of the {{chem2|\sC\tN}}, suffixed with "nitrile", so for example {{chem2|CH3CH2C\tN}} is called "[[propionitrile]]" (or propanenitrile).<ref>[[IUPAC Gold Book]] [http://goldbook.iupac.org/N04151.html ''nitriles'']</ref> The prefix ''[[cyano]]-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including [[methyl cyanoacrylate]], used in [[super glue]], and [[nitrile rubber]], a nitrile-containing [[polymer]] used in [[latex|latex-free]] laboratory and [[medical gloves]]. 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 [[cyanocarbon]]s.

[[Inorganic compound]]s containing the {{chem2|\sC\tN}} group are not called nitriles, but [[cyanide]]s instead.<ref>NCBI-MeSH [https://www.ncbi.nlm.nih.gov/mesh/68009570 ''Nitriles'']</ref> 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&nbsp;[[Ångström|Å]], consistent with a [[triple bond]].<ref>{{cite journal | last1 = Karakida | first1 = Ken-ichi | last2 = Fukuyama | first2 = Tsutomu | last3 = Kuchitsu | first3 = Kozo | year = 1974 | title = Molecular Structures of Hydrogen Cyanide and Acetonitrile as Studied by Gas Electron Diffraction | journal = Bulletin of the Chemical Society of Japan | volume = 47 | issue = 2| pages = 299–304 | doi=10.1246/bcsj.47.299| doi-access = free }}</ref> Nitriles are polar, as indicated by high dipole moments.  As liquids, they have high [[relative permittivity|relative permittivities]], often in the 30s.

==History==
The first compound of the homolog row of nitriles, the nitrile of [[formic acid]], [[hydrogen cyanide]] was first synthesized by [[Carl Wilhelm Scheele|C. W. Scheele]] in 1782.<ref>See:
*  Carl W. Scheele (1782) [https://books.google.com/books?id=mHVJAAAAcAAJ&pg=PA264 "Försök, beträffande det färgande ämnet uti Berlinerblå"] (Experiment concerning the colored substance in Berlin blue), ''Kungliga Svenska Vetenskapsakademiens handlingar'' (Royal Swedish Academy of Science's Proceedings), 3:  264–275 (in Swedish).
*  Reprinted in Latin as:  [https://books.google.com/books?id=BLo5AAAAcAAJ&pg=PA148 "De materia tingente caerulei berolinensis"] in:  Carl Wilhelm Scheele with Ernst Benjamin Gottlieb Hebenstreit (ed.) and Gottfried Heinrich Schäfer (trans.), ''Opuscula Chemica et Physica'' (Leipzig ("Lipsiae"), (Germany):  Johann Godfried Müller, 1789), vol. 2, pages 148–174.</ref><ref name=CR48>{{cite journal
 | title = The Preparation of Nitriles
 | journal = [[Chemical Reviews]]
 | pages = 189–283
 | author = David T. Mowry
 | doi = 10.1021/cr60132a001
 | volume = 42
 | issue = 2
 | year = 1948
 | pmid=18914000}}</ref> In 1811 [[Joseph Louis Gay-Lussac|J. L. Gay-Lussac]] was able to prepare the very toxic and volatile pure acid.<ref>Gay-Lussac produced pure, liquified hydrogen cyanide in: {{cite journal | last1 = Gay-Lussac | first1 = J | year = 1811 | title = "Note sur l'acide prussique" (Note on prussic acid) | url = https://books.google.com/books?id=uJs5AAAAcAAJ&pg=PA128 | journal = Annales de chimie | volume = 44 | pages = 128–133 }}</ref> 
Around 1832 [[benzonitrile]], the nitrile of [[benzoic acid]], was prepared by [[Friedrich Wöhler]] and [[Justus von Liebig]], but due to minimal yield of the synthesis neither physical nor chemical properties were determined nor a structure suggested. In 1834 [[Théophile-Jules Pelouze]] synthesized [[propionitrile]], suggesting it to be an ether of propionic alcohol and hydrocyanic acid.<ref name="Pelouze1834">{{cite journal
 | title = Notiz über einen neuen Cyanäther 
 |trans-title= Note on a new cyano-ether
 | url = https://books.google.com/books?id=P0s9AAAAcAAJ&pg=PA249
 | journal = Annalen der Pharmacie
 | page = 249
 | author = J. Pelouze
 | doi=  10.1002/jlac.18340100302
 | volume = 10
 | issue = 3
 | year = 1834}}</ref>
The synthesis of benzonitrile by [[Hermann von Fehling|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]]. He coined the name "nitrile" for the newfound substance, which became the name for this group of compounds.<ref>{{cite journal
 | journal = [[Annalen der Chemie und Pharmacie]]
 | volume = 49
 | issue = 1 
 | pages = 91–97
 | year = 1844
 | title = Ueber die Zersetzung des benzoësauren Ammoniaks durch die Wärme (On the decomposition of ammonium benzoate by heat)
 | author = Hermann Fehling
 | url = https://books.google.com/books?id=2U09AAAAcAAJ&pg=PA91
 | doi = 10.1002/jlac.18440490106 }}  On page 96, Fehling writes:  "Da Laurent den von ihm entdeckten Körper schon Nitrobenzoyl genannt hat, auch schon ein Azobenzoyl existirt, so könnte man den aus benzoësaurem Ammoniak entstehenden Körper vielleicht Benzonitril nennen."  (Since Laurent named the substance that was discovered by him "nitrobenzoyl" – also an "azobenzoyl" already exists – so one could name the substance that originates from ammonium benzoate perhaps "benzonitril".)</ref>

== Synthesis ==<!-- This section is linked from [[Organic reaction]] -->
Industrially, the main methods for producing nitriles are [[ammoxidation]] and [[hydrocyanation]]. Both routes are [[green chemistry|green]] in the sense that they do not generate stoichiometric amounts of salts.

===Ammoxidation===
In [[ammoxidation]], a [[hydrocarbon]] is partially [[oxidized]] in the presence of [[ammonia]]. This conversion is practiced on a large scale for [[acrylonitrile]]:<ref>{{Ullmann|doi=10.1002/14356007.a17_363|chapter=Nitriles|year=2000|last1=Pollak|first1=Peter|last2=Romeder|first2=Gérard|last3=Hagedorn|first3=Ferdinand|last4=Gelbke|first4=Heinz-Peter|isbn=3527306730}}</ref>
:<chem>CH3CH=CH2  + 3/2 O2  +  NH3  -> N#CCH=CH2  +  3 H2O</chem>
In the production of acrylonitrile, a side product is [[acetonitrile]]. On an industrial scale, several derivatives of [[benzonitrile]], [[phthalonitrile]], as well as Isobutyronitrile are prepared by ammoxidation.  The process is catalysed by [[metal oxide]]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 catalyst]]s.  An example of hydrocyanation is the production of [[adiponitrile]], a precursor to [[nylon-6,6]] from [[1,3-butadiene]]:
:{{chem2|CH2\dCH\sCH\dCH2  +  2 HC\tN  -> NC(CH2)4C\tN}}

===From organic halides and cyanide salts===
Two [[salt metathesis reaction]]s are popular for laboratory scale reactions. In the [[Kolbe nitrile synthesis]], [[alkyl halide]]s undergo [[nucleophilic aliphatic substitution]] with alkali metal [[cyanide]]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]] and [[temperature]] can minimize the latter.  An [[alkyl sulfate]] obviates the problem entirely, particularly in nonaqueous conditions (the [[Pelouze]] synthesis).<ref name=CR48/>

===Cyanohydrins===
[[File:Synthesis of Cyanoarenes.png|thumb|class=skin-invert-image|Synthesis of aromatic nitriles via silylated cyanohydrins]]
The [[cyanohydrin]]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]] in the presence of a catalyst (silylcyanation).  Cyanohydrins are also prepared by transcyanohydrin reactions starting, for example, with [[acetone cyanohydrin]] as a source of HCN.<ref>{{Cite journal|title=Cyanohydrins in Nature and the Laboratory: Biology, Preparations, and Synthetic Applications|author=Gregory, Robert J. H.|journal=Chemical Reviews|year=1999|volume=99|issue=12|pages=3649–3682|doi=10.1021/cr9902906|pmid=11849033}}</ref>

===Dehydration of amides===
Nitriles can be prepared by the [[dehydration reaction|dehydration]] of primary [[amide]]s. Common reagents for this include [[phosphorus pentoxide]] ({{chem2|P2O<sub>5</sub>}})<ref>{{cite journal |title=ISOBUTYRONITRILE |journal=Organic Syntheses |date=1945 |volume=25 |page=61 |doi=10.15227/orgsyn.025.0061 |doi-access=}}</ref> and [[thionyl chloride]] ({{chem2|SOCl2}}).<ref>{{cite journal |title=2-ETHYLHEXANONITRILE |journal=Organic Syntheses |date=1952 |volume=32 |page=65 |doi=10.15227/orgsyn.032.0065 |doi-access=}}</ref> In a related dehydration, secondary [[amide]]s give nitriles by the [[von Braun amide degradation]]. In this case, one C-N bond is cleaved.

:[[Image:7 Dehydratisierung-2.svg|class=skin-invert-image|200px|Amide dehydration]]

===Oxidation of amines===
Numerous traditional methods exist for nitrile preparation by [[amine]] oxidation. <ref>{{cite journal |title=Developments in the Aerobic Oxidation of Amines |journal=ACS Catal. |date=2021 |volume=2 |pages=1108–1117 |doi=10.1021/cs300212q |doi-access= |last1=Schümperli |first1=Martin T. |last2=Hammond |first2=Ceri |last3=Hermans |first3=Ive |issue=6 }}</ref> In addition, several selective methods have been developed in the last decades for [[electrochemical]] processes. <ref>{{cite journal |title=Beyond traditional synthesis: Electrochemical approaches to amine oxidation for nitriles and imines |journal=ACS Org Inorg Au |date=2024 |doi=10.1021/acsorginorgau.4c00025 |doi-access=free |last1=Xu |first1=Zhining |last2=Kovács |first2=Ervin |volume=4 |issue=5 |pages=471–484 |pmc=11450732 }}</ref>

===From aldehydes and oximes===
The conversion of [[aldehydes]] to nitriles via [[aldoxime]]s is a popular laboratory route. Aldehydes react readily with [[hydroxylamine]] salts, sometimes at temperatures as low as ambient, to give aldoximes. These can be dehydrated to nitriles by simple heating,<ref>{{cite journal |last1=Chill |first1=Samuel T. |last2=Mebane |first2=Robert C. |title=A Facile One-Pot Conversion of Aldehydes into Nitriles |journal=Synthetic Communications |date=18 September 2009 |volume=39 |issue=20 |pages=3601–3606 |doi=10.1080/00397910902788174|s2cid=97591561 }}</ref> although a wide range of reagents may assist with this, including [[triethylamine]]/[[sulfur dioxide]], [[zeolite]]s, or [[sulfuryl chloride]]. The related [[hydroxylamine-O-sulfonic acid]] reacts similarly.<ref>{{cite journal|surname1=C. Fizet|surname2=J. Streith|periodical=[[Tetrahedron Lett.]]|title=Hydroxylamine-''O''-sulfonic acid: A convenient reagent for the oxidative conversion of aldehydes into nitriles|volume=15|issue=36 |year=1974|pages=3187–3188|language=German|doi=10.1016/S0040-4039(01)91857-X}}</ref>

:[[Image:2,5-Diformylfuran Bildung von 2,5-Dicyanofuran.svg|360px|thumb|class=skin-invert-image|One-pot synthesis from aldehyde (Amberlyst is an acidic [[ion-exchange resin]].) ]]

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.<ref>"''o''-Tolunitrile and ''p''-Tolunitrile" H. T. Clarke and R. R. Read ''Org. Synth.'' 1941, Coll. Vol. 1, 514.</ref>
:{{chem2|ArN2+ + CuC\tN -> ArC\tN + N2 + Cu+}}

===Other methods===
*A commercial source for the cyanide group is diethylaluminum cyanide {{chem2|Et2AlCN}} which can be prepared from [[triethylaluminium]] and HCN.<ref>{{OrgSynth | collvol = 6 | collvolpages = 436 | year = 1988 | title = Diethylaluminum cyanide | author = W. Nagata and M. Yoshioka | prep = cv6p0436}}</ref> It has been used in [[nucleophilic addition]] to [[ketone]]s.<ref>{{OrgSynth | collvol = 6 | collvolpages = 307 | year = 1988 | title = Preparation of cyano compounds using alkylaluminum intermediates:  1-cyano-6-methoxy-3,4-dihydronaphthalene| author = W. Nagata, M. Yoshioka, and M. Murakami | prep = cv6p0307}}</ref> For an example of its use see: [[Kuwajima Taxol total synthesis]]
* Cyanide ions facilitate the coupling of dibromides. Reaction of α,α′-dibromo[[adipic acid]] with [[sodium cyanide]] in [[ethanol]] yields the cyano [[cyclobutane]]:<ref>{{cite journal | title = Ring Closures in the Cyclobutane Series. II. Cyclization Of α,α′-Dibromo-Adipic Esters |author1=Reynold C. Fuson |author2=Oscar R. Kreimeier |author3=Gilbert L. Nimmo  |name-list-style=amp | journal = [[J. Am. Chem. Soc.]] | year = 1930 | volume = 52 | issue = 10 | pages = 4074–4076 | doi = 10.1021/ja01373a046}}</ref> [[Image:Cyclobutane by cyanide mediated dibromide coupling.svg|center|class=skin-invert-image|300px]]  <!--Presumably, the some of the cyanide is oxidized to cyanogen.  The molar masses in the original paper suggest as much — a ≈3:1 molar ratio of cyanide to diethyldibromoadipate — but they don't seem to have attempted to isolate the dicyanogen, so this imputation is all WP:OR.-->  
* Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines ({{chem2|RC(CCl3)\dNH}}) in the Houben-Fischer synthesis<ref>J. Houben, Walter Fischer (1930) "Über eine neue Methode zur Darstellung cyclischer Nitrile durch katalytischen Abbau (I. Mitteil.)," ''Berichte der deutschen chemischen Gesellschaft'' (A and B Series) 63 (9): 2464 – 2472. {{doi|10.1002/cber.19300630920}}</ref>
* Nitriles can be obtained from [[Primary (chemistry)|primary]] [[amines]] via [[oxidation]]. Common methods include the use of [[potassium persulfate]],<ref>{{cite journal|last1=Yamazaki|first1=Shigekazu|last2=Yamazaki|first2=Yasuyuki|title=Nickel-catalyzed dehydrogenation of amines to nitriles|journal=Bulletin of the Chemical Society of Japan|date=1990|volume=63|issue=1|pages=301–303|doi=10.1246/bcsj.63.301|doi-access=free}}</ref> [[Trichloroisocyanuric acid]],<ref>{{cite journal|last1=Chen|first1=Fen-Er|last2=Kuang|first2=Yun-Yan|last3=Hui-Fang|first3=Dai|last4=Lu|first4=Liang|title=A Selective and Mild Oxidation of Primary Amines to Nitriles with Trichloroisocyanuric Acid|journal=Synthesis|date=2003|volume=17|issue=17|pages=2629–2631|doi=10.1055/s-2003-42431}}</ref> or [[anode|anodic]] [[electrosynthesis]].<ref>{{cite journal|last1=Schäfer|first1=H. J.|last2=Feldhues|first2=U.|title=Oxidation of Primary Aliphatic Amines to Nitriles at the Nickel Hydroxide Electrode|date=1982|volume=1982|issue=2|pages=145–146|doi=10.1055/s-1982-29721|journal=Synthesis|s2cid=97172564 }}</ref>
* [[Alpha and beta carbon|α]]-[[Amino acid]]s form nitriles and [[carbon dioxide]] via various means of [[oxidative decarboxylation]].<ref>{{cite journal|last1=Hiegel|first1=Gene|last2=Lewis|first2=Justin|last3=Bae|first3=Jason|title=Conversion of α-Amino Acids into Nitriles by Oxidative Decarboxylation with Trichloroisocyanuric Acid|journal=Synthetic Communications|date=2004|volume=34|issue=19|pages=3449–3453|doi=10.1081/SCC-200030958|s2cid=52208189}}</ref><ref>{{cite journal|last1=Hampson|first1=N|last2=Lee|first2=J|last3=MacDonald|first3=K|title=The oxidation of amino compounds at anodic silver|journal=Electrochimica Acta|date=1972|volume=17|issue=5|pages=921–955|doi=10.1016/0013-4686(72)90014-X}}</ref> [[Henry Drysdale Dakin]] discovered this oxidation in 1916.<ref>{{cite journal|last1=Dakin|first1=Henry Drysdale|title=The Oxidation of Amino-Acids to Cyanides|journal=Biochemical Journal|date=1916|volume=10|issue=2|pages=319–323|pmc=1258710|pmid=16742643|doi=10.1042/bj0100319}}</ref>
* 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]] of nitriles RCN proceeds in the distinct steps under acid or base treatment to first give [[Amide|carboxamides]] {{chem2|RC(O)NH2}} and then [[carboxylic acid]]s {{chem2|RC(O)OH}}. The hydrolysis of nitriles to carboxylic acids is efficient.  In acid or base, the balanced equations are as follows:

:{{chem2|RC\tN + 2 H2O + HCl -> RC(O)OH + NH4Cl}}
:{{chem2|RC\tN + H2O + NaOH -> RC(O)ONa + NH3}}

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]] to [[acetamide]] is 1.6{{x10^|-6}}&nbsp;M<sup>−1</sup>&nbsp;s<sup>−1</sup>, which is slower than the hydrolysis of the amide to the carboxylate (7.4{{x10^|-5}}&nbsp;M<sup>−1</sup>&nbsp;s<sup>−1</sup>). 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.<ref>{{cite journal|first1=V. Yu. |last1=Kukushkin |first2=A. J. L. |last2=Pombeiro |title=Metal-mediated and metal-catalyzed hydrolysis of nitriles |journal=Inorg. Chim. Acta |volume=358 |date=2005 |pages=1–21 |doi=10.1016/j.ica.2004.04.029}}</ref> The classical procedure to convert a nitrile to the corresponding primary amide calls for adding the nitrile to cold concentrated [[sulfuric acid]].<ref>{{Cite journal|last=Abbas|first=Khamis A.|date=2008-01-01|title=Substituent Effects on the Hydrolysis of p-Substituted Benzonitriles in Sulfuric Acid Solutions at (25.0± 0.1) °C|journal=Zeitschrift für Naturforschung A|volume=63|issue=9|pages=603–608|doi=10.1515/zna-2008-0912|issn=1865-7109|bibcode=2008ZNatA..63..603A|doi-access=free}}</ref> The further conversion to the carboxylic acid is disfavored by the low temperature and low concentration of water.
:{{chem2|RC\tN + H2O -> RC(O)NH2}}

Two families of enzymes catalyze the hydrolysis of nitriles.  [[Nitrilase]]s hydrolyze nitriles to carboxylic acids:
:{{chem2|RC\tN  +  2 H2O   -> RC(O)OH  +  NH3}}
[[Nitrile hydratase]]s are [[metalloenzyme]]s that hydrolyze nitriles to amides.  
:{{chem2|RC\tN  +  H2O   -> RC(O)NH2}}
These enzymes are used commercially to produce [[acrylamide]].

The "anhydrous hydration" of nitriles to amides has been demonstrated using an oxime as water source:<ref>{{cite journal |doi=10.15227/orgsyn.089.0066|author=Dahye Kang |author2=Jinwoo Lee |author3=Hee-Yoon Lee
|title =Anhydrous Hydration of Nitriles to Amides: ''p''-Carbomethoxybenzamide|journal=Organic Syntheses|year=2012|volume=89|page=66|doi-access=free}}</ref>
:{{chem2|RC\tN  +  R'C(H)\dNOH  -> RC(O)NH2  +  R'C\tN}}

=== Reduction ===
{{Main|Nitrile reduction}}
Nitriles are susceptible to [[hydrogenation]] over diverse metal catalysts.  The reaction can afford either the primary amine ({{chem2|RCH2NH2}}) or the tertiary amine ({{chem2|(RCH2)3N}}), depending on conditions.<ref>{{cite journal|first1=J. |last1=Barrault |first2=Y. |last2=Pouilloux |title=Catalytic Amination Reactions: Synthesis of fatty amines. Selectivity control in presence of multifunctional catalysts |journal=Catalysis Today |date=1997 |volume=1997 |issue=2 |pages=137–153 |doi=10.1016/S0920-5861(97)00006-0}}</ref> In conventional [[organic reduction]]s, nitrile is reduced by treatment with [[lithium aluminium hydride]] to the amine.  Reduction to the [[imine]] 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 {{chem2|C\tN}} group.<ref>{{cite book |doi=10.1002/0471264180.or031.01|chapter=Addition and Substitution Reactions of Nitrile-Stabilized Carbanions |title=Organic Reactions |year=1984 |last1=Arseniyadis |first1=Siméon |last2=Kyler |first2=Keith S. |last3=Watt |first3=David S. |pages=1–364 |isbn=978-0-471-26418-7 }}</ref><ref>{{cite journal |doi=10.1021/acs.accounts.7b00329|title=C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity |year=2017 |last1=Yang |first1=Xun |last2=Fleming |first2=Fraser F. |journal=Accounts of Chemical Research |volume=50 |issue=10 |pages=2556–2568 |pmid=28930437 }}</ref> Strong bases are required, such as [[lithium diisopropylamide]] and [[butyl lithium]].  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 {{chem2|C\tN}} 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]], hence it is susceptible to [[nucleophilic addition]] reactions:
* with an [[organozinc compound]] in the [[Blaise reaction]]
* with alcohols in the [[Pinner reaction]].
* with amines, e.g. the reaction of the [[amine]] [[sarcosine]] with [[cyanamide]] yields [[creatine]]<ref>{{cite journal |author1=Smith, Andri L. |author2=Tan, Paula | title = Creatine Synthesis: An Undergraduate Organic Chemistry Laboratory Experiment | journal = [[J. Chem. Educ.]] | year = 2006 | volume = 83 | page = 1654 | doi = 10.1021/ed083p1654|bibcode = 2006JChEd..83.1654S | issue = 11 }}</ref>
* with arenes to form ketones in the [[Houben–Hoesch reaction]] via an [[imine]] intermediate.
* with [[Grignard reagent]]s to form [[imine|primary ketimine]]s in the Moureau-Mignonac ketimine synthesis.<ref>{{Cite book|date=2010-09-15|chapter=Moureau-Mignonac Ketimine Synthesis|title=Comprehensive Organic Name Reactions and Reagents|language=en|location=Hoboken, NJ, USA|publisher=John Wiley & Sons, Inc.|pages=1988–1990|doi=10.1002/9780470638859.conrr446|isbn=9780470638859}}</ref> While not a classical [[Grignard reaction]], it may be considered one under broader modern definitions.

=== Miscellaneous methods and compounds ===
* In reductive decyanation the nitrile group is replaced by a proton.<ref name=DecyanationReview>''The reductive decyanation reaction: chemical methods and synthetic applications'' Jean-Marc Mattalia, Caroline Marchi-Delapierre, Hassan Hazimeh, and Michel Chanon [[Arkivoc]] (AL-1755FR) pp. 90–118 2006 [http://www.arkat-usa.org/ark/journal/2006/I04_Lattes/1755/AL-1755FR%20as%20published%20mainmanuscript.asp Article]{{Dead link|date=January 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Decyanations can be accomplished by [[dissolving metal reduction]] (e.g. [[HMPA]] and [[potassium]] metal in [[Tert-Butanol|''tert''-butanol]]) or by [[Melting|fusion]] of a nitrile in [[Potassium hydroxide|KOH]].<ref>{{cite journal|last1=Berkoff|first1=Charles E.|last2=Rivard|first2=Donald E.|last3=Kirkpatrick|first3=David|last4=Ives|first4=Jeffrey L.|title=The Reductive Decyanation of Nitriles by Alkali Fusion|journal=Synthetic Communications|date=1980|volume=10|issue=12|pages=939–945|doi=10.1080/00397918008061855}}</ref> Similarly, α-aminonitriles can be decyanated with other [[reducing agents]] such as [[lithium aluminium hydride]].<ref name=DecyanationReview />
* 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 [[decarboxylation|decarboxylates]] to a dimer.<ref>{{Cite journal | first = Antoine&nbsp;Paul Nicholas |last=Franchimont | title =  Ueber die Dibenzyldicarbonsäure |trans-title= On 2,3-diphenylsuccinic acid | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 5 | issue =  2 | pages = 1048–1050 | date = 1872 | doi = 10.1002/cber.187200502138 | url = https://babel.hathitrust.org/cgi/pt?id=uc1.b3481750;seq=1012}}</ref>
* Nitriles self-react in presence of base in the [[Thorpe reaction]] in a [[nucleophilic addition]]
* In [[organometallic chemistry]] nitriles are known to add to [[alkyne]]s in carbocyanation:<ref>{{cite journal | title = A Dramatic Effect of Lewis-Acid Catalysts on Nickel-Catalyzed Carbocyanation of Alkynes |author1=Yoshiaki Nakao |author2=Akira Yada |author3=Shiro Ebata |author4=Tamejiro Hiyama  |name-list-style=amp | journal = [[J. Am. Chem. Soc.]] | year = 2007 | volume = 129 | issue = 9 | pmid = 17295484 | pages = 2428–2429| type = Communication | doi = 10.1021/ja067364x}}</ref>
:[[Image:Carbocyanation.png|400px|class=skin-invert-image|Carbocyanation Nakao 2007]]

===Complexation===
Nitriles are precursors to [[transition metal nitrile complexes]], which are reagents and catalysts.  Examples include [[tetrakis(acetonitrile)copper(I) hexafluorophosphate]] ({{chem2|[Cu(MeCN)4]+}}) and [[bis(benzonitrile)palladium dichloride]] ({{chem2|PdCl2(PhCN)2}}).<ref>{{cite journal|author1=Rach, S. F. |author2=Kühn, F. E. |title=Nitrile Ligated Transition Metal Complexes with Weakly Coordinating Counteranions and Their Catalytic Applications|journal=Chemical Reviews|year=2009|volume=109|issue=5|pages=2061–2080|doi=10.1021/cr800270h|pmid=19326858}}</ref>
[[File:Sample of PdCl2(PhCN)2.jpg|thumb|left|Sample of the nitrile complex {{chem2|PdCl2(PhCN)2}}]]

==Nitrile derivatives==

===Organic cyanamides===
{{See also|von Braun reaction|Cyanamide#Cyanamide functional group}}
Cyanamides are ''N''-cyano compounds with general structure {{chem2|R^{1}R^{2}N\sC\tN}} and related to the parent [[cyanamide]].<ref>{{March4th|page=436–7}}</ref>

===Nitrile oxides===
Nitrile oxides have the [[chemical formula]] {{chem2|RCNO}}. Their general structure is {{chem2|R\sC\tN+\sO-}}. The R stands for any group (typically [[organyl]], e.g., acetonitrile oxide {{chem2|CH3\sC\tN+\sO−}}, [[hydrogen]] in the case of [[fulminic acid]] {{chem2|H\sC\tN+\sO−}}, or [[halogen]] (e.g., chlorine fulminate {{chem2|Cl\sC\tN+\sO−}}).<ref name=March/>{{rp|1187–1192}}  

Nitrile oxides are quite different from nitriles: they are highly reactive [[1,3-dipole]]s, and cannot be synthesized from the direct oxidation of nitriles.<ref>{{cite book|page=794|doi=10.1002/9780470771242.ch14|title=The Chemistry of the Cyano Group|editor-first=Zvi|editor-last=Rappoport|year=1970|first=Ch.|last=Grundmann|chapter=Nitrile oxides|series=PATai's Chemistry of Functional Groups |isbn=978-0-471-70913-8 }}</ref>  Instead, they can be synthesised by [[nitroalkane]] dehydration, [[oxime]] dehydrogenation,<ref name="Clayden">{{Clayden}}</ref>{{rp|934–936}} or halooxime elimination in base.<ref>{{cite journal|doi=10.1016/S0040-4039(00)71175-0|journal=Tetrahedron Letters|volume=21|pp=229-230|publisher=Pergamon|year=1980|location=Great Britain|title=Direct synthesis of the antitumor agent ''erythro''-&alpha;&#x2011;amino-3&#x2011;bromo-4,5&#x2011;dihydro&shy;oxazole-5&#x2011;acetic acid|first1=Alfred&nbsp;A.|last1=Hagedorn|first2=Bryan&nbsp;J.|last2=Miller|first3=Jon&nbsp;O.|last3=Nagy|orig-date=12 Oct 1979|postscript=none}}, alluding to a large-scale modification later detailed in {{cite journal|doi=10.1016/S0040-4039(00)99918-0|journal=Tetrahedron Letters|volume=25|issue=5|at=fn.&nbsp;10|location=Great Britain|year=1984|publisher=Pergamon|title=A short, efficient total synthesis of (&pm;) acivicin and (&pm;) bromo-acivicin|first1=D.&nbsp;M.|last1=Vyas|first2=Y.|last2=Chiang|first3=T.&nbsp;W.|last3=Doyle}}</ref>  They are used in [[1,3-dipolar cycloaddition]]s,<ref name="March">{{cite book | first1 = Michael B. | last1 = Smith | first2 = Jerry | last2 = March | title = March's Advanced Organic Chemistry | publisher = John Wiley & Sons | year = 2007 | edition=6th | isbn =  978-0-471-72091-1 }}</ref>{{rp|1187–1192}} such as to [[isoxazole]]s.<ref name="Clayden" />{{rp|1201–1202}} They undergo type 1 [[dyotropic rearrangement]] to [[isocyanate]]s.<ref name="March" />{{rp|1700}}

The heavier nitrile sulfides are extremely reactive and rare, but temporarily form during the [[thermolysis]] of [[oxathiazolones]].  They [[oxathiazolones#Decarboxylation leading to isothiazole derivatives|react similarly]] to nitrile oxides.<ref>{{cite book|pages=506–507|last=Argyropoulos|first=Nikolaos&nbsp;G.|chapter=1,4-Oxa/thia-2-azoles|year=1996|title=Comprehensive Heterocyclic Chemistry|volume=4: Five-membered rings with more than two heteroatoms and fused carbocyclic derivatives|doi=10.1016/B978-008096518-5.00092-7|isbn=978-0-08-096518-5|editor-first1=Alan&nbsp;R.|editor-last1=Katritzky|editor-link1=Alan Katritzky|editor-first2=Charles&nbsp;W.|editor-last2=Rees|editor-first3=Eric&nbsp;F.&nbsp;V.|editor-last3=Scriven}}</ref>

==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]] produced by ingesting almonds or some fruit pits, releases hydrogen cyanide and is responsible for the toxicity of cyanogenic glycosides.<ref>[[Natural Product Reports]] Issue 5, 1999 [http://pubs.rsc.org/en/Content/ArticleLanding/1999/NP/a804370a ''Nitrile-containing natural products'']</ref>

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]], 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.<ref>{{cite journal |last1=Fleming |first1=Fraser F. |last2=Yao |first2=Lihua |last3=Ravikumar |first3=P. C. |last4=Funk |first4=Lee |last5=Shook |first5=Brian C. |title=Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore |journal=[[Journal of Medicinal Chemistry|J Med Chem]] |volume=53 |issue=22 |pages=7902–17 |date=November 2010 |pmid=20804202 |pmc=2988972 |doi=10.1021/jm100762r }}</ref> The nitrile functional group is found in several drugs.

<gallery class="skin-invert-image">
File:Periciazine.svg|Structure of [[periciazine]], an [[antipsychotic]] studied in the treatment of [[opiate]] dependence
File:Citalopram structure.svg|Structure of [[citalopram]], an [[antidepressant]] drug of the selective [[serotonin reuptake inhibitor]] (SSRI) class
File:Cyamemazine.svg|Structure of [[cyamemazine]], an [[antipsychotic]] drug
File:Fadrozole.png|Structure of [[fadrozole]], an [[aromatase inhibitor]] for the treatment of breast cancer
File:Letrozole.svg|Structure of [[letrozole]], an oral [[nonsteroidal]] [[aromatase inhibitor]] for the treatment of certain breast cancers
</gallery>

==See also==
* Protonated nitriles: [[Nitrilium]]
* Deprotonated nitriles: [[Nitrile anion]]
* [[Cyanocarbon]]
* [[Nitrile ylide]]

== References ==
{{reflist}}

== External links ==
* {{GoldBookRef | file = N04151 | title = nitrile}}
* {{GoldBookRef | file = C01486 | title = cyanide}}

{{Functional Groups}}
{{Nitrogen compounds}}

[[Category:Nitriles| ]]
[[Category:Functional groups]]