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| {{SI}}
| | #REDIRECT:[[Nitrile]] |
| {{about|the group of organic compounds|the synthetic rubber product|Nitrile rubber}}
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| [[Image:Nitrile Structural Formulae V.1.png|thumb|The structure of a nitrile, the functional group is highlighted <span style="color:blue;">'''blue'''</span>.]]
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| A '''nitrile''' is any [[organic compound]] that has a -[[Carbon|C]]'''≡'''[[Nitrogen|N]] [[functional group]].<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|nitrile butadiene rubber]], a nitrile-containing [[polymer]] used in [[latex|latex-free]] laboratory and medical gloves. Organic compounds containing multiple nitrile groups are known as [[cyanocarbon]]s.
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| [[Inorganic compound]]s containing the -C'''≡'''N group are not called nitriles, but cyanides instead.<ref>NCBI-MeSH [http://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.
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| ==History==
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| 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>{{cite journal
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| | title = The Preparation of Nitriles
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| | journal = [[Chemical Reviews]]
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| | pages = 189–283
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| | author = David T. Mowry
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| | doi = 10.1021/cr60132a001
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| | volume = 42
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| | issue = 2
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| | year = 1948
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| | url = http://pubs.acs.org/cgi-bin/abstract.cgi/chreay/1942/42/i02/f-pdf/f_cr60132a001.pdf
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| | format = – <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3AThe+Preparation+of+Nitriles&as_publication=%5B%5BChemical+Reviews%5D%5D&as_ylo=1948&as_yhi=1948&btnG=Search Scholar search]</sup>}} {{dead link|date=May 2009}}</ref> In 1811 [[Joseph Louis Gay-Lussac|J. L. Gay-Lussac]] was able to prepare the very toxic and volatile pure acid.
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| The nitrile of [[benzoic acids]] was first 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. [[Théophile-Jules Pelouze]] synthesized [[propionitrile]] in 1834 suggesting it to be an ether of propionic alcohol and hydrocyanic acid.<ref name="Pelouze1834">{{cite journal
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| | title = Notiz über einen neuen Cyanäther
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| | journal = [[Annalen der Chemie und Pharmacie]]
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| | pages = 249
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| | author = J. Pelouze
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| | doi= 10.1002/jlac.18340100302
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| | volume = 10
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| | issue = 2
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| | year = 1834}}</ref>
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| 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.
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| He determined the structure by comparing it to the already known synthesis of hydrogen cyanide by heating ammonium [[formate]] to his results. He coined the name nitrile for the newfound substance, which became the name for the compound group.<ref>{{cite journal
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| | journal = [[Annalen der Chemie und Pharmacie]]
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| | volume = 49
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| | issue = 1
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| | pages = 91–97
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| | year = 1844
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| | title = Ueber die Zersetzung des benzoësauren Ammoniaks durch die Wärme
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| | author = Hermann Fehling
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| | doi = 10.1002/jlac.18440490106 }}</ref>
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| <!--==History==
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| [[Hydrogen cyanide]] was first synthesized by [[Carl Wilhelm Scheele|K.W. Scheele]] in 1782 and he was killed in an attempt to get the [[anhydrous]] compound.<ref>{{cite journal | title = The Preparation of Nitriles | author = David T. Mowry | journal = [[Chem. Rev.]] | year = 1948 | volume = 42 | issue = 2 | pages = 189–283 | doi = 10.1021/cr60132a001}}</ref> [[Joseph Louis Gay-Lussac|J. L. Gay-Lussac]] was the first to prepare the pure acid in 1811 and [[Friedrich Wohler]] and [[Justus von Liebig]] were the first to prepare the first nitriles ''benzoyl cyanide'' and [[benzonitrile]] in 1832. [[Théophile-Jules Pelouze]] synthesized [[propionitrile]] in 1834.<ref name="Pelouze1834" />
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| Word by word coppy of the article {{cite journal
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| | title = The Preparation of Nitriles
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| | journal = [[Chemical reviews]]
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| | pages = 189–283
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| | author = David T. Mowry
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| | doi = 10.1021/cr60132a001
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| | volume = 42
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| | issue = 2
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| | year = 1948
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| | url = http://pubs.acs.org/cgi-bin/abstract.cgi/chreay/1942/42/i02/f-pdf/f_cr60132a001.pdf
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| | format = {{dead link|date=May 2009}} – <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3AThe+Preparation+of+Nitriles&as_publication=%5B%5BChemical+reviews%5D%5D&as_ylo=1948&as_yhi=1948&btnG=Search Scholar search]</sup>}}-->
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| == Synthesis ==<!-- This section is linked from [[Organic reaction]] -->
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| Industrially, the main methods for producing nitriles are [[ammoxidation]] and [[hydrocyanation]]. Both routes are green in the sense that they do not generate stoichiometric amounts of salts.
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| ===Ammoxidation===
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| In ammonoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile:<ref>Peter Pollak, Gérard Romeder, Ferdinand Hagedorn, Heinz-Peter Gelbke "Nitriles" Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. {{DOI|10.1002/14356007.a17_363}}</ref>
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| :CH<sub>3</sub>CH=CH<sub>2</sub> + 3/2 O<sub>2</sub> + NH<sub>3</sub> → NCCH=CH<sub>2</sub> + 3 H<sub>2</sub>O
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| A side product of this process is [[acetonitrile]]. Most derivatives of benzonitrile as well as Isobutyronitrile are prepared by ammoxidation.
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| ===Hydrocyanation===
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| An example of hydrocyanation is the production of [[adiponitrile]] from [[1,3-butadiene]]:
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| :CH<sub>2</sub>=CH-CH=CH<sub>2</sub> + 2 HCN → NC(CH<sub>2</sub>)<sub>4</sub>CN
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| ===From organic halides and cyanide salts===
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| Often for more specialty applications, nitriles can be prepared by a wide variety of other methods. For example, [[alkyl halide]]s undergo [[nucleophilic aliphatic substitution]] with alkali metal [[cyanide]]s in the [[Kolbe nitrile synthesis]]. Aryl nitriles are prepared in the [[Rosenmund-von Braun synthesis]].
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| ===Cyanohydrins===
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| The cyanohydrins are a special class of nitriles that result from the addition of 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.
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| ====Dehydration of amides and oximes====
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| Nitriles can be prepared by the [[Dehydration reaction|Dehydration]] of primary [[amide]]s. Many reagents are available, the combination of [[ethyl dichlorophosphate]] and [[DBU (chemistry)|DBU]] just one of them in this conversion of [[benzamide]] to [[benzonitrile]]:<ref>{{cite journal | title = A convenient new procedure for converting primary amides into nitriles | author = Chun-Wei Kuo, Jia-Liang Zhu, Jen-Dar Wu, Cheng-Ming Chu, Ching-Fa Yao and Kak-Shan Shia | journal = [[Chem. Commun.]] | year = 2007 | volume = 2007 | issue = 3 | pmid = 17299646 | pages = 301–303 | doi = 10.1039/b614061k}}</ref>
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| :[[Image:Amidedehydration.png|400px|Amide dehydration]]
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| :Two intermediates in this reaction are amide [[tautomer]] '''A''' and its [[Organophosphate|phosphate]] adduct '''B'''.
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| In a related [[Dehydration reaction|dehydration]], secondary [[amide]]s give nitriles by the [[von Braun amide degradation]]. In this case, one C-N bond is cleaved.
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| The dehydration of [[aldoxime]]s (RCH=NOH) also affords nitriles. Typical reagents for this transformation arewith [[triethylamine]]/[[sulfur dioxide]], [[zeolite]]s, or [[sulfuryl chloride]]. Exploiting this approach is the [[One-pot synthesis]] of nitriles from [[aldehyde]] with [[hydroxylamine]] in the presence of [[sodium sulfate]].<ref>{{cite journal | title = One pot synthesis of nitriles from aldehydes and hydroxylamine hydrochloride using sodium sulfate (anhyd) and sodium bicarbonate in dry media under microwave irradiation | author = Sharwan K, Dewan, Ravinder Singh, and Anil Kumar | journal = [[Arkivoc]] | year = 2006 | pages = (ii) 41–44 | url = http://www.arkat-usa.org/ark/journal/2006/I02_General/1646/05-1646D%20as%20published%20mainmanuscript.pdf | format = [[Open access (publishing)|open access]]}}</ref>
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| :[[Image:Aldehyde to nitril conversion.png|400px|one-pot synthesis from aldehyde]]
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| * from [[aryl]] [[carboxylic acid]]s ([[Letts nitrile synthesis]])
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| ===Sandmeyer reaction===
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| Aromatic nitriles are often prepared in the laboratory form 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>
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| :ArN<sub>2</sub><sup>+</sup> + CuCN → ArCN + N<sub>2</sub> + Cu<sup>+</sup>
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| ===Other methods===
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| *A commercial source for the cyanide group is '''diethylaluminum cyanide''' Et<sub>2</sub>AlCN 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]]
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| * 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 | author = Reynold C. Fuson, Oscar R. Kreimeier, and Gilbert L. Nimmo | journal = [[J. Am. Chem. Soc.]] | year = 1930 | volume = 52 | issue = 10 | pages = 4074–4076 | doi = 10.1021/ja01373a046}}</ref>
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| :[[Image:CyclobutaneByCyanideMediatedDibromideCoupling.png|300px]]
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| : In the so-called '''Franchimont Reaction''' (A. P. N. Franchimont, 1872) an α-bromocarboxylic acid is dimerized after hydrolysis of the cyanogroup and [[decarboxylation]] <ref>[http://www.drugfuture.com/OrganicNameReactions/ONR143.htm Franchimont Reaction<!-- Bot generated title -->]</ref>
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| * Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl<sub>3</sub>)=NH) in the '''Houben-Fischer synthesis''' <ref>''Über eine neue Methode zur Darstellung cyclischer Nitrile durch katalytischen Abbau'' (I. Mitteil.) (p 2464-2472) J. Houben, Walter Fischer '''Berichte der deutschen chemischen Gesellschaft''' (A and B Series)
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| Volume 63, Issue 9 , Pages 2464 - 2472 {{DOI|10.1002/cber.19300630920}}</ref><ref>http://www.drugfuture.com/OrganicNameReactions/ONR197.htm Merck & Co., Inc., Whitehouse Station</ref>
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| == Reactions ==
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| Nitrile groups in organic compounds can undergo various reactions when subject to certain reactants or conditions. A nitrile group can be hydrolyzed, reduced, or ejected from a molecule as a cyanide ion. | |
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| === Hydrolysis ===
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| The [[hydrolysis]] of nitriles RCN proceeds in the distinct steps under acid or base treatment to achieve carboxamides RC(=O)NH<sub>2</sub> and then carboxylic acids RCOOH. The hydrolysis of nitriles is generally considered to be one of the best methods for the preparation of carboxylic acids. However, these base or acid catalyzed reactions have certain limitations and/or disadvantages for preparation of amides. The general restriction is that the final neutralization of either base or acid leads to an extensive salt formation with inconvenient product contamination and pollution effects. Particular limitations are as follows:
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| * '''The base catalyzed reactions'''. The kinetic studies allowed the estimate of relative rates for the hydration at each step of the reaction and, as a typical example, the second-order rate constants for hydroxide-ion catalyzed hydrolysis of [[acetonitrile]] and [[acetamide]] are 1.6×10<sup>−6</sup> and 7.4×10<sup>−5</sup>M<sup>−1</sup>s<sup>−1</sup>, respectively. Comparison of these two values indicates that the second step of the hydrolysis for the base-catalyzed reaction is faster than the first one, and the reaction should proceed to the final hydration product (the carboxylate salt) rather than stopping at the amide stage. This implies that amides prepared in the conventional metal-free base-catalyzed reaction should be contaminated with carboxylic acids and they can be isolated in only moderate yields.
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| * '''The acid catalyzed reactions'''. Application of strong acidic solutions 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>V. Yu. Kukushkin, A. J. L. Pombeiro, Metal-mediated and metal-catalyzed hydrolysis of nitriles (a review), Inorg. Chim. Acta, 358 (2005) 1–21</ref>
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| === Reduction ===
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| In [[organic reduction]] the nitrile is reduced by reacting it with [[hydrogen]] with a [[nickel]] [[catalyst]]; an [[amine]] is formed in this reaction (see [[nitrile reduction]]). Reduction to the amine followed by hydrolysis to the aldehyde takes place in the [[Stephen aldehyde synthesis]]
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| === Alkylation ===
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| Alkyl nitriles are sufficiently acidic to form the carbanion, which alkylate a wide variety of electrophiles. Key to the exceptional nucleophilicity is the small steric demand of the CN unit combined with its inductive stabilization. These features make nitriles ideal for creating new carbon-carbon bonds in sterically demanding environments for use in syntheses of medicinal chemistry. Recent developments have shown that the nature of the metal counter-ion causes different coordination to either the nitrile nitrogen or the adjacent nucleophilic carbon, often with profound differences in reactivity and stereochemistry.<ref>[[Tetrahedron (journal)|Tetrahedron]] Volume 61, Issue 4, 24 January 2005, Pages 747-789 [[Digital object identifier|doi]]:[http://dx.doi.org/10.1016/j.tet.2004.11.012 ''10.1016/j.tet.2004.11.012'']</ref>
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| === Nucleophiles ===
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| A nitrile is an [[electrophile]] at the carbon atom in a [[nucleophilic addition]] reactions:
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| * with an [[organozinc compound]] in the [[Blaise reaction]]
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| * and with [[alcohol]]s in the [[Pinner reaction]].
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| * likewise, the reaction of the [[amine]] [[sarcosine]] with [[cyanamide]] yields [[creatine]] <ref>{{cite journal | author = Smith, Andri L.; Tan, Paula | url = http://jchemed.chem.wisc.edu/Journal/Issues/2006/Nov/abs1654.html | title = Creatine Synthesis: An Undergraduate Organic Chemistry Laboratory Experiment | journal = [[J. Chem. Educ.]] | year = 2006 | volume = 83 | pages = 1654 | doi = 10.1021/ed083p1654}}</ref>
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| * Nitriles react in Friedel-Crafts acylation in the [[Houben-Hoesch reaction]] to ketones
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| === Miscellaneous methods and compounds ===
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| * In '''reductive decyanation''' the nitrile group is replaced by a proton.<ref>''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]</ref> An effective decyanation is by a [[dissolving metal reduction]] with [[HMPA]] and [[potassium]] metal in [[Tert-Butanol|''tert''-butanol]]. α-Amino-nitriles can be decyanated with [[lithium aluminium hydride]].
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| * Nitriles self-react in presence of base in the [[Thorpe reaction]] in a [[nucleophilic addition]]
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| * 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 | author = Yoshiaki Nakao, Akira Yada, Shiro Ebata, and Tamejiro Hiyama | journal = [[J. Am. Chem. Soc.]] | year = 2007 | volume = 129 | issue = 9 | pmid = 17295484 | pages = 2428–2429| format = Communication | doi = 10.1021/ja067364x}}</ref>
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| :[[Image:Carbocyanation.png|400px|Carbocyanation Nakao 2007]]
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| ==Nitrile derivatives==
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| ===Organic cyanamides===
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| '''Cyanamides''' are N-cyano compounds with general structure R<sub>1</sub>R<sub>2</sub>N-CN and related to the inorganic parent [[cyanamide]]. For an example see: [[von Braun reaction]].
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| ===Nitrile oxides===
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| '''Nitrile oxides''' have the general structure R-CNO.
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| :[[File:Nitrile-oxide-2D-B.png|200px|General structure nitrile oxide]]
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| ==Occurrence and applications==
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| 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, brussel sprouts, and cauliflower), which release nitriles being released 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>
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| 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 nitrile group is quite robust and, in most cases, is not readily metabolized but passes through the body unchanged. The types of pharmaceuticals containing nitriles is diverse, from Vildagliptin an antidiabetic drug to Anastrazole 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 |year=2010 |month=November |pmid=20804202 |pmc=2988972 |doi=10.1021/jm100762r |url=}}</ref>The nitrile functional group is found in several drugs.
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| <gallery>
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| File:Periciazine.png|Structure of [[periciazine]], an [[antipsychotic]] studied in the treatment of [[opiate]] dependence.
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| File:Citalopram structure.svg|Structure of [[citalopram]], an [[antidepressant]] drug of the selective [[serotonin reuptake inhibitor]] (SSRI) class.
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| File:Cyamemazine.png|Structure of [[cyamemazine]], an [[antipsychotic]] [[drug]].
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| File:Fadrozole.png|Structure of [[fadrozole]], an [[aromatase inhibitor]] for the treatment of breast cancer.
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| File:Letrozole.svg|Structure of [[letrozole]], an oral non-steroidal [[aromatase inhibitor]] for the treatment of certain [[breast cancer]]s.
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| </gallery>
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| ==See also==
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| * For the [[polymer]] used to make safety gloves, see [[Nitrile rubber]].
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| * Protonated nitriles: [[Nitrilium]]
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| * Deprotonated nitriles: [[Nitrile anion]]
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| * [[Cyanocarbon]]
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| * [[Nitrile ylide]]
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| == References ==
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| {{reflist|colwidth=35em}}
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| :External links:
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| * {{GoldBookRef | file = N04151 | title = nitrile}}
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| * {{GoldBookRef | file = C01486 | title = cyanide}}
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| {{Functional Groups}}
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| [[Category:Nitriles| ]]
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| [[ar:نتريل]]
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| [[be:Нітрылы]]
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| [[ca:Nitril]]
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| [[da:Nitril]]
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| [[de:Nitrile]]
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| [[es:Nitrilo]]
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| [[fa:نیتریل]]
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| [[fr:Nitrile]]
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| [[hr:Nitrili]]
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| [[ja:ニトリル]]
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| [[simple:Nitrile]]
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| [[sv:Nitril]]
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| [[uk:Нітрили]]
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| [[zh-yue:腈]]
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