Nitrile

Ammoxidation

In ammoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile:^[9]

${\displaystyle {\ce {CH3CH=CH2 + 3/2 O2 + NH3 -> N#CCH=CH2 + 3 H2O}}}$ N#CCH=CH2 + 3 H2O}}}">

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 oxides 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, a precursor to nylon-6,6 from 1,3-butadiene:

CH₂=CH−CH=CH₂ + 2 HC≡N → NC(CH₂)₄C≡N

From organic halides and cyanide salts

Two salt metathesis reactions are popular for laboratory scale reactions. In the Kolbe nitrile synthesis, alkyl halides undergo nucleophilic aliphatic substitution with alkali metal cyanides. 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).^[5]

Cyanohydrins

The cyanohydrins 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.^[10]

Dehydration of amides

Nitriles can be prepared by the dehydration of primary amides. Common reagents for this include phosphorus pentoxide (P₂O₅)^[11] and thionyl chloride (SOCl₂).^[12] In a related dehydration, secondary amides give nitriles by the von Braun amide degradation. In this case, one C-N bond is cleaved.

Oxidation of amines

Numerous traditional methods exist for nitrile preparation by amine oxidation. ^[13] In addition, several selective methods have been developed in the last decades for electrochemical processes. ^[14]

From aldehydes and oximes

The conversion of aldehydes to nitriles via aldoximes 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,^[15] although a wide range of reagents may assist with this, including triethylamine/sulfur dioxide, zeolites, or sulfuryl chloride. The related hydroxylamine-O-sulfonic acid reacts similarly.^[16]

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.^[17]

ArN+2 + CuC≡N → ArC≡N + N₂ + Cu⁺

Other methods

• A commercial source for the cyanide group is diethylaluminum cyanide Et₂AlCN which can be prepared from triethylaluminium and HCN.^[18] It has been used in nucleophilic addition to ketones.^[19] For an example of its use see: Kuwajima Taxol total synthesis
• Cyanide ions facilitate the coupling of dibromides. Reaction of α,α′-dibromoadipic acid with sodium cyanide in ethanol yields the cyano cyclobutane:^[20]

  

• Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl₃)=NH) in the Houben-Fischer synthesis^[21]
• Nitriles can be obtained from primary amines via oxidation. Common methods include the use of potassium persulfate,^[22] Trichloroisocyanuric acid,^[23] or anodic electrosynthesis.^[24]
• α-Amino acids form nitriles and carbon dioxide via various means of oxidative decarboxylation.^[25][26] Henry Drysdale Dakin discovered this oxidation in 1916.^[27]
• From aryl carboxylic acids (Letts nitrile synthesis)

Hydrolysis

The hydrolysis of nitriles RCN proceeds in the distinct steps under acid or base treatment to first give carboxamides RC(O)NH₂ and then carboxylic acids RC(O)OH. The hydrolysis of nitriles to carboxylic acids is efficient. In acid or base, the balanced equations are as follows:

RC≡N + 2 H₂O + HCl → RC(O)OH + NH₄Cl

RC≡N + 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 1.6×10⁻⁶ M⁻¹ s⁻¹, which is slower than the hydrolysis of the amide to the carboxylate (7.4×10⁻⁵ 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.^[28] The classical procedure to convert a nitrile to the corresponding primary amide calls for adding the nitrile to cold concentrated sulfuric acid.^[29] The further conversion to the carboxylic acid is disfavored by the low temperature and low concentration of water.

RC≡N + H₂O → RC(O)NH₂

Two families of enzymes catalyze the hydrolysis of nitriles. Nitrilases hydrolyze nitriles to carboxylic acids:

RC≡N + 2 H₂O → RC(O)OH + NH₃

Nitrile hydratases are metalloenzymes that hydrolyze nitriles to amides.

RC≡N + 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:^[30]

RC≡N + R'C(H)=NOH → RC(O)NH₂ + R'C≡N

Reduction

Nitriles are susceptible to hydrogenation over diverse metal catalysts. The reaction can afford either the primary amine (RCH₂NH₂) or the tertiary amine ((RCH₂)₃N), depending on conditions.^[31] In conventional organic reductions, 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 C≡N group.^[32][33] 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 C≡N 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^[34]
• with arenes to form ketones in the Houben–Hoesch reaction via an imine intermediate.
• with Grignard reagents to form primary ketimines in the Moureau-Mignonac ketimine synthesis.^[35] 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.^[36] Decyanations can be accomplished by dissolving metal reduction (e.g. HMPA and potassium metal in tert-butanol) or by fusion of a nitrile in KOH.^[37] Similarly, α-aminonitriles can be decyanated with other reducing agents such as lithium aluminium hydride.^[36]
• 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.^[38]
• Nitriles self-react in presence of base in the Thorpe reaction in a nucleophilic addition
• In organometallic chemistry nitriles are known to add to alkynes in carbocyanation:^[39]

Complexation

Nitriles are precursors to transition metal nitrile complexes, which are reagents and catalysts. Examples include tetrakis(acetonitrile)copper(I) hexafluorophosphate ([Cu(MeCN)₄]⁺) and bis(benzonitrile)palladium dichloride (PdCl₂(PhCN)₂).^[40]

Organic cyanamides

Cyanamides are N-cyano compounds with general structure R¹R²N−C≡N and related to the parent cyanamide.^[41]

Nitrile oxides

Nitrile oxides have the chemical formula RCNO. Their general structure is R−C≡N⁺−O⁻. The R stands for any group (typically organyl, e.g., acetonitrile oxide CH₃−C≡N⁺−O⁻, hydrogen in the case of fulminic acid H−C≡N⁺−O⁻, or halogen (e.g., chlorine fulminate Cl−C≡N⁺−O⁻).^{[42]: 1187–1192}

Nitrile oxides are quite different from nitriles: they are highly reactive 1,3-dipoles, and cannot be synthesized from the direct oxidation of nitriles.^[43] Instead, they can be synthesised by nitroalkane dehydration, oxime dehydrogenation,^{[44]: 934–936} or halooxime elimination in base.^[45] They are used in 1,3-dipolar cycloadditions,^{[42]: 1187–1192} such as to isoxazoles.^{[44]: 1201–1202} They undergo type 1 dyotropic rearrangement to isocyanates.^[42]: 1700

The heavier nitrile sulfides are extremely reactive and rare, but temporarily form during the thermolysis of oxathiazolones. They react similarly to nitrile oxides.^[46]