In organic chemistry, a nitrile is any organic compound that has a −C≡N functional group. The name of the compound is composed of a base, which includes the carbon of the −C≡N, suffixed with "nitrile", so for example CH3CH2C≡N is called "propionitrile" (or propanenitrile). [1] 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-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 cyanocarbons.
Inorganic compounds containing the −C≡N group are not called nitriles, but cyanides instead. [2] Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic.
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. [3] Nitriles are polar, as indicated by high dipole moments. As liquids, they have high relative permittivities, often in the 30s.
The first compound of the homolog row of nitriles, the nitrile of formic acid, hydrogen cyanide was first synthesized by C. W. Scheele in 1782. [4] [5] In 1811 J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid. [6] 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. [7] 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. He coined the name "nitrile" for the newfound substance, which became the name for this group of compounds. [8]
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.
In ammoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile: [9]
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 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:
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]
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]
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.
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, [13] 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. [14]
In specialised cases the Van Leusen reaction can be used. Biocatalysts such as aliphatic aldoxime dehydratase are also effective.
Aromatic nitriles are often prepared in the laboratory from the aniline via diazonium compounds. This is the Sandmeyer reaction. It requires transition metal cyanides. [15]
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.
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 RCOOH. 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 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. [26] The classical procedure to convert a nitrile to the corresponding primary amide calls for adding the nitrile to cold concentrated sulfuric acid. [27] 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 metalloenzymes that hydrolyze nitriles to amides.
These enzymes are used commercially to produce acrylamide.
The "anhydrous hydration" of nitriles to amides has been demonstrated using an oxime as water source: [28]
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. [29] 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.
Alkyl nitriles are sufficiently acidic to undergo deprotonation of the C-H bond adjacent to the CN group. [30] [31] 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 CN unit combined with its inductive stabilization. These features make nitriles ideal for creating new carbon-carbon bonds in sterically demanding environments.
The carbon center of a nitrile is electrophilic, hence it is susceptible to nucleophilic addition reactions:
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). [37]
Cyanamides are N-cyano compounds with general structure R1R2N−C≡N and related to the parent cyanamide. [38]
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−). They and are used in 1,3-dipolar cycloadditions. [39] : 1187–1192 They undergo type 1 dyotropic rearrangement to isocyanates. [39] : 1700 Nitrile oxides can be synthesised by dehydrogenation of oximes or by dehydration of nitroalkanes. [40] : 934–936 They can be used to synthesise isoxazoles. [40] : 1201–1202
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. [41]
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. [42] The nitrile functional group is found in several drugs.
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula R−C(=O)−NR′R″, where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a peptide bond when it is part of the main chain of a protein, and an isopeptide bond when it occurs in a side chain, as in asparagine and glutamine. It can be viewed as a derivative of a carboxylic acid with the hydroxyl group replaced by an amine group ; or, equivalently, an acyl (alkanoyl) group joined to an amine group.
Sodium cyanide is a poisonous compound with the formula NaCN. 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 exploits its high reactivity toward metals. It is a moderately strong base.
In chemistry, a hydration reaction is a chemical reaction in which a substance combines with water. In organic chemistry, water is added to an unsaturated substrate, which is usually an alkene or an alkyne. This type of reaction is employed industrially to produce ethanol, isopropanol, and butan-2-ol.
Ethylene oxide is an organic compound with the formula C2H4O. It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly sweet odor. Because it is a strained ring, ethylene oxide easily participates in a number of addition reactions that result in ring-opening. Ethylene oxide is isomeric with acetaldehyde and with vinyl alcohol. Ethylene oxide is industrially produced by oxidation of ethylene in the presence of a silver catalyst.
Hydroxylamine is an inorganic compound with the chemical formula NH2OH. The compound is in a form of a white hygroscopic crystals. Hydroxylamine is almost always provided and used as an aqueous solution. It is consumed almost exclusively to produce Nylon-6. The oxidation of NH3 to hydroxylamine is a step in biological nitrification.
Hydrazones are a class of organic compounds with the structure R1R2C=N−NH2. They are related to ketones and aldehydes by the replacement of the oxygen =O with the =N−NH2 functional group. They are formed usually by the action of hydrazine on ketones or aldehydes.
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 R2C(OH)CN, where R is H, alkyl, or aryl. Cyanohydrins are industrially important precursors to carboxylic acids and some amino acids. Cyanohydrins can be formed by the cyanohydrin reaction, which involves treating a ketone or an aldehyde with hydrogen cyanide (HCN) in the presence of excess amounts of sodium cyanide (NaCN) as a catalyst:
Benzonitrile is the chemical compound with the formula C6H5(CN), abbreviated PhCN. This aromatic organic compound is a colorless liquid with a sweet bitter almond odour. It is mainly used as a precursor to the resin benzoguanamine.
In organic chemistry, hydrocyanation is a process for conversion of alkenes to nitriles. The reaction involves the addition of hydrogen cyanide and requires a catalyst. This conversion is conducted on an industrial scale for the production of precursors to nylon.
Methyl methacrylate (MMA) is an organic compound with the formula CH2=C(CH3)COOCH3. This colorless liquid, the methyl ester of methacrylic acid (MAA), is a monomer produced on a large scale for the production of poly(methyl methacrylate) (PMMA).
The Strecker amino acid synthesis, also known simply as the Strecker synthesis, is a method for the synthesis of amino acids by the reaction of an aldehyde with cyanide in the presence of ammonia. The condensation reaction yields an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino acid. The method is used for the commercial production of racemic methionine from methional.
Trimethylsilyl cyanide is the chemical compound with the formula (CH3)3SiCN. 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 hydrogen cyanide. It is prepared by the reaction of lithium cyanide and trimethylsilyl chloride:
Stephen aldehyde synthesis, a named reaction in chemistry, was invented by Henry Stephen (OBE/MBE). This reaction involves the preparation of aldehydes (R-CHO) from nitriles (R-CN) using tin(II) chloride (SnCl2), hydrochloric acid (HCl) and quenching the resulting iminium salt ([R-CH=NH2]+Cl−) with water (H2O). During the synthesis, ammonium chloride is also produced.
In organic chemistry, a homologation reaction, also known as homologization, is any chemical reaction that converts the reactant into the next member of the homologous series. A homologous series is a group of compounds that differ by a constant unit, generally a methylene group. The reactants undergo a homologation when the number of a repeated structural unit in the molecules is increased. The most common homologation reactions increase the number of methylene units in saturated chain within the molecule. For example, the reaction of aldehydes or ketones with diazomethane or methoxymethylenetriphenylphosphine to give the next homologue in the series.
In organic synthesis, cyanation is the attachment or substitution of a cyanide group on various substrates. Such transformations are high-value because they generate C-C bonds. Furthermore nitriles are versatile functional groups.
In nitrile reduction a nitrile is reduced to either an amine or an aldehyde with a suitable chemical reagent.
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 substrates are alkenes. Several million tons of acrylonitrile are produced in this way annually:
Glycolonitrile, also called hydroxyacetonitrile or formaldehyde cyanohydrin, is the organic compound with the formula HOCH2CN. It is the simplest cyanohydrin and it is derived from formaldehyde. It is a colourless liquid that dissolves in water and ether. Because glycolonitrile decomposes readily into formaldehyde and hydrogen cyanide, it is listed as an extremely hazardous substance. In January 2019, astronomers reported the detection of glycolonitrile, another possible building block of life among other such molecules, in outer space.
In chemistry, a fatty amine is loosely defined as any amine possessing a mostly linear hydrocarbon chain of eight or more carbon atoms. They are typically prepared from the more abundant fatty acids, with vegetable or seed-oils being the ultimate starting material. As such they are often mixtures of chain lengths, ranging up to about C22. They can be classified as oleochemicals. Commercially important members include coco amine, oleylamine, tallow amine, and soya amine. These compounds and their derivatives are used as fabric softeners, froth flotation agents, corrosion inhibitors, lubricants and friction modifiers. They are also the basis for a variety of cosmetic formulations.
Transition metal nitrile complexes are coordination compounds containing nitrile ligands. Because nitriles are weakly basic, the nitrile ligands in these complexes are often labile.
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