Inorganic compounds containing the −C≡N group are not called nitriles, but cyanides instead. Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic.
The N-C-C skeleton 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. Nitriles are polar, as indicated by high dipole moments. As liquids, they have high dielectric constants, 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. In 1811 J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid. 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. 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. 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 this group of compounds.
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 the production of acrylonitrile, a side product is acetonitrile. Most 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 aldehyde.
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.
In the so-called Franchimont Reaction (A. P. N. Franchimont, 1872) an α-bromocarboxylic acid is dimerized after hydrolysis of the cyanogroup and decarboxylation
Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl3)=NH) in the Houben-Fischer synthesis
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.
The hydrolysis of nitriles RCN proceeds in the distinct steps under acid or base treatment to achieve carboxamides RC(=O)NH2 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:
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 1.6×10−6 and 7.4×10−5M−1s−1, 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.
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.
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.
Cyanamides are N-cyano compounds with general structure R1R2N-CN and related to the inorganic parent cyanamide. For an example see: von Braun reaction.
Nitrile oxides have the general structure R-CNO.
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, brussel 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.
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.The nitrile functional group is found in several drugs.
^Karakida, Ken-ichi, Tsutomu Fukuyama, and Kozo Kuchitsu. "Molecular Structures of Hydrogen Cyanide and Acetonitrile as Studied by Gas Electron Diffraction" Bulletin of the Chemical Society of Japan 1974, vol. 47, pp. 299-304.
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^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