hydrolisis of nitrile

Hydrolisis of nintrile

The hydrolysis of nitriles RCN proceeds in the distinct steps under acid or base treatment to achieve carboxamides RC(=O)NH ₂ 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 andacetamide are 1.6×10 ⁻⁶ and 7.4×10 ⁻⁵ M ⁻¹ s ⁻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.

Reduction

In organic reduction the nitrile is reduced by reacting it with hydrogen with a nickel catalyst ; an amine is formed in this reaction (seenitrile reduction). Reduction to the amine followed by hydrolysis to the aldehyde takes place in the Stephen aldehyde synthesis

Alkylation

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.

Nucleophiles

A nitrile is an electrophile at the carbon atom in a nucleophilic addition reactions:

·         with an organozinc compound in the Blaise reaction

·         and with alcohols in the Pinner reaction

·         likewise, the reaction of the amine sarcosine with cyanamide yields creatine

·         Nitriles react in Friedel-Crafts acylation in the Houben-Hoesch reaction to ketones

Miscellaneous methods and compounds

§  In reductive decyanation the nitrile group is replaced by a proton. An effective decyanation is by a dissolving metal reductionwith HMPA and potassium metal in tert -butanol . α-Amino-nitriles can be decyanated with lithium aluminium hydride .

§  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

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 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.

 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.