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
·
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.
