The Ritter reaction (sometimes called the Ritter amidation) is a chemical reaction that transforms a nitrile into an N-alkyl amide using various electrophilic alkylating reagents. The original reaction formed the alkylation using an alkene in the presence of a strong acid.
Mechanism and scope
The Ritter reaction proceeds by the electrophilic addition of either a
carbenium ion or covalent species
to the
nitrile. The resulting
nitrilium ion is
hydrolysis to the desired amide.
Primary,
secondary,
tertiary,
and benzylic
alcohols,
as well as
tert-butyl acetate,
also successfully react with nitriles in the presence of strong acids to form amides via the Ritter reaction. A wide range of nitriles can be used. In particular,
cyanide can be used to prepare formamides, which are useful precursors to
, or may also be hydrolysed to give
.
Applications
A large scale application of the Ritter reaction is in the synthesis of
tert-octylamine, by way of the intermediate formamide. This process was originally described by Ritter in 1948,
and an estimated 10,000 tons/y (year: 2000) of this and related lipophilic amines are prepared in this way.
[ Otherwise, the Ritter reaction is most useful in the formation of amines and amides of pharmaceutical interest. Real world applications include Merck's industrial-scale synthesis of anti-HIV drug Crixivan (indinavir);][Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry; Oxford Press: New York, 2001.] the production of the falcipain-2 inhibitor PK-11195; the synthesis of the alkaloid aristotelone;[Kurti, L.; Czako, B. (2005). Strategic Applications of Named in Organic Synthesis. Burlington, MA Elsevier Academic Press.] and synthesis of Amantadine, an antiviral and antiparkinsonian drug.[Vardanyan, R.; Hruby, V.J. Synthesis of Essential Drugs, 1st Ed. Amsterdam: Elsevier, 2006; pp. 137] Other applications of the Ritter reaction include synthesis of dopamine receptor ligands[Fujisawa and Deguchi, Chemical Abstracts, 52, 11965 (1958)]
The Ritter reaction is inferior to most amination methods because it cogenerates substantial amounts of salts. Illustrative is the conversion of isobutylene to tert-butylamine using HCN and sulfuric acid followed by base neutralization. The weight of the salt byproduct is greater than the weight of the amine.
In the laboratory, the Ritter reaction suffers from the necessity of an extremely strong acid catalyst. Other methods have been proposed in order to promote carbocation formation, including photocatalytic electron transfer
History
The reaction is named after John J. Ritter, who supervised the Ph.D. thesis work of P. Paul Minieri.
