Pyrrolidine

Production and synthesis

Industrial production

Pyrrolidine is prepared industrially by the reaction of 1,4-butanediol and ammonia at a temperature of 165–200 °C and a pressure of 17–21 MPa in the presence of a cobalt- and nickel oxide catalyst, which is supported on alumina.

:[[File:Industrial synthesis of pyrrolidine.svg|600px|upright=2.5|frameless|Reaction of 1,4-butanediol with ammonia to form pyrrolidine and water in the presence of a nickel oxide catalyst supported on alumina]]

The reaction is carried out in the liquid phase in a continuous tube- or tube bundle reactor, which is operated in the cycle gas method. The catalyst is arranged as a fixed-bed and the conversion is carried out in the downflow mode. The product is obtained after multistage purification and separation by extractive and azeotropic distillation.

Laboratory synthesis

In the laboratory, pyrrolidine was usually synthesised by treating 4-chlorobutan-1-amine with a strong base:

:[[File:Pyrrolidine synthesis.jpg|350px|upright=2.5|frameless|Synthesis of pyrrolidine]] Furthermore, 5-membered N-heterocyclic ring of the pyrrolidine derivatives can be synthesized via cascade reactions.

Occurrence

Many modifications of pyrrolidine are found in natural and synthetic drugs and drug candidates. The pyrrolidine ring structure is present in numerous natural alkaloids i.a. nicotine and hygrine. It is found in many drugs such as procyclidine and bepridil. It also forms the basis for the racetam compounds (e.g. piracetam, aniracetam). The amino acids proline and hydroxyproline are, in a structural sense, derivatives of pyrrolidine. :[[File:Nicotine.svg|thumb|120 px|left|Nicotine contains an N-methylpyrrolidine ring linked to a pyridine ring.]]

Reactions

Pyrrolidine is a base. Its basicity is typical of other dialkyl amines. Relative to many secondary amines, pyrrolidine is distinctive because of its compactness, a consequence of its cyclic structure.

Pyrrolidine is used as a building block in the synthesis of more complex organic compounds. It is used to activate ketones and aldehydes toward nucleophilic addition by formation of enamines (e.g. used in the Stork enamine alkylation): :[[File:Enamine.png|320px]]

References

References

1. [[International Union of Pure and Applied Chemistry]]. (2014). "Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013". [[Royal Society of Chemistry.
2. (1957). "Correlation of the Base Strengths of Amines". Journal of the American Chemical Society.
3. (2005). "Extension of the Self-Consistent Spectrophotometric Basicity Scale in Acetonitrile to a Full Span of 28 pKa Units: Unification of Different Basicity Scales". The Journal of Organic Chemistry.
4. [http://www.thegoodscentscompany.com/data/rw1009391.html Pyrrolidine] {{Webarchive. link. (2017-11-21 , The Good Scents Company)
5. "Process for the preparation of pyrrolidine". BASF SE.
6. (2022). "Tandem construction of biological relevant aliphatic 5-membered N-heterocycles". [[European Journal of Medicinal Chemistry]].
7. H. K. Hall Jr.. (1957). "Correlation of the Base Strengths of Amines". J. Am. Chem. Soc..
8. [[R. B. Woodward]], I. J. Pachter, and M. L. Scheinbaum. (1974). "2,2-(Trimethylenedithio)cyclohexanone".