Pyrrolidine

Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most organic solvents. It has a characteristic odor that has been described as "ammoniacal, fishy, shellfish-like".[4] In addition to pyrrolidine itself, many substituted pyrrolidines are known.

Pyrrolidine
Names
Preferred IUPAC name
Pyrrolidine[1]
Other names
Azolidine
Azacyclopentane
Tetrahydropyrrole
Prolamine
Azolane
Identifiers
3D model (JSmol)
102395
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.004.227
EC Number
  • 204-648-7
1704
RTECS number
  • UX9650000
UNII
UN number 1922
  • InChI=1S/C4H9N/c1-2-4-5-3-1/h5H,1-4H2 checkY
    Key: RWRDLPDLKQPQOW-UHFFFAOYSA-N checkY
  • InChI=1/C4H9N/c1-2-4-5-3-1/h5H,1-4H2
    Key: RWRDLPDLKQPQOW-UHFFFAOYAX
  • C1CCNC1
Properties
C4H9N
Molar mass 71.123 g·mol−1
Appearance Clear colorless liquid
Density 0.866 g/cm3
Melting point −63 °C (−81 °F; 210 K)
Boiling point 87 °C (189 °F; 360 K)
Miscible
Acidity (pKa) 11.27 (pKa of conjugate acid in water),[2]

19.56 (pKa of conjugate acid in acetonitrile)[3]

-54.8·10−6 cm3/mol
1.4402 at 28°C
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 highly flammable, harmful, corrosive, possible mutagen
GHS labelling:
GHS02: FlammableGHS05: CorrosiveGHS07: Exclamation mark
Danger
H225, H302, H314, H332
P210, P233, P240, P241, P242, P243, P260, P261, P264, P270, P271, P280, P301+P312, P301+P330+P331, P303+P361+P353, P304+P312, P304+P340, P305+P351+P338, P310, P312, P321, P330, P363, P370+P378, P403+P235, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamond
3
3
1
Flash point 3 °C (37 °F; 276 K)
345 °C (653 °F; 618 K)
Safety data sheet (SDS) MSDS
Related compounds
Related nitrogen heterocyclic compounds
 Pyrrole (aromatic with two double bonds)
Pyrroline (one double bond)
Pyrrolizidine (two pentagonal rings)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references

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.[5]

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.[5]

Laboratory synthesis

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

Synthesis of pyrrolidine

Furthermore, 5-membered N-heterocyclic ring of the pyrrolidine derivatives can be synthesized via cascade reactions.[6]

Occurrence

Many modifications of pyrrolidine are found in natural and synthetic drugs and drug candidates.[6] 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.

Nicotine contains an N-methylpyrrolidine ring linked to a pyridine ring.

Reactions

Pyrrolidine is a base. Its basicity is typical of other dialkyl amines.[7] 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):[8]

References
  1. International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 142. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4.
  2. Hall, H. K. (1957). "Correlation of the Base Strengths of Amines". Journal of the American Chemical Society. 79 (20): 5441–5444. doi:10.1021/ja01577a030.
  3. Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. (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. 70 (3): 1019–1028. doi:10.1021/jo048252w. PMID 15675863.
  4. Pyrrolidine Archived 2017-11-21 at the Wayback Machine, The Good Scents Company
  5. Bou Chedid, Roland; Melder, Johann-Peter; Dostalek, Roman; Pastre, Jörg; Tan, Aik Meam. "Process for the preparation of pyrrolidine". Google Patents. BASF SE. Archived from the original on 5 July 2019. Retrieved 5 July 2019.
  6. Łowicki, Daniel; Przybylski, Piotr (2022). "Tandem construction of biological relevant aliphatic 5-membered N-heterocycles". European Journal of Medicinal Chemistry. 235: 114303. doi:10.1016/j.ejmech.2022.114303. PMID 35344904. S2CID 247580048.
  7. H. K. Hall Jr. (1957). "Correlation of the Base Strengths of Amines". J. Am. Chem. Soc. 79 (20): 5441. doi:10.1021/ja01577a030.
  8. R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum (1974). "2,2-(Trimethylenedithio)cyclohexanone". Organic Syntheses. 54: 39.{{cite journal}}: CS1 maint: multiple names: authors list (link); Collective Volume, vol. 6, p. 1014
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