Pyrrolidine
{{chembox
| Watchedfields = changed
| verifiedrevid = 464377817
| ImageFileL1=Pyrrolidine_svg.svg
| ImageSizeL1=80px
| ImageFileR1=Pyrrolidine3d.png
| PIN = Pyrrolidine{{cite book |author=International Union of Pure and Applied Chemistry |date=2014 |title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 |publisher=The Royal Society of Chemistry |pages=142 |doi=10.1039/9781849733069 |isbn=978-0-85404-182-4}}
| OtherNames=Azolidine
Azacyclopentane
Tetrahydropyrrole
Prolamine
Azolane
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 29008
| InChI = 1/C4H9N/c1-2-4-5-3-1/h5H,1-4H2
| InChIKey = RWRDLPDLKQPQOW-UHFFFAOYAX
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 22830
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H9N/c1-2-4-5-3-1/h5H,1-4H2
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RWRDLPDLKQPQOW-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 123-75-1
| PubChem = 31268
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = LJU5627FYV
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 33135
| SMILES = C1CCNC1
| RTECS = UX9650000
| Beilstein = 102395
| Gmelin = 1704
| UNNumber = 1922
| EC_number = 204-648-7
}}
|Section2={{Chembox Properties
| C=4 | H=9 | N=1
| Appearance=Clear colorless liquid
| Density=0.866 g/cm3
| MeltingPtC=-63
| BoilingPtC=87
| Solubility=Miscible
| RefractIndex = 1.4402 at 28°C
| MagSus = −54.8·10−6 cm3/mol
| pKa = 11.27 (pKa of conjugate acid in water),{{Cite journal | last1 = Hall | first1 = H. K. | title = Correlation of the Base Strengths of Amines | doi = 10.1021/ja01577a030 | journal = Journal of the American Chemical Society | volume = 79 | issue = 20 | pages = 5441–5444 | year = 1957 }}
}}
|Section3={{Chembox Hazards
| ExternalSDS = [https://fscimage.fishersci.com/msds/96268.htm MSDS]
| MainHazards=highly flammable, harmful, corrosive, possible mutagen
| FlashPtC = 3
| AutoignitionPtC = 345
| NFPA-H = 3
| NFPA-F = 3
| NFPA-R = 1
| GHSPictograms = {{GHS02}}{{GHS05}}{{GHS07}}
| GHSSignalWord = Danger
| HPhrases = {{H-phrases|225|302|314|332}}
| PPhrases = {{P-phrases|210|233|240|241|242|243|260|261|264|270|271|280|301+312|301+330+331|303+361+353|304+312|304+340|305+351+338|310|312|321|330|363|370+378|403+235|405|501}}
}}
|Section8={{Chembox Related
| OtherFunction_label = nitrogen heterocyclic compounds
| OtherFunction = Pyrrole (aromatic with two double bonds)
Pyrroline (one double bond)
Pyrrolizidine (two pentagonal rings)
}}
}}
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".[http://www.thegoodscentscompany.com/data/rw1009391.html Pyrrolidine] {{Webarchive|url=https://web.archive.org/web/20171121194519/http://www.thegoodscentscompany.com/data/rw1009391.html |date=2017-11-21 }}, The Good Scents Company In addition to pyrrolidine itself, many substituted pyrrolidines are known.
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.{{cite web |last1=Bou Chedid |first1=Roland |last2=Melder |first2=Johann-Peter |last3=Dostalek |first3=Roman |last4=Pastre |first4=Jörg |last5=Tan |first5=Aik Meam |title=Process for the preparation of pyrrolidine |url=https://patents.google.com/patent/EP2872494B1/en |website=Google Patents |publisher=BASF SE |access-date=5 July 2019 |archive-date=5 July 2019 |archive-url=https://web.archive.org/web/20190705134726/https://patents.google.com/patent/EP2872494B1/en |url-status=live }}
:File:Industrial synthesis of pyrrolidine.svg
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
Furthermore, 5-membered N-heterocyclic ring of the pyrrolidine derivatives can be synthesized via cascade reactions.{{cite journal |last1=Łowicki |first1=Daniel |last2=Przybylski |first2=Piotr |title=Tandem construction of biological relevant aliphatic 5-membered N-heterocycles |journal=European Journal of Medicinal Chemistry |date=2022 |volume=235 |pages=114303 |doi=10.1016/j.ejmech.2022.114303|pmid=35344904|s2cid=247580048 }}
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.
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Reactions
Pyrrolidine is a base. Its basicity is typical of other dialkyl amines.{{cite journal|title=Correlation of the Base Strengths of Amines|author=H. K. Hall Jr. |journal=J. Am. Chem. Soc.|year=1957|volume=79|issue=20|page=5441|doi=10.1021/ja01577a030}} 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):{{OrgSynth|author=R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum |year=1974|title=2,2-(Trimethylenedithio)cyclohexanone |volume=54| pages=39|collvol=6|collvolpages=1014|prep=CV6P1014}}
