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Piperidine

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Piperidine[1]
Names
IUPAC name
Piperidine
Other names
Hexahydropyridine
Azacyclohexane
Pentamethyleneamine
Azinane
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.003.467 Edit this at Wikidata
RTECS number
  • TM3500000
UNII
  • InChI=1S/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2 checkY
    Key: NQRYJNQNLNOLGT-UHFFFAOYSA-N checkY
  • InChI=1/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2
  • InChI=1/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2
    Key: NQRYJNQNLNOLGT-UHFFFAOYAY
  • C1CCNCC1
Properties
C5H11N
Molar mass 85.150 g·mol−1
Appearance colourless liquid
Density 0.862 g/mL, liquid
Melting point −7 °C (19 °F; 266 K)
Boiling point 106 °C (223 °F; 379 K)
miscible
Acidity (pKa) 11.22[2]
Viscosity 1.573 cP at 25 °C
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g. gasolineInstability 3: Capable of detonation or explosive decomposition but requires a strong initiating source, must be heated under confinement before initiation, reacts explosively with water, or will detonate if severely shocked. E.g. hydrogen peroxideSpecial hazards (white): no code
3
3
3
Safety data sheet (SDS) MSDS1,MSDS2
Related compounds
Related compounds
 pyridine
pyrrolidine
piperazine
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 ?)

Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (-CH
2-) and one amine bridge (-NH-). It is a colorless fuming liquid with an odor described as ammoniacal or pepper-like;[3] the name comes from the genus name Piper, which is the Latin word for pepper.[4] Piperidine is a widely used building block and chemical reagent in the synthesis of organic compounds, including pharmaceuticals.

Production

Piperidine was first reported in 1850 by the Scottish chemist Thomas Anderson (1819-1874) and again, independently, in 1852 by the French chemist Auguste Cahours (1813-1891), who named it.[5] Both men obtained piperidine by reacting piperine with nitric acid.

Industrially, piperidine is produced by the hydrogenation of pyridine, usually over a molybdenum disulfide catalyst:[6]

C5H5N + 3 H2 → C5H10NH

Pyridine can also be reduced to piperidine via a modified Birch reduction using sodium in ethanol.[7]

Natural occurrence of piperidine and derivatives

Piperidine itself has been obtained from black pepper,[8] from Psilocaulon absimile N.E.Br (Aizoaceae),[9] and in Petrosimonia monandra.[10]

The piperidine structural motif is present in numerous natural alkaloids. These include piperine, which gives black pepper its spicy taste. This gave the compound its name. Other examples are the fire ant toxin solenopsin,[11] the nicotine analog anabasine of the Tree Tobacco (Nicotiana glauca), lobeline of the Indian tobacco, and the toxic alkaloid coniine from poison hemlock, which was used to put Socrates to death.[12]

Conformation

Piperidine prefers a chair conformation, similar to cyclohexane. Unlike cyclohexane, piperidine has two distinguishable chair conformations: one with the N–H bond in an axial position, and the other in an equatorial position. After much controversy during the 1950s–1970s, the equatorial conformation was found to be more stable by 0.72 kcal/mol in the gas phase.[13] In nonpolar solvents, a range between 0.2 and 0.6 kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable.[14] The two conformers interconvert rapidly through nitrogen inversion; the free energy activation barrier for this process, estimated at 6.1 kcal/mol, is substantially lower than the 10.4 kcal/mol for ring inversion.[15] In the case of N-methylpiperidine, the equatorial conformation is preferred by 3.16 kcal/mol,[13] which is much larger than the preference in methylcyclohexane, 1.74 kcal/mol.

axial conformation
equatorial conformation

Reactions

Piperidine is a widely used secondary amine. It is widely used to convert ketones to enamines.[16] Enamines derived from piperidine can be used in the Stork enamine alkylation reaction.[17]

Piperidine can be converted to the chloramine C5H10NCl with calcium hypochlorite. The resulting chloramine undergoes dehydrohalogenation to afford the cyclic imine.[18]

NMR chemical shifts

13C NMR = (CDCl3, ppm) 47.27.2, 25.2
1H NMR = (CDCl3, ppm) 2.79, 2.19, 1.51

Uses

Piperidine is used as a solvent and as a base. The same is true for certain derivatives: N-formylpiperidine is a polar aprotic solvent with better hydrocarbon solubility than other amide solvents, and 2,2,6,6-tetramethylpiperidine is a highly sterically hindered base, useful because of its low nucleophilicity and high solubility in organic solvents.

A significant industrial application of piperidine is for the production of dipiperidinyl dithiuram tetrasulfide, which is used as a rubber vulcanization accelerator.[6]

List of piperidine medications

Piperidine and its derivatives are ubiquitous building blocks in the synthesis of pharmaceuticals and fine chemicals. The piperidine structure is e.g. found in the pharmaceuticals:

Piperidine is also commonly used in chemical degradation reactions, such as the sequencing of DNA in the cleavage of particular modified nucleotides. Piperidine is also commonly used as a base for the deprotection of Fmoc-amino acids used in solid-phase peptide synthesis.

Piperidine is listed as a Table II precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances due to its use (peaking in the 1970s) in the clandestine manufacture of PCP (1-(1-phenylcyclohexyl)piperidine, also known as angel dust, sherms, wet, etc.).[19]

References

  1. ^ International Chemical Safety Card 0317
  2. ^ Hall, H.K. (1957). "Correlation of the Base Strengths of Amines". J. Am. Chem. Soc. 79: 5441. doi:10.1021/ja01577a030.
  3. ^ Frank Johnson Welcher (1947). Organic Analytical Reagents. D. Van Nostrand. p. 149.
  4. ^ Alexander Senning (2006). Elsevier's Dictionary of Chemoetymology. Amsterdam: Elsevier. ISBN 0-444-52239-5.
  5. ^ See:
    • Edgar W. Warnhoff (1998) "When piperidine was a structural problem," Bulletin of the History of Chemistry, 22 : 29-34. Available on-line at: University of Illinois
    • Thomas Anderson (1850) "Vorläufiger Bericht über die Wirkung der Salpetersäure auf organische Alkalien" (Preliminary report on the effect of nitric acid on organic alkalies), Annalen der Chemie und Pharmacie, 75 : 80-83 ; see p. 82.
    • Auguste Cahours (1852) "Recherches sur un nouvel alcali dérivé de la pipérine" (Investigations of a new alkali derived from piperine), Comptes rendus, 34 : 481-484. Cahours named piperidine on p. 483: "L'alcali nouveau dérivé de la piperine, que je désignerai sous le nom de piperidine, … " (The new alkali derived from piperine, which I will designate by the name of piperidine, … ") (Note: Cahours' empirical formula for piperidine, C10H11N, is wrong because, like many chemists at that time, he used the wrong atomic mass for carbon, 6 instead of 12.)
  6. ^ a b Karsten Eller, Erhard Henkes, Roland Rossbacher, Hartmut Höke "Amines, Aliphatic" Ullmann's Encyclopedia of Industrial Chemistry 2002 Wiley-VCH. doi:10.1002/14356007.a02_001
  7. ^ C. S. Marvel and W. A. Lazier (1941). "Benzoyl Piperidine". Organic Syntheses; Collected Volumes, vol. 1, p. 99.
  8. ^ Spaeth and Englaender, Ber.1935,68, 2218; cf. Pictet; Pictet (1927). Helv. Chim. Acta. 10: 593. {{cite journal}}: Missing or empty |title= (help)
  9. ^ Rimington (1934). S. Afr. J. Sci. 31: 184. {{cite journal}}: Missing or empty |title= (help)
  10. ^ Juraschewski; Stepanov (1939). J. Gen. Chem., U.R.S.S. 9: 1687. {{cite journal}}: Missing or empty |title= (help)
  11. ^ Arbiser JL, Kau T, Konar M, et al. (2007). "Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis". Blood. 109 (2): 560–5. doi:10.1182/blood-2006-06-029934. PMC 1785094. PMID 16990598.
  12. ^ Thomas Anderson Henry (1949). The Plant Alkaloids (4th ed.). The Blakiston Company.
  13. ^ a b Luis Carballeira, Ignacio Pérez-Juste (1998). "Influence of calculation level and effect of methylation on axial/equatorial equilibria in piperidines". Journal of Computational Chemistry. 19 (8): 961–976. doi:10.1002/(SICI)1096-987X(199806)19:8<961::AID-JCC14>3.0.CO;2-A.
  14. ^ Ian D. Blackburne, Alan R. Katritzky, Yoshito Takeuchi (1975). "Conformation of piperidine and of derivatives with additional ring hetero atoms". Acc. Chem. Res. 8 (9): 300–306. doi:10.1021/ar50093a003.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ F.A.L. Anet, Issa Yavari (1977). "Nitrogen inversion in piperidine". J. Am. Chem. Soc. 99 (8): 2794–2796. doi:10.1021/ja00450a064.
  16. ^ Vinayak V. Kane and Maitland Jones Jr (1990). "Spiro[5.7]trideca-1,4-dien-3-one". Organic Syntheses; Collected Volumes, vol. 7, p. 473.
  17. ^ Michael B. Smith, Jerry March (2001). March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (5th ed.). Wiley-Interscience. ISBN 0-471-58589-0.
  18. ^ George P. Claxton, Lloyd Allen, and J. Martin Grisar (1988). "2,3,4,5-Tetrahydropyridine trimer". Organic Syntheses{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 6, p. 968.
  19. ^ List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control, International Narcotics Control Board (link is dead)
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