Piperidine

Piperidine is an organic compound with

the molecular formula (CH2)5NH. This
heterocyclic amine consists of a six-
membered ring containing five methylene
bridges (–CH2–) and one amine bridge (–
NH–). It is a colorless liquid with an odor
described as objectionable, and typical of
amines.[5] The name comes from the
genus name Piper, which is the Latin word
for pepper.[6] Although piperidine is a
common organic compound, it is best
known as a representative structure
element within many pharmaceuticals and
alkaloids.
 Piperidine
[1]

Names

Preferred IUPAC name

Piperidine[2]
Other names
Hexahydropyridine
Azacyclohexane
Pentamethyleneamine
Azinane

Identifiers
CAS Number 110 89 4
CAS Number 110-89-4  

3D model (JSmol) Interactive image

ChEBI CHEBI:18049  

ChEMBL ChEMBL15487  

ChemSpider 7791  

ECHA InfoCard 100.003.467

IUPHAR/BPS 5477
PubChem CID 8082

RTECS number TM3500000

UNII 67I85E138Y  

InChI
InChI=1S/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2 
Key: NQRYJNQNLNOLGT-UHFFFAOYSA-N 

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

SMILES
C1CCNCC1

Properties
Chemical formula 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)

Solubility in water miscible

Acidity (pKa) 11.22[3][4]

Magnetic susceptibility -64.2·10−6 cm3/mol
(χ)
Viscosity 1.573 cP at 25 °C

Hazards

Safety data sheet MSDS1 ,MSDS2

EU classification (DSD) Flammable (F)
(outdated)
Toxic (T)

R-phrases (outdated) R11, R23/24, R34

 p ( ) , ,

3
NFPA 704 3 0

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).

 verify (what is   ?)

Infobox references

Production
Piperidine was first reported in 1850 by the
Scottish chemist Thomas Anderson and
again, independently, in 1852 by the
French chemist Auguste Cahours, who
named it.[7][8][9] 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:[10]

C5H5N + 3 H2 →C H5 10NH

Pyridine can also be reduced to piperidine

via a modified Birch reduction using
sodium in ethanol.[11]

Natural occurrence of
piperidine and derivatives
Piperidine itself has been obtained from
black pepper,[12][13] from Psilocaulon
absimile (Aizoaceae),[14] and in
Petrosimonia monandra.[15]

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,[16] the nicotine analog
anabasine of tree tobacco (Nicotiana
glauca), lobeline of Indian tobacco, and the
toxic alkaloid coniine from poison
hemlock, which was used to put Socrates
to death.[17]

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.[18] 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.[19]
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.[20] In the case of N-
methylpiperidine, the equatorial
conformation is preferred by
3.16 kcal/mol,[18] 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.[21] Enamines derived from
piperidine can be used in the Stork
enamine alkylation reaction.[22]

Piperidine can be converted to the

chloramine C5H10NCl with calcium
hypochlorite. The resulting chloramine
undergoes dehydrohalogenation to afford
the cyclic imine.[23]

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 an accelerator of the sulfur
vulcanization of rubber.[10]

List of piperidine
medications

Minoxidil is a piperidine derivative widely used to

 pp y
prevent hair loss.

Piperidine and its derivatives are

ubiquitous building blocks in
pharmaceuticals[24] and fine chemicals.
The piperidine structure is found in, for
example:

Icaridin (Insect repellent)

SSRIs (selective serotonin reuptake
inhibitors)
stimulants and nootropics:
Methylphenidate
Ethylphenidate
Pipradrol
 Desoxypipradrol
SERM (selective estrogen receptor
modulators)
Raloxifene
Vasodilators
Minoxidil
Antipsychotic medications:
Droperidol
Haloperidol
Melperone
Mesoridazine
Risperidone
Thioridazine
Opioids:
 Dipipanone
Fentanyl and analogs
Loperamide
Pethidine (meperidine)
Prodine
anticholinergic chemical weapons
Ditran
N-Methyl-3-piperidyl benzilate (JB-
336, BZ)

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.).[25]

References
1. International Chemical Safety Card 0317
2. "Front Matter". Nomenclature of Organic
Chemistry : IUPAC Recommendations and
Preferred Names 2013 (Blue Book).
Cambridge: The Royal Society of Chemistry.
2014. p. 142. doi:10.1039/9781849733069-
FP001 . ISBN 978-0-85404-182-4.
3. Hall, H. K. (1957). "Correlation of the
Base Strengths of Amines". J. Am. Chem.
Soc. 79 (20): 5441–5444.
doi:10.1021/ja01577a030 .
4. pKa value of piperidinium (protonated
piperidine), corresponding to a pKb value of
2.78 for piperidine.
5. Frank Johnson Welcher (1947). Organic
Analytical Reagents. D. Van Nostrand.
p. 149.
6. Senning, Alexander (2006). Elsevier's
Dictionary of Chemoetymology.
Amsterdam: Elsevier. ISBN 978-0-444-
52239-9.
7. Warnhoff, Edgar W. (1998). "When
piperidine was a structural problem" (PDF).
Bulletin for the History of Chemistry. 22:
29–34.
8. Anderson, Thomas (1850). "Vorläufiger
Bericht über die Wirkung der Salpetersäure
auf organische Alkalien" [Preliminary report
on the effect of nitric acid on organic
alkalis]. Annalen der Chemie und
Pharmacie. 75: 80–83.
doi:10.1002/jlac.18500750110 .
9. Cahours, Auguste (1852). "Recherches
sur un nouvel alcali dérivé de la pipérine"
[Investigations of a new alkali derived from
piperine]. Comptes Rendus. 34: 481–484.
"L'alcali nouveau dérivé de la pipérine, que je
désignerai sous le nom de 'pipéridine',…
(The new alkali derived from piperine, which
I will designate by the name of 'piperidine',
…"
10. Eller, Karsten; Henkes, Erhard;
Rossbacher, Roland; Höke, Hartmut,
"Amines, aliphatic", Ullmann's Encyclopedia
of Industrial Chemistry, Weinheim: Wiley-
VCH, doi:10.1002/14356007.a02_001
11. Marvel, C. S.; Lazier, W. A. (1941).
"Benzoyl Piperidine" . Organic Syntheses.;
Collective Volume, 1, p. 99
12. Späth; Englaender (1935). "Über das
Vorkommen von Piperidin im schwarzen
Pfeffer". Chemische Berichte. 68 (12):
2218–2221.
doi:10.1002/cber.19350681211 .
13. Pictet, Amé; Pictet, René (1927). "Sur
l'alcaloïde volatil du poivre". Helvetica
Chimica Acta. 10: 593–595.
doi:10.1002/hlca.19270100175 .
14. Rimington, Claude (1934). "Psilocaulon
absimile N.E.Br. as a stock poison". South
African Journal of Science. 31: 184–193.
hdl:10520/AJA00382353_6425 .
15. Juraschewski; Stepanov (1939). J. Gen.
Chem. USSR. 9: 1687. Missing or empty
|title= (help)
16. Arbiser, J. L.; 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 .
17. Thomas Anderson Henry (1949). The
Plant Alkaloids (4th ed.). The Blakiston
Company.
18. Carballeira, Luis; Pérez Juste, Ignacio
(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 .
19. Blackburne, Ian D.; Katritzky, Alan R.;
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 .
20. Anet, F. A. L.; Yavari, Issa (1977).
"Nitrogen inversion in piperidine". J. Am.
Chem. Soc. 99 (8): 2794–2796.
doi:10.1021/ja00450a064 .
21. Kane, Vinayak V.; Jones, Maitland, Jr.
(1990). "Spiro[5.7]trideca-1,4-dien-3-one" .
Organic Syntheses.; Collective Volume, 7,
p. 473
22. Smith, Michael B.; March, Jerry (2001).
March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure (5th
ed.). Wiley-Interscience. ISBN 978-0-471-
58589-3.
23. Claxton, George P.; Allen, Lloyd; Grisar, J.
Martin (1988). "2,3,4,5-Tetrahydropyridine
trimer" . Organic Syntheses.; Collective
Volume, 6, p. 968
24. Vitaku, E., D. T. Smith and J. T.
Njardarson (2014). "Analysis of the
Structural Diversity, Substitution Patterns,
and Frequency of Nitrogen Heterocycles
among U.S. FDA Approved
Pharmaceuticals". Journal of Medicinal
Chemistry. 57 (24): 10257–10274.
doi:10.1021/jm501100b . PMID 25255204 .
25. "List of Precursors and Chemicals
Frequently Used in the Illicit Manufacture of
Narcotic Drugs and Psychotropic
Substances Under International Control"
(PDF). International Narcotics Control
Board. Archived from the original (PDF) on
2008-02-27.

External links
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