Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, typical of .
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.
[ ][ ][ ] Both of them obtained piperidine by reacting
piperine with
nitric acid.
Industrially, piperidine is produced by the hydrogenation of pyridine, usually over a molybdenum disulfide catalyst:
- C5H5N + 3 H2 → C5H10NH
Pyridine can also be reduced to piperidine via a modified Birch reduction using sodium in ethanol.
Natural occurrence of piperidine and derivatives
Piperidine itself has been obtained from
black pepper,
from
Psilocaulon absimile (
Aizoaceae),
and in
Petrosimonia monandra.
The piperidine structural motif is present in numerous natural . These include piperine, which gives black pepper its spicy taste. This gave the compound its name. Other examples are the fire ant toxin solenopsin,
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.
In
, a range between 0.2 and 0.6 kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable.
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.
In the case of
N-methylpiperidine, the equatorial conformation is preferred by 3.16 kcal/mol,
which is much larger than the preference in methylcyclohexane, 1.74 kcal/mol.
Reactions
Piperidine is widely used to convert
to
.
Enamines derived from piperidine are substrates in the Stork enamine alkylation reaction.
Upon treatment with calcium hypochlorite, piperidine converts to N-chloropiperidine, a chloramine with the formula C5H10NCl. The resulting chloramine undergoes dehydrohalogenation to afford the cyclic imine.
NMR chemical control
-
13C NMR: (CDCl3, ppm) 47, 27.2, 25.2
-
Proton 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
steric effects base, useful because of its low
nucleophilicity and high solubility in
.
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.
List of piperidine medications
Piperidine and its derivatives are ubiquitous building blocks in pharmaceuticals
and fine chemicals. The piperidine structure is found in, for example:
-
Icaridin (Insect repellent)
-
SSRIs (selective serotonin reuptake inhibitors)
-
Stimulants and :
-
Histamine 1 (H1) receptor antagonists/inverse agonists:
-
Histamine 3 (H3) receptor antagonists/:
-
SERM (selective estrogen receptor modulators)
-
-
Antipsychotic medications:
-
:
-
Arylcyclohexylamines:
-
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
Protecting group of
Fmoc-
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 phencyclidine.
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