Piperidine is an organic compound with the molecular formula5NH. This
heterocyclic amine consists of a six-membered ring containing five
methylene bridges (-CH 2-) and one amine bridge. It is a
colorless fuming liquid with an odor described as ammoniacal or pepper-like;
the name comes from the genus name Piper, which is the Latin word for
pepper. Piperidine is a widely used building block and chemical reagent in
the synthesis of organic compounds, including pharmaceuticals.
Production 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
N.E.Br, and in Petrosimonia monandra. 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, the nicotine analog anabasine of the Tree
Tobacco, lobeline of the Indian tobacco, and the toxic alkaloid coniine from
poison hemlock, which was used to put Socrates to death.
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 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. 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 a widely used secondary
amine. It is widely used to convert ketones to enamines. Enamines derived
from piperidine can be used in the Stork enamine alkylation reaction.
Piperidine can be converted to the chloramine C5H10NCl with calcium
hypochlorite. The resulting chloramine undergoes dehydrohalogenation to afford
the cyclic imine. NMR chemical shifts
13C NMR = 47.27.2, 25.21H NMR = 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.
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:
SSRI paroxetine
Analeptics/Nootropics methylphenidate
ethylphenidate pipradrol
desoxypipradrol SERM
raloxifene Vasodilators
minoxidil Neuroleptics
risperidone thioridazine
haloperidol droperidol
mesoridazine Opioids
Pethidine loperamide
Other agents Psychochemical compounds
melperone the psychochemical agents Ditran-B, N-methyl-3-piperidyl benzilate
and in many others. 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 in the
clandestine manufacture of PCP. References