Piperidine
Encyclopedia
Piperidine is an organic compound
with the molecular formula (CH2)5NH. This heterocyclic
amine
consists of a six-membered ring containing five methylene units and one nitrogen
atom. It is a colorless fuming liquid with an odor described as ammoniacal, 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.
of pyridine
, usually over a molybdenum disulfide
catalyst:
Pyridine can also be reduced to piperidine by sodium
in ethanol
.
, from Psilocaulon absimile N.E.Br (Aizoaceae), and in Petrosimonia monandra.
The piperidine structural motif is present in numerous natural alkaloid
s. 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 (Nicotiana glauca
), lobeline
of the indian tobacco, and the toxic alkaloid coniine
from poison hemlock, which was used to put Socrates
to death.
. 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.
. It is widely used to convert ketone
s to enamine
s. 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.
1H NMR = (CDCl3, ppm) 2.79, 2.19, 1.51
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 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.
Otherwise 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 paroxetine
, risperidone
, methylphenidate
, raloxifene
, minoxidil
, thioridazine
, haloperidol
, droperidol
, mesoridazine
, meperidine, melperone
the psychochemical agents Ditran
-B (JB-329), N-methyl-3-piperidyl benzilate
(JB-336) 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 (peaking in the 1970s) in the clandestine manufacture of PCP (also known as angel dust, sherms, wet, etc.).
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
with the molecular formula (CH2)5NH. This heterocyclic
Heterocyclic compound
A heterocyclic compound is a cyclic compound which has atoms of at least two different elements as members of its ring. The counterparts of heterocyclic compounds are homocyclic compounds, the rings of which are made of a single element....
amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
consists of a six-membered ring containing five methylene units and one nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atom. It is a colorless fuming liquid with an odor described as ammoniacal, pepper-like; the name comes from the genus name Piper
Piper (genus)
Piper, the pepper plants or pepper vines , are an economically and ecologically important genus in the family Piperaceae...
, 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 hydrogenationHydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
of pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
, usually over a molybdenum disulfide
Molybdenum disulfide
Molybdenum disulfide is the inorganic compound with the formula MoS2. This black crystalline sulfide of molybdenum occurs as the mineral molybdenite. It is the principal ore from which molybdenum metal is extracted. The natural amorphous form is known as the rarer mineral jordisite. MoS2 is less...
catalyst:
- C5H5N + 3 H2 → C5H10NH
Pyridine can also be reduced to piperidine by sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
in ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
.
Natural occurrence of piperidine and derivatives
Piperidine itself has been obtained from black pepperBlack pepper
Black pepper is a flowering vine in the family Piperaceae, cultivated for its fruit, which is usually dried and used as a spice and seasoning. The fruit, known as a peppercorn when dried, is approximately in diameter, dark red when fully mature, and, like all drupes, contains a single seed...
, from Psilocaulon absimile N.E.Br (Aizoaceae), and in Petrosimonia monandra.
The piperidine structural motif is present in numerous natural alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s. These include piperine
Piperine
Piperine is the alkaloid responsible for the pungency of black pepper and long pepper, along with chavicine . It has also been used in some forms of traditional medicine and as an insecticide. Piperine forms monoclinic needles, is slightly soluble in water and more so in alcohol, ether or...
, which gives black pepper
Black pepper
Black pepper is a flowering vine in the family Piperaceae, cultivated for its fruit, which is usually dried and used as a spice and seasoning. The fruit, known as a peppercorn when dried, is approximately in diameter, dark red when fully mature, and, like all drupes, contains a single seed...
its spicy taste. This gave the compound its name. Other examples are the fire ant
Fire ant
Fire ants are a variety of stinging ants with over 285 species worldwide. They have several common names, including ginger ants, tropical fire ants and red ants.- Appearance :...
toxin solenopsin
Solenopsin
Solenopsin is an alkaloid which inhibits angiogenesis via the phosphoinositol-3 kinase signaling pathway, in addition to contributing to the toxic effect of fire ant venom. Solenopsin has also been shown to have cytotoxic, hemolytic, necrotic, insecticidal, antibacterial, antifungal, and ...
, the nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
analog anabasine
Anabasine
Anabasine is a pyridine alkaloid found in the Tree Tobacco plant, a close relative of the common tobacco plant . Chemically, it is similar to nicotine...
of the Tree Tobacco (Nicotiana glauca
Nicotiana glauca
Nicotiana glauca is a species of wild tobacco known by the common names tree tobacco and incorrectly also Mustard tree. Its leaves are attached to the stalk by petioles , and its leaves and stems are neither pubescent nor sticky like Nicotiana tabacum...
), lobeline
Lobeline
Lobeline is a natural alkaloid found in "Indian tobacco" , "Devil's tobacco" , "cardinal flower" , "great lobelia" , and Hippobroma longiflora...
of the indian tobacco, and the toxic alkaloid coniine
Coniine
Coniine is a poisonous alkaloid found in poison hemlock and the yellow pitcher plant, and contributes to hemlock's fetid smell. It is a neurotoxin which disrupts the peripheral nervous system. It is toxic to humans and all classes of livestock; less than 0.2g is fatal to humans, with death caused...
from poison hemlock, which was used to put Socrates
Socrates
Socrates was a classical Greek Athenian philosopher. Credited as one of the founders of Western philosophy, he is an enigmatic figure known chiefly through the accounts of later classical writers, especially the writings of his students Plato and Xenophon, and the plays of his contemporary ...
to death.
Conformation
Piperidine prefers a chair conformation, similar to cyclohexaneCyclohexane
Cyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which being intermediates used in the production of nylon...
. 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
Nitrogen inversion
In chemistry, a nitrogen compound like ammonia in a trigonal pyramid geometry undergoes rapid nitrogen inversion whereby the molecule turns inside out. This interconversion is a room temperature process because the energy barrier is relatively small. Contrast this to phosphine which does not show...
; 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
Methylcyclohexane
Methylcyclohexane is a colourless liquid with a faint benzene-like odour. Its molecular formula is C7H14. Methylcyclohexane is used in organic synthesis and as a solvent for cellulose ethers. It is a component of jet fuel and is also a component of correction fluids.-Structure:Monosubstituted...
, 1.74 kcal/mol.
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Reactions
Piperidine is a widely used secondary amineAmine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
. It is widely used to convert ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
s to enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
s. Enamines derived from piperidine can be used in the Stork enamine alkylation
Stork enamine alkylation
Stork enamine alkylation, also known as the Stork-Enamine reaction, involves the addition of an enamine to an alpha, beta-unsaturated carbonyl acceptor in a process similar to the Michael reaction...
reaction.
Piperidine can be converted to the chloramine
Chloramine
Chloramines are derivatives of ammonia by substitution of one, two or three hydrogen atoms with chlorine atoms. Monochloramine is an inorganic compound with the formula NH2Cl. It is an unstable colourless liquid at its melting point of -66° temperature, but it is usually handled as a dilute...
C5H10NCl with calcium hypochlorite
Calcium hypochlorite
Calcium hypochlorite is a chemical compound with formula 2. It is widely used for water treatment and as a bleaching agent...
. The resulting chloramine undergoes dehydrohalogenation
Dehydrohalogenation
Dehydrohalogenation is an organic reaction from which an alkene is obtained from an alkyl halide . It is also called a β-Elimination reaction and is a type of elimination reaction....
to afford the cyclic imine.
NMR chemical shifts
13C NMR = (CDCl3, ppm) 47.5, 27.2, 25.21H NMR = (CDCl3, ppm) 2.79, 2.19, 1.51
Uses
Piperidine is used as a solventSolvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
and as a base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
. The same is true for certain derivatives: N-formylpiperidine
N-Formylpiperidine
N-Formylpiperidine is an organic compound with the formula C6H11NO. It is the amide of formic acid and piperidine. It can be used as a polar aprotic solvent, with better hydrocarbon solubility than other amide solvents such as dimethylformamide...
is a polar aprotic solvent with better hydrocarbon solubility than other amide solvents, and 2,2,6,6-tetramethylpiperidine
2,2,6,6-Tetramethylpiperidine
2,2,6,6-Tetramethylpiperidine or TMP or HTMP is a clear liquid with an amine odor. This amine is used in chemistry as a hindered base because it can dissolve in organic solvents unlike ordinary bases such as potassium hydroxide....
is highly sterically hindered
Steric effects
Steric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and reactivity.-Steric...
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
Vulcanization
Vulcanization or vulcanisation is a chemical process for converting rubber or related polymers into more durable materials via the addition of sulfur or other equivalent "curatives." These additives modify the polymer by forming crosslinks between individual polymer chains. Vulcanized material is...
accelerator.
Otherwise 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 paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, risperidone
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
, methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
, raloxifene
Raloxifene
Raloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast...
, minoxidil
Minoxidil
Minoxidil is an antihypertensive vasodilator medication which also slows or stops hair loss and promotes hair regrowth. Now off-patent, it is available over-the-counter for the treatment of androgenic alopecia. Minoxidil must be used indefinitely for continued support of existing hair follicles and...
, thioridazine
Thioridazine
Thioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
, haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
, droperidol
Droperidol
Droperidol is an antidopaminergic drug used as an antiemetic and antipsychotic...
, mesoridazine
Mesoridazine
Mesoridazine is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine...
, meperidine, melperone
Melperone
Melperone is an atypical antipsychotic of the butyrophenone chemical class.- External links :*...
the psychochemical agents Ditran
Ditran
Ditran is an anticholinergic drug mixture, related to the chemical warfare agent 3-Quinuclidinyl benzilate .Ditran is composed of a mixture of 70% 1-ethyl- 2-pyrrolidinylmethyl- alpha- phenylcyclopentylglycolate and 30% 1-ethyl- 3-piperidyl- alpha- phenylcyclopentylglycolate. These compounds are...
-B (JB-329), N-methyl-3-piperidyl benzilate
N-Methyl-3-piperidyl benzilate
N-Methyl-3-piperidyl benzilate is an anticholinergic drug related to the chemical warfare agent 3-Quinuclidinyl benzilate....
(JB-336) 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
Peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds which are also known as peptide bonds...
.
Piperidine is listed as a Table II precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances
United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances
The United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 is one of three major drug control treaties currently in force. It provides additional legal mechanisms for enforcing the 1961 Single Convention on Narcotic Drugs and the 1971 Convention on...
due to its use (peaking in the 1970s) in the clandestine manufacture of PCP (also known as angel dust, sherms, wet, etc.).