# Piperidine

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Not to be confused with [Piperine](/source/Piperine) or [Pethidine](/source/Pethidine) or [Pyridine](/source/Pyridine).

**Piperidine** is an [organic compound](/source/Organic_compound) with the molecular formula (CH2)5NH. This [heterocyclic](/source/Heterocyclic_compound) [amine](/source/Amine) consists of a six-membered ring containing five [methylene bridges](/source/Methylene_bridge) (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, [human](/source/Human) [sperm](/source/Sperm)-like[3][4], typical of [amines](/source/Amine).[5] The name comes from the genus name *[Piper](/source/Piper_(genus))*, which is the Latin word for [pepper](/source/Black_pepper).[6] Although piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and [alkaloids](/source/Alkaloid), such as naturally-occurring [solenopsins](/source/Solenopsin).[7]

## Production

Piperidine was first reported in 1850 by the Scottish chemist [Thomas Anderson](/source/Thomas_Anderson_(chemist)) and again, independently, in 1852 by the French chemist [Auguste Cahours](/source/Auguste_Andr%C3%A9_Thomas_Cahours), who named it.[8][9][10] Both of them obtained piperidine by reacting [piperine](/source/Piperine) with [nitric acid](/source/Nitric_acid).

Industrially, piperidine is produced by the [hydrogenation](/source/Hydrogenation) of [pyridine](/source/Pyridine), usually over a [molybdenum disulfide](/source/Molybdenum_disulfide) catalyst:[11]

- C5H5N + 3 H2 → C5H10NH

Pyridine can also be reduced to piperidine via a modified [Birch reduction](/source/Birch_reduction) using [sodium](/source/Sodium) in [ethanol](/source/Ethanol).[12]

## Natural occurrence of piperidine and derivatives

Piperidine itself has been obtained from [black pepper](/source/Black_pepper),[13][14] from *[Psilocaulon absimile](/source/Psilocaulon_absimile)* ([Aizoaceae](/source/Aizoaceae)),[15] and in *[Petrosimonia monandra](/source/Petrosimonia_monandra)*.[16]

The piperidine structural motif is present in numerous natural [alkaloids](/source/Alkaloid). These include [piperine](/source/Piperine), which gives [black pepper](/source/Black_pepper) its spicy taste. This gave the compound its name. Other examples are the [fire ant](/source/Fire_ant) toxin [solenopsin](/source/Solenopsin),[17] the [nicotine](/source/Nicotine) analog [anabasine](/source/Anabasine) of tree tobacco (*[Nicotiana glauca](/source/Nicotiana_glauca)*), [lobeline](/source/Lobeline) of [Indian tobacco](/source/Lobelia_inflata), and the toxic alkaloid [coniine](/source/Coniine) from [poison hemlock](/source/Poison_hemlock), which was used to put [Socrates](/source/Socrates) to death.[18]

## Conformation

Piperidine prefers a [chair conformation](/source/Chair_conformation), similar to [cyclohexane](/source/Cyclohexane). Unlike cyclohexane, piperidine has two distinguishable chair conformations: one with the N–H bond in an [axial position](/source/Axial_position#Chair_conformation), 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.[19] In [nonpolar solvents](/source/Nonpolar_solvent), a range between 0.2 and 0.6 kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable.[20] The two conformers interconvert rapidly through [nitrogen inversion](/source/Nitrogen_inversion); the free energy [activation barrier](/source/Activation_barrier) for this process, estimated at 6.1 kcal/mol, is substantially lower than the 10.4 kcal/mol for [ring inversion](/source/Ring_inversion).[21] In the case of [*N*-methylpiperidine](/source/N-methylpiperidine), the equatorial conformation is preferred by 3.16 kcal/mol,[19] which is much larger than the preference in [methylcyclohexane](/source/Methylcyclohexane), 1.74 kcal/mol.

axial conformation equatorial conformation

## Reactions

Piperidine is widely used to convert [ketones](/source/Ketone) to [enamines](/source/Enamine).[22] Enamines derived from piperidine are substrates in the [Stork enamine alkylation](/source/Stork_enamine_alkylation) reaction.[23]

Upon treatment with [calcium hypochlorite](/source/Calcium_hypochlorite), piperidine converts to [N-chloropiperidine](/source/N-Chloropiperidine), a [chloramine](/source/Chloramine) with the formula C5H10NCl. The resulting chloramine undergoes [dehydrohalogenation](/source/Dehydrohalogenation) to afford the cyclic imine.[24]

## NMR chemical control

- [13C NMR](/source/Carbon-13_NMR): ([CDCl3](/source/Deuterated_chloroform), ppm) 47, 27.2, 25.2[citation needed]
- [1H NMR](/source/Proton_NMR): (CDCl3, ppm) 2.79, 2.19, 1.51[citation needed]

## Uses

Piperidine is used as a [solvent](/source/Solvent) and as a [base](/source/Base_(chemistry)). The same is true for certain derivatives: [*N*-formylpiperidine](/source/N-formylpiperidine) is a [polar aprotic solvent](/source/Polar_aprotic_solvent) with better hydrocarbon solubility than other amide solvents, and [2,2,6,6-tetramethylpiperidine](/source/2,2,6,6-tetramethylpiperidine) is a highly [sterically hindered](/source/Steric_effects) base, useful because of its low [nucleophilicity](/source/Nucleophilicity) and high solubility in [organic solvents](/source/Organic_solvent).

A significant industrial application of piperidine is for the production of dipiperidinyl dithiuram tetrasulfide, which is used as an accelerator of the [sulfur vulcanization](/source/Sulfur_vulcanization) of rubber.[11]

## List of piperidine medications

Piperidine and its derivatives are ubiquitous building blocks in pharmaceuticals[25] and fine chemicals. The piperidine structure is found in, for example:

- [Icaridin](/source/Icaridin) (Insect repellent)
- SSRIs ([selective serotonin reuptake inhibitors](/source/Selective_serotonin_reuptake_inhibitors)) - [Paroxetine](/source/Paroxetine)
- [Stimulants](/source/Stimulants) and [nootropics](/source/Nootropic): - [Methylphenidate](/source/Methylphenidate) - [Ethylphenidate](/source/Ethylphenidate) - [Pipradrol](/source/Pipradrol) - [Desoxypipradrol](/source/Desoxypipradrol)
- Histamine 1 (H1) receptor antagonists/inverse agonists: - [Loratadine](/source/Loratadine)
- [Histamine 3 (H3) receptor](/source/Histamine_H3_receptor) antagonists/[inverse agonists](/source/Inverse_agonist): - [Pitolisant](/source/Pitolisant)
- SERM ([selective estrogen receptor modulators](/source/Selective_estrogen_receptor_modulators)) - [Raloxifene](/source/Raloxifene)
- [Vasodilators](/source/Vasodilator) - [Minoxidil](/source/Minoxidil)
- [Antipsychotic](/source/Antipsychotic) medications: - [Droperidol](/source/Droperidol) - [Haloperidol](/source/Haloperidol) - [Melperone](/source/Melperone) - [Mesoridazine](/source/Mesoridazine) - [Risperidone](/source/Risperidone) - [Thioridazine](/source/Thioridazine)
- [Opioids](/source/Opioid): - [Dipipanone](/source/Dipipanone) - [Fentanyl](/source/Fentanyl) and analogs - [Loperamide](/source/Loperamide) - [Pethidine](/source/Pethidine) (meperidine) - [Prodine](/source/Prodine)
- [Arylcyclohexylamines](/source/Arylcyclohexylamine): - [PCP](/source/Phencyclidine) and analogs
- [anticholinergic](/source/Anticholinergic) [chemical weapons](/source/Chemical_weapons) - [Ditran](/source/Ditran) - [*N*-Methyl-3-piperidyl benzilate](/source/N-methyl-3-piperidyl_benzilate) (JB-336, BZ)

Piperidine is also commonly used in chemical degradation reactions, such as the sequencing of [DNA](/source/DNA) in the cleavage of particular modified [nucleotides](/source/Nucleotides). Piperidine is also commonly used as a base for the [deprotection](/source/Protecting_group) of [Fmoc](/source/Fmoc)-[amino acids](/source/Amino_acid) used in solid-phase [peptide synthesis](/source/Peptide_synthesis).

Piperidine is listed as a Table II precursor under the [United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances](/source/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](/source/Phencyclidine).[26]

## References

1. ["International Chemical Safety Card 0317"](http://www.ilo.org/public/english/protection/safework/cis/products/icsc/dtasht/_icsc03/icsc0317.htm). 28 January 2024.

1. "Front Matter". *Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book)*. Cambridge: [The Royal Society of Chemistry](/source/Royal_Society_of_Chemistry). 2014. p. 142. [doi:10.1039/9781849733069-FP001](https://doi.org/10.1039/9781849733069-FP001). ISBN 978-0-85404-182-4.

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1. Marvel, C. S. & Lazier, W. A. (1929). "Benzoyl Piperidine". *Org. Synth.*. **9**: 16. [doi:10.15227/orgsyn.009.0016](https://doi.org/10.15227/orgsyn.009.0016)

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Adapted from the Wikipedia article [Piperidine](https://en.wikipedia.org/wiki/Piperidine) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Piperidine?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.