piperidine

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.{{cite journal|first=Edgar W. |last=Warnhoff |date=1998 |title=When piperidine was a structural problem |journal=Bulletin for the History of Chemistry |volume=22 |pages=29–34 |url=http://www.scs.illinois.edu/~mainzv/HIST/bulletin_open_access/num22/num22%20p29-34.pdf}} {{open access}}{{cite journal|author-link=Thomas Anderson (chemist) |first=Thomas |last=Anderson |date=1850 |url=http://babel.hathitrust.org/cgi/pt?id=chi.47401536;view=1up;seq=92 |title=Vorläufiger Bericht über die Wirkung der Salpetersäure auf organische Alkalien |trans-title=Preliminary report on the effect of nitric acid on organic alkalis |journal=Annalen der Chemie und Pharmacie |volume=75 |pages=80–83 |doi=10.1002/jlac.18500750110}} {{open access}}{{cite journal|author-link=Auguste André Thomas Cahours |first=Auguste |last=Cahours |date=1852 |url=http://gallica.bnf.fr/ark:/12148/bpt6k2991b/f485.item.r=.zoom |title=Recherches sur un nouvel alcali dérivé de la pipérine |trans-title=Investigations of a new alkali derived from piperine |journal=Comptes Rendus |volume=34 |pages=481–484 |quote=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',…}} {{open access}} 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:{{Ullmann|first1=Karsten |last1=Eller |first2=Erhard |last2=Henkes |first3=Roland |last3=Rossbacher |first4=Hartmut |last4=Höke |title=Amines, Aliphatic |doi=10.1002/14356007.a02_001}}

: C₅H₅N + 3 H₂ → C₅H₁₀NH

Pyridine can also be reduced to piperidine via a modified Birch reduction using sodium in ethanol.{{cite journal |journal=Org. Synth.| first1= C. S. |last1=Marvel |first2= W. A. |last2=Lazier| title = Benzoyl Piperidine| volume = 9 | pages = 16 | year = 1929| doi = 10.15227/orgsyn.009.0016}}

Piperidine itself has been obtained from black pepper,{{cite journal|last1=Späth |last2=Englaender |journal=Chemische Berichte |date=1935|volume=68 |issue=12 |pages=2218–2221 |doi=10.1002/cber.19350681211 |title=Über das Vorkommen von Piperidin im schwarzen Pfeffer}}{{cite journal | last1 = Pictet | first1 = Amé | last2 = Pictet | first2 = René | year = 1927 | title = Sur l'alcaloïde volatil du poivre | journal = Helvetica Chimica Acta | volume = 10 | pages = 593–595 | doi = 10.1002/hlca.19270100175}} from Psilocaulon absimile (Aizoaceae),{{cite journal | last1 = Rimington | first1 = Claude | year = 1934 | title = Psilocaulon absimile N.E.Br. as a stock poison | journal = South African Journal of Science | volume = 31 | pages = 184–193 | hdl = 10520/AJA00382353_6425 }} and in Petrosimonia monandra.{{cite journal | last1 = Juraschewski | last2 = Stepanov | year = 1939 | journal = J. Gen. Chem. USSR | volume = 9 | page = 1687 }}

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,{{cite journal |last1=Arbiser |first1=J. L. |last2=Kau |first2=T. |last3=Konar |first3=M. |display-authors=etal | title = Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis | journal = Blood | year = 2007 | volume = 109 | issue = 2 | pages = 560–5 | doi = 10.1182/blood-2006-06-029934 | pmid = 16990598 | pmc = 1785094}} 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.{{cite book | title = The Plant Alkaloids | author = Thomas Anderson Henry | edition = 4th | date = 1949 | publisher = The Blakiston Company}}

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.{{cite journal |title=Influence of calculation level and effect of methylation on axial/equatorial equilibria in piperidines |journal=Journal of Computational Chemistry |volume=19 |issue=8 |year=1998 |pages=961–976 |first1=Luis |last1=Carballeira |first2=Ignacio |last2=Pérez Juste |doi=10.1002/(SICI)1096-987X(199806)19:8<961::AID-JCC14>3.0.CO;2-A|s2cid=98028598 }} 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.{{cite journal |title=Conformation of piperidine and of derivatives with additional ring hetero atoms |first1=Ian D. |last1=Blackburne |first2=Alan R. |last2=Katritzky |author3=Yoshito Takeuchi |journal=Acc. Chem. Res. |year=1975 |volume=8 |issue=9 |pages=300–306 |doi=10.1021/ar50093a003}} 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.{{cite journal |title=Nitrogen inversion in piperidine|first1=F. A. L. |last1=Anet |first2=Issa |last2=Yavari |journal=J. Am. Chem. Soc. |year=1977 |volume=99 |issue=8 |pages=2794–2796 |doi=10.1021/ja00450a064}} 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.

Piperidine is widely used to convert ketones to enamines.{{OrgSynth | first1= Vinayak V. |last1=Kane | first2= Maitland Jr. |last2=Jones | title = Spiro[5.7]trideca-1,4-dien-3-one| collvol = 7 | collvolpages = 473 | year = 1990 | prep = CV7P0473}} Enamines derived from piperidine are substrates in the Stork enamine alkylation reaction.{{cite book | title = March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure |first1=Michael B. |last1=Smith |first2=Jerry |last2=March | publisher = Wiley-Interscience | edition = 5th | date = 2001 | isbn = 978-0-471-58589-3}}

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.{{OrgSynth | first1= George P.|last1= Claxton |first2=Lloyd|last2= Allen|first3= J. Martin |last3=Grisar | title = 2,3,4,5-Tetrahydropyridine Trimer| volume = 56 | pages = 118| year = 1977| doi= 10.15227/orgsyn.056.0118}}

• ¹³C NMR: (CDCl₃, ppm) 47, 27.2, 25.2{{citation needed|date=July 2016}}
• ¹H NMR: (CDCl₃, ppm) 2.79, 2.19, 1.51{{citation needed|date=July 2016}}

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.

File:Minoxidil structure.svg is a piperidine derivative widely used to prevent hair loss.]]

Piperidine and its derivatives are ubiquitous building blocks in pharmaceuticals{{cite journal|author1=Vitaku, E. |author2=D. T. Smith |author3=J. T. Njardarson |year=2014|title=Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals|journal=Journal of Medicinal Chemistry |volume=57|issue=24|pages=10257–10274|doi=10.1021/jm501100b|pmid=25255204}} and fine chemicals. The piperidine structure is found in, for example:

• Icaridin (Insect repellent)
• SSRIs (selective serotonin reuptake inhibitors)
• Paroxetine
• Stimulants and nootropics:
• Methylphenidate
• Ethylphenidate
• Pipradrol
• Desoxypipradrol
• Histamine 1 (H₁) receptor antagonists/inverse agonists:
• Loratadine
• Histamine 3 (H₃) receptor antagonists/inverse agonists:
• Pitolisant
• 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
• Arylcyclohexylamines:
• PCP and analogs
• 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 phencyclidine.{{cite web|url=http://www.incb.org/pdf/e/list/red.pdf |title=List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control |publisher=International Narcotics Control Board |url-status=dead |archive-url=https://web.archive.org/web/20080227224025/http://www.incb.org/pdf/e/list/red.pdf |archive-date=2008-02-27 }}

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• {{Commonscat-inline|Piperidine}}

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Category:Amine solvents

Category:Foul-smelling chemicals

Category:Substances discovered in the 19th century