Piperidine: Difference between revisions

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{{Distinguish|Piperine|Pethidine|Pyridine}}

[[image:piperidine.png|right|Chemical structure of piperidine]]

{{Chembox

'''Piperidine''' is a cyclic [[amine]]. The piperidine skeleton is present in [[piperine]], the main active chemical agent in [[pepper]] (''[[Piper]] sp.''), therefore the name.

| Watchedfields = changed

| verifiedrevid = 464207528

| Reference = <ref>{{cite web| url = http://www.ilo.org/public/english/protection/safework/cis/products/icsc/dtasht/_icsc03/icsc0317.htm| title = International Chemical Safety Card 0317| date = 28 January 2024}}</ref>

| Name = Piperidine

| ImageFileL1_Ref = {{chemboximage|correct|??}}

| ImageFile =

| ImageFileL1 = Piperidin.svg

| ImageSizeL1 = 80px

| ImageClassL1 = skin-invert

| ImageFileR1 = Piperidine-equatorial-3D-balls-B.png

| ImageSizeR1 = 140px

| ImageFile2 = Piperidine-3D-vdW.png

| ImageSize2 = 150px

| PIN = Piperidine<ref name=iupac2013>{{cite book | title = Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | ___location = Cambridge | page = 142 | doi = 10.1039/9781849733069-FP001 | isbn = 978-0-85404-182-4| chapter = Front Matter }}</ref>

| SystematicName =

| OtherNames = Hexahydropyridine<br/>Azacyclohexane<br/>Pentamethyleneamine<br/>Azinane

| IUPACName = Piperidine

| Section1 = {{Chembox Identifiers

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo = 110-89-4

| IUPHAR_ligand = 5477

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 18049

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 15487

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 7791

| EC_number = 203-813-0

| KEGG = C01746

| PubChem = 8082

| RTECS = TM3500000

| UNNumber = 2401

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 67I85E138Y

| InChI1 = 1/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2

| InChIKey1 = NQRYJNQNLNOLGT-UHFFFAOYAY

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = NQRYJNQNLNOLGT-UHFFFAOYSA-N

| InChI=1/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2

| SMILES = C1CCNCC1

}}

| Section2 = {{Chembox Properties

| C=5 | H=11 | N=1

| Appearance = Colorless liquid

| Odor = Semen-like,<ref>{{cite journal | last1 = Amoore | first1 = J. E. | year = 1975 | title = Specific anosmia to 1-pyrroline: The spermous primary odor | journal = J. Chem. Ecol. | volume = 1 | issue = 3| pages = 299–310 | doi=10.1007/BF00988831| bibcode = 1975JCEco...1..299A | s2cid = 19318345 }}</ref> fishy-ammoniacal, pungent

| Density = 0.862 g/mL

| Solubility = Miscible

| MeltingPtC = −7

| BoilingPtC = 106

| pKa = 11.22 (protonated)<ref>{{cite journal | last1 = Hall | first1 = H. K. | year = 1957 | title = Correlation of the Base Strengths of Amines | journal = J. Am. Chem. Soc. | volume = 79 | issue = 20| pages = 5441–5444 | doi=10.1021/ja01577a030}}</ref>

| Viscosity = 1.573 [[Poise (unit)|cP]] at 25&nbsp;°C

| MagSus = −64.2·10⁻⁶ cm³/mol

}}

| Section3 =

| Section4 =

| Section5 =

| Section6 =

| Section7 = {{Chembox Hazards

| NFPA-H = 3

| NFPA-F = 3

| NFPA-R = 0

| GHSPictograms = {{GHS02}}{{GHS05}}{{GHS06}}

| GHSSignalWord = Danger

| HPhrases = {{H-phrases|225|311|314|331}}

| PPhrases = {{P-phrases|210|233|240|241|242|243|260|261|264|271|280|301+330+331|302+352|303+361+353|304+340|305+351+338|310|311|312|321|322|361|363|370+378|403+233|403+235|405|501}}

| ExternalSDS = [https://www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do?country=US&language=en&productNumber=411027&brand=ALDRICH&PageToGoToURL=https%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fsearch%3Fterm%3Dpiperidine%26interface%3DAll%26N%3D0%26mode%3Dmatch%2520partialmax%26lang%3Den%26region%3DUS%26focus%3Dproduct MSDS1]

}}

|Section8={{Chembox Legal status

| legal_AU =

| legal_BR = D1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-15 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_US =

| legal_UK =

| legal_UN =

}}

| Section9 = {{Chembox Related

| OtherCompounds = [[Pyridine]]<br />[[Pyrrolidine]]<br />[[Piperazine]]<br/>[[Phosphorinane]]<br/>[[Arsinane]]

}}

}}

'''Piperidine''' is an [[organic compound]] with the molecular formula (CH₂)₅NH. This [[heterocyclic compound|heterocyclic]] [[amine]] consists of a six-membered ring containing five [[methylene bridge]]s (–CH₂–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, typical of [[amine]]s.<ref>{{cite book |title=Organic Analytical Reagents |url=https://archive.org/details/in.ernet.dli.2015.7833 | author=Frank Johnson Welcher |year=1947 |publisher=D. Van Nostrand |page=[https://archive.org/details/in.ernet.dli.2015.7833/page/n165 149]}}</ref> The name comes from the genus name ''[[Piper (genus)|Piper]]'', which is the Latin word for [[Black pepper|pepper]].<ref>{{cite book |first=Alexander |last=Senning |title=Elsevier's Dictionary of Chemoetymology |year=2006 |isbn=978-0-444-52239-9 |___location=Amsterdam |publisher=Elsevier}}</ref> Although piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and [[alkaloid]]s, such as natural-occurring [[Solenopsin|solenopsins]].<ref>{{Cite journal|last1=Pianaro|first1=Adriana|last2=Fox|first2=Eduardo G.P.|last3=Bueno|first3=Odair C.|last4=Marsaioli|first4=Anita J.|date=May 2012|title=Rapid configuration analysis of the solenopsins|journal=Tetrahedron: Asymmetry|language=en|volume=23|issue=9|pages=635–642|doi=10.1016/j.tetasy.2012.05.005}}</ref>

It is also a byproduct of burning [[phencyclidine]] (PCP).

== Production ==

It is also found in [[marijuana]].

Piperidine was first reported in 1850 by the Scottish chemist [[Thomas Anderson (chemist)|Thomas Anderson]] and again, independently, in 1852 by the French chemist [[Auguste André Thomas Cahours|Auguste Cahours]], who named it.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref> 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:<ref name="Ullmann">{{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}}</ref>

Piperidine is listed as a Table II precursor under the [[United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances]][http://www.incb.org/pdf/e/list/red.pdf].

: C₅H₅N + 3&nbsp;H₂ → C₅H₁₀NH

Pyridine can also be reduced to piperidine via a modified [[Birch reduction]] using [[sodium]] in [[ethanol]].<ref>{{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}}</ref>

Piperidine is often used for its mild [[basic (chemistry)|basic]] properties, most notably in Fmoc-strategy solid phase [[peptide]] [[chemistry]].

== Natural occurrence of piperidine and derivatives ==

Piperidine itself has been obtained from [[black pepper]],<ref>{{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}}</ref><ref>{{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}}</ref> from ''[[Psilocaulon absimile]]'' ([[Aizoaceae]]),<ref>{{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 }}</ref> and in ''[[Petrosimonia monandra]]''.<ref>{{cite journal | last1 = Juraschewski | last2 = Stepanov | year = 1939 | journal = J. Gen. Chem. USSR | volume = 9 | page = 1687 }}</ref>

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]],<ref name="bowen">{{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}}</ref> the [[nicotine]] analog [[anabasine]] of tree tobacco (''[[Nicotiana glauca]]''), [[lobeline]] of [[Lobelia inflata|Indian tobacco]], and the toxic alkaloid [[coniine]] from [[poison hemlock]], which was used to put [[Socrates]] to death.<ref>{{cite book | title = The Plant Alkaloids | author = Thomas Anderson Henry | edition = 4th | date = 1949 | publisher = The Blakiston Company}}</ref>

{{organic-compound-stub}}

== Conformation ==

[[pl:Piperydyna]]

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#Chair conformation|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&nbsp;kcal/mol in the gas phase.<ref name="conf1">{{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 }}</ref> In [[nonpolar solvent]]s, a range between 0.2 and 0.6&nbsp;kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable.<ref>{{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}}</ref> The two conformers interconvert rapidly through [[nitrogen inversion]]; the free energy [[activation barrier]] for this process, estimated at 6.1&nbsp;kcal/mol, is substantially lower than the 10.4&nbsp;kcal/mol for [[ring inversion]].<ref>{{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}}</ref> In the case of ''N''-methylpiperidine, the equatorial conformation is preferred by 3.16&nbsp;kcal/mol,<ref name="conf1" /> which is much larger than the preference in [[methylcyclohexane]], 1.74&nbsp;kcal/mol.

{| class="wikitable" style="margin:1em auto; text-align:center;"

|[[Image:Piperidine-axial-3D-balls-A.png|200px]]||[[Image:Piperidine-equatorial-3D-balls-A.png|200px]]

|-

|axial conformation||equatorial conformation

|}

== Reactions ==

Piperidine is widely used to convert [[ketone]]s to [[enamine]]s.<ref>{{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}}</ref> Enamines derived from piperidine are substrates in the [[Stork enamine alkylation]] reaction.<ref>{{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}}</ref>

Upon treatment with [[calcium hypochlorite]], piperidine converts to [[N-Chloropiperidine|N-chloropiperidine]], a [[chloramine]] with the formula C₅H₁₀NCl. The resulting chloramine undergoes [[dehydrohalogenation]] to afford the cyclic imine.<ref>{{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}}</ref>

== NMR chemical control==

*[[Carbon-13 NMR|¹³C NMR]]: ([[Deuterated chloroform|CDCl₃]], ppm) 47, 27.2, 25.2{{citation needed|date=July 2016}}

*[[Proton NMR|¹H NMR]]: (CDCl₃, ppm) 2.79, 2.19, 1.51{{citation needed|date=July 2016}}

== Uses ==

Piperidine is used as a [[solvent]] and as a [[base (chemistry)|base]]. The same is true for certain derivatives: [[N-formylpiperidine|''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|sterically hindered]] base, useful because of its low [[nucleophilicity]] and high solubility in [[organic solvent]]s.

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.<ref name="Ullmann" />

==List of piperidine medications==

[[File:Minoxidil structure.svg|class=skin-invert-image|thumb|right|160px|[[Minoxidil]] is a piperidine derivative widely used to prevent hair loss.]]

Piperidine and its derivatives are ubiquitous building blocks in pharmaceuticals<ref>{{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}}</ref> and fine chemicals. The piperidine structure is found in, for example:

* [[Icaridin]] (Insect repellent)

*SSRIs ([[selective serotonin reuptake inhibitors]])

**[[Paroxetine]]

*[[Stimulants]] and [[nootropic]]s:

**[[Methylphenidate]]

**[[Ethylphenidate]]

**[[Pipradrol]]

**[[Desoxypipradrol]]

*Histamine 1 (H₁) receptor antagonists/inverse agonists:

**[[Loratadine]]

* [[Histamine H3 receptor|Histamine 3 (H₃) receptor]] antagonists/[[inverse agonist]]s:

**[[Pitolisant]]

*SERM ([[selective estrogen receptor modulators]])

**[[Raloxifene]]

*[[Vasodilator]]s

**[[Minoxidil]]

*[[Antipsychotic]] medications:

**[[Droperidol]]

**[[Haloperidol]]

**[[Melperone]]

**[[Mesoridazine]]

**[[Risperidone]]

**[[Thioridazine]]

*[[Opioid]]s:

**[[Dipipanone]]

**[[Fentanyl]] and analogs

**[[Loperamide]]

**[[Pethidine]] (meperidine)

**[[Prodine]]

*[[Arylcyclohexylamine]]s:

**[[Phencyclidine|PCP]] and analogs

*[[anticholinergic]] [[chemical weapons]]

**[[Ditran]]

**[[N-methyl-3-piperidyl benzilate|''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|deprotection]] of [[Fmoc]]-[[amino acid]]s 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]].<ref>{{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 }}</ref>

== References ==

{{reflist|30em}}

==External links==

*{{Commonscat-inline|Piperidine}}

{{Authority control}}

[[Category:Piperidines| ]]

[[Category:Amine solvents]]

[[Category:Foul-smelling chemicals]]

[[Category:Substances discovered in the 19th century]]