Piperidine

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Piperidine
Piperidin.svg Piperidine-equatorial-3D-balls-B.png
Piperidine-3D-vdW.png
Identifiers
CAS number 110-89-4 YesY
PubChem 8082
ChemSpider 7791 YesY
UNII 67I85E138Y YesY
ChEBI CHEBI:18049 YesY
ChEMBL CHEMBL15487 YesY
RTECS number TM3500000
Jmol-3D images Image 1
Properties
Molecular formula C5H11N
Molar mass 85.15 g mol−1
Appearance colourless liquid
Density 0.862 g/mL, liquid
Melting point −7 °C (19 °F; 266 K)
Boiling point 106 °C (223 °F; 379 K)
Solubility in water miscible
Acidity (pKa) 11.22[1]
Viscosity 1.573 cP at 25 °C
Hazards
EU classification Flammable (F)
Toxic (T)
R-phrases R11, R23/24, R34
NFPA 704
Flammability code 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g., gasoline) Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 3: Capable of detonation or explosive decomposition but requires a strong initiating source, must be heated under confinement before initiation, reacts explosively with water, or will detonate if severely shocked. E.g., fluorine Special hazards (white): no codeNFPA 704 four-colored diamond
Related compounds
Related compounds pyridine
pyrrolidine
piperazine
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Piperidine (Azinane after the Hantzsch–Widman nomenclature) is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (-CH
2
-) and one amine bridge (-NH-). It is a colorless fuming liquid with an odor described as ammoniacal, pepper-like,[2] or semen-like;[3] the name comes from the genus name Piper, which is the Latin word for pepper.[4] Piperidine is a widely used building block and chemical reagent in the synthesis of organic compounds, including pharmaceuticals.

Production[edit]

Industrially, piperidine is produced by the hydrogenation of pyridine, usually over a molybdenum disulfide catalyst:[5]

C5H5N + 3 H2 → C5H10NH

Pyridine can also be reduced to piperidine via a modified Birch reduction using sodium in ethanol.[6]

Natural occurrence of piperidine and derivatives[edit]

Piperidine itself has been obtained from black pepper,[7] from Psilocaulon absimile N.E.Br (Aizoaceae),[8] and in Petrosimonia monandra.[9]

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,[10] 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.[11]

Conformation[edit]

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.[12] 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.[13] 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.[14] In the case of N-methylpiperidine, the equatorial conformation is preferred by 3.16 kcal/mol,[12] which is much larger than the preference in methylcyclohexane, 1.74 kcal/mol.

Piperidine-axial-3D-balls-A.png
Piperidine-equatorial-3D-balls-A.png
axial conformation
equatorial conformation

Reactions[edit]

Piperidine is a widely used secondary amine. It is widely used to convert ketones to enamines.[15] Enamines derived from piperidine can be used in the Stork enamine alkylation reaction.[16]

Piperidine can be converted to the chloramine C5H10NCl with calcium hypochlorite. The resulting chloramine undergoes dehydrohalogenation to afford the cyclic imine.[17]

NMR chemical shifts[edit]

13C NMR = (CDCl3, ppm) 47.5, 27.2, 25.2
1H NMR = (CDCl3, ppm) 2.79, 2.19, 1.51

Uses[edit]

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.[5]

List of Piperidine Medications[edit]

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:

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.).[18]

References[edit]

  1. ^ Hall, H.K., J. Am. Chem. Soc., 1957, 79, 5441.
  2. ^ Frank Johnson Welcher (1947). Organic Analytical Reagents. D. Van Nostrand. p. 149. 
  3. ^ http://www.slcc-science.org/chem/giddings/chem1120/ch15/15_index.htm
  4. ^ Alexander Senning (2006). Elsevier's Dictionary of Chemoetymology. Amsterdam: Elsevier. p. publisher=Elsevier. ISBN 0-444-52239-5. 
  5. ^ a b Karsten Eller, Erhard Henkes, Roland Rossbacher, Hartmut Höke “Amines, Aliphatic” Ullmann's Encyclopedia of Industrial Chemistry 2002 Wiley-VCH. doi:10.1002/14356007.a02_001
  6. ^ C. S. Marvel and W. A. Lazier (1941), "Benzoyl Piperidine", Org. Synth. ; Coll. Vol. 1: 99 
  7. ^ Spaeth and Englaender, Ber.1935,68, 2218; cf. Pictet and Pictet, Helv. Chim. Acta, 1927, 10, 593
  8. ^ Rimington, S. Afr. J. Sci, 1934, 31, 184
  9. ^ Juraschewski and Stepanov, J. Gen. Chem., U.R.S.S., 1939, 9, 1687
  10. ^ Arbiser JL, Kau T, Konar M et al. (2007). "Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis". Blood 109 (2): 560–5. doi:10.1182/blood-2006-06-029934. PMC 1785094. PMID 16990598. 
  11. ^ The Plant Alkaloids, Thomas Anderson Henry, 4th ed. 1949, The Blakiston Company
  12. ^ a b Luis Carballeira, Ignacio Pérez-Juste (1998). "Influence of calculation level and effect of methylation on axial/equatorial equilibria in piperidines". Journal of Computational Chemistry 19 (8): 961–976. doi:10.1002/(SICI)1096-987X(199806)19:8<961::AID-JCC14>3.0.CO;2-A. 
  13. ^ Ian D. Blackburne, Alan R. Katritzky, Yoshito Takeuchi (1975). "Conformation of piperidine and of derivatives with additional ring hetero atoms". Acc. Chem. Res. 8 (9): 300–306. doi:10.1021/ar50093a003. 
  14. ^ F.A.L. Anet, Issa Yavari (1977). "Nitrogen inversion in piperidine". J. Am. Chem. Soc. 99 (8): 2794–2796. doi:10.1021/ja00450a064. 
  15. ^ Vinayak V. Kane and Maitland Jones Jr (1990), "Spiro[5.7]trideca-1,4-dien-3-one", Org. Synth. ; Coll. Vol. 7: 473 
  16. ^ March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure Michael B. Smith, Jerry March Wiley-Interscience, 5th edition, 2001, ISBN 0-471-58589-0
  17. ^ George P. Claxton, Lloyd Allen, and J. Martin Grisar (1988), "2,3,4,5-Tetrahydropyridine trimer", Org. Synth. ; Coll. Vol. 6: 968 
  18. ^ List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control, International Narcotics Control Board (link is dead)