Limonene

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Not to be confused with Lemonene.
Limonene
Skeletal structure of the R-isomer Ball-and-stick model of the R-isomer
Identifiers
CAS number 138-86-3 N
PubChem 22311, 439250 (S)
ChemSpider 20939 (R/S) YesY, 388386 (S), 389747 (R)
UNII GFD7C86Q1W YesY
KEGG D00194 YesY
ChEBI CHEBI:15384 YesY
ChEMBL CHEMBL449062 N
Jmol-3D images Image 1
Properties
Molecular formula C10H16
Molar mass 136.23 g mol−1
Density 0.8411 g/cm³
Melting point −74.35 °C (−101.83 °F; 198.80 K)
Boiling point 176 °C (349 °F; 449 K)
Chiral rotation [α]D 87° - 102°
Hazards
R-phrases R10 R38 R43 R50/53
S-phrases (S2) S24 S37 S60 S61
NFPA 704
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g., diesel fuel Health code 1: Exposure would cause irritation but only minor residual injury. E.g., turpentine Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Flash point 50 °C (122 °F; 323 K)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Limonene is a colourless liquid hydrocarbon classified as a cyclic terpene. The more common D-isomer possesses a strong smell of oranges.[1] It is used in chemical synthesis as a precursor to carvone and as a renewables-based solvent in cleaning products.

Limonene takes its name from the lemon, as the rind of the lemon, like other citrus fruits, contains considerable amounts of this compound, which contributes to their odor. Limonene is a chiral molecule, and biological sources produce one enantiomer: the principal industrial source, citrus fruit, contains D-limonene ((+)-limonene), which is the (R)-enantiomer (CAS number 5989-27-5, EINECS number 227-813-5). Racemic limonene is known as dipentene.[2] D-Limonene is obtained commercially from citrus fruits through two primary methods: centrifugal separation or steam distillation.

Chemical reactions[edit]

Limonene is a relatively stable terpene and can be distilled without decomposition, although at elevated temperatures it cracks to form isoprene.[3] It oxidizes easily in moist air to produce carveol, carvone, and limonene oxide.[4] With sulfur, it undergoes dehydrogenation to p-cymene.[5]

Limonene occurs naturally as the (R)-enantiomer, but racemizes to dipentene at 300 °C. When warmed with mineral acid, limonene isomerizes to the conjugated diene α-terpinene (which can also easily be converted to p-cymene). Evidence for this isomerization includes the formation of Diels-Alder adducts between α-terpinene adducts and maleic anhydride.

It is possible to effect reaction at one of the double bonds selectively. Anhydrous hydrogen chloride reacts preferentially at the disubstituted alkene, whereas epoxidation with mCPBA occurs at the trisubstituted alkene.

In another synthetic method Markovnikov addition of trifluoroacetic acid followed by hydrolysis of the acetate gives terpineol.

Biosynthesis[edit]

Limonene is formed from geranyl pyrophosphate, via cyclization of a neryl carbocation or its equivalent as shown.[6] The final step involves loss of a proton from the cation to form the alkene.

Biosynthesis of limonene from geranyl pyrophosphate

The most widely practiced conversion of limonene is to carvone. The three step reaction begins with the regioselective addition of nitrosyl chloride across the trisubstituted double bond. This species is then converted to the oxime with base, and the hydroxylamine is removed to give the ketone-containing carvone.[1]

Biological properties[edit]

The principle metabolites of limonene are (+)- and (−)-trans–carveol, a product of 6-hydroxylation) and (+)- and (−)-perillyl alcohol, a product of 7-hydroxylation by CYP2C9 and CYP2C19 cytochromes in human liver microsomes.[7] The enantiomers of perillyl alcohol have been investigated for their pharmacological activities as dietary chemotherapeutic agents. They are viewed as novel therapeutic options in some CNS neoplasms and other solid tumours, particularly for the treatment of gliomas.[8] The cytotoxic activities of perillyl alcohol and limonene metabolites are likely due to their antiangiogenic activities, hyperthermia inducing effects as well as negative apoptosis regulation and Ras pathways.[9]

Uses[edit]

Limonene is common in cosmetic products. As the main odor constituent of citrus (plant family Rutaceae), D-limonene is used in food manufacturing and some medicines, e.g. as a flavoring to mask the bitter taste of alkaloids, and as a fragrant in perfumery; it is also used as botanical insecticide,[10] particularly the (R)-(+)-enantiomer is most active as an insecticide. It is added to cleaning products such as hand cleansers to give a lemon-orange fragrance (see orange oil) and because of its ability to dissolve oils. In contrast, L-limonene has a piney, turpentine-like odor.

In natural and alternative medicine, D-limonene is marketed to relieve gastroesophageal reflux disease and heartburn.[11]

Limonene is increasingly being used as a solvent for cleaning purposes, such as the removal of oil from machine parts, as it is produced from a renewable source (citrus oil, as a byproduct of orange juice manufacture). It is used as a paint stripper and is also useful as a fragrant alternative to turpentine. Limonene is also used as a solvent in some model airplane glues and as a constituent in some paints. All-natural commercial air fresheners, with air propellants, containing limonene are used by philatelists to remove self-adhesive postage stamps from envelope paper.[12]

Limonene is also finding increased use as a solvent for filament-fused 3D printing. Printers can print the plastic of choice for the model, but erect supports and binders from HIPS, a polystyrene plastic that is easily solvable in limonene.

As it is combustible, limonene has also been considered as a biofuel.[13]

In preparing tissues for histology or histopathology, D-limonene is often used as a less toxic substitute for xylene when clearing dehydrated specimens. Clearing agents are liquids miscible with alcohols (such as ethanol or isopropanol) and with melted paraffin wax, in which specimens are embedded to facilitate cutting of thin sections for microscopy.[14][15][16]

Limonene is an adenosine agonist which may explain its anti-stress and sedative properties.[17][18][19]

Safety[edit]

Limonene and its oxidation products are skin and respiratory irritants, and limonene-1,2-oxide (formed by aerial oxidation) is a known skin sensitizer. Most reported cases of irritation have involved long-term industrial exposure to the pure compound, e.g. during degreasing or the preparation of paints. However, a study of patients presenting dermatitis showed that 3% were sensitized to limonene.[20]

Although high doses have been shown to cause renal cancer in male rats,[21] limonene is considered by some researchers to be a potential chemopreventive agent [22] with value as a dietary anti-cancer tool in humans.[23] There is no evidence for carcinogenicity or genotoxicity in humans. The IARC classifies D-limonene as a Group 3 carcinogen: not classifiable as to its carcinogenicity to humans.[20][24]

No information is available on the health effects of inhalation exposure to D-limonene in humans,[dubious ] and no long-term inhalation studies have been conducted in laboratory animals.[citation needed]

D-Limonene is biodegradable, but due to its low flash point, it must be treated as hazardous waste for disposal.[citation needed]

Compendial status[edit]


See also[edit]

References[edit]

  1. ^ a b Fahlbusch, Karl-Georg; Hammerschmidt, Franz-Josef; Panten, Johannes; Pickenhagen, Wilhelm; Schatkowski, Dietmar; Bauer, Kurt; Garbe, Dorothea; Surburg, Horst (2003). "Flavors and Fragrances". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a11_141. ISBN 978-3-527-30673-2. 
  2. ^ J. L. Simonsen (1947). The Terpenes 1 (2nd ed.). Cambridge University Press. OCLC 477048261. [page needed]
  3. ^ Pakdel, H (2001). "Production of dl-limonene by vacuum pyrolysis of used tires". Journal of Analytical and Applied Pyrolysis 57: 91–107. doi:10.1016/S0165-2370(00)00136-4. 
  4. ^ Karlberg, Ann-Therese; Magnusson, Kerstin; Nilsson, Ulrika (1992). "Air oxidation of d-limonene (the citrus solvent) creates potent allergens". Contact Dermatitis 26 (5): 332–40. doi:10.1111/j.1600-0536.1992.tb00129.x. PMID 1395597. 
  5. ^ Weitkamp, A. W. (1959). "I. The Action of Sulfur on Terpenes. The Limonene Sulfides". Journal of the American Chemical Society 81 (13): 3430. doi:10.1021/ja01522a069.  edit
  6. ^ Mann, J. C.; Hobbs, J. B.; Banthorpe, D. V.; Harborne, J. B. (1994). Natural products: their chemistry and biological significance. Harlow, Essex, England: Longman Scientific & Technical. pp. 308–9. ISBN 0-582-06009-5. 
  7. ^ Miyazawa1 M, Shindo M, and Shimada S (2002). Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos 30(5):602-7. PMID: 11950794 article doi:10.1124/dmd.30.5.602
  8. ^ da Fonseca CO et al. (2011). J Cancer Res Clin Oncol.137(2):287-93. PMID: 20401670 doi:10.1007/s00432-010-0873-0
  9. ^ de Saldanha da Gama Fischer et al. (2011). Chemo-resistant protein expression pattern of glioblastoma cells (A172) to perillyl alcohol.J Proteome Res.10(1):153-60. PMID: 20806975
  10. ^ EPA R.E.D. Fact Sheet on Limonene, September 1994
  11. ^ Sun, J (2007). "D-Limonene: safety and clinical applications". Alternative medicine review: a journal of clinical therapeutic 12 (3): 259–64. PMID 18072821. 
  12. ^ Butler, Peter (October 2010). "It's Like Magic; Removing Self-Adhesive Stamps from Paper". American Philatelist (American Philatelic Society) 124 (10): 910–13. 
  13. ^ Cyclone Power to Showcase External Combustion Engine at SAE Event, Green Car Congress, 20 September 2007
  14. ^ Wynnchuk, Maria (1994). "Evaluation of Xylene Substitutes For A Paraffin Tissue Processing". Journal of Histotechnology (2): 143–9. doi:10.1179/014788894794710913. 
  15. ^ Carson F 1997 Histotechnology. A Self-Instructional Text. Chicago: ASCP Press, pp.28-31. ISBN 0-89189-411-X.
  16. ^ Kiernan JA 2008 Histological and Histochemical Methods. 4th ed. Bloxham, UK, pp.54,57. ISBN 978-1-904842-42-2.
  17. ^ Park, HM (2011). "Limonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptors.". Biochem Biophys Res Commun.: 345–8. doi:10.1016/j.bbrc.2010.11.121. 
  18. ^ Zhou, W (2009). "Sub-chronic effects of s-limonene on brain neurotransmitter levels and behavior of rats.". J Nutr Sci Vitaminol (Tokyo). 55 (4): 367–73. doi:10.3177/jnsv.55.367. PMID 19763039. 
  19. ^ do Vale, TG (2002). "Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown.". Phytomedicine 9 (8): 709–14. doi:10.1078/094471102321621304. PMID 12587690. 
  20. ^ a b "d-LIMONENE". Some Chemicals that Cause Tumours of the Kidney or Urinary Bladder in Rodents and Some Other Substances. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 73. International Agency for Research on Cancer. 1999. pp. 307–27. ISBN 978-92-832-1273-7. 
  21. ^ National Toxicology, Program (1990). "NTP Toxicology and Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies)". National Toxicology Program technical report series 347: 1–165. PMID 12704437. 
  22. ^ Crowell, PL (1999). "Prevention and therapy of cancer by dietary monoterpenes". The Journal of nutrition 129 (3): 775S–778S. PMID 10082788. 
  23. ^ Tsuda, Hiroyuki; Ohshima, Yutaka; Nomoto, Hiroshi; Fujita, Ken-Ichi; Matsuda, Eiji; Iigo, Masaaki; Takasuka, Nobuo; Moore, Malcolm A. (2004). "Cancer Prevention by Natural Compounds". Drug Metabolism and Pharmacokinetics 19 (4): 245–63. doi:10.2133/dmpk.19.245. PMID 15499193. 
  24. ^ "Ranking Possible Cancer Hazards on the HERP Index". Retrieved 19 March 2007. 
  25. ^ The British Pharmacopoeia Secretariat (2009). "Index, BP 2009". Retrieved 31 March 2010. 

Further reading[edit]

  • E. E. Turner, M. M. Harris (1952). Organic Chemistry. London: Longmans, Green & Co. OCLC 41665654. 
  • Wallach, O. (1888). "Zur Kenntniss der Terpene und der ätherischen Oele". Justus Liebig's Annalen der Chemie 246 (2): 221–39. doi:10.1002/jlac.18882460205. 
  • Blumann, A.; Zeitschel, O. (1914). "Ein Beitrag zur Autoxydation des Limonens". Berichte der deutschen chemischen Gesellschaft 47 (3): 2623–8. doi:10.1002/cber.19140470339. 
  • "Limonene". Workplace Hazardous Materials Information System. Commission de la santé et de la sécurité du travail. 3 November 2005. 
  • Matura, M; Goossens, A; Bordalo, O; Garcia-Bravo, B; Magnusson, K; Wrangsjö, K; Karlberg, AT (2002). "Oxidized citrus oil (R-limonene): A frequent skin sensitizer in Europe". Journal of the American Academy of Dermatology 47 (5): 709–14. doi:10.1067/mjd.2002.124817. PMID 12399762. 
  • Hirota, Ryoji; Roger, Ngatu Nlandu; Nakamura, Hiroyuki; Song, Hee-Sun; Sawamura, Masayoshi; Suganuma, Narufumi (2010). "Anti-inflammatory Effects of Limonene from Yuzu (Citrus junos Tanaka) Essential Oil on Eosinophils". Journal of Food Science 75 (3): H87–92. doi:10.1111/j.1750-3841.2010.01541.x. PMID 20492298. 
  • Yoon, Weon-Jong; Lee, Nam Ho; Hyun, Chang-Gu (2010). "Limonene Suppresses Lipopolysaccharide-Induced Production of Nitric Oxide, Prostaglandin E2, and Pro-inflammatory Cytokines in RAW 264.7 Macrophages". Journal of Oleo Science 59 (8): 415–21. doi:10.5650/jos.59.415. PMID 20625233. 

External links[edit]