Humulene

Not to be confused with humulone.
Humulene
Names
IUPAC name
2,6,6,9-Tetramethyl-1,4-8-cycloundecatriene
Other names
alpha-Caryophyllene; 3,7,10-Humulatriene
Identifiers
6753-98-6 Yes
ChEBI CHEBI:5768 Yes
ChEMBL ChEMBL251280 Yes
ChemSpider 4444853 Yes
Jmol-3D images Image
PubChem 5281520
Properties[1]
Molecular formula
 C15H24
Molar mass 204.35 g·mol−1
Appearance Pale yellowish green clear liquid
Density 0.886 g/cm3
Melting point < 25 °C (77 °F; 298 K)
Boiling point 106 to 107 °C (223 to 225 °F; 379 to 380 K) at 5 mmHg
Hazards
MSDS MSDS
>48 mg/kg
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Humulene, also known as α-humulene or α-caryophyllene, is a naturally occurring monocyclic sesquiterpene (C15H24), which is an 11-membered ring,consisting of 3 isoprene units containing three nonconjugated C═C double bonds, two of them being triply substituted and one being doubly substituted terpenoid. It was first found in the essential oils of Humulus lupulus (hops), from which it derives its name.[2] Humulene is an isomer of β-caryophyllene, and the two are often found together as a mixture in many aromatic plants (see "Occurrence" below).

Preparation and synthesis

Humulene is one of many sesquiterpenoids that are derived from farnesyl diphosphate (FPP). The biosynthesis begins with the loss of diphosphate from FPP under the action of sesquiterpene synthesis enzymes, generating an allylic cation that is highly susceptible to intramolecular attacks.[3]

This biosynthesis can be mimicked in the laboratory by preparing allylic stanane from farnesol, termed Corey synthesis. There are diverse ways to synthesize humulene in the laboratory, involving differing closures of the C-C bond in the macrocycle. The McMurry synthesis uses a titanium-catalyzed carbonyl coupling reaction; the Takahashi synthesis uses intramolecular alkylation of an allyl halide by a protected cyanohydrin anion; the Suginome synthesis utilizes a geranyl fragment; and the de Groot synthesis synthesizes humulene from a crude distillate of eucalyptus oil.[4] Humulene can also by synthesized using a combination of four-component assembly and palladium-mediated cyclization, outlined below. This synthesis is noteworthy for the simplicity of the C−C bond constructions and cyclization steps, which it is believed will prove advantageous in the synthesis of related polyterpenoids.[5]

To understand humulene's regioselectivity,the fact that one of the two triply substituted C═C double bonds is significantly more reactive,its conformational space was explored computationally and four different conformations were identified.[6]

Occurrence

Humulus lupulus

Humulene is one of the essential oils made in the flowering cone of the hops plant Humulus lupulus. The concentration of humulene varies among different varieties of the plant but can be up to 40% of the essential oil.[7] Humulene and its reaction products in the brewing process of beer gives many beers their “hoppy” aroma. Noble hop varieties have been found to have higher levels of humulene, while other bitter hop varieties contain low levels.[8] Multiple epoxides of humulene are produced in the brewing process. In a scientific study involving Gas Chromatography/Mass Spectrometry analysis of samples and a trained sensory panel, it was found that the hydrolysis products of humulene epoxide II specifically produces a “hoppy” aroma in beer.[9][10]

α-Humulene has been found in an ever increasing number of aromatic plants on all continents, often together with its isomer β-caryophyllene. Proven α-humulene emitters into the atmosphere are pine trees,[11] orange orchards,[12] marsh elders,[13] tobacco,[14] and sunflower fields.[15] α-Humulene is contained in the essential oils of aromatic plants such as Salvia officinalis (common sage, culinary sage),[16] Lindera strychnifolia Uyaku or Japanese spicebush, ginseng species,[17] up to 29.9% of the essential oils of Mentha spicata,[18] the ginger family (Zingiberaceae),[19] 10% of the leaf oil of Litsea mushaensis, a Chinese laurel tree,[20] 4% of the leaf extract of Cordia verbenacea, a bush in coastal tropical South America (erva baleeira), but with 25% trans-Caryophyllene[21] and is one of the chemical compounds that contribute to the taste of the spice Persicaria odorata or Vietnamese coriander and the characteristic aroma of Cannabis sativa.

Uses and reactions

Biological effects

Humulene has been found to produce anti-inflammatory effects in mammals, and has potential to be a tool in the management of inflammatory diseases. It produces similar effects to dexamethasone, and was found to decrease the edema formation caused by histamine injections.[22] Humulene produced inhibitory effects on tumor necrosis factor-α (TNFα) and interleukin-1 β (IL1B) generation in carrageenan-injected rats.[23]

History

It was first found in the essential oils of Humulus lupulus (hops), from which it derives its name.

Atmospheric chemistry

α-Humulene is a biogenic volatile organic compound, emitted by numerous plants (see occurrence) with a relatively high potential for secondary organic aerosol formation in the atmosphere. It is eager to react with ozone in sunlight (photooxidation) and capable of ozonolysis. α-Humulene has a very high reaction rate coefficient (1.17 × 10−14 cm3 molecule−1 s−1) as compared to most monoterpenes. Since it contains three double bonds, it can produce first-, second- and third-generation products and aerosols, respectively. At typical tropospheric ozone mixing ratios of 30 ppb the lifetime of α-humulene is about 2 min, whereas the first- and second-generation products have average lifetimes of 1 h and 12.5 h, respectively.[24]

References

  1. ↑ Merck Index, 12th Edition, 4789
  2. ↑ Glenn Tinseth, "Hop Aroma and Flavor", January/February 1993, Brewing Techniques. <http://realbeer.com/hops/aroma.html> Accessed July 21, 2010
  3. ↑ Moss, G.P., "Humulene derived sesquiterpenoid biosynthesis." International Union of Biochemistry and Molecular Biology Enzyme Nomenclature. Accessed April 10, 2011. http://www.enzyme-database.org/reaction/terp/humul.html
  4. ↑ Goldsmith, David. "The total synthesis of natural products". Canada: John Wiley & Sons. 1997 pp 129-133
  5. ↑ Hu, Tao & Corey, E.J. (2002). "Short Syntheses of (±)-δ-Araneosene and Humulene Utilizing a Combination of Four-Component Assembly and Palladium-Mediated Cyclization". Organic Letters 4 (14): 2441–2443. doi:10.1021/ol026205p. PMID 12098267.
  6. ↑ Neuenschwander, U et al. (2012). "Origin of Regioselectivity in α-Humulene Functionalization". J. Org. Chem 77 (6): 2865–2869. doi:10.1021/jo3000942.
  7. ↑ Katsiotis, S. T.; Langezaal, C. R.; Scheffe, J. J. C. (1989). Planta Med. 55: 634. doi:10.1055/s-2006-962205. Missing or empty |title= (help)
  8. ↑ http://www.homebrewtalk.com/wiki/index.php/Humulene#Humulene
  9. ↑ Yange, Xiaogen; Lederer, Cindy; McDaniel, Mina & Deinzer, Max. (1993). "Evaluation of hydrolysis products of humulene epoxides II and III". Journal of Agricultural and Food Chemistry 41 (8): 1300–1304. doi:10.1021/jf00032a026.
  10. ↑ Peackock, Val & Deinzer, Max (1981). "Chemistry of hop aroma in beer". Journal of the American Society of Brewing Chemists 39.
  11. ↑ D. Helmig, J. Ortega, T. Duhl, D. Tanner, A. Guenther, P. Harley, C. Wiedinmyer, J. Milford and T. Sakulyanontvittaya (2007). "Sesquiterpene emissions from pine trees--identifications, emission rates and flux estimates for the contiguous United States". Environ. Sci. Technol. 41 (5): 1545–1553. doi:10.1021/es0618907. PMID 17396639.
  12. ↑ P. Ciccioli, E. Brancaleoni, M. Frattoni, V. Di Palo, R. Valentini, G. Tirone, G. Seufert, N. Bertin, U. Hansen, O. Csiky, R. Lenz and M. Sharma (1999). "Emission of reactive terpene compounds from orange orchards and their removal by within-canopy processes". J. Geophys. Res. 104: 8077–8094. Bibcode:1999JGR...104.8077C. doi:10.1029/1998JD100026.
  13. ↑ D. Degenhardt and D. Lincoln, J. (2006). Chem. Ecol. 32: 725–743. Missing or empty |title= (help)
  14. ↑ C. De Moraes, M. Mescher and J. Tumlinson (2001). "Caterpillar-induced nocturnal plant volatiles repel conspecific females". Nature 410 (6828): 577–580. doi:10.1038/35069058. PMID 11279494.
  15. ↑ G. Schuh, A. Heiden, T. Hoffmann, J. Kahl, P. Rockel, J. Rudolph and J. Wildt (1997). J. Atmos. Chem. 27 (3): 291–318. doi:10.1023/A:1005850710257. Missing or empty |title= (help)
  16. ↑ Bouajaj S, Benyamna A, Bouamama H, Romane A, Falconieri D, Piras A, Marongiu B. Antibacterial, allelopathic and antioxidant activities of essential oil of Salvia officinalis L. growing wild in the Atlas Mountains of Morocco. Nat Prod Res. 2013; 27(18):1673-6.
  17. ↑ Cho IH, Lee HJ, Kim YS. Differences in the volatile compositions of ginseng species (Panax sp.). J Agric Food Chem. 2012 Aug 8;60(31):7616-22.
  18. ↑ Chauhan SS, Prakash O, Padalia RC, Vivekanand, Pant AK, Mathela CS. Chemical diversity in Mentha spicata: antioxidant and potato sprout inhibition activity of its essential oils. Nat Prod Commun. 2011; 6(9):1373-8.
  19. ↑ Suthisut, D; Fields, PG; Chandrapatya, A (2011). "Contact toxicity, feeding reduction, and repellency of essential oils from three plants from the ginger family (Zingiberaceae) and their major components against Sitophilus zeamais and Tribolium castaneum". J Econ Entomol 104 (4): 1445–54. doi:10.1603/ec11050.
  20. ↑ Ho, CL; Wang, EI; Tseng, YH; Liao, PC; Lin, CN; Chou, JC; Su, YC (2010). "Composition and antimicrobial activity of the leaf and twig oils of Litsea mushaensis and L. linii from Taiwan". Nat Prod Commun 5 (11): 1823–8.
  21. ↑ P.M. de Carvalho Jr., R.F. Rodrigues, A.C. Sawaya, M.O. Marques, M.T. Shimizu. Chemical composition and antimicrobial activity of the essential oil of Cordia verbenacea D.C" Journal of Ethnopharmacology 2004; 95: 297–301.
  22. ↑ Passosa, G.F.; Fernandesa, ES. et al. (August 2007). "Anti-inflammatory and anti-allergic properties of the essential oil and active compounds from Cordia verbenacea". Journal of Ethnopharmacology 110 (2): 323–333. doi:10.1016/j.ejphar.2007.04.059. PMID 17559833.
  23. ↑ Fernandes E.S., Passos G.F., Medeiros R., da Cunha F.M., Ferreira J., Campos M.M., Pianowski L.F., Calixto J.B. (2007). "Anti-inflammatory effects of compounds alpha-humulene and (−)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea". European Journal of Pharmacology 569 (3): 228–236. doi:10.1016/j.ejphar.2007.04.059. PMID 17559833.
  24. ↑ Beck, M.; Winterhalter, R.; Herrmanna, F.; Moortgat, G. K. (2011). "The gas-phase ozonolysis of α-humulene". Phys. Chem. Chem. Phys. 13: 10970–11001. doi:10.1039/c0cp02379e.