View source for Humulene

{{distinguish|humulone}}
{{chembox
| Watchedfields = changed
| verifiedrevid = 461771110
| Name = Humulene
| ImageFile = Humulene.png
| ImageSize = 150px
| ImageName = Humulene
| ImageFile2 = Alpha-humulene-from-xtal-Mercury-3D-bs.png
| IUPACName = [1(11)''E'',4''E'',8''E'']-Humula-1(11),4,8-triene
| SystematicName = (1''E'',4''E'',8''E'')-2,6,6,9-Tetramethylcycloundeca-1,4-8-triene
| OtherNames = alpha-Caryophyllene;  3,7,10-Humulatriene
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4444853
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 251280
| PubChem = 5281520
| InChI = 1/C15H24/c1-13-7-5-8-14(2)10-12-15(3,4)11-6-9-13/h6-7,10-11H,5,8-9,12H2,1-4H3/b11-6+,13-7+,14-10+
| InChIKey = FAMPSKZZVDUYOS-HRGUGZIWBF
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C15H24/c1-13-7-5-8-14(2)10-12-15(3,4)11-6-9-13/h6-7,10-11H,5,8-9,12H2,1-4H3/b11-6+,13-7+,14-10+
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FAMPSKZZVDUYOS-HRGUGZIWSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 6753-98-6
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 54W56MD2WD
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 5768
| SMILES = C\1=C/C(C)(C)C/C=C(/CC/C=C(/C/1)C)C}}
|Section2={{Chembox Properties
| Properties_ref = <ref>''[[Merck Index]]'', 12th Edition, '''4789'''</ref>
| C=15 | H=24
| Density = 0.886 g/cm<sup>3</sup>
| Appearance = Pale yellowish green clear liquid
| MeltingPt= <
| MeltingPtC = 25
| BoilingPtC = 106 to 107
| BoilingPt_notes = at 5 mmHg
}}
|Section3={{Chembox Hazards
| ExternalSDS = [http://www.carl-roth.de/jsp/en-de/sdpdf/9385e.PDF MSDS]
| LD50 = >48 mg/kg}}
}}
'''Humulene''', also known as '''α-humulene''' or '''α-caryophyllene''', is a naturally occurring monocyclic [[sesquiterpene]] (C<sub>15</sub>H<sub>24</sub>), containing an 11-membered ring and consisting of 3 [[isoprene]] units containing three nonconjugated C=C double bonds, two of them being triply substituted and one being doubly substituted. It was first found in the [[essential oil]]s of ''[[Humulus lupulus]]'' ([[hops]]), from which it derives its name.<ref>Glenn Tinseth, "Hop Aroma and Flavor", January/February 1993, Brewing Techniques. <http://realbeer.com/hops/aroma.html> Accessed July 21, 2010</ref> Humulene is an [[isomer]] of [[caryophyllene|β-caryophyllene]], and the two are often found together as a mixture in many aromatic plants.
==Occurrence==
[[File:Hopfen2.jpg|thumb|left|''[[Humulus lupulus]]'']]
Humulene is one of the components of the [[essential oil]] from the flowering cone of the hops plant, ''[[Humulus lupulus]]'', from which it derives its name. The concentration of humulene varies among different varieties of the plant but can be up to 40% of the essential oil.<ref>{{cite journal | last1 = Katsiotis | first1 = S. T. | last2 = Langezaal | first2 = C. R. | last3 = Scheffe | first3 = J. J. C. | year = 1989 | journal = Planta Med. | volume = 55 | issue = 7| page = 634 | doi=10.1055/s-2006-962205 | title = Analysis of the Volatile Compounds from Cones of Ten Humulus lupulus Cultivars}}</ref> 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.<ref>{{Cite web |url=http://www.homebrewtalk.com/wiki/index.php/Humulene#Humulene |title=Archived copy |access-date=2011-04-17 |archive-url=https://web.archive.org/web/20150924031107/http://www.homebrewtalk.com/wiki/index.php/Humulene#Humulene |archive-date=2015-09-24 |url-status=dead }}</ref>{{Unreliable source?|date=June 2011}} Multiple [[epoxide]]s 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.<ref>{{cite journal |author1=Yange, Xiaogen |author2=Lederer, Cindy |author3=McDaniel, Mina |author4=Deinzer, Max. | year = 1993 | title = Evaluation of hydrolysis products of humulene epoxides II and III | journal = Journal of Agricultural and Food Chemistry | volume = 41 | pages = 1300–1304 | doi = 10.1021/jf00032a026 | issue = 8}}</ref><ref>{{cite journal | author1 = Peackock, Val | author2 = Deinzer, Max | year = 1981 | title = Chemistry of hop aroma in beer | journal = Journal of the American Society of Brewing Chemists | volume = 39 | url = http://www.asbcnet.org/journal/abstracts/backissues/39-39.htm | url-status = dead | archive-url = https://web.archive.org/web/20131230232825/http://www.asbcnet.org/journal/abstracts/backissues/39-39.htm | archive-date = 2013-12-30 }}</ref>
α-Humulene has been found in many aromatic plants on all continents, often together with its isomer β-caryophyllene. Proven α-humulene emitters into the atmosphere are pine trees,<ref>{{cite journal|author1=D. Helmig |author2=J. Ortega |author3=T. Duhl |author4=D. Tanner |author5=A. Guenther |author6=P. Harley |author7=C. Wiedinmyer |author8=J. Milford |author9=T. Sakulyanontvittaya |journal=Environ. Sci. Technol.|year=2007|volume=41|pages=1545–1553|doi=10.1021/es0618907|pmid=17396639|title=Sesquiterpene emissions from pine trees--identifications, emission rates and flux estimates for the contiguous United States|issue=5|bibcode=2007EnST...41.1545H|s2cid=20810373 |url=https://escholarship.org/uc/item/9264b24t }}</ref> orange orchards,<ref>{{cite journal|author1=P. Ciccioli |author2=E. Brancaleoni |author3=M. Frattoni |author4=V. Di Palo |author5=R. Valentini |author6=G. Tirone |author7=G. Seufert |author8=N. Bertin |author9=U. Hansen |author10=O. Csiky |author11=R. Lenz |author12=M. Sharma |journal=J. Geophys. Res.|year=1999|volume=104|issue=D7 |pages=8077–8094|doi=10.1029/1998JD100026|title=Emission of reactive terpene compounds from orange orchards and their removal by within-canopy processes|bibcode=1999JGR...104.8077C|doi-access=free }}</ref> [[Iva frutescens|marsh elder]]s,<ref>{{cite journal|author1=D. Degenhardt  |author2=D. Lincoln, J.|journal=Chem. Ecol.|year=2006|volume=32|issue=4|pages=725–743 | title = Volatile Emissions from an Odorous Plant in Response to Herbivory and Methyl Jasmonate Exposure|doi=10.1007/s10886-006-9030-2|pmid=16718568|s2cid=6017606}}</ref> tobacco,<ref>{{cite journal|author1=C. De Moraes |author2=M. Mescher |author3=J. Tumlinson |journal=Nature|year=2001|volume=410|pages=577–580|doi=10.1038/35069058|pmid=11279494|title=Caterpillar-induced nocturnal plant volatiles repel conspecific females|issue=6828|bibcode=2001Natur.410..577D |s2cid=4408480 }}</ref> and sunflower fields.<ref>{{cite journal|author1=G. Schuh |author2=A. Heiden |author3=T. Hoffmann |author4=J. Kahl |author5=P. Rockel |author6=J. Rudolph |author7=J. Wildt |journal=J. Atmos. Chem.|year=1997|volume=27|pages=291–318|doi=10.1023/A:1005850710257|issue=3 | title = Emissions of Volatile Organic Compounds from Sunflower and Beech: Dependence on Temperature and Light Intensity|bibcode=1997JAtC...27..291S|s2cid=94314856 }}</ref>  α-Humulene is contained in the essential oils of aromatic plants such as ''[[Salvia officinalis]]'' (common sage, culinary sage),<ref>{{cite journal | last1 = Bouajaj | first1 = S | last2 = Benyamna | first2 = A | last3 = Bouamama | first3 = H | last4 = Romane | first4 = A | last5 = Falconieri | first5 = D | last6 = Piras | first6 = A | last7 = Marongiu | first7 = B | year = 2013 | title = Antibacterial, allelopathic and antioxidant activities of essential oil of Salvia officinalis L. growing wild in the Atlas Mountains of Morocco | journal = Nat Prod Res | volume = 27 | issue = 18| pages = 1673–6 | doi=10.1080/14786419.2012.751600| pmid = 23240623 | s2cid = 29522122 }}</ref> ''[[Lindera strychnifolia]]'' Uyaku or Japanese spicebush, [[ginseng]] species,<ref>{{cite journal | last1 = Cho | first1 = IH | last2 = Lee | first2 = HJ | last3 = Kim | first3 = YS | date = Aug 2012 | title = Differences in the volatile compositions of ginseng species (Panax sp.) | journal = J Agric Food Chem | volume = 60 | issue = 31| pages = 7616–22 | doi=10.1021/jf301835v| pmid = 22804575 }}</ref> up to 29.9% of the essential oils of ''[[Mentha spicata]]'',<ref>{{cite journal | last1 = Chauhan | first1 = SS | last2 = Prakash | first2 = O | last3 = Padalia | first3 = RC | last4 = Vivekanand | first4 = Pant AK | last5 = Mathela | first5 = CS | year = 2011 | title = Chemical diversity in Mentha spicata: antioxidant and potato sprout inhibition activity of its essential oils | journal = Nat Prod Commun | volume = 6 | issue = 9| pages = 1373–8 | pmid = 21941918 }}</ref> the [[ginger]] family (Zingiberaceae),<ref>{{cite journal | last1 = Suthisut | first1 = D | last2 = Fields | first2 = PG | last3 = Chandrapatya | first3 = A | year = 2011 | title = 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 | journal = J Econ Entomol | volume = 104 | issue = 4| pages = 1445–54 | doi=10.1603/ec11050| pmid = 21882715 | s2cid = 45872520 }}</ref> 10% of the leaf oil of ''Litsea mushaensis'', a Chinese laurel tree,<ref>{{cite journal | last1 = Ho | first1 = CL | last2 = Wang | first2 = EI | last3 = Tseng | first3 = YH | last4 = Liao | first4 = PC | last5 = Lin | first5 = CN | last6 = Chou | first6 = JC | last7 = Su | first7 = YC | year = 2010 | title = Composition and antimicrobial activity of the leaf and twig oils of Litsea mushaensis and L. linii from Taiwan | journal = Nat Prod Commun | volume = 5 | issue = 11| pages = 1823–8 | pmid = 21213991 }}</ref> 4% of the leaf extract of ''Cordia verbenacea'', a bush in coastal tropical South America (erva baleeira), but with 25% ''trans''-caryophyllene<ref>{{cite journal | last1 = de Carvalho | first1 = Jr. | last2 = Rodrigues | first2 = R.F. | last3 = Sawaya | first3 = A.C. | last4 = Marques | first4 = M.O. | last5 = Shimizu | first5 = M.T. | year = 2004 | title = Chemical composition and antimicrobial activity of the essential oil of Cordia verbenacea D.C | journal = Journal of Ethnopharmacology | volume = 95 | issue = 2–3| pages = 297–301 | doi=10.1016/j.jep.2004.07.028| pmid = 15507352 }}</ref> 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]]''.<ref>{{Cite journal|last=Hillig|first=Karl W|date=October 2004|title=A chemotaxonomic analysis of terpenoid variation in Cannabis|journal=Biochemical Systematics and Ecology|volume=32|issue=10|pages=875–891|doi=10.1016/j.bse.2004.04.004|issn=0305-1978}}</ref>
==Preparation and synthesis==
Humulene is one of many sesquiterpenoids that are derived from [[farnesyl diphosphate]] (FPP). The formation of humulene from FPP is catalyzed by sesquiterpene synthesis enzymes.<ref>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</ref>
This biosynthesis can be mimicked in the laboratory by preparing allylic stannane 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.<ref>Goldsmith, David. "The total synthesis of natural products". Canada: John Wiley & Sons. 1997 pp 129-133</ref> Humulene can also be 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.<ref>{{cite journal | author = Hu, Tao & [[E. J. Corey|Corey, E.J.]] | year = 2002 | title = Short Syntheses of (±)-δ-Araneosene and Humulene Utilizing a Combination of Four-Component Assembly and Palladium-Mediated Cyclization | journal = Organic Letters | volume = 4 | issue = 14 | pages = 2441–2443 | doi = 10.1021/ol026205p | pmid = 12098267}}</ref>
:[[File:Humulene synthesis.gif|left|600px]]{{clear left}}
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.<ref>{{cite journal | last1 = Neuenschwander | first1 = U | display-authors = etal   | year = 2012 | title = Origin of Regioselectivity in α-Humulene Functionalization | journal = J. Org. Chem. | volume = 77 | issue = 6| pages = 2865–2869 | doi = 10.1021/jo3000942 | pmid = 22332847 }}</ref>
==Research==
In laboratory studies, humulene is being studied for potential [[anti-inflammatory]] effects.<ref>{{cite journal | last1 = Passosa | first1 = G.F. | last2 = Fernandesa | first2 = ES. | display-authors = etal   | title = Anti-inflammatory and anti-allergic properties of the essential oil and active compounds from Cordia verbenacea | journal = Journal of Ethnopharmacology | volume = 110 | issue = 2| pages = 323–333 | doi = 10.1016/j.jep.2006.09.032 | date=2007 | pmid=17084568}}</ref><ref>{{cite journal |author1=Fernandes E.S. |author2=Passos G.F. |author3=Medeiros R. |author4=da Cunha F.M. |author5=Ferreira J. |author6=Campos M.M. |author7=Pianowski L.F. |author8=Calixto J.B. | year = 2007 | title = Anti-inflammatory effects of compounds alpha-humulene and (−)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea | journal = European Journal of Pharmacology | volume = 569 | issue = 3 | pages = 228–236 | doi = 10.1016/j.ejphar.2007.04.059 | pmid = 17559833}}</ref>
In 2015 researchers in Brazil identified α-humulene as an active contributor to the [[insect repellent]] properties of [[Commiphora|''Commiphora leptophloeos'']] leaf oil, specifically against “the yellow fever mosquito,” ''[[Aedes aegypti]]''.<ref name = JLassalle>{{cite web |url=https://cannigma.com/plant/terpenes/humulene/ |title=Humulene |author=Janelle Lassalle |date=2020-09-19 |website=The Cannigma |access-date=2021-01-27}}</ref><ref>{{cite journal | last1 =  Santos da Silva | first1 = R.C. | last2 = Milet-Pinheiro | first2 = P.
| last3 = Bezerra da Silva | first3 = P.C. | last4 = Gomes da Silva | first4 = A. | last5 = Vanusa da Silva | first5 = M. | last6 = Amaral Ferraz Navarro | first6 = D.M. | last7 = da Silva | first7 = N.H. | display-authors = etal | editor-last = Boudko | editor-first = Dmitri | title = (E)-Caryophyllene and α-Humulene: Aedes aegypti Oviposition Deterrents Elucidated by Gas Chromatography-Electrophysiological Assay of Commiphora leptophloeos Leaf Oil | journal = [[PLOS ONE]] | doi = 10.1371/journal.pone.0144586 | date=2015-12-19| volume = 10 | issue = 12 | pages = e0144586 | pmid = 26650757 | pmc = 4674132 | bibcode = 2015PLoSO..1044586D | doi-access = free }}</ref>
==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 quickly reacts with ozone in sunlight (photooxidation) to form oxygenated products. α-Humulene has a very high reaction rate coefficient (1.17 × 10<sup>−14</sup>&nbsp;cm<sup>3</sup> molecule<sup>−1</sup> s<sup>−1</sup>) compared to most monoterpenes. Since it contains three double bonds, first-, second- and third-generation products are possible that can each condense to form secondary organic aerosol. At typical tropospheric ozone mixing ratios of 30 ppb the lifetime of α-humulene is about 2 min, while the first- and second-generation products have average lifetimes of 1 h and 12.5 h, respectively.<ref>{{cite journal | last1 = Beck | first1 = M. | last2 = Winterhalter | first2 = R. | last3 = Herrmanna | first3 = F. | last4 = Moortgat | first4 = G. K. | year = 2011 | title = The gas-phase ozonolysis of α-humulene | journal = Phys. Chem. Chem. Phys. | volume = 13 | issue = 23| pages = 10970–11001 | doi=10.1039/c0cp02379e| pmid = 21461420 | bibcode = 2011PCCP...1310970B }}</ref>
== References ==
{{reflist|2}}
==Further reading==
*{{Cite journal |title=Gram-scale production of the sesquiterpene α-humulene with Cupriavidus necator |journal=[[Biotechnology and Bioengineering]] |last=Milker |first=Sofia |date=2021-04-12 |url=https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/bit.27788 |volume=118 |issue=7 |last2=Sydow |first2=Anne |last3=Torres-Monroy |first3=Ingrid |last4=Jach |first4=Guido |last5=Faust |first5=Frederik |last6=Kranz |first6=Lea |last7=Tkatschuk |first7=Ljubov |last8=Holtmann |first8=Dirk |language=en |page=2694 |doi=10.1002/bit.27788 |doi-access=free}}
[[Category:Cycloalkenes]]
[[Category:Sesquiterpenes]]
[[Category:Humulus]]