Article No : a26_205

Terpenes

MANFRED EGGERSDORFER, BASF Aktiengesellschaft, Ludwigshafen, Germany

1. General ...... 29 4.1. 3-Carene ...... 36 1.1. Definition and Basic Structures ...... 29 4.2. Pinane ...... 37 1.2. Occurrence ...... 31 4.3. 2-Pinane Hydroperoxide ...... 37 1.3. Biosynthesis ...... 31 4.4. 2-Pinanol ...... 38 1.4. Biodegradation ...... 31 4.5. Camphene ...... 38 1.5. Importance and Extraction ...... 31 5. Acyclic Sesquiterpenes...... 39 2. Acyclic Monoterpenes ...... 33 6. Monocyclic Sesquiterpenes ...... 39 2.2. Myrcene...... 33 6.1. Bisabolene ...... 39 2.3. Ocimene...... 34 6.2. Bisabolol ...... 40 2.4. 2,6-Dimethyl-2,4,6-octatriene ...... 34 7. Bicyclic Sesquiterpenes ...... 40 3. Monocyclic Monoterpenes ...... 34 8. Tricyclic Sesquiterpenes ...... 40 3.1. p-Menthane ...... 34 9. Acyclic Diterpenes ...... 41 3.2. a-Terpinene ...... 35 10. Acyclic Triterpenes ...... 41 3.3. Terpinolene ...... 35 11. Toxicology ...... 41 3.4. p-Cymene...... 35 References ...... 43 3.5. 1,8-Cineole ...... 36 4. Bicyclic Monoterpenes ...... 36

1. General the molecule during biosynthesis. The broader term terpenoids also covers natural degradation 1.1. Definition and Basic Structures products, such as ionones, and natural and syn- thetic derivatives, e.g., terpene alcohols, alde- Terpenes are natural products, whose structures hydes, ketones, acids, esters, epoxides, and hy- are built up from isoprene units. They are classi- drogenation products. fied according to the number of these units: An overview of the most important basic structures demonstrates the structural variety of terpenes [8]. The compounds are normally

Monoterpenes C10 known by their trivial names, as the systematic Sesquiterpenes C15 nomenclature is frequently less practicable for Diterpenes C20 complicated structures. Sesterpenes C25 Triterpenes C30 Tetraterpenes C40

Terpenes can be acyclic, or mono-, bi-, tri-, tetra-, and pentacyclic with 3-membered to 14- membered rings [1–7]. Deviations from the rule occur through rear- rangement reactions or degradation of parts of

2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/14356007.a26_205 30 Terpenes Vol. 36 Vol. 36 Terpenes 31

Monoterpenes are formed by stereospecific condensation of IDP with DMADP, whereby a diphosphate anion (PP) is eliminated from DMADP. Geranyl diphosphate is thus formed in a head-to-tail condensation. Neryl diphosphate with the Z-double bond is formed when the S- proton in isopentenyl diphosphate is eliminated stereospecifically. Neryl diphosphate is also formed from geranyl diphosphate by double bond isomerization. The hydrolysis of geranyl or neryl diphos- phate by a prenolpyrophosphatase gives the monoterpene alcohols geraniol and nerol. The acyclic monoterpene hydrocarbons, such as myr- cene and ocimene, are formed by dehydration and isomerization of geraniol. The monoterpene aldehydes geranial and neral are formed from geraniol, and the biosynthesis of cyclic mono- terpenes involves the loss of diphosphate from neryl diphosphate. The carbonium ion formed is stabilized by ring closure, sometimes after rear- rangement, elimination of a proton, or addition of an anion. 1.2. Occurrence The head-to-tail condensation of IDP with geranyl diphosphate gives farnesyl diphosphate, Terpenes occur everywhere and in all organisms, which rearranges further to give geranylgeranyl in particular in higher plants. Certain compo- diphosphate. A large number of sesqui-, di-, and nents or their combinations are often character- polyterpenes are formed from farnesyl and ger- istic of individual types of plant, so terpenes are anyl diphosphates in the same way as the mono- used for chemotaxonomy [8]. In vegetable raw terpenes. Triterpenes (and hence, steroids) are materials mono- and sesquiterpenes are predom- formed by head-to-head condensation of two C15 inantly found in essential oils [9], [10], sesqui-, units (farnesyl diphosphate), and tetraterpenes di-, and triterpenes in balsams and resins [11], from two molecules of geranylgeranyl diphos- tetraterpenes in pigments (carotenoids) [12], and phate. polyterpenes in latexes [13]. Animal organisms also contain terpenes and terpenoids, which are predominantly incorporated by consumption of 1.4. Biodegradation plants. Terpenes are degraded by microorganisms, such as Pseudomonas and Aspergillus species [17]. 1.3. Biosynthesis Generally both acyclic and cyclic terpenes are oxidized. Plants are known to be capable of The biosynthesis of terpenes was explained by degrading as well as forming terpenes. F. LYNEN. Starting from (3 R)-(þ)-mevalonic In animals acyclic terpenes are degraded by acid (C6), isopentenyl diphosphate (IDP) and di- w-, a- and/or b-oxidation and cyclic terpenes by methylallyl diphosphate (DMADP) [8], [14–16] hydroxylation (elimination as glucuronides). are formed by decarboxylation and isomerization as active C5 building blocks (Scheme 1). (3 R)- (þ)-Mevalonic acid is formed from three C2 units 1.5. Importance and Extraction from acetyl-CoA [8]. Plants synthesize IDP in the chloroplasts, mitochondria, and microsomes; Since the study of organic chemistry began, it has animals synthesize IDP in the liver. been intensively concerned with terpenes. Many 32 Terpenes Vol. 36

Figure 1. Biosynthesis of terpenes reactions, such as the Wagner – Meerwein rear- synthesis of other optically active products and rangement, theories of conformational analysis, reagents for cleaving racemates [18]. and the Woodward – Hoffmann rules have their Various essential oils and the terpenes isolat- basis in terpene chemistry. The postulation of the ed from them are still used in pharmaceutical isoprene rule by O. WALLACH (1887) and its preparations, e.g., turpentine, camomile oil, eu- confirmation and extension by L. RUZICKA calyptus oil, and camphor. The activity of some (1921, 1953) gave this area of chemistry direc- plants used in medicine and flavoring is due to tion and unity. their terpene content [19]. Terpenes are also used Monoterpenes and a few sesquiterpenes are in the production of synthetic resins [20–22], and important economically as perfumes and fra- as solvents or diluting agents for dyes and grances (! Perfumes, ! Flavors and Fra- varnishes [23]. grances). Depending on the properties, terpenes In the following sections only the industrially (mostly essential oils) are obtained from the cor- most important terpenes are dealt with, insofar as responding plants by steam distillation, extrac- they are not part of other articles (! Flavors and tion, or enfleurage. The pure terpenes are mostly Fragrances, ! Turpentines, and ! Tall Oil). isolatedfromtheextractsbyfractionaldistillation. For natural resins, gibberellic acid (! Plant As readily available, optically active pro- Growth Regulators), vitamins A and E (! Vi- ducts, some monoterpenes, such as ()-a-pinene tamins, 2. Vitamin A (Retinoids), ! Vitamins, and ()- and (þ)-limonene are used for the 4. Vitamin E (Tocopherols, Tocotrienols)), Vol. 36 Terpenes 33 triterpenes (! Steroids), tetraterpenes, and the Although myrcene occurs naturally in many other terpenes the specialist literature must be organisms, its extraction is uneconomic; it is consulted. produced industrially by pyrolysis of b-pinene [24]. 2. Acyclic Monoterpenes

The following acyclic terpenes and terpene deri- vatives are described elsewhere (! Flavors and Fragrances): The fragmentation of linalool and linalyl ace- Alcohols:geraniol, nerol, linalool, myrcenol, tate and the catalytic dimerization of isoprene citronellol, dihydromyrcenol, tetrahydrogera- have been described as laboratory methods [25]. niol, and tetrahydrolinalool. Because of its functionality, myrcene is the starting material for a range of industrially im- Aldehydes and Acetals:citral, citraldimethyla- portant products, e.g., geraniol, nerol, linalool, cetal, citronellal, hydroxydihydrocitronellal, hy- and isophytol [26]. Addition of hydrogen chlo- droxydihydrocitronellal dimethylacetal, and ride is industrially important. Depending on re- methoxydihydrocitronellal action conditions, this gives 1- chloro-3,7-di- methyl-2,6-octadiene (geranyl chloride and/or Esters and Nitriles:geranyl formate, acetate, neryl chloride), 3- chloro-3,7-dimethyl-1,6-octa- isobutyrate, isovalerate, phenylacetate, and pro- diene (linaloyl chloride), and 7- chloro-7-meth- pionate; neryl acetate; linalyl acetate, butyrate, yl-3-methylen-1-octene (myrcenyl chloride) formate, isobutyrate, and propionate; lavanduyl [27]. The alcohols are produced from the chlor- acetate; and citronellyl acetate, formate, isobu- ides by saponification. tyrate, isovalerate, propionate, and tiglate.

2.2. Myrcene

Myrcene [123-35-3], 2-methyl-6-methylene- 2,7-octadiene, C10H16, Mr 136.23, is a colorless liquid with a pleasant odor.

Some physical properties are listed below: The 1,3-diene system of myrcene reacts with a large number of dienophiles. For example, the bp 166 – 168 C (101.3 kPa) maleic anhydride adduct is used to characterize d 20 0.7905 and determine the quality of the product [28]. 20 1.4697 nD Isophytol is formed by transition-metal- cata- 50 C mp lyzed addition of malonic ester and subsequent acidification [29]. Myrcene is very reactive. It polymerizes slow- In the hydrogenation of myrcene 2,6-dimeth- ly at room temperature. For this reason it is stored yl-2,6-octadiene, 2,6-dimethyl-2,7-octadiene, in a cool place from which light and air are and 2,6-dimethyloctane are formed, depending excluded. It can be stabilized by the addition of on the catalyst and the reaction conditions [30:1H 0.1 % 4-(tert-butyl)catechol. 260, 1EIII 1054]. 34 Terpenes Vol. 36

Besides its main use as an intermediate for the (4E,6Z )-2,6-Dimethyl-2,4,6-octatriene, C10H16, production of terpene alcohols, myrcene is used Mr 136.23, is a colorless liquid with an intense in the production of terpene polymers [20], ter- odor, and is sensitive to oxidation. pene – phenol resins [21], and terpene – male- ate resins [22]. It can also be used as a solvent or diluting agent for dyes and varnishes [23]. bp 80 C (1.9 kPa) d 20 0.8161 n20 1.5437 2.3. Ocimene D

Ocimene [673-84-7], (Z, E )-2,6-dimethyl-2,5,7- (4E,6Z )-2,6-Dimethyl-2,4,6-octatriene is octatriene, C10H16, Mr 136.23, is a colorless liquid with a pleasant odor. produced as a mixture with other products by the thermolysis of a-pinene at 350 C [35], or by heating Z-ocimene to 190 C [36]. The products are separated by fractional distillation. (4E,6E )-2,6-Dimethyl-2,4,6-octatriene, C10H16, Mr 136.23, has physical properties simi- lar to those of the (4E,6Z )-isomer.

The Z/E mixture has the following properties:

bp 79 C (1.9 kPa) 20 0.8106 d bp 176 – 178 C (101.3 kPa) 20 nD 1.5438 d 20 0.800 20 nD 1.4862 mp 50 C (4E,6E )-2,6-Dimethyl-2,4,6-octatriene is formed as a mixture with the (4E,6Z )-isomer Ocimene is very sensitive to oxidation and and other products in the thermolysis of pinene at therefore can be kept for long periods only with 320 – 330 C [37], by dehydration of 3,7-di- the exclusion of air. At elevated temperatures it methyl-3,6-octadien-1-ol [38], and by treating rearranges to alloocimene [31]. Z-ocimene with base [39]. Ocimene is produced by the flash pyrolysis or 2,6-Dimethyl-2,4,6-octatriene is used to a photochemical isomerization of a-pinene [32]. small extent in the perfume industry. It is also Ocimene is mainly used as a perfume compo- used as a diluting agent for varnishes and dyes nent. The derivatives ocimenol (2,6-dimethyl- [23], and as a component for terpene polymers 5,7-octadien-2-ol), produced by acid- catalyzed [20], [22]. hydration, and the partially and completely hy- drogenated products are also important [33], [34]. 3. Monocyclic Monoterpenes 3.1. p-Menthane 2.4. 2,6-Dimethyl-2,4,6-octatriene p-Menthane[99-82-1], 1-isopropyl-4-methylcy- 2,6-Dimethyl-2,4,6-octatriene exists as two clohexane, C10H20, Mr 140.25, occurs widely as stereoisomers: a cis/trans mixture, e.g., in essential oils in the eucalyptus fruit. Vol. 36 Terpenes 35

The cis/trans mixture of p-menthane is a 3.3. Terpinolene colorless liquid with a fennel-like odor. Terpinolene [586-62-9], 4-isopropylidene-1- methyl-1- cyclohexane, C10H16, Mr 136.23, oc- cis-1-Isopropyl-4-methylcyclohexane curs in many essential oils and in sulfate turpen- bp 168.8 C (99.2 kPa) tine. d 20 0.8086 20 nD 1.4443 trans-1-Isopropyl-4-methylcyclohexane mp 86 C bp 168.1 C (99.2 kPa) d 20 0.7941 20 nD 1.4369 Terpinolene is a colorless liquid with an odor p-Menthane is obtained as a cis/trans mixture resembling that of turpentine. by the catalytic hydrogenation of limonene, ter- pinols, and p- cymene [40]. Raney nickel, plati- bp 186 C num, or copper and aluminum oxides are used as d 20 0.8623 20 1.4861 catalyst [41]. nD p-Menthane is predominantly used as a pre- cursor in the production of 1-isopropyl-4- It forms a hydroperoxide on autoxidation [45], methylcyclohexane hydroperoxide, a catalyst for [46]. radical polymerization [42]. Terpinolene used to be extracted by fractional distillation of wood turpentine [46]. It is now produced by treating a-pinene with aqueous 3.2. a-Terpinene H3PO4 at 75 C [47]. It is preferable to distill terpinolene under vacuum to minimize the for- a-Terpinene [99-85-4], 4-isopropyl-1-methyl- mation of polymeric products at elevated temperatures. 1,3- cyclohexadiene, C10H16, Mr 136.23, is the main component of terpinene, the other compo- Terpinolene is mainly used to improve the odor nents being the b- and g-isomers. It occurs in of industrial and household products [48–50]. various essential oils, almost always as a mixture with its isomers. 3.4. p-Cymene

p-Cymene [99-87-6], 4-(isopropyl)methylben- zene, C10H14, Mr 134.21, is the main component of sulfite turpentine and occurs in many essential oils [51].

a-Terpinene is a colorless liquid with a lem- on-like odor. It resinifies on prolonged storage. bp 172.5 – 173.5 C p-Cymene is a colorless liquid with an odor 20 1.4780 nD typical of aromatic hydrocarbons.

a-Terpinene is obtained by fractional distilla- mp 67.7 C tion of pine oil [43] and by the thermolysis of a- bp 177.3 C pinene in the presence of catalysts, such as d 20 0.8573 20 1.4906 manganese oxide [44]. nD a-Terpinene is used in essential oils and as an intermediate for perfumes. The enthalpy of evaporation is 44.670 J/mol. 36 Terpenes Vol. 36

p-Cymene undergoes catalytic hydrogenation other terpenes, for example, treatment with to 1-isopropyl-4-methylcyclohexane [40]. It H2SO4 in the cold [60], distillation in the pres- must be stored in the absence of light and air. ence of phenols, such as cresols or resorcinol p-Cymene is formed during the sulfite leach- [61], which form loose addition compounds, or ing of wood [52]. A range of production process- by addition to b-naphthol [62]. 1,8-Cineole can es starting from mono- and bicyclic terpenes also be enriched by rectification. The yield is have also been described. For example, p- cym- increased by gasification in the presence of a ene is obtained in good yields from a-pinene in chromium – nickel catalyst [63]. the presence of copper catalysts [53], [54]. In this 1,8-Cineole is used as a perfume and fra- process a significant proportion of 1-isopropyl-4- grance. In the past it was also used as an expec- methyl- cyclohexane is also formed, which is torant and an antiseptic. dehydrogenated in the presence of palladium catalysts at 260 – 280 Ctop- cymene [55]. The Friedel – Crafts alkylation of toluene with pro- 4. Bicyclic Monoterpenes pene is used industrially [56]. Products contain- ing more than one isopropyl group are converted The industrially most important bicyclic mono- terpenes are subdivided into caranes, pinanes, into p- cymene with aluminum chloride and hy- drochloric acid [57]. and bicyclo[2.2.1]heptanes, depending on their basic structure. p-Cymene is used to improve the odor of soaps and as a masking odor for industrial pro- ducts. Its use as an intermediate for musk per- 4.1. 3-Carene fumes [58], the oxidation to terephthalic acid, and its addition to antiseptic preparations have 3-Carene [498-15-7], 3,7,7-trimethylbicyclo- also been described [59]. p-Cymene is also used [4.1.0]hept-3-ene, C10H16, Mr 136.23, occurs in as a solvent for dyes and varnishes. a rangeof turpentines as the enantiomerically pure compound, but also as the racemate [64], [65]. 3.5. 1,8-Cineole

1,8-Cineole [470-82-6], 1,8-epoxy-p-menthane, eucalyptol, C10H18O, Mr 154.25, occurs widely in natural essential oils, mainly eucalyptus oil. 3-Carene is a colorless compound with a sweet, penetrating odor.

bp 176 – 176.4 C 20 d4 0.9232 20 nD 1.4575 25 ½aD þ17.6 (undiluted) 1,8-Cineole is a colorless liquid. Its odor and taste resemble those of camphor. It readily undergoes autoxidation and resini- fication in air. Addition of pyrogallol or resor- mp 1.55 C cinol as stabilizers is recommended [66]. On bp 176 – 176.4 C treatment with peracetic acid in glacial acetic d 20 0.9232 20 acid and subsequent saponification, 3- carene is nD 1.4575 oxidized to 3,4- caranediol [67]. On warming, particularly in the presence of acids, 1,8- cineole forms other terpenes of the p- menthane type. It reacts with a range of sub- stances, forming sparingly soluble products. 1,8-Cineole is extracted exclusively from eu- calyptus oils with a high 1,8- cineole content. Various processes are used to separate it from the Vol. 36 Terpenes 37

Pyrolysis at 300 – 580 C in the presence of FeIII oxide on carriers gives p- cymene as the main product [68]. 3-Carene is obtained exclusively by fractional distillation of certain turpentines [69]. 3-Carene is predominantly used in the per- fume industry for producing essential oils [70]. It is also an intermediate in perfume synthesis and a cis-Pinane is obtained, together with small precursor for insecticides of the pyrethroid type quantities of -pinane, by the catalytic hy- [71], [72]. trans drogenation of a- and b-pinene. If ()-a- and ()-b-pinene are hydrogenated, the ()-enantio- mer is obtained, and from the (þ)-pinenes, (þ)- 4.2. Pinane cis-pinane. In industry, a-pinene is predominant- ly used for the hydrogenation. Raney nickel, Pt, Pinane [ ], 2,6,6-trimethylnorpinane, 473-55-2 or Pd (and their oxides) on carriers are used as 2,6,6-trimethylbicyclo[3.1.1]heptane, C H , 10 18 catalysts [77], [78]. The hydrogenation with 138.25. Mr Raney nickel is carried out at 2 – 10 MPa at 150 C. In the presence of halogen compounds cis-pinane is obtained predominantly [79]. trans-Pinane can be obtained from b-pinene by treatment with sodium borohydride in the presence of boron trifluoride in di(ethylene gly- Pinane derivatives occur in wood, the leaves col) and subsequent heating of the reaction mix- of many plants, algae, and insects. Pinane itself ture in propionic acid [80]. apparently does not occur naturally. However, it Pinane is used in industry for the production of is formed on hydrogenation of pinane derivatives pinane hydroperoxide [81]. It is also important as [73]. an intermediate in the production of 3,7-dimethy- cis-Pinane (colorless liquid) locta-1,6-diene, which is used to produce per- fumes, such as citronellol, citronellal, and hydroxycitronellal. bp 167.2 – 168 C 20 d4 0.8575 20 nD 1.4626 25 4.3. 2-Pinane Hydroperoxide ½aD 23.6 (undiluted) 2-Pinane hydroperoxide [5405-84-5], 2,6,6-tri- methylbicyclo[3.1.1]heptane-2-hydroperoxide, trans-Pinane (colorless liquid) C10H18O2, Mr 170.25, is a colorless liquid, which is readily flammable and insoluble in water. bp 164 C 20 d4 0.854 20 nD 1.4610 25 ½aD þ21.4 (undiluted)

The oxidation of pinane with air or oxygen bp 48 – 52 C (1.3 Pa) gives 2-pinane hydroperoxide or 2-pinanol [74]. 20 d4 1.021 In industry, oxidation is carried out in the pres- 20 nD 1.4898 25 ence of catalysts [75]. ½aD 27.4 (undiluted) The pyrolysis of ()-(1S )- cis-pinane at 500 C gives a mixture of (3R)-3,7-dimethyl- On heating 2-pinane hydroperoxide to > 110 1,6-octadiene and (1 )-isopropyl-2,3-dimethyl- R C 1-((1R)- cis-3-ethyl-2,2-dimethylcyclobutyl) cyclopentane [76]. ethanone is formed [82]. (1R,2S )-2-pinanol is 38 Terpenes Vol. 36 formed in good yields by catalytic hydro- aqueous sodium hydroxide [93] or with sodium genation. methoxide [94]. cis-2-Pinanol can also be ob- 2-Pinane hydroperoxide is produced by oxi- tained directly from pinane by air oxidation in the dation of pinane with air or oxygen at 95 C presence of alkalis, such as sodium hydroxide, at [83–85]. cis-Pinane reacts more rapidly than 80 – 100 C [95]. trans-pinane [86]. 2-Pinanol is used to produce linalool by py- 2-Pinane hydroperoxide is used as a radical rolysis [96]. initiator for polymerization reactions [87], e.g., for the polymerization of diolefins and aromatic vinyl compounds, or for hardening unsaturated 4.5. Camphene polyester resins. It is also an intermediate in the production of perfumes, such as pinanol, linalool, Camphene [5794-03-6], 2,2-dimethyl-3-methy- nerol, and geraniol [88]. lenenorbornane, C10H16, Mr 136.23, occurs in a large number of essential oils in optically active form, both as the R and S enantiomers. 4.4. 2-Pinanol

2-Pinanol [473-54-1], 2,6,6-trimethylbicyclo [3.1.1]heptan-2-ol, C10H18O, Mr 154.25, is ob- tained as the cis or trans isomer, depending on the production process. Camphene is a colorless, crumbly crystalline solid with a camphor-like odor. It has a tendency to sublime.

mp 52.5 C -2-Pinanol forms colorless crystals with a bp 157.8 C (98.8 kPa) cis 25 d4 0.84225 camphor-like odor. 54 nD 1.4564 25 ½aD þ106.8 (CHCl3, 44 g/L) mp 78 – 79.2 C bp 90 – 91 C (1.5 kPa) Camphene is stable in air and light. At elevat- ½a25 24.5 (CHCl ,C¼ 8 g/L) D 3 ed temperatures, in the presence of oxygen, it undergoes autoxidation to camphenilone [97]. Peracids attack the double bond, giving cam- trans-2-Pinanol forms colorless needles. phene oxide [98]. Catalytic hydrogenation gives the saturated hydrocarbon isocamphane [99]. mp 58 – 59 C bp 88 – 89 C (0.12 kPa) 25 ½aD 2.3 (ether, 10 g/L)

The pyrolysis of 2-pinanol at 500 C gives linalool. ()-Linalool is formed from (þ)- cis- and ()-trans-2-pinanol, and (þ)-linalool from ()- cis- and (þ)-trans-2-pinanol. The process is used industrially [89], [90]. cis-2-Pinanol is produced industrially by the catalytic hydrogenation of 2-pinane hydroperox- ide [91], [92]. Alternatively 2-pinane hydroper- The extraction of camphene by distillation of oxide can be treated with sodium sulfide in turpentine is now hardly used in industry. Instead Vol. 36 Terpenes 39 camphene is produced from a-pinene. Mixtures of a- and b-farnesenes are obtained by heating farnesol with potassium hydrogen sulfate to 160 – 170 C [108]. Other syntheses of the mixture, involving dehydration of farnesol, nerolidol, and isoprene, have also been described [109], [110]. (þ)-a-Pinene is converted into (þ)-bornyl Farnesene is used in small quantities in the chloride by the action of dry hydrogen chloride fragrance industry. in a Wagner – Meerwein rearrangement. Base- catalyzed dehydrohalogenation of the (þ)-bor- nyl chloride gives racemic camphene [100], 6. Monocyclic Sesquiterpenes [101]. The reaction of a-pinene with boropho- 6.1. Bisabolene sphoric acid in the gas phase [102], or on TiO2 catalysts [103] has also been described. Camphene is used to improve the odor of Bisabolene, C15H24, Mr 204.33, occurs in myrrh industrial products. It is an intermediate in the oil and limett oil. The isomers a-, b-, and g- production of camphor, isobornyl esters, and the bisabolene are known. insecticide Toxaphen.

5. Acyclic Sesquiterpenes

Farnesene. a-Farnesene, 2,6,10-trimethyl- 2,6,9,11-dodecatetraene, C15H24, Mr 204.36. a- and b-Farnesenes and their Z- and E-iso- mers occur in many essential oils, e.g., in apples a-Bisabolene, (E, Z )-4-(1,5-dimethyl-1,4- [104], citrus fruits [105], and hop oil. a-Farne- hexadienyl)-1-methyl-1- cyclohexane sene is a natural attractant for the larvae of the bp 95 C (0.02 kPa) codlin moth [106]. It is also found in the gland b-Bisabolene, 1-methyl-4-(5-methyl-1-meth- secretions of certain ants [107]. ylene-4-hexenyl)-1- cyclohexane

bp 148 C (2.4 kPa) 15 nD 1.4893 25 ½aD 67 (undiluted)

g-Bisabolene, ( )-4-(1,5-dimethyl-4-hex- a- and b-Farnesenes are colorless liquids with E, Z enylidene)-1-methyl-1- cyclohexene fruity odors. They are sensitive to autoxidation and can be stored for long periods only with the exclusion of light and air. bp 132 C (1.4 – 1.6 kPa) 25 nD 1.4928 a-Farnesene bp 98 – 102 C (0.5 kPa) 25 nD 1.4790 The individual isomers and their mixtures are b-Farnesene colorless liquids with pleasant, balsamic odors. bp 95 – 107 C (0.5 kPa) Isomer mixtures are produced by treating d 20 0.8363 20 nerolidol and farnesol with acid [111]. Targeted nD 1.4899 Mixture syntheses of a- and b-bisabolene by the Wittig bp 129 – 132 C (1.2 kPa) reaction have been described [112–114]. 18 d 0.8770 Bisabolene mixtures are used in the perfume 20 1.4995 nD and fragrance industries. 40 Terpenes Vol. 36

6.2. Bisabolol undecene, C15H24, Mr 204.36, occurs in many essential oils. Bisabolol [515-69-5], C15H26O, Mr 222.37, oc- curs in various plants.

Caryophyllene is a colorless, oily liquid with an odor resembling that of cloves.

(þ)-a-Bisabolol, (þ)-2-methyl-6-(4-methyl- bp 254 – 256 C 3- cyclohexenyl)-6-hepten-2-ol 20 d4 0.9019 20 nD 1.4995 25 ½aD 9.2 (undiluted) bp 120 – 122 C (0.13 kPa) 20 d4 0.9213 Catalytic hydrogenation on platinum gives tet- 20 1.4919 nD rahydrocaryophyllene [118], and on palladium a ½a25 þ51.7 (undiluted) D dihydrocaryophyllene [119]. On oxidation with potassium permanganate, a glycol (mp 120 – ()-a-Bisabolol, ()-2-methyl-6-(4-methyl- 120.5 C) is formed [120], and with perbenzoic 3- cyclohexenyl)-6-hepten-2-ol acid[121]orperaceticacid,acaryophylleneoxide. Caryophyllene is best extracted from clove bp 153 C (1.59 kPa) oil. It can also be obtained from other sources, 20 d4 0.9211 such as certain American pine oil fractions. 20 1.4936 nD Caryophyllene is used as a perfume and fra- [a]D 55.7 (undiluted) grance, for example in chewing gum (ca. 200 mg/kg). It is also used as a fixative. It can rac-Bisabolol, 2-methyl-6-(4-methyl-3- cy- be used as an intermediate in the synthesis of clohexenyl)-6-hepten-2-ol other perfumes and fragrances [123].

bp 157 C (1.59 kPa) 23 8. Tricyclic Sesquiterpenes d4 0.9223 23 nD 1.4917 Longifolene. Longifolene [475-20-7], 3,3,7-trimethyl-8-methylenetricyclo[5.4.0.9-Z9] The bisabolols are colorless liquids with undecane, C15H24, Mr 204.36, occurs in the d- slightly flowery odors. and l-forms in a range of essential oils. Indian rac-Bisabolol is produced by acid- catalyzed turpentine contains up to 20 % longifolene. cyclization of farnesol or nerolidol [115]. The individual enantiomers are obtained by extrac- tion from the appropriate plants. Because of their anti-inflammatory and spas- molytic properties [117], both ()- and rac-bi- sabolol are predominantly used in the cosmetics industry and to a small extent in the pharmaceu- tical industry. Longifolene is a colorless, oily liquid.

7. Bicyclic Sesquiterpenes bp 254 – 256 C (93.9 kPa) 18 d4 0.9319 20 nD 1.5040 Caryophyllene. Caryophyllene [87-44-5], [a] þ42.73 (undiluted) 6,10,10-trimethyl-2-methylenebicyclo[7.2.0]-5- D Vol. 36 Terpenes 41

Longifolene forms crystalline products with oil [136], in vegetable fats and oils [137], and in hydrogen halides [124]. On treatment with bro- human skin fat. mine followed by N,N-dimethylaniline, w-bro- molongifolene is formed, and with nitrogen oxi- des w-nitrolongifolene [125]. Longifolene is obtained by distillation, e.g., Indian turpentine. Longifolene is used as a solvent additive. It Squalene is a colorless, air-sensitive, almost has been described as a starting material for the odorless liquid. production of perfumes, e.g., by oxidation [126], or by treatment with formic acid [127].

bp 223 – 226 C (0.26 kPa) 20 d4 0.8577 25 9. Acyclic Diterpenes nD 1.4961

Phytol. Phytol [150-86-7], (7R,11R)- 3,7,11,15-tetramethyl-trans-2-hexadecen-1-ol, Squalene is extracted from shark liver [138] C20H40O, Mr 295.52, is formed by saponification or synthesized from hexaphenyl-1,4-butane- of chlorophyll. diyldiphosphonium dibromide and 6,10-di- methyl-5,9-undecadien-2-one (geranylacetone, industrial intermediate in the vitamin E synthe- sis) [139]. Squalene is hydrogenated on platinum or Phytol is a colorless liquid with a slightly nickel catalysts to dodecahydrosqualene (perhy- flowery odor. The action of acids or heat effects drosqualene, squalane, cosbiol) [140], which is dehydration to phytadiene. widely used in cosmetics [141], [142].

bp 136 C (1.3 kPa) 11. Toxicology 21 d4 0.8533 25 1.4637 nD There are excellent reviews of the toxicology of terpenes [143]. The known toxicological test Phytol can be obtained from natural raw ma- results (Table 1) show that most terpenes have terials by a variety of processes [128]. The in- low acute oral toxicity and, in spite of occasion- dustrial synthesis of phytol starts from isophytol. ally good skin resorption, low dermal toxicity. The latter is first treated with formic acid to give Some are irritant to the skin of rabbits in concen- phytyl formate, from which (Z, E )-phytol (iso- trated form, but a 4 – 16 % solutions in vaseline, mer ratio 3 : 7) is obtained by saponification or are generally not irritant to humans. Only 3- transesterification [129]. carene, which occurs in turpentine, has been Phytol is used in the perfume and cosmetics shown to have a sensitizing potential in humans industries [130]. It can also be used, like iso- and animals. phytol, as the starting material for the synthesis of To investigate detoxification in mammals, a vitamins E and K1 [131–133]. The hydrogenation metabolism study on rabbits has been carried out. and oxidation products are also known [134]. On oral administration several characteristic ox- idation reactions have been detected:

10. Acyclic Triterpenes 1. Stereoselective oxidation: formation of 3- ca- ren-9-ol, 3- caren-9- carboxylic acid, and 3- Squalene. Squalene [111-02-4], 2,6,10,15, caren-9,10-dicarboxylic acid from 3- carene 19,23-hexamethyltetracosa-2,t-6,t-10,t-14,t-18, 2. Regioselective oxidation: 3,10-myrcenediol, r-22-hexaene, C30H50, Mr 410.73, occurs in liver 1,2-myrcenediol, and 2-hydroxymyrcene-1- oils of various species of shark [135], in cod-liver carboxylic acid from myrcene 42 Terpenes Vol. 36

Table 1. Toxicity data for terpenes

Acute Acute oral oral toxicity toxicity Irritation of Sensitiza- (rat), (rabbit), Skin irritation rabbit eye tion (H ¼ Specific

LD50,g/ LD50,g/ Skin (R ¼ rabbit; mucous human; G ¼ properties/ Substance kg kg resorption IRT* (rat) H ¼ human) membrane guinea pig) tests References

Myrcene >5 >5 þ R: moderately H: negative [145] irritant; H: 4 % not irritant Ocimene >5 >5 R: moderately H: negative [145] irritant; H: 5 % not irritant a-Terpinene 1.68 H: 5 % not H: negative damage to irritant liver and blood (forms methemoglobin) [145] Terpinolene 4.39 >5 R: not irritant; H: H: negative [145] ml/kg 20 % not irritant p-Cymene 4.74 >5 þ 0/6 after 6 h H: irritant; R: not irritant H : negative affects cen- [145], [146] irritant; H: 4 % tral nervous not irritant system (narcosis) 1,8-Cineole 2.48 >5 R: not irritant; H: H: negative canceriza- [145], [146] 16 % not irritant tion study in progress 3-Carene 4.8 >5 R: irritant H: positive [145] G: positive Camphene >5 2.5 þ R: slightly irri- H: negative [145], [146] tant; H: 4 % not irritant Bisabolene >5 >5 0/12 after R: slightly irri- not irritant H: negative 7h tant; H: 10 % not irritant Bisabolol >5 >5 0/12 after R: not irritant slightly [146] 7h irritant Caryophyllene >5 >5 R: irritant; H: H: negative 4 % not irritant** Phytol >10 R: moderately not irritant [145], [146] irritant * IRT: inhalation risk test (rat, test result dependent on toxicity and volatility; 0/6 after 6 h means that after 6 h exposure in an enriched or saturated atmosphere at room temperature no animals died). ** In light petroleum jelly.

3. Allylic oxidation: verbenol and myrtenic acid from a-pinene, and pinocarveol from b- pinene Table 2. Terpenes licensed as food additives 4. Homoallylic oxidation: 6-exo-hydroxycam- phene and 10-hydroxytricyclene from Substance Licensing authority camphene Myrcene FDA (GRAS classification), European Council 5. Hydrolysis of epoxides: camphenediol from Ocimene FDA, European Council camphene a-Terpinene FDA Terpinolene FDA, European Council With - cymene, three different oxidation p-Cymene FDA p 1,8-Cineole FDA, European Council products were detected in the first step. The Camphene FDA, European Council alcohols 2-(4-methylphenyl)-1-propanol and 2- Caryophyllene FDA, European Council (4-methyl-phenyl)-2-propanol are formed by the FDA ¼ Food and Drug Administration; w- and (w-1)-oxidation of the isopropyl group, GRAS ¼ generally recognized as safe. Vol. 36 Terpenes 43 and 4-isopropylbenzyl alcohol by oxidation of 20 C. D. Ender, Nav. Stores Rev. 66 (1956) 10. W. H. 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133 Nisshin Flour Milling, JP-Kokai 10 235, 1960. Further Reading 134 E. Jellum, L. Eldjarn, K. Try, Acta Chem. Scand. 20 (1966) 2535. (1947 – 1973) R. G. Berger (ed.): Flavours and Fragrances, Springer, 135 M. Tsujmoto, Chem. Zentralbl. 1918 I, 638, 1048. Berlin 2007. 136 J. C. Drummond, H. J. Channon, K. H. Coward, Bio- E. Breitmaier: Terpenes, Wiley-VCH, Weinheim 2006. 19/23 (1919/1923) 1055/279. chem. J. K. Husn€ u€ Can Baser, G. Buchbauer (eds.): Handbook of 137 K. T€aufel, H. Thaler, H. Schreyegg, Fettchem. Umsch. Essential Oils, CRC Press/Taylor & Francis, Boca Raton, 43 (1936) 26. FL 2010. 138 M. Hamaya, JP-Kokai 00 3158, 1977. J.-M. Kornprobst: Encyclopedia of Marine Natural Products, 139 D. W. Dicker, M. L. Whiting, J. Chem. Soc. 1958, 1994. Wiley-VCH, Weinheim 2010. 140 J. M. Heilbron, T. P. Hildrich, E. D. Kamm, J. Chem. J. H. Langenheim: Plant Resins, Timber Press, Portland, OR Soc. 1926, 3135. 2003. 141 H. Janistyk: , Handbuch der Kosmetik und Riechstoffe A. E. Osbourn, V. Lanzotti (eds.): Plant-derived Natural 2nd ed., vol. 1,Huthig€ Verlag, Heidelberg 1969, p. 753. Products, Springer, New York, NY 2009. 142 E. S. Lower, 1 (1981) no. 1, 34. Spec. Chem. C. S. Sell: Terpenoids, ‘‘Kirk Othmer Encyclopedia of 143 E. L. J. Opdyke (ed): Monographs on Fragrance Raw Chemical Technology’’, 5th edition, John Wiley & Sons, Materials, Pergamon Press, Oxford 1979. Hoboken, NJ, online DOI: 10.1002/0471238961. 144 T. Ishida et al.: ‘‘Biotransformations of Terpenoids in 2005181602120504.a01.pub2. Mammals, ’’ 93 (1980) 8986003. Chem. Abstr. H. Surburg, J. Panten: Common Fragrance and Flavor Ma- 145 terials, 5th ed., Wiley-VCH, Weinheim 2006. 146 NIOSH: Registry of Toxic Effects of Chemical Sub- stances 1979, II, Washington, D. C., 1979, p. 33.