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| Names | |
|---|---|
| Preferred IUPAC name 5-(Prop-2-en-1-yl)-2H-1,3-benzodioxole | |
| Other names 5-(2-Propenyl)-1,3-benzodioxole 5-Allylbenzo[d][1,3]dioxole 3,4-Methylenedioxyphenyl-2-propene | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| ECHA InfoCard | 100.002.133 |
| EC Number |
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| KEGG |
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| RTECS number |
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| UNII | |
| UN number | 3082 |
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| Properties | |
| C10H10O2 | |
| Molar mass | 162.188 g·mol−1 |
| Density | 1.096 g/cm3 |
| Melting point | 11 °C (52 °F; 284 K) |
| Boiling point | 232 to 234 °C (450 to 453 °F; 505 to 507 K) |
| −97.5×10−6 cm3/mol | |
| Hazards | |
| GHS labelling: | |
  | |
| Danger | |
| H302,H341,H350 | |
| P201,P281,P308+P313 | |
| Legal status | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Safrole is apossibly-carcinogenic,[6]organic compound with the formula CH2O2C6H3CH2CH=CH2. It is a colorless oily liquid, although impure samples can appear yellow. A member of thephenylpropanoid family of natural products, it is found insassafras plants, among others. Small amounts are found in a wide variety of plants, where it functions as a naturalantifeedant.[7]Ocotea pretiosa,[8] which grows inBrazil, andSassafras albidum,[7] which grows in easternNorth America, are the main natural sources of safrole. It has a characteristic "sweet-shop" aroma.
It is aprecursor in the synthesis of theinsecticide synergistpiperonyl butoxide, the fragrancepiperonal viaisosafrole, and the empathogenic/entactogenic substanceMDMA.
Safrole was obtained from a number of plants, but especially from the sassafras tree (Sassafras albidum), which is native to North America, and from Japanese star anise (Illicium anisatum, calledshikimi in Japan).[9] In 1844, the French chemistÉdouard Saint-Èvre (1817–1879)[10] determined safrole'sempirical formula.[11] In 1869, the French chemistsÉdouard Grimaux (1835–1900) and J. Ruotte investigated and named safrole.[12]: 928 They observed its reaction with bromine, suggesting the presence of anallyl group.[12]: 929 By 1884, the German chemistTheodor Poleck (1821–1906) suggested that safrole was a derivative ofbenzene, to which two oxygen atoms were joined asepoxides (cyclic ethers).[13]
In 1885, the Dutch chemistJohann Frederik Eijkman (1851–1915) investigated shikimol, the essential oil that is obtained from Japanese star anise, and he found that, upon oxidation, shikimol formed piperonylic acid,[14]: 39–40 whose basic structure had been determined in 1871 by the German chemistWilhelm Rudolph Fittig (1835–1910) and his student, the American chemistIra Remsen (1846–1927).[15] Thus, Eijkman inferred the correct basic structure for shikimol.[14]: 40–41 He also noted that shikimol and safrole had the same empirical formula and had other similar properties, and thus he suggested that they were probably identical.[14]: 41–42 In 1886, Poleck showed that upon oxidation, safrole also formed piperonylic acid, and thus shikimol and safrole were indeed identical.[16] It remained to be determined whether the molecule's C3H5 group was apropenyl group (R−CH=CH−CH3) or anallyl group (R−CH2−CH=CH2). In 1888, the German chemist Julius Wilhelm Brühl (1850–1911) determined that the C3H5 group was an allyl group.[17]
Safrole is the principal component of browncamphor oil made fromOcotea pretiosa,[8] a plant growing inBrazil, and sassafras oil made fromSassafras albidum.
In the United States, commercially availableculinary sassafras oil is usually devoid of safrole due to a rule passed by theUS FDA in 1960.[18]
Safrole can be obtained through naturalextraction fromSassafras albidum andOcotea cymbarum. Sassafras oil for example is obtained bysteam distillation of the root bark of the sassafras tree. The resulting steam distilled product contains about 90% safrole by weight. The oil is dried by mixing it with a small amount ofanhydrous calcium chloride. After filtering-off the calcium chloride, the oil is vacuum distilled at 100 °C under a vacuum of 11 mmHg (1.5 kPa) or frozen to crystallize the safrole out. This technique works with other oils in which safrole is present as well.[19][20]
Safrole is typically extracted from the root-bark or the fruit ofSassafras albidum[7] (native to eastern North America) in the form of sassafras oil, or fromOcotea odorifera,[8] a Brazilian species. Safrole is also present in certain essentials oils and in browncamphor oil, which is present in small amounts in many plants. Safrole can be found inanise,nutmeg,cinnamon, andblack pepper. The safrole content of perfume, cologne, and toilet water can be determined by dilution with ethanol, followed by separation usinghigh-performance liquid chromatography. and quantization using spectrophotofluorometry[21]
Safrole is a member of the methylenedioxybenzene group, of which many compounds are used asinsecticide synergists; for example, safrole is used as a precursor in the synthesis of the insecticidepiperonyl butoxide. Safrole is also used as a precursor in the synthesis of the drugecstasy (MDMA, 3,4-methylenedioxymethamphetamine). Before safrole was banned by the US FDA in 1960 for use in food, it was used as afood flavor for its characteristic 'candy-shop' aroma. It was used as an additive inroot beer,chewing gum,toothpaste,soaps, and certain pharmaceutical preparations.
Safrole exhibitsantibiotic[22] andanti-angiogenic[23] functions.
It can be synthesized fromcatechol[20] first by conversion to methylenedioxybenzene, which is brominated and coupled withallyl bromide.[24]
Safrole is a versatile precursor to many compounds. Examples areN-acylarylhydrazones and isosters,[25] aryl-sulfonamide derivatives,[26] acidic sulfonylhydrazone derivatives,[27] benzothiazine derivatives[28] and many more.
Isosafrole is produced synthetically from safrole. It is not found in nature. Isosafrole comes in two forms,trans-isosafrole andcis-isosafrole. Isosafrole is used as a precursor for the psychoactive drugMDMA (ecstasy). When safrole is metabolized, several metabolites can be identified. Some of these metabolites have been shown to exhibit toxicological effects, such as 1′-hydroxysafrole and 3′-hydroxysafrole in rats. Further metabolites of safrole that have been found in urine of both rats and humans include 1,2-dihydroxy-4-allylbenzene or 1(2)-methoxy-2(1)hydroxy-4-allylbenzene.[29]
Safrole can undergo many forms of metabolism. The two major routes are the oxidation of theallyl side chain and the oxidation of the methylenedioxy group.[30] The oxidation of the allyl side chain is mediated by acytochrome P450 complex, which will transform safrole into 1′-hydroxysafrole. The newly formed 1′-hydroxysafrole will undergo a phase IIdrug metabolism reaction with asulfotransferase enzyme to create 1′-sulfoxysafrole, which can causeDNA adducts.[31] A different oxidation pathway of the allyl side chain can formsafrole epoxide. So far, this has only been found in rats and guinea pigs. The formed epoxide is a small metabolite due to the slow formation and further metabolism of the compound. Anepoxide hydratase enzyme will act on the epoxide to form dihydrodiol, which can be secreted in urine.[citation needed]
The metabolism of safrole through the oxidation of the methylenedioxy proceeds via the cleavage of the methylenedioxy group. This results in two major metabolites:allylcatechol and its isomer,propenylcatechol.Eugenol is a minor metabolite of safrole in humans, mice, and rats. The intact allyl side chain of allylcatechol may then be oxidized to yield 2′,3′-epoxypropylcatechol. This can serve as a substrate for an epoxide hydratase enzyme, and will hydrate the 2′,3′-epoxypropylcatechol to 2′,3′-dihydroxypropylcatechol. This new compound can be oxidized to formpropionic acid (PPA),[30] which is a substance that is related to an increase in oxidative stress andglutathioneS-transferase activity. PPA also causes a decrease in glutathione andGlutathione peroxidase activity.[32] The epoxide of allylcatechol may also be generated from the cleavage of the methylenedioxy group of the safrole epoxide. The cleavage of the methylenedioxy ring and the metabolism of the allyl group involve hepatic microsomal mixed-function oxidases.[30]
Toxicological studies have shown that safrole is a weakhepatocarcinogen at higher doses in rats and mice. Safrole requires metabolic activation before exhibiting toxicological effects.[30]Metabolic conversion of theallyl group in safrole is able to produce intermediates which are directly capable of binding covalently withDNA andproteins. Metabolism of themethylenedioxy group to acarbene allows the molecule to formligand complexes withcytochrome P450 andP448. The formation of this complex leads to lower amounts of available free cytochrome P450. Safrole can also directly bind to cytochrome P450, leading tocompetitive inhibition. These two mechanisms result in lowered mixed functionoxidase activity.
Furthermore, because of the altered structural and functional properties of cytochrome P450, loss ofribosomes which are attached to theendoplasmic reticulum through cytochrome P450 may occur.[29] The allyl group thus directly contributes tomutagenicity, while the methylenedioxy group is associated with changes in the cytochrome P450 system and epigenetic aspects of carcinogenicity.[29] In rats, safrole and related compounds produced both benign and malignanttumors after intake through the mouth. Changes in the liver are also observed through the enlargement ofliver cells andcell death.
In theUnited States, it was once widely used as a food additive inroot beer, sassafras tea, and other common goods, but was banned for human consumption by theFDA after studies in the 1960s suggested that safrole wascarcinogenic, causing permanent liver damage in rats;[33][34][35] food products sold there purporting to contain sassafras instead contain a safrole-free sassafras extract. Safrole is also banned for use insoap andperfumes by theInternational Fragrance Association.
According to a 1977 study of the metabolites of safrole in both rats and humans, two carcinogenic metabolites of safrole found in the urine of rats, 1′-hydroxysafrole and 3′-hydroxyisosafrole, were not found in human urine.[36] The European Commission on Health and consumer protection assumes safrole to be genotoxic and carcinogenic.[37] It occurs naturally in a variety of spices, such ascinnamon,nutmeg, andblack pepper, and herbs such asbasil. In that role, safrole, like many naturally occurring compounds, may have a small but measurable ability to induce cancer in rodents. Despite this, the effects in humans were estimated by theLawrence Berkeley National Laboratory to be similar to risks posed by breathing indoor air or drinking municipally supplied water.[38]
Besides being a hepatocarcinogen, safrole exhibits further adverse effects in that it will induce the formation of hepatic lipid hydroperoxides.[35] Safrole also inhibits the defensive function ofneutrophils against bacteria. In addition to the inhibition of the defensive function of neutrophils, it has also been discovered that safrole interferes with the formation of superoxides by neutrophils.[22] Furthermore, safrole oxide, a metabolite of safrole, has a negative effect on thecentral nervous system. Safrole oxide inhibits the expression of integrin β4/SOD, leading toapoptosis of thenerve cells.[39]
Safrole is listed as a Table Iprecursor under theUnited Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[4]Due to their role in the manufacture ofMDMA, safrole,isosafrole, andpiperonal are Category I precursors under regulation no. 273/2004 of theEuropean Community.[5] In the United States, safrole is currently aList I chemical.[3]
The root bark of Americansassafras contains a low percentage of steam-volatile oil, which is typically 75% safrole.[40] Attempts to refine safrole from sassafras bark in mass quantities are generally not economically viable due to low yield and high effort. However, smaller quantities can be extracted quite easily viasteam distillation (about 10% of dry sassafras root bark by mass, or about 2% of fresh bark).[19] Demand for safrole is causing rapid and illicit harvesting of theCinnamomum parthenoxylon tree inSoutheast Asia, in particular theCardamom Mountains inCambodia.[41] However, it is not clear what proportion of illicitly harvested safrole is going toward MDMA production, as over 90% of the global safrole supply (about 2,000 tonnes or 2,200 short tons per year) is used to manufacture pesticides, fragrances, and other chemicals.[42][43] Sustainable harvesting of safrole is possible from leaves and stems of certain plants, including the roots of camphor seedlings.[42][43]
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