Names | |
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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 | |
3D model (JSmol) | |
ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard | 100.002.133 |
EC Number |
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KEGG | |
PubChem CID | |
RTECS number |
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UNII | |
UN number | 3082 |
CompTox Dashboard (EPA) | |
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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 their standard state (at 25 °C [77 °F], 100 kPa). |
Safrole is an organic compound with the formula CH2O2C6H3CH2CH=CH2. It is a colorless oily liquid, although impure samples can appear yellow. A member of the phenylpropanoid family of natural products, it is found in sassafras plants, among others. Small amounts are found in a wide variety of plants, where it functions as a natural antifeedant. [3] Ocotea pretiosa , [4] which grows in Brazil, and Sassafras albidum , [3] which grows in eastern North America, are the main natural sources of safrole. It has a characteristic "sweet-shop" aroma.
It is a precursor in the synthesis of the insecticide synergist piperonyl butoxide, the fragrance piperonal via isosafrole, and the empathogenic/entactogenic substance MDMA.
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 , called shikimi in Japan). [5] In 1844, the French chemist Édouard Saint-Èvre (1817–1879) [6] determined safrole's empirical formula. [7] In 1869, the French chemists Édouard Grimaux (1835–1900) and J. Ruotte investigated and named safrole. [8] : 928 They observed its reaction with bromine, suggesting the presence of an allyl group. [8] : 929 By 1884, the German chemist Theodor Poleck (1821–1906) suggested that safrole was a derivative of benzene, to which two oxygen atoms were joined as epoxides (cyclic ethers). [9]
In 1885, the Dutch chemist Johann 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, [10] : 39–40 whose basic structure had been determined in 1871 by the German chemist Wilhelm Rudolph Fittig (1835–1910) and his student, the American chemist Ira Remsen (1846–1927). [11] Thus Eijkman inferred the correct basic structure for shikimol. [10] : 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. [10] : 41–42 In 1886, Poleck showed that upon oxidation, safrole also formed piperonylic acid, and thus shikimol and safrole were indeed identical. [12] It remained to be determined whether the molecule's C3H5 group was a propenyl group (R−CH=CH−CH3) or an allyl group (R−CH2−CH=CH2). In 1888, the German chemist Julius Wilhelm Brühl (1850–1911) determined that the C3H5 group was an allyl group. [13]
Safrole is the principal component of brown camphor oil made from Ocotea pretiosa , [4] a plant growing in Brazil, and sassafras oil made from Sassafras albidum .
In the United States, commercially available culinary sassafras oil is usually devoid of safrole due to a rule passed by the U.S. FDA in 1960. [14]
Safrole can be obtained through natural extraction from Sassafras albidum and Ocotea cymbarum . Sassafras oil for example is obtained by steam 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 of anhydrous 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. [15] [16]
Safrole is typically extracted from the root-bark or the fruit of Sassafras albidum [3] (native to eastern North America) in the form of sassafras oil, or from Ocotea odorifera , [4] a Brazilian species. Safrole is also present in certain essentials oils and in brown camphor oil, which is present in small amounts in many plants. Safrole can be found in anise, nutmeg, cinnamon, and black pepper. Safrole can be detected in undiluted liquid beverages and pharmaceutical preparations by high-performance liquid chromatography. [17]
Safrole is a member of the methylenedioxybenzene group, of which many compounds are used as insecticide synergists; for example, safrole is used as a precursor in the synthesis of the insecticide piperonyl butoxide. Safrole is also used as a precursor in the synthesis of the drug ecstasy (MDMA, 3,4-methylenedioxymethamphetamine). Before safrole was banned by the US FDA in 1960 for use in food, it was used as a food flavor for its characteristic 'candy-shop' aroma. It was used as an additive in root beer, chewing gum, toothpaste, soaps, and certain pharmaceutical preparations.
Safrole exhibits antibiotic [18] and anti-angiogenic [19] functions.
It can be synthesized from catechol [16] first by conversion to methylenedioxybenzene, which is brominated and coupled with allyl bromide. [20]
Safrole is a versatile precursor to many compounds. Examples are N-acylarylhydrazones, isosters, [21] aryl-sulfonamide derivatives, [22] acidic sulfonylhydrazone derivatives, [23] benzothiazine derivatives. [24] and many more.
Isosafrole is produced synthetically from safrole. It is not found in nature. Isosafrole comes in two forms, trans-isosafrole and cis-isosafrole. Isosafrole is used as a precursor for the psychoactive drug MDMA (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. [25]
Safrole can undergo many forms of metabolism. The two major routes are the oxidation of the allyl side chain and the oxidation of the methylenedioxy group. [26] The oxidation of the allyl side chain is mediated by a cytochrome P450 complex, which will transform safrole into 1′-hydroxysafrole. The newly formed 1′-hydroxysafrole will undergo a phase II drug metabolism reaction with a sulfotransferase enzyme to create 1′-sulfoxysafrole, which can cause DNA adducts. [27] A different oxidation pathway of the allyl side chain can form safrole 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. An epoxide hydratase enzyme will act on the epoxide to form dihydrodiol, which can be secreted in urine.
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 form propionic acid (PPA), [26] which is a substance that is related to an increase in oxidative stress and glutathione S-transferase activity. PPA also causes a decrease in glutathione and Glutathione peroxidase activity. [28] 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. [26]
Toxicological studies have shown that safrole is a weak hepatocarcinogen at higher doses in rats and mice. Safrole requires metabolic activation before exhibiting toxicological effects. [26] Metabolic conversion of the allyl group in safrole is able to produce intermediates which are directly capable of binding covalently with DNA and proteins. Metabolism of the methylenedioxy group to a carbene allows the molecule to form ligand complexes with cytochrome P450 and P448. The formation of this complex leads to lower amounts of available free cytochrome P450. Safrole can also directly bind to cytochrome P450, leading to competitive inhibition. These two mechanisms result in lowered mixed function oxidase activity.
Furthermore, because of the altered structural and functional properties of cytochrome P450, loss of ribosomes which are attached to the endoplasmatic reticulum through cytochrome P450 may occur. [25] The allyl group thus directly contributes to mutagenicity, while the methylenedioxy group is associated with changes in the cytochrome P450 system and epigenetic aspects of carcinogenicity. [25] In rats, safrole and related compounds produced both benign and malignant tumors after intake through the mouth. Changes in the liver are also observed through the enlargement of liver cells and cell death.
In the United States, it was once widely used as a food additive in root beer, sassafras tea, and other common goods, but was banned for human consumption by the FDA after studies in the 1960s suggested that safrole was carcinogenic, causing permanent liver damage in rats; [29] [30] [31] food products sold there purporting to contain sassafras instead contain a safrole-free sassafras extract. Safrole is also banned for use in soap and perfumes by the International 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. [32] The European Commission on Health and consumer protection assumes safrole to be genotoxic and carcinogenic. [33] It occurs naturally in a variety of spices, such as cinnamon, nutmeg, and black pepper, and herbs such as basil. 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 the Lawrence Berkeley National Laboratory to be similar to risks posed by breathing indoor air or drinking municipally supplied water. [34]
Besides being a hepatocarcinogen, safrole exhibits further adverse effects in that it will induce the formation of hepatic lipid hydroperoxides. [31] Safrole also inhibits the defensive function of neutrophils 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. [18] Furthermore, safrole oxide, a metabolite of safrole, has a negative effect on the central nervous system. Safrole oxide inhibits the expression of integrin β4/SOD, which leads to apoptosis of the nerve cells. [35]
Safrole is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. [36] Due to their role in the manufacture of MDMA, safrole, isosafrole, and piperonal are Category I precursors under regulation no. 273/2004 of the European Community. [37] In the United States, safrole is currently a List I chemical.
The root bark of American sassafras contains a low percentage of steam-volatile oil, which is typically 75% safrole. [38] 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 via steam distillation (about 10% of dry sassafras root bark by mass, or about 2% of fresh bark). [15] Demand for safrole is causing rapid and illicit harvesting of the Cinnamomum parthenoxylon tree in Southeast Asia, in particular the Cardamom Mountains in Cambodia. [39] 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. [40] [41] Sustainable harvesting of safrole is possible from leaves and stems of certain plants, including the roots of camphor seedlings. [40] [41]
Myristicin is a naturally occurring compound found in common herbs and spices, such as nutmeg. It is an insecticide, and has been shown to enhance the effectiveness of other insecticides.
3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as “sass,” is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.
Benzo[a]pyrene (BaP or B[a]P) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites, more commonly known as BPDE, react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.
Methylcholanthrene is a highly carcinogenic polycyclic aromatic hydrocarbon produced by burning organic compounds at very high temperatures. Methylcholanthrene is also known as 3-methylcholanthrene, 20-methylcholanthrene or the IUPAC name 3-methyl-1,2-dyhydrobenzo[j]aceanthrylene. The short notation often used is 3-MC or MCA. This compound forms pale yellow solid crystals when crystallized from benzene and ether. It has a melting point around 180 °C and its boiling point is around 280 °C at a pressure of 80 mmHg. Methylcholanthrene is used in laboratory studies of chemical carcinogenesis. It is an alkylated derivative of benz[a]anthracene and has a similar UV spectrum. The most common isomer is 3-methylcholanthrene, although the methyl group can occur in other places.
Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.
Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzymatic metabolism in the organisms, as well as by abiotic chemical reactions. While the parent drug is usually less active, both the parent drug and its metabolite can be chemically active and cause toxicity, leading to mutagenesis, teratogenesis, and carcinogenesis. Different classes of enzymes, such as P450 monooxygenases, epoxide hydrolase, or acetyltransferases can catalyze the process in the cell, mostly in the liver.
Sudan I is an organic compound typically classified as an azo dye. It is an orange-red solid, used to color waxes, oils, petrol, solvents, and polishes. Historically, Sudan I used to serve as a food coloring agent, notably for curry powder and chili powder. However, along with its derivatives Sudan III and Sudan IV, the compound has been banned in many countries due to its classification as a category 3 carcinogenic hazard by the International Agency for Research on Cancer. Nevertheless, Sudan I remains valuable as a coloring reagent for non-food-related uses, such as in the formulation of orange-colored smoke.
3,4-Methylenedioxyphenylpropan-2-one or piperonyl methyl ketone is a chemical compound consisting of a phenylacetone moiety substituted with a methylenedioxy functional group. It is commonly synthesized from either safrole or its isomer isosafrole via oxidation using the Wacker oxidation or peroxyacid oxidation methods. MDP2P is unstable at room temperature and must be kept in the freezer in order to be preserved properly.
Phenylacetone, also known as phenyl-2-propanone, is an organic compound with the chemical formula C6H5CH2COCH3. It is a colorless oil that is soluble in organic solvents. It is a mono-substituted benzene derivative, consisting of an acetone attached to a phenyl group. As such, its systematic IUPAC name is 1-phenyl-2-propanone.
Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.
Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.
4-Aminobiphenyl (4-ABP) is an organic compound with the formula C6H5C6H4NH2. It is an amine derivative of biphenyl. It is a colorless solid, although aged samples can appear colored. 4-Aminobiphenyl was commonly used in the past as a rubber antioxidant and an intermediate for dyes. Exposure to this aryl-amine can happen through contact with chemical dyes and from inhalation of cigarette smoke. Researches showed that 4-aminobiphenyl is responsible for bladder cancer in humans and dogs by damaging DNA. Due to its carcinogenic effects, commercial production of 4-aminobiphenyl ceased in the United States in the 1950s.
2,5-Dimethoxy-3,4-methylenedioxyamphetamine is a lesser-known psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin and was described in his book PiHKAL. Shulgin listed the dosage as 30–75 mg and the duration as 6–8 hours. He reported DMMDA as producing LSD-like images, mydriasis, ataxia, and time dilation. DMMDA isn't mentioned much in literature outside PiHKAL unlike 2C-B.
o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula CH3C6H4NH2. It is the most important of the three isomeric toluidines. It is a colorless liquid although commercial samples are often yellowish. It is a precursor to the herbicides metolachlor and acetochlor.
Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities.
3',4'-Methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) is a stimulant designer drug. It was sold in Germany in the late 1990s and early 2000s as an ingredient in imitation ecstasy (MDMA) pills. It shares a similar chemical structure with α-PPP and MDPV, and has been shown to have reinforcing effects in rats.
Diepoxybutane is an epoxide which is a colorless liquid at room temperature. It is therefore highly reactive, more than other ethers. An epoxide is a cyclic ether that contains a three atom ring that comes close to an equilateral triangle. The primary structure of an epoxide contains two carbon atoms and a hydrocarbon attached to an oxygen atom. It polymerizes in the presence of catalysts or when heated. It’s hydrophilic, very flammable and easily ignited by heat or sparks.
Methacrylonitrile, MeAN in short, is a chemical compound that is an unsaturated aliphatic nitrile, widely used in the preparation of homopolymers, copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. MeAN is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. It is a clear and colorless liquid, that has a bitter almond smell.
Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide. It is a chiral molecule.
(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is an organic compound with molecular formula C20H14O3. It is a metabolite and derivative of benzo[a]pyrene (found in tobacco smoke) as a result of oxidation to include hydroxyl and epoxide functionalities. (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a guanine nucleobase in DNA, distorting the double helix structure by intercalation of the pyrene moiety between base pairs through π-stacking. The carcinogenic properties of tobacco smoking are attributed in part to this compound binding and inactivating the tumor suppression ability of certain genes, leading to genetic mutations and potentially to cancer.