Safrole

chemical information about safrole and some of its application

1. SAFROLE ABDULHAMID MOHAMED : 1302D901

2. DEFINITION Safrole  is a phenylpropene. It is a colorless or slightly yellow oily liquid typically extracted from the root-bark or the fruit of sassafras plants in the form of sassafras oil, or is synthesized from catechol or other related  methylenedioxy compounds Safrole is a member of the BENZODIOXOLES that is a constituent of several VOLATILE OILS, notably SASSAFRAS oil. It is a precursor in the synthesis of the insecticide PIPERONYL BUTOXIDE and the drug N-methyl-3,4-methylenedioxyamphetamine .

3. STRUCTURE Property Name Property Value Molecular Weight 162.188 g/mol Canonical SMILES C=CCC1=CC2=C(C=C1)OCO2 IUPAC Name 5-prop-2-enyl-1,3-benzodioxole Hydrogen Bond Donor Count Hydrogen Bond Acceptor Count 2 Rotatable Bond Count 2 Complexity 167 Topological Polar Surface Area 18.5 A^2 Monoisotopic Mass 162.068 g/mol Exact Mass 162.068 g/mol Molecular Formula C10H10O2

4. PHYSICAL PROPERTIES Clear colorless or slightly yellow liquid. Denser than water (density 1.09 g / cm3) and insoluble in water . Hence sinks in water. Obtained from oil of sassafras or oil of camphor. prisms, or crystals . Sassafras odor . Boiling Point 232–234 °C . Melting Point 11.2 °C . Solubility Miscible with chloroform, ether , Soluble in alcohol; slightly soluble in propylene glycol; insoluble in water, glycerol Decomposition : When heated to decomposition it emits acrid smoke and irritating fumes.

5. Methods of Manufacturing Distillation of essential oils rich in /safrole/ An uneconomical synthesis starts with catechol methylene ether reacted with allyl chloride; also 4-allyl alcohol with methylene iodide. In addition to safrole, oil of sassafras contains small amounts of eugenol, pinene, phellandrene, sesquiterpene and d-camphor. These are potential impurities in technical safrole. catechol

6. NATURAL PRODUCTION Steam distillation of dried root bark produces an essential oil consisting mostly of safrole that once was extensively used as a fragrance in perfumes and soaps, food and for aromatherapy. The yield of this oil from American sassafram is quite low and great effort is needed to produce useful amounts of the root bark. Commecial "sassafras oil" generally is a by product of camphor production in Asia or comes from related trees in Brazil. Safrole is a precursor for the clandestine manufacture of the drug ecstacy , and as such, its transport is monitored internationally."

7. CHEMICAL SYNTHESIS Safrole can be synthesized in three steps from unwatched chemicals in good yield:

8. EXPERIMENTAL PROCEDURE : 1,2-Methylenedioxybenzene (1,3-benzodioxole) In a 2L-round bottom flask with two neck adapter (reflux condenser, dropping funnel) immersed in an oil bath / magnetic stirrer, are placed 95 mL (1.36 moles) of dibromomethane , 180 mL water and 4-5 mL trioctylmethylammonium chloride (PTC, " Adogen 464, Aliquat 336"). On the top of the reflux condenser, a tube is drawn to a gas washing bottle to give some protection against the atmosphere.) The contents of the flask are heated and stirred to reflux and a previous made solution of 100 g (0.91 moles) 1,2-dihydroxybenzene (catechol), 91 g sodium hydroxide (2.275 moles) and 450 mL water is added to the flask (the contents are stirred vigorously and refluxed continously ). The addition time is 120 min, thereafter the contents are stirred and refluxed 90 min. The product is distilled with steam (add water continously to flask, distill off water and product). After 1.5 liters of distillate are collected, the distillate is saturated with table salt, and extracted three times with ether (better: tert-butyl methyl ether, non watched, and not so dangerous). The etheral extracts are dried with sodium sulfate , the whole is filtered, and the drying agent washed with 2x30 mL of solvent. The combined filtrates are evaporated ( rotavap ), and the residue is distilled in vacuum. At 60-80°C (20 mmHg), 87 g 1,2-methylenedioxybenzene distills , containing about 8% of unreacted dibromomethane . The gum in the reaction/distillation flasks is removed with organic solvents.

9. 4-Bromo-1,2-methylenedioxybenzene In a 500 mL-round bottom flask with reflux condenser (situated in an oil bath and with magnetic stirrer) are placed 70 g of the product from step 1 (92% pure 1,2-methylenedioxybenzene, 0.53 moles), 100 g N- bromosuccinimide and 260 mL chloroform (dry). After three hours of refluxing and stirring, the solution is cooled to room temp, and the the succinimide is filtered off with suction, and washed with 2x20 mL of chloroform. The combined filtrates are evaporated, and the residue is vacuum distilled. At 125-135°C (40 mmHg), a mixture of product and succinimide distills , which is diluted with twice the volume of diethyl ether, stored 3 hrs. over solid sodium hydroxide and washed thoroughly with water. After thorough drying over sodium sulfate , the drying agent is filtered off and washed with 20 mL diethyl ether. The ether is evaporated ( rotavap ), the yellow-brownish residual oil is sufficiently pure for the next step (the refractive index at 25°C is 1.583). The yield is 72 g, 67% of theory calculated to pure 1,2-methylenedioxybenzene being used.

10. 3,4-Methylenedioxy-allylbenzene (Safrole) In a 500 mL flask (immersed in a magnetic stirrer / oil bath) are placed 10-11g magnesium turnings, and 150 mL tetrahydrofuran (freshly distilled from sodium). After the addition of a little iodine crystal and 2 mL dibromomethane to start the Grignard reaction, the 72 g of 4-bromo-1,2-methylenedioxybenzene (step 2) are added to maintain gently reflux. To start up, heating of the bath to 50°C is recommended. After the addition, which takes about 60 min., the whole is stirred and refluxed 1 hr., and the brown liquid is rapidly decanted to a very dry 500 mL flask with dropping funnel and reflux condenser. The magnesium turnings are washed with additional 20 mL dry THF, the washing is added to the Grignard solution. A little (0.5 g) copper(I)iodide is added, and with cooling in an ice-bath, 40 mL (0.47 moles) allyl bromide are added dropwise, the internal temperature should not exceed 40°C. After standing overnight, followed by 1 hr of refluxing, the reaction mixture is suspended in a solution of 20 mL 37% hydrochloric acid in 500 mL water and this is added to 80 mL 25% ammonia, and the solution is steam distilled as above. After collecting 2 L distillate, the distillate is acidified to congo red (pH 4) with hydrochloric acid, saturated with table salt, and extracted with 4x200 mL ether. The combined extracts are dried with sodium hydroxide, evaporated ( rotavap ), and the residue taken up in ether, and washed thorougly with sodium hydroxide. After drying (sodium sulfate ), the drying agent is filtered, washed with 20 mL ether, and the combined extracts are evaporated. The residue is vacuum distilled, 39 g (67% of theory) of safrole, boiling at 120-130°C (20-25 mmHg), are obtained. Colourless and typically smelling oil. Total yield (from the catechol), 32-33% of theory.

11. HAZARDS PrintMSDSAction.pdf

12.  Antiseptic: Safrole oil has been used as an antiseptic for many centuries. It is an antimicrobial extract. Safrole oil contains many antibacterial, antifungal and antiviral properties. It has thus been slated to be an effective antiseptic. Its antifungal properties also make it a great fungicide. Hair Care: Safrole is an effective agent that combats dandruff and lice. A few drops of oil in the water that you use to wash your hair will go a long way in improving your hair health. Also, its natural moisture trapping tendency helps soften the hair. Skin Care: Safrole oil has many uses for the skin. Its natural emollient characteristics help you get supple skin, while it’s many antimicrobial properties help cure ailments like acne, boils, ringworm and minor cuts and bruises. Safrole oil can also be used to relieve pain from insect bites. APPLICATIONS of safrole oıl

13. Perfume/Aroma: Safrole essential oil was initially used as a perfume. It has also been used widely in aromatherapy. It has a unique calming aroma. The ancient world used safrole for soaps and perfumes. It is still used as a popular essential oil, with a distinct aroma. Strengthens Liver: We know that safrole oil treats acne and other skin ailments. It achieves this by fortifying the liver. The liver’s processes flush excess toxins from the system. Safrole oil fortifies the liver and thus helps cure acne, eczema and even psoriasis. Other Uses: Safrole oil works as a great cleanser. It can be used to clean and polish the floors, surfaces and pretty much anything. Safrole mixes with the other chemicals to give your cleaning solution a uniquely pleasant aroma. Thus, you can use copious amounts of Safrole to keep your floor clean.

14. Side Effects Of Safrole Oil: Although safrole oil has many benefits, there are some side effects that you should be aware of: Apart from being a known carcinogen, excess amounts of safrole oil can induce nausea, drowsiness and hallucinations. Pregnant women should refrain from using safrole as it may cause complications in childbirth. FDA has banned the use of Safrole. It can no longer be used for flavoring food and as an additive because of its carcinogenic nature.

15. Patent ID Patent Title Submitted Date Granted Date US9522913 Pesticidally active bicyclic heterocycles with sulphur containing substituents 2014-11-07 2016-12-20 US9498435 Compositions and methods for combination ingredient delivery 2016-05-19 2016-11-22 US9493482 Compounds and methods for preventing or treating sensory hair cell death 2016-02-05 2016-11-15 US9463154 Topical skin care formulations comprising plant extracts 2016-04-06 2016-10-11 US2016278408 Organic Compounds 2013-10-02 2016-09-29 US2016280730 CARBON FIBRE COMPOSITIONS COMPRISING LIGNIN DERIVATIVES 2016-06-09 2016-09-29 US2016271025 ABRASIVE CLEANING COMPOSITION 2014-12-12 2016-09-22 US2016271033 SKIN RENEWAL ENHANCER 2016-03-21 2016-09-22 US2016271102 COMPOUNDS AND FORMS OF TREATMENT FOR FEMALE SEXUAL DISORDERS 2016-03-18 2016-09-22 US2016271209 ANTIBACTERIAL COMPOSITION 2013-11-08 2016-09-22

16. REFERENCES HSDB SAFROLE http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+94-59-7 CAMEO Chemicals Safrole https://cameochemicals.noaa.gov/chemical/16079 Human Metabolome Database Safrole http://www.hmdb.ca/metabolites/HMDB33591 NJDOH RTK Hazardous Substance List safrole http://nj.gov/health/eoh/rtkweb/documents/fs/1642.pdf NIST Safrole http://www.nist.gov/srd/nist1a.cfm

17. The National Institute for Occupational Safety and Health – NIOSH Benzene, 4-allyl-1,2-( methylenedioxy )- https://www.cdc.gov/niosh-rtecs/CY2AB980.html European Chemicals Agency – ECHA 5-allyl-1,3-benzodioxole https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/126462 EU REGULATION (EC) No 1272/2008 safrole;5-allyl-1,3-benzodioxole http://ec.europa.eu/growth/sectors/chemicals/classification-labelling/index_en.htm PubChem Data safrole https://pubchem.ncbi.nlm.nih.gov WIPO International Patent Classification http://www.wipo.int/classifications/ipc/