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Synthesis of p-Methoxyphenylacetone

by Psycho Chemist


In a 1000 mL flask with double surface condenser/drierite tube, reflux 600 mL acetic anhydride, 100 mL pyridine (dry) and 100 g 4-methoxyphenylacetic acid for 18 hrs with good stirring. Thereafter, distill off 600 mL acetic acid, acetic anhydride and pyridine over a 30x500 mm helices packed column. The residue is added - when cooled down (!) - to 500 mL water, and stirred for 30 min. to hydrolyze any present acetic anhydride. The mixture is then extracted with 5x200 mL methyl tert-butyl ether, and the pooled extracts are washed with 4x100 mL 20% sodium hydroxide (keep the alkaline washings), and 200 mL saturated aqueous NaCl. The organic layer is dried over sodium sulfate, evaporated (rotary evaporator, recover the solvent), and the residue distilled to give 60 g p-methoxyphenylacetone, bp 145-165C at about 20 mmHg.

Recovery of unreacted 4-methoxyphenylacetic acid

The alkaline washings are pooled, acidified (pH 1) with hydrochloric acid, and extracted with 4x100 mL methyl tert-butyl ether. The pooled organic extracts are evaporated (rotary evaporator, recover solvent), and the residue is mixed with 100 mL toluene or benzene. The solution is refluxed with a Dean-Stark adapter/double surface condenser, to remove any present water, then the solvent is distilled off in vacuum to get 25g of unreacted p-methoxyphenylacetic acid.


4-Methoxy-Phenyl-2-Nitropropene (10 g, 51 mmol) was dissolved in 75 ml HOAc and slowly dripped into a refluxing slurry of Fe powder (32 g, 0.57 mol) in 140 ml HOAc. The mixture first turned brownish, and then white and foamy, and the mixture was refluxed on low heat for 1.5 h. The reaction mixture was poured into 2000ml water, and was extracted with 3x100 ml CH2Cl2. The combined extracts was washed with 2x150 ml H2O and dried over MgSO4. The solvent was distilled off at atmospherical pressure, and the residue distilled under vacuum to give 6.1g (37 mmol, 72%) of an orange-pink oil at 110C at 3mmHg.

Reference: Shulgin & Shulgin, Pihkal, #109