Transformation #91-Phenylethanone (acetophenone) 2-Bromo-1-phenylethanone

Route #1

Procedure (modified): 1-Phenylethanone (120.2 mg, 1 mmol) and N-bromosuccinimide (NBS, 178.0 mg, 1 mmol) were mixed together with p-toluenesulfonic acid (PTSA, 0.1 mmol) in a porcelain mortar for 2–10 min. The reaction mixture melted during reaction at room temperature. After the 3 h, water (5 mL) was added, followed by extraction with tert-butyl methyl ether (10mL). The organic phase was washed with water (10 mL), dried over Na2SO4 and solvent evaporated under reduced pressure. The crude product was crystallized from ethanol to yield 2-bromo-1-phenylethanone in 95%.

Reference: I. Pravst et al. Tetrahedron 2008, 64, 5191.

Route #2

Zn + Br2 → ZnBr2

Procedure (modified): To a mixture of 1-phenylethanone (601.0 mg, 5 mmol), Zn dust (163.5 mg, 2.5 mmol), and distilled water (5 mL) in a round-bottomed flask (50 mL), bromine (7.5 mmol) was added. The reaction mixture was stirred at room temperature for 45 min. On cooling, the solid obtained was filtered, washed with water, and dried. Finally, it was purified by crystallization from petroleum ether–ethyl acetate (93% yield). Hint: The ZnBr2 forms in situ and then acts as a catalyst for the bromination of acetophenone.

Reference: S. K. Juneja, D. Choudhary, S. Paul, R. Gupta, Synth. Commun. 2006, 36, 2877.

Route #3

Procedure: A solution of tert-butylhydroperoxide (70% aq., 0.25 mL, 2 mmol) was added to a cooled mixture of HBr (48% aq., 0.34 mL, 2 mmol) in dioxan (5 mL) and the mixture stirred for 5 min. To this cold solution 1-phenylethanone (240.4 mg, 2 mmol) was added, stirred at same temperature for 30 min and then refluxed for 20 h. On completion of reaction the solvent was evaporated and the product was dissolved in 5 mL water, extracted with ethyl acetate (3 x 10 mL) washed with 10 ml water and 10 ml brine, dried on sodium sulphate and concentrated on rotary evaporator to afford a yellowish solid. The product was purified by flash column chromatography over silica gel to afford pure product in 85% yield.

Reference: V. H. Tillu, Synth. Commun. 2003, 33, 1399.

Route #4

Procedure (modified from a related synthesis by Langley): In a 500 ml flask are placed 30 g (0.25 mole) of acetophenone and 100 mL of glacial acetic acid. To the resulting solution is very slowly added 40 g (12.5 mL, 0.25 mole) of bromine, keeping the temperature below 20 °C. The mixture is vigorously shaken by hand during the addition. 2-Bromo-1-phenylethanone begins to separate as needles when about one-half of the bromine has been added. The addition requires about thirty minutes. When all the bromine has been added, the flask is cooled in ice-water and the product filtered with suction. The crude crystals are washed with 50% ethanol in water until colorless (about 100 mL are required). The material so obtained, when air-dried, melts at 106–108° and weighs ~40 g. It is recrystallized from 400 mL of 95% ethanol, from which it separates as colorless needles melting at 108–109°. The yield is 36 g (72% yield).

Reference: W. D. Langley, Organic Syntheses, Coll. Vol. 1, p.127 (1941); Vol. 9, p.20 (1929).

Route #5

Hint: the balanced reaction equation for the oxidation step is the following:

Procedure (modified): Preparation of 1,2-Dipyridiniumditribromide-Ethane (DPTBE): Pyridine (9 mL, 100 mmol) and 1,2-dibromoethane (4.3 mL, 50 mmol) were refluxed for 0.5 h. The resultant solid, 1,2-dipyridiniumdibromide-ethane (DPDBE), was washed with ether (2 × 20 mL) and dissolved in water (50 mL). To this was added KBr (26.7 g, 225 mmol) followed by an aqueous solution of oxone (30.7 g, 100 mmol dissolved in 80 mL of water) over a period of 10 min. Oxone is officially KHSO5 but in practice it is sold as KHSO5•0.5KHSO4•0.5K2SO4 (MW of 307.38 g/mol), where the 0.5KHSO4 and 0.5K2SO4

are present but not useful. The orange precipitate was filtered, dried in a vacuum desiccator, and recrystallized from acetonitrile to yield 58.6 g (88% yield) of 1,2-dipyridinium- ditribromide-ethane (DPTBE).

Bromination of 1-phenylethanone: A mixture of 1-phenylethanone (0.601 g, 5 mmol) and 1,2-dipyridiniumditribromide-ethane (1.66 g, 2.5 mmol) was ground in a mortar and pestle at room temperature. After disappearance of the starting material, the reaction mixture was transferred into a G3 sintered funnel and washed with water (5 × 5 mL), and the solid was dried to yield 945 mg (95%) of 2-bromo-1-phenylethanone.

Reference: V. Kavala et al., J. Org. Chem. 2005, 70, 4267.