Phenylacetone (P2P) syntheses via Grignard reagents

[G.Patton]

Introduction​

There are two brilliant methods of phenylacetone (P2P) syntheses via Grignard reagents, which I described below.
Excellent yields of methyl ketones may be obtained by the addition of Grignard reagents to an ether solution of acetic anhydride at about -70 °C. Primary, secondary, tertiary aliphatic, and aromatic Grignard reagents give 70-79% yields of the corresponding methyl ketones, while the allyl and benzyl reagents give 42 and 52%, respectively. The success of these reactions depends on low temperature to the thermal stability of the complex formed by the addition of one molecule of Grignard reagent to one of the carbonyl groups of acetic anhydride, and to its decreased solubility. These factors both tend to reduce the further reaction of the complex with more Grignard reagent to form the tertiary alcohol. At the low temperature involved there is probably no cleavage of this complex to form ketone which might further react.

Another method via acetonitrile has some advantages. The intermediate phenyl-2-propanone imine magnesium salt can also be prepared from methylmagnesium iodide and benzyl cyanide. Both are hydrolyzed to phenyl-2-propanone with dilute hydrochloric acid. The imine salt can also be reduced directly to amphetamine by sodium borohydride in methanol in high yield. This method could be of interest for producing P2P from acetonitrile, as it greatly simplifies the procedure by eliminating any need for extensive extraction of the ketone.​

Procedures vie acetic anhydride​

In a 500 ml three-necked flask, situated in a dry ice/acetone slush in a Dewar flask, there was added a solution of acetic anhydride (40 g, 2.55 mol) in diethyl ether 100 ml, and the flask was equipped with a magnetic stirrer, a thermometer and an addition funnel (modified so that the added liquid was cooled externally by dry ice/acetone).​

Spoiler: Dewar flask

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To this was added an ethereal solution of benzyl magnesium chloride, prepared from benzyl chloride (25.5 g, 0.2 mol) and magnesium shavings (4.9 g, 0.2 mol) to make benzyl magnesium bromide (Grignard reagent), an iodine crystal being added after the first portion to initiate Grignard reaction.​

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After the addition after one hour was finished, the reaction mixture was allowed to stir at dry ice temperature (-78 °C) for 2-3 hours, the cooling bath removed and the reaction quenched by the careful addition of saturated aqueous ammonium chloride (NH4Cl).​

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The aqueous layer was separated in the separating funnel, the organic phase washed with 10% sodium carbonate (NaCO3 aq) solution until the washes were no longer acidic to universal pH paper, followed by 50 ml brine. The organic phase was dried over MgSO4, filtered, the ether evaporated on a water bath and the residue fractionally distilled to yield phenyl-2-propanone (14 g, 52 %), bp 214-215 °C/760 mm Hg (100-101 °C/13 mm Hg).​

Equipment and glassware:​

500 ml Three-necked round bottom flask;
Dry ice/acetone bath (-78 °C) with Dewar flask;
Magnetic stirrer;
Distillation apparatus;
Retort stand and clamp for securing apparatus;
Laboratory grade thermometer (-100 °C to 100 °C) with flask adapter;
Laboratory scale (0.1 - 200 g is suitable);
250 ml Drip funnel;
500 ml Separating funnel;
Universal pH paper;
100 ml Measuring cylinder;
100 ml x2 and 200 ml x2 Erlenmeyer flasks with cap;
200 ml x2; 100 ml x2 Beakers.

Reagents:​

Acetic anhydride (40 g, 2.55 mol);
Diethyl ether (Et2O) 100 ml;
Benzyl chloride (25.5 g, 0.2 mol);
Magnesium shavings (4.9 g, 0.2 mol);
Couple of iodine crystals;
Ammonium chloride (NH4Cl) 50 g;
Distilled water 2 L;
Sodium carbonate (NaCO3) 50 g;
Sodium chloride (NaCl) 50 g.

Procedures via acetonitrile​

127 g Benzyl chloride was dissolved in 250 ml Et2O, to this was added 27 g Mg turnings in portions, an iodine crystal being added after the first portion to initiate the Grignard reaction. A thick white precipitate built up and clogged up some Mg, but after all was added, there was excess unclogged Mg which would not react. Submersion of the flask in cold H2O was used as necessary during addition to prevent excessive boiling of the Et2O. After all Mg was added, and no further reaction occurred, the reaction mixture was cooled in an ice-salt bath. A solution of 62 g acetonitrile in 100 ml Et2O was added slowly while stirring w/a thermometer. The reaction temperature rose to 30 °C.​

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After completion of addition, the mixture was refluxed gently, stirred thoroughly, then left to cool to room temp. 500 ml 10% HCl was added slowly under stirring. [NOTE: This seemed to cause the Et2O layer to take on a reddish tint. I think the purity of the final product would be higher if the reaction mixture was first poured onto ice, then acidified].​

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After all effervescence had stopped, the organic layer was separated. NaCl was added to the aqueous layer, which was then extracted with Et2O [NOTE: I think a lot of products was left behind in this aqueous layer; it was still very orange even after adding NaCl and extracting with Et2O (which was a lighter shade of orange than the aq. layer!)]. The combined Et2O layers were washed with H2O, dried over MgSO4. Et2O and a small amount of toluene were evaporated to give 42 g crude phenyl-2-propanone as a clear orange oil. Vacuum distillation of this oil afforded pure phenyl-2-propanone (bp 91-96 °C at 11 mm Hg).​

Equipment and glassware:​

1000 ml Three-necked round bottom flask;
Water and ice-salt bath (-10 °C);
Magnetic stirrer;
Distillation apparatus;
Retort stand and clamp for securing apparatus;
Laboratory grade thermometer (0 °C to 100 °C) with flask adapter;
Reflux condenser;
Water-jet aspirator;
500 ml Drip funnel;
100 ml x2 and 200 ml x2 Erlenmeyer flasks with cap;
200 ml; 500 ml; 100 ml x2 Beakers;
1 L Separating funnel.

Reagents:​

Benzyl chloride 127 g;
Diethyl ether (Et2O) 350 ml;
Magnesium (Mg) 27 g;
Acetonitrile (CH3CN) 62 g;
HCl 500 ml 10% aq.;
Sodium chloride (NaCl) 50 g;
Anhydrous magnesium sulphate (MgSO4) 50 g;
Couple of iodine crystals.