This blog provides several methods for synthesizing phenyl-2-propanone (P2P) from various starting materials. It begins with methods starting from benzyl cyanide, phenylacetic acid, and benzene. Subsequent sections describe other routes including Friedel-Crafts alkylation, reduction, hydrolysis, electrochemical coupling, nickel-mediated coupling, semi pinacol rearrangement, radical alkylation, Wittig reaction, and more. Yield percentages for many of the reactions are provided.
Introduction
Aside from the often amateurish reduction of (pseudo)ephedrine to methamphetamine, the most popular precursor to amphetamine and methamphetamine is phenyl-2-propanone (also called P2P, BMK, Benzyl Methyl Ketone or Phenylacetone). There is an astounding array of synthetic routes to this compound, both due to the relative simple structure of the compound, and also because of its popularity. Many of the earliest routes to the compound has been more or less abandoned due to restrictions on the pre-precursors used to make it, but there has always sprung up new methods of performing the feat of making this compound.
Here is a collection of some of the possible methods of synthesizing phenyl-2-propanone, ranging from simple one-step methods to elaborate multi-step variants, and from the very easy to the very complicated. Welcome to the world of P2P. The Nitrostyrene Method Used For P2P Production
Many of the syntheses can also be tweaked to produce substituted phenyl-2-propanones, such as the ever popular MDMA precursor MDP2P (3,4-methylenedioxyphenyl-2-propanone) by using starting materials with the desirable aromatic substituents.
Appearance: Clear oil, flowery odor
Boiling Point: 214-216°C/760mmHg, 86-87°C/6mmHg
Melting Point: -15°C Molecular Weight: 134.19 g/mol
Density : 1.0057 g/ml (20°C)
Refractive Index: 1.5168
Phenyl-2-Propanone from Benzyl Cyanide
alpha-Phenylacetoacetonitrile
A solution of sodium ethoxide is prepared from 60 g (2.6 mol) of clean sodium and 700 ml of absolute alcohol (dried over calcium oxide or sodium) in a 2000 ml round-bottomed flask equipped with a reflux condenser. To the hot solution is added a mixture of 234 g (2 moles) of pure benzyl cyanide and 264 g (3 moles) of dry ethyl acetate (dried by refluxing over P₂O₅ for 30 minutes followed by distillation).
The mixture is thoroughly shaken, the condenser is closed with a calcium chloride tube, and the solution is heated on a steam bath for two hours before standing overnight.
The next morning, the mixture is stirred with a wooden rod to break up lumps, cooled in a freezing mixture to -10°C, and kept at this temperature for two hours. The sodium salt is collected on a 6-inch Büchner funnel and washed four times on the funnel with 250 ml portions of ether. The filter cake is practically colorless and corresponds to 250-275 g of dry sodium salt, or 69-76% of the calculated amount. The combined filtrates are placed in the freezing mixture until they can be worked up as indicated below.
The sodium salt, still wet with ether, is dissolved in 1.3 liters of distilled water at room temperature. The solution is cooled to 0°C, and the nitrile is precipitated by adding slowly, with vigorous shaking, 90 ml of glacial acetic acid, while the temperature is kept below 10°C. The precipitate is separated by suction filtration and washed four times on the funnel with 250 ml portions of water. The moist cake, weighing about 300 g, corresponds to 188-206 g (59-64%) of dry, colorless alpha-phenylacetoacetonitrile, mp 87-89°C.
Phenyl-2-Propanone
350 ml of concentrated sulfuric acid is placed in a 3000 ml flask and cooled to -10°C. The total first crop of moist alpha-phenylacetoacetonitrile obtained according to the procedure above (corresponding to 188-206 g or 1.2-1.3 moles of dry product) is added slowly, with shaking, the temperature being kept below 20°C (If pure, dry alpha-phenylacetoacetonitrile is used, half its weight of water should be added to the sulfuric acid or charring will take place on the steam bath). After all is added, the flask is warmed on the steam bath until solution is complete and then for five minutes longer. The solution is cooled to 0°C, 1750 ml of water is added rapidly, and the flask is placed on a vigorously boiling water bath and heated for two hours, with occasional shaking.
The ketone forms a layer and, after cooling, is separated. The acid layer is extracted with 600 ml of ether. The oil and ether layers are washed successively with 100 ml of water. The ether is combined with the oil and dried over 20 g of anhydrous sodium sulfate. The sodium sulfate is collected on a filter, washed with ether, and discarded. The ether is removed from the filtrates, and the residue is distilled from a modified Claisen flask with a 25 cm fractionating side arm. The fraction boiling at 110-112°C at 24 mmHg is collected; it weighs 125-150 g (77-86% of the theoretical amount).
A somewhat higher yield has been obtained by a different variation of this synthesis, originating from Russia.
Phenyl-2-Propanone from Phenylacetic Acid
In this reaction, it is important that acetic anhydride is present in the reaction mixture in a large molar excess over the phenylacetic acid. If the ratio is too small, the phenylacetone will condense with itself to form useless Dibenzyl Ketone
Sodium Acetate Method (alternative)
Phenylacetic Acid (PAA), Acetic Anhydride (AA), and Sodium Acetate (NaOAc) are placed into a large round-bottomed flask equipped with a reflux condenser fitted with a drying tube. Heating the reaction mixture to 145-150°C on an oil bath provides sufficiently energetic evolution of carbon dioxide. Formation of the ketone is monitored by mixing an aliquot of the reaction mixture with excess water and ammonium hydroxide until weakly alkaline – upon heating to boiling, the oily layer must not disappear.
The reflux setup is rearranged for distillation, and excess solvent (acetic acid and acetic anhydride) is removed (purify and reuse). To the residue, 400 ml of water is added, and the mixture is extracted with 3x100 ml dichloromethane (or chloroform). The solvent is stripped off under vacuum, and by vacuum distilling at 125-135°C/30-32 mmHg, the crude product is obtained. A second distillation yields 50-55% of product boiling at 210-215°C at atmospheric pressure. Phenyl-2-Propanone Ketoxime was obtained in 88-90% yield, which distilled at 154-156°C/30 mmHg.
Sodium Acetate Method (alternative)
50 g phenylacetic acid, 25 g anhydrous sodium acetate, and 850 ml acetic anhydride are refluxed with stirring under moisture protection for 40 h. 500 ml of acetic anhydride and acetic acid are distilled off. After cooling, the remainder is mixed with 1000 ml water. The crude product is extracted with 2x250 ml dichloromethane, and the pooled organic layers are washed with cold diluted sodium hydroxide solution (any formed P2P enol ester must be hydrolyzed) until no more acids are present in the organic layer. The solution is dried over Na₂SO₄. The dichloromethane is distilled off under ordinary pressure (and saved for reuse), the remaining volatiles are evaporated in vacuo, and the crude phenyl-2-propanone is vacuum distilled at 25 mmHg, bp 120-140°C. The yield is about 30 ml (70%). Bmk oil
Potassium Acetate/Copper Sulfate
To a mixture of 136 g (1.0 mol) phenylacetic acid, 70 g sodium or potassium acetate, and 16 g (0.1 mol) anhydrous cupric sulphate in a 4000 ml flask, 2000 ml anhydrous acetic anhydride is introduced. The mixture is refluxed for 24 h. After cooling, 500 ml of solvent (CCl₄, CHCl₃, CH₂Cl₂) is added, and the mixture is poured into a flask containing 2000 ml ice-water. After separation of layers, the upper layer is removed, and the lower layer is decanted three times with water, separated, dried (Na₂SO₄, CaCl₂), and distilled. The solvent is distilled off, a fractionation column is placed on the flask, and the remaining acetic acid and acetic anhydride are removed. Pure product is collected at 100°C/15 mmHg. Yield: 70-90 g (52-67%).
Pyridine Method
A mixture of phenylacetic acid (13.6 g, 0.1 mol), acetic anhydride (50 ml), and pyridine (50 ml) was refluxed for six hours (carbon dioxide evolution was vigorous at the beginning). After removal of the solvent, the residue was taken up in toluene and washed with 10% sodium hydroxide. Removal of the solvent left a residue weighing 12 g, which on fractional vacuum distillation gave 7.5 g (56%) phenyl-2-propanone, bp 30-64°C/0.1 mmHg.
Lead Acetate Method
Place 1000 g phenylacetic acid and 3000 g anhydrous (or trihydrate) lead acetate in a distillation apparatus and heat. First, an amount of water will distill, followed by phenyl-2-propanone in this destructive distillation, which requires liberal application of heat. The distillate will separate into two layers.
Phenyl-2-propanone Synthesis Methods
The organic layer is separated and redistilled to yield pure phenyl-2-propanone, with a boiling point of 105°C at 10 mmHg or 216°C at atmospheric pressure.
A significant large-scale improvement to this method has been developed by Xtaldoc.
The use of Lead(II) Acetate can be replaced with Calcium(II) Acetate, resulting in a more environmentally friendly synthesis.
Methylthium Addition to Phenylacetic Acid
In a 100ml round-bottom flask equipped with a side tube for a gas inlet capillary, a reflux condenser protected by a sodium hydroxide drying tube, and a magnetic stirrer, 0.026 moles (3.5 g) of phenylacetic acid dissolved in 50 ml of ether was placed. The air was expelled with a rapid stream of dry nitrogen. After 2-3 minutes, the gas flow was reduced to a rate just sufficient to create bubbles for stirring the solution during the experiment.
Once all air had been expelled, 0.055 moles of an ethereal solution of methylthium was added through the condenser. A vigorous reaction occurred, causing the ether to reflux and forming a white precipitate (the lithium salt of the acid). After all the methylthium was added, the precipitate partially dissolved, yielding a weakly opalescent solution. If necessary, the solution was then refluxed for 10-30 minutes to complete the reaction. After the solution reached room temperature, water was slowly added. This destroyed the excess methylthium and formed lithium hydroxide from the intermediate dilithium salt.
The alkaline aqueous layer, containing the lithium salt of unreacted acid, was removed in a separatory funnel. The ethereal layer was washed three times with half its volume of water. The ether solution was then dried over magnesium sulfate, filtered, and the ether was removed—first at ordinary pressure and then under aspirator vacuum—to yield 2.65g (76%) of phenylacetone, which is usually pure enough for most purposes.
Phenyl-2-propanone by Nitroalkylation of Benzene
Titanium Tetrachloride Method
To a stirred solution of 2-nitropropene (0.1 mol, 8.7g) in dry CH₂Cl₂ (300ml) at room temperature, benzene (0.5 mol, 39g) was added. Titanium tetrachloride (0.1 mol, 19g) was then added dropwise into the mixture with stirring at the same temperature. After stirring for 60 minutes (or until the starting material completely disappeared on TLC), water (150 ml) was added, and the resulting heterogeneous mixture was stirred under reflux for 2 hours. The organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂. The combined organic extracts were washed with a 1 M Na₂CO₃ solution and dried over MgSO₄. Evaporation of the solvent followed by vacuum distillation (boiling point 100-101°C at 14 mmHg) yielded phenyl-2-propanone (approximately 9g, 70% yield).
Triflic Acid Method
A solution of 2-nitropropene (300 mg) in benzene (30 equivalents) was added to a well-stirred solution of CF₃SO₃H (10 equivalents relative to 2-nitropropene) and benzene, with methylene chloride as a co-solvent, cooled to -40°C in a dry ice-acetone bath. The reaction mixture was immediately (after 1 minute) poured into a large excess of dry methanol (100 mL) cooled to -78°C with vigorous stirring. After warming to ambient temperature (10-15 minutes), the yellow solution was diluted with water (150 mL), neutralized with powdered NaHCO₃, and saturated with NaCl. The solution was extracted with CH₂Cl₂, dried over Na₂SO₄, and concentrated. The residue was purified by flash chromatography (on SiO₂, eluting with CH₂Cl₂:n-hexane 12:7) to yield pure phenyl-2-propanone, 392 mg (85%), as a colorless oil. The 2,4-dinitrophenylhydrazone derivative, recrystallized from methanol, had a melting point of 152.5-153.5°C.
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