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Synthesis of Phenylacetone From Benzene

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Apart from the frequent-unskillful lessening of (pseudo)ephedrine to methamphetamine, the most common predecessor to amphetamine and methamphetamine is phenyl-2-propanone (also known as P2P, BMK, Benzyl Methyl Ketone or Phenylacetone). There is a huge variety of synthetic routes to this compound, mostly both due to the relative basic structure of the compound, and because its common. Most of the earliest pathways to the compound has been neglected due to restrictions on the pre-precursors which from the compound, but there has always been a rise in new ways of performing the feat of making this compound. Here are several possible ways of synthesizing phenyl-2-propanone, which includes basic simple one-step methods to indepth multi-step variants, and from the simple to technical. We introduce you to the synthesis of phenylacetone from benzene. For more information visit

The synthesis of phenylacetone can also be re-arranged to generate alternative phenyl-2-propanones, including popular MDMA precursors MDP2P (3,4-methylenedioxyphenyl-2-propanone) by using starting materials with the necessary aromatized substituents.

Phenyl-2-Propanone from Benzyl Cyanide

  • alpha-Phenylacetoacetonitrile1

We begin by preparing a solution of sodium ethoxide from 60 g. (2.6 mol) clean sodium and 700 ml of absolute alcohol (dried over calcium oxide or sodium) in a 2000 ml round-bottomed flask filled with a reflux condenser. We mix the hot solution with a blend of 234g (2 moles) of pure benzyl cyanide 264g (3 moles) of dry ethyl acetate (dried by refluxing over P2O5 for 30min followed by distillation). We then thoroughly shake the mixture after closing the condenser with a calcium chloride tube. Afterwards the solution is heated on the steam bath for two hours and allowing it overnight. The next morning, stir the mixture with a wooden rod to break lumps, cooled in a freezing mixture to -10°C, allowing it at this temperature for two hours. Collect the sodium salt on a 6-inch Buchner funnel and wash four times on the funnel with 250 ml portions of ether. The filter cake lacks any colors and corresponds 250-275g of dry sodium salt, or 69-76% of the calculated mount. The blended filtrates are placed in the freezing mixture until they are ready for work up as indicated below.

Dissolve the sodium salt still wet with ether in 1.3 liters of distilled water at room temperature, the solution cooled to 0°C, and the nitrile precipitated by adding gently, with intense shaking, 90 ml of glacial acetic acid, while keeping the temperature below 10°C. Separate the precipitate by suction filtration and wash four times on the funnel with 250 ml portions of water. The moist cake weighing about 300g corresponds to 188-206g (59-64%) of dry colorless alpha-phenylacetoacetonitrile, mp 87-89°C.

  • Phenyl-2-Propanone2

Place 350 ml of concentrated sulfuric acid in a 3000ml flask and cool to -10°C. The total first crop of moist alpha-phenylacetoacetonitrile obtained according to the procedure above (corresponding to 188-206g or 1.2-1.3 moles of dry product) is slowly added, with shaking, the temp maintained below 20°C (If pure dry alpha-phenylacetoacetonitrile is used, half its weight of water should is mixed with the sulfuric acid or charring will occur on the steam bath). After adding them all, warm the flask on the steam bath until solution is becomes effective and then for five minutes longer.

Cool the solution to 0°C by adding 1750ml of water rapidly and place the flask on a vigorously boiling water bath and heat for two hours, with constant shaking. The ketone builds a layer and, after cooling, is separated and the acid layer extracted with 600ml of ether. Wash the oil and ether layers successively with 100ml of water, the ether blended with the oil and dried over 20g of anhydrous sodium sulfate. Collect the sodium sulfate on a filter, washed with ether, and discard. Remove the ether from the filtrates and distill the residue 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 125-150g (77-86% of the theoretical amount).

Phenyl-2-Propanone from Phenylacetic Acid

This reaction works well in the presence of acetic anhydride in a large molar excess over the phenylacetic acid. If the ratio is minimal, the phenylacetone condenses with itself resulting to useless Dibenzyl Ketone.

  • Sodium Acetate Method (alternative)3b

Place the Phenylacetic Acid (PAA), Acetic Anhydride (AA) and Sodium Acetate (NaOAc) in a large round-bottomed flask built with a reflux condenser fitted with a drying tube. Heating the reaction mixture to 145-150°C on an oil bath offers necessary energetic evolution of carbon dioxide. Ketone Formation is controlled by blending an aliquot of the reaction mixture with excess of water and ammonium hydroxide until alkaline becomes weak– When heating to boiling point, the oily layer must remain.

The reflux setup is restructured for distillation and excessive solvent is removed (acetic acid and acetic anhydride, purify and reuse). Add 400ml water to the residue and extract the mixture with 3x100mL 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. Distillation for the second time gives 50-55% yield of product boiling at 210-215°C at atmospherical pressure. Phenyl-2-Propanone Ketoxime was obtained in 88-90% yield, which was distilled at 154-156°C/30mmHg.

  • Sodium Acetate Method (alternative)3b

Reflux 50 g phenylacetic acid, 25 g anhydrous sodium acetate and 850 ml acetic anhydride with stirring under moisture protection for 40 h. 500 ml acetic anhydride and acetic acid are distilled off, mix the rest with 1000 ml water after cooling down, extract the crude product with 2x250ml dichloromethane and wash the pooled organic layers with cold diluted sodium hydroxide solution (any formed P2P enol ester must be hydrolyzed) until all acids disappear in the organic layer. Dry the solution over Na2SO4 and distill the dichloromethane under ordinary pressure (and is saved for reuse) the rest of the volatiles are evaporated in vacuo, and the crude phenyl-2-propanone is vacuum distilled at 25 mmHg, bp 120-140°C. The yield about 30ml (70%).

Phenyl-2-Propanone by Nitroalkylation of Benzene

  • Titanium Tetrachloride Method7

Add benzene (0.5 mol, 39g) to a stirred solution of 2-nitropropene (0.1 mol, 8.7g) in dry CH2Cl2 (300ml) at room temperature. Afterwards, add dropwise of Titanium tetrachloride (0.1 mol, 19g) into the mixture with stirring at the same temperature. Stir for 60 min (or when the starting material completely disappears on TLC) and add water (150 ml) and stir the resultant heterogenous mixture at reflux for 2h. Separate the organic phase, and extract the aqueous phase with CH2Cl2, and wash the pooled organic extracts with 1 M Na2CO3 solution and dried over MgSO4. Evaporation of the solvent followed by vacuum distillation (bp 100-101°C at 14mmHg) afforded Phenyl-2-propanone (ca 9g, 70% of theory).

  • Triflic Acid Method14

Add a solution of 2-nitropropene (300 mg) in benzene (30 equivalents) to a well-stirred solution of CF3SO3H (10 equivalents with respect to 2-nitropropene) and benzene with the co-solvent of methylene chloride cooled to -40°C in a dry ice-acetone bath. Pour the resultant mixture immediately (after 1 minute) into large excess dry methanol (100 mL) and cool to -78°C with vigorous stirring. After warming it to ambient temperature (10-15 min), dilute the yellow solution with water (150 mL), neutralize with powdered NaHCO3 and saturate with NaCl. Extract the solution with CH2Cl2, dry over Na2SO4, and concentrated, and flash chromatograph the residue (on SiO2, eluting with CH2Cl2:n-hexane 12:7) to give pure phenyl-2-propanone, 392 mg (85%), as a colorless oil. The 2,4 dinitrophenylhydrazone derivative, recrystallized from methanol, had mp 152.5-153.5°C.

Phenyl-2-Propanone from Phenyl-2-Nitropropene8

  • Sodium Borohydride/Nef Reaction

This preparation involves reducing phenyl-2-nitropropene to phenyl-2-nitropropane with NaBH4 in methanol, then the hydrolysis of the nitro group with hydrogen peroxide and potassium carbonate, a variety of the Nef reaction. The preparation is a one-pot synthesis, free of isolation of the intermediate. This synthesis doesn’t work for ring-substituted phenyl-2-nitropropenes, as the side chain tends to be oxidized when electron-donating substituents surround the ring.

Dissolve 16.3g (0.1 mole) phenyl-2-nitropropene in 200ml methanol in a 250ml Erlenmeyer flask found on a magnetic stirrer, and chil to 0°C with an ice/salt bath. Afterward, with occasional stirring, add 7.6g (0.2 mole) of NaBH4 little at the time, and don’t allow the temperature to rise above 15°C. When the generation of heat subsides, remove the ice/salt- bath and stir the solution at room temperature for two hours. When this period comes to an end, place the flask once again in an ice/salt bath and allow the solution to cool to 0°C again. Add 100 ml of 30% H2O2, together with 30 grams of anhydrous potassium carbonate, and allow the solution to stir for 18-24 hours at room temp. When adding H2O2/K2CO3 a white, sticky precipitate forms, which can be a bit too dense for a weak magnetic stirrer to handle, therefore, you can stir the mass with a glass rod now and then during the first two hours, after which the precipitate will be less dense and suitable for any mag-stirrer.

The following day, acidify the solution with 2M HCl with good stirring, take care for the evolution of heat and CO2. It requires about 300 ml of acid. When the pH of the solution becomes acidic, the color becomes more yellow, but the acidity was acknowledged with pH paper. All the precipitate also disappeared at this point. Extract the solution with 3x100ml CH2Cl2 and wash the pooled organic extracts with 100ml 2M NaOH and 200ml H2O. Dry the organic phase over MgSO4, filtered with suction, and remove the solvent under vacuum to give a clear yellow oil. After distilling of said oil at aspirator vacuum, the yield turns to 60-70% of phenyl-2-propanone (P2P) as a light yellow oil.

Phenyl-2-Propanone from Chloroacetone9

Put 41 grams (0.31 mole) of anhydrous aluminum chloride and 100 ml of anhydrous benzene (free from thiophene) in a 500ml three-necked flask which included a mercury-sealed stirrer, a reflux water condenser and a small addition funnel. Connect the top of the condenser to a sulfuric acid trap and connect this trap to a gas absorption bottle. Stir the mixture and heat to refluxing on a steam bath and 13.9 g (0.15 mole) of chloroacetone was allowed drop in slowly for 30 minutes.

After 5 hours of refluxing, the solution becomes practically black. After cooling to room temperature, decompose the reaction mixture by slowly adding water through the condenser, stirring while adding. Add 20 ml of water and 20 ml of concentrated hydrochloric acid when no more hydrogen chloride was evolved. Sperate the benzene layer and extract the aqueous layer with four 25 ml portions of benzene. All the benzene solutions were blended and filtered. Distill the benzene, and the leftover viscous oil distilled under reduced pressure. This results to nine grams of liquid boiling below 123°C/20-22mmHg. Approximately 10g of high-boiling material remain in the distilling flask. Phenyl-2-Propanone was retrieved from the distillate by making the bisulfite addition product, filtering, decomposing the addition product with sodium carbonate solution, and steam distilled if any oil distilled over. Extract the distillate with ether and dry the ether over anhydrous MgSO4 and distill the ether on a steam bath. Distill the phenyl-2-Propanone under reduced pressure, bp 108-114°C/20-22mmHg. Yield 6.5 g (32%).

Phenyl-2-propanone from Ephedrine Derivatives10

Heating ephedrine and related compounds in strong aqueous acid, dehydrates them to the enamine, which spontaneously can re-structure to the isomeric imine (Schiff Base), which can then be hydrolyzed into phenyl-2-propanone and an amine salt. Since all the steps are reversible processes, the reaction equilibrium is targeted towards the desired product by constantly removing the resultant phenyl-2-propanone using steam distillation.

Ephedrine derivatives that are suitable for this process include Ephedrine, Pseudoephedrine, Norephedrine and Norpseudoephedrine (Phenylpropanolamine). Many other metal salts can act as an alternative instead of the zinc chloride.

Mix 1025g 75% sulfuric acid with 1g ZnCl2, and 192g (1.16 mol) Ephedrine or dissolve pseudoephedrine freebase at a temperature of 50-100°C, and heat the reaction mixture further to 145-150°C. At 125°C use steam through the solution to enhance the mixture of the contents. At 145°C the stream is enhanced, and for 2.5-3 hours, steam distill the phenylacetone from the reaction mixture. The crude phenyl-2-propanone, which lacks propiophenone, is isolated by toluene extraction of the distillate. After distillation through a short vigreaux column, 130g (82%) of phenyl-2-propanone is isolated in a purity of 99.8%.

Electrosynthesis of P2P from Benzyl Chloride4

Synthesis of phenylacetone clandestine from benzyl chloride (79 mmol) and acetic anhydride (686 mmol) by electrolysis of the reaction mixture. The anode is structured from magnesium or aluminium, the cathode of nickel, the solvent is DMF (110g) and the aiding electrolyte is tetrabutylammonium fluoroborate (2 g, 6 mmol). After electrolyzing with a current of 1A at a temperature of 0°C (2.2 faradays per mole of benzyl chloride), the leftover benzyl chloride, the toluene which results from the reduction of benzyl chloride, and phenyl-2-propanone, both in free form and in the form of its enol acetate, are found in the solution. After evaporating the DMF and hydrolyzing the residue with hot dilute HCl, phenyl-2-propanone is isolated by extraction with ether in 64% yield.

In another method, using a lead cathode and a carbon anode, DMF as the solvent and a tetrabutylammonium tosylate electrolyte results to a 73% yield of phenyl-2-propanone after hydrolysis of the resulting enol ester.

Metallic Nickel-Mediated Synthesis of P2P from Benzyl Chloride and Acetyl Chloride28,29

A 50-mL two-neck flask came along with a magnetic stirrer, a rubber septum, and a condenser topped with argon inlet and outlet to oil pump. Lithium metal was trimmed under mineral oil. One piece of lithium with a glowing metal surface was washed in hexane and placed into a glass tube with a stopcock and a rubber septum which contains argon. The glass tube helped to evaporate the hexane, filled with argon, and weighed. Nickel halide (1.0 equiv, 9-13 mmol), lithium (2.3 equiv, 21-30 mmol), and naphthalene (0.1 equiv, 0.9-1.3 mmol) were transferred in the flask through the side neck. The flask was emptied and filled with argon twice or thrice. You don’t need to use a glovebox or -bag if contact of the lithium with air is small. Then, glyme (25-30 mL) was inserted via the septum using a syringe, and the mixture was constantly stirred for 12 h. When reducing, the surface of lithium turned pink. After the lithium metal was totally consumed, the stirring was halted; metallic nickel that sticked to the walls of the flask was removed with a stirrer and a magnet. The nickel precipitated in the form of a bulky black powder in a clear colorless solution after standing. The septum on the side neck was replaced with an extra funnel, and a blend of necessary reagents in glyme (10 mL) was blended to the nickel.

Reaction of Benzyl Chloride with Acetyl Chloride in the Presence of Metallic Nickel

Metallic nickel in glyme (25 mL), prepared from nickel iodide (2.97 mmol), lithium (0.152 g, 21.9 mmol), and naphthalene (0.122 g, 0.95 mmol), was put under heat to reflux. A blend of benzyl chloride (1.0 g, 7.9 mmol) and acetyl chloride (0.65 g, 8.3 mmol) in glyme (10 mL) was gently added for 30 min. Extra heating was placed for 15 min, and the resulting red-brown solution mixture was cooled to room temperature, transferred into a separatory funnel containing hydrochloric acid solution (37%, 100 mL), and removed twice with chloroform. The chloroform solution was rinsed with water, and the aqueous phase went through extraction with additional chloroform. The combination of both extracts was dried using anhydrous sodium sulfate and concentrated. The crude oil was purified by silica gel chromatography. It was eluted with hexane and afterwards chloroform resulting to phenyl-2-propanone (0.72 g, 68%), bp 95-96°C (11 mmHg); IR (neat) 1710 cm-1 (C=O).

Phenyl-2-Propanone by Rearrangement of 2-Phenylpropanal11

2-Phenylpropanal can be restructured with the help of mercuric chloride (HgCl2) or sulfuric acid (H2SO4) resulting to the isomeric phenyl-2-Propanone (P2P). 2-Phenyl-propanal (hydratropic aldehyde) is an unnoticeable industrial chemical common in the perfume industry. 2-phenylpropanal also results from alpha-methylstyrene.

The CAS number for 2-phenyl-propanal is [93-53-8], and other names for it include Hydratropic aldehyde; 2-Phenylpropionaldehyde; Cumenealdehyde; alpha-methyl benzeneacetaldehyde and alpha-methyl phenylacetaldehyde. Boiling point 92-94°C/12mmHg, 222°C/760mmHg.

Other ways to perform this rearrangement include 2-phenylpropanal isomerization to phenyl-2-propanone in up to 87% yield by sending its vapor over an iron zeolite catalyst bed at 500°C, afterwards the condensation of the vapors and redistilling the P2P12.

Even if the following method which utilizes mercuric chloride is yields higher than the one using cold sulfuric acid, it’s best to use the one with sulfuric acid, since it’s affordable and not disastrous for your wellbeing or the environment. 60g of mercuric chloride contains 45 grams of mercury, which is sufficient to destroy a medium-sized lake if thrown to the environment, and if you consume it yourself, it will destroy your body.

You can’t possibly separate 2-phenylpropanal (bp 222°C/760mmHg) from phenyl-2-propanone (bp 214°C/760mmHg) by simple distillation and not through vacuum distillation since the boiling points are too near. Fractional distillation may be the best way to separate them, but the size of the column necessarily makes that option impractical. A good way of separating a mixture of the two involves oxidizing the mixture with a mild oxidant which won’t react with the P2P, but instead oxidize the aldehyde to 2-phenylpropionic acid. You can then separate the acid from the ketone by dissolving the mixture in a non-polar solvent and rinsing the solution with dilute sodium hydroxide. The P2P remains in the organic layer, which can be dried using MgSO4, the solvent removed under vacuum and the residue vacuum distilled to give pure P2P.

Phenyl-2-Propanone from Acetone Enolate

If you mix acetone with a strong base, which can deprotonate one of the relatively acidic alpha protons of the ketone, it leads to the formation of acetone enolate in quantitative yield. Such strong bases include sodium amide, lithium diisopropylamide and several alkoxides, such as potassium tert-butoxide.

If this enolate of acetone is exposed to a halobenzene (preferably iodobenzene, but bromobenzene should also work) in DMSO under extremely anhydrous conditions, both species will blend to form phenyl- 2-propanone.

There is the lack of real-life attempts at this synthesis using acetone enolate and a halobenzene in DMSO (but it has been done in liquid ammonia), but several ketone enolates, including pinacolone has been widely studied.


Phenylacetone is a compound that is used in the synthesis of various drugs, including synthesis of amphetamine from phenylacetone. It is also used as an analytical reagent to measure the concentration of dinucleotide phosphate in wastewater. Phenylacetone can be synthesized by reacting phenylacetic acid with either sodium or methyl ethyl ketone. The reaction mechanism for this reaction includes the formation of a nitro group from sodium nitrite, which then reacts with phenylacetic acid to form an intermediate. This intermediate reacts with methyl ethyl ketone to form phenylacetone, which is then hydrolyzed to produce methamphetamine. Phenylacetone also can react with hydrogen peroxide and form 3-hydroxybenzaldehyde and benzene.


What is Electro-organic synthesis?

It refers to molecular transformations initiated by the electron transfer at electrode surface.[1] In general, electro-organic synthesis does not require toxic reagents and/or precious-metal catalysts, and therefore has attracted much attention, especially in the areas of green and

industrial chemistry. While many anodic conversions (oxidative reactions) have been reported, cathodic conversions (reductive reactions) remain scarce. This is mainly

due to the limited variety of electrode materials suitable for cathodic reduction.

What is the function of Phenylacetone?

Phenylacetone is an organic compound with the chemical formula C6H5CH2COCH3. It is a colorless oil that is soluble in organic solvents. This substance is used in the manufacture of methamphetamine and amphetamine, where it is commonly known as P2P.

What is the source of Phenylacetone?

Phenylacetone is a natural product found in Streptomyces and Gossypium hirsutum with data available.

Where is phenyl found?

Phenyl groups are found in many organic compounds, both natural and synthetic (see figure). Most common among natural products is the amino acid phenylalanine, which contains a phenyl group.