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S Y N T H E S I S O F P H E N Y L - 2 - P R O P A N O N E ( P 2 P )

B Y R H O D I U M

T A B L E O F C O N T E N T S

Table of ContentsIntroductionP2P from Benzyl CyanideP2P from Phenylacetic AcidFriedel-Crafts Alkylation of Benzene with 2-NitropropaneReduction of Phenyl-2-NitropropeneFriedel-Crafts Alkylation of Benzene with ChloroacetoneHydrolysis of Ephedrine DerivativesElectrochemical Coupling of Benzyl Chloride and Acetic AnhydrideNickel-mediated Coupling of Benzyl Chloride and Acetyl ChlorideSemipinacol Rearrangement of Phenyl-2-PropanalP2P from Bromobenzene/Acetone Enolate

Radical Alkylation of Benzene with Acetone, catalyzed by Mn3+

Oxythallation of alpha-methylstyreneWittig reaction of BenzaldehydeCu(I)-catalyzed Arylation of Potassium AcetylacetonatePd-catalyzed Arylation of Isopropenyl AcetateAlkylation of Benzyl cyanide with TrimethylaluminiumP2P from Phenylacetaldehyde and Dimethyl CadmiumP2P from Phenylacetyl Chloride and Dimethyl CadmiumP2P via Grignard Addition to Acetic AnhydrideP2P via Grignard Addition to Benzyl CyanideReferences

I N T R O D U C T I O N

Aside from the often amateurish reduction of (pseudo)ephedrine to methamphetamine, the most popularprecursor to amphetamine and methamphetamine is phenyl-2-propanone (also called P2P, BMK, Benzyl MethylKetone or Phenylacetone). There is an astounding array of synthetic routes to this compound, both due to therelative simple structure of the compound, and also because of its popularity. Many of the earliest routes to thecompound has been more or less abandoned due to restrictions on the pre-precursors used to make it, butthere has always sprung up new methods of performing the feat of making this compound. Here is a collectionof some of the possible methods of synthesizing phenyl-2-propanone, ranging from simple one-step methods toelaborate multi-step variants, and from the very easy to the very complicated. Welcome to the world of P2P.

Many of the syntheses can also be tweaked to produce substituted phenyl-2-propanones, such as the everpopular MDMA precursor MDP2P (3,4-methylenedioxyphenyl-2-propanone) by using starting materials with thedesirable aromatic substituents.

Appearance: Clear oil, flowery odorBoiling Point: 214-216°C/760mmHg, 86-87°C/6mmHgMelting Point: -15°CMolecular Weight: 134.19 g/mol

Density: 1.0057 g/ml (20°C)Refractive Index: 1.5168

P H E N Y L - 2 - P R O P A N O N E F R O M B E N Z Y L C Y A N I D E

alpha-Phenylacetoacetonitrile1

A solution of sodium ethoxide isprepared from 60 g. (2.6 mol) cleansodium and 700 ml of absolutealcohol (dried over calcium oxide orsodium) in a 2000 ml round-bottomed flask equipped with areflux condenser. To the hotsolution added a mixture of 234g (2moles) of pure benzyl cyanide 264g(3 moles) of dry ethyl acetate (dried by refluxing over P2O5 for 30min followed by distillation). The mixture is

thoroughly shaken, the condenser closed with a calcium chloride tube, and the solution heated on the steambath for two hours before standing overnight. The next morning the mixture is stirred with a wooden rod tobreak lumps, cooled in a freezing mixture to -10°C, and kept at this temperature for two hours. The sodium saltis collected on a 6 inch Buchner funnel and washed four times on the funnel with 250 ml portions of ether. Thefilter cake is practically colorless and corresponds 250-275g of dry sodium salt, or 69-76% of the calculatedmount. 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 solutioncooled to 0°C, and the nitrile precipitated by adding slowly, with vigorous shaking, 90 ml of glacial acetic acid,while the temperature is kept below 10°C. The precipitate separated by suction filtration and washed four timeson 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

350 ml of concentrated sulfuric acid is placed in a3000ml flask and cooled to -10°C. The total first cropof moist alpha-phenylacetoacetonitrile obtainedaccording to the procedure above (corresponding to188-206g or 1.2-1.3 moles of dry product) is addedslowly, with shaking, the temp being kept below 20°C(If pure dry alpha-phenylacetoacetonitrile is used, halfits weight of water should be added to the sulfuric acidor charring will take place on the steam bath). After allis added the flask is warmed on the steam bath until solution is complete and then for five minutes longer. Thesolution is cooled to 0°C, 1750ml of water added rapidly, and the flask placed on a vigorously boiling water bathand heated for two hours, with occasional shaking. The ketone forms a layer and, after cooling, is separatedand the acid layer extracted with 600ml of ether. The oil and ether layers are washed successively with 100ml ofwater, the ether combined with the oil and dried over 20g of anhydrous sodium sulfate. The sodium sulfate iscollected on a filter, washed with ether, and discarded. The ether is removed from the filtrates, and the residuedistilled from a modified Claisen flask with a 25 cm fractionating side arm. The fraction boiling at 110-112°C at24 mmHg is collected; it weighs 125-150g (77-86% of the theoretical amount).

A somewhat higher yield has been obtained by a different variation of this synthesis, originating from Russia.

P H E N Y L - 2 - P R O P A N O N E F R O M P H E N Y L A C E T I C A C I D

In this reaction, it is important that acetic anhydride is present in the reaction mixture in a large molar excessover the phenylacetic acid. If the ratio is too small, the phenylacetone will condense with itself to form uselessDibenzyl Ketone.

PAA AA AA:PAA NaOAc Time Yield

60 g 600 g 10 30 g 5 h 0%

60 g 600 g 10 30 g 8 h 33.0%

60 g 600 g 10 30 g 12 h 46.3%

60 g 600 g 10 30 g 20 h 50.8%

60 g 1000 g 16.6 30 g 20 h 51.6%

60 g 600 g 11.5 90 g 20 h 51.5%

100 g 600 g 6 50 g 20 h 49.0%

100 g 600 g 2 50 g 20 h 33.0%

100 g 600 g 6 500 g 20 h 56.0%

Sodium Acetate Method

(alternative)3b

The Phenylacetic Acid(PAA), Acetic Anhydride(AA) and Sodium Acetate(NaOAc) is put in to a large round-bottomed flaskequipped with a reflux condenser fitted with a dryingtube. Heating of the reaction mixture to 145-150°C onan oil bath provides sufficiently energetic evolution ofcarbon dioxide. Formation of the ketone is controlled bymixing an aliquot of the reaction mixture with excess ofwater and ammonium hydroxide until weakly alkaline –upon heating to boiling the oily layer must notdisappear.

The reflux setup is rearranged for distillation andexcess solvent is removed (acetic acid and aceticanhydride, purify and reuse). To the residue there isadded 400ml water and the mixture is extracted with3x100mL dichloromethane (or chloroform). The solventis stripped off under vacuum and by vacuum distilling at125-135°C/30-32 mmHg the crude product is obtained.A second distillation gives 50-55% yield of productboiling 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

50 g phenylacetic acid, 25 g anhydrous sodium acetate and 850 ml acetic anhydride are refluxed with stirringunder moisture protection for 40 h. 500 ml acetic anhydride and acetic acid are distilled off, the rest is mixedwith 1000 ml water after cooling down, the crude product is extracted with 2x250ml dichloromethane and thepooled organic layers are washed with cold diluted sodium hydroxide solution (any formed P2P enol ester mustbe hydrolyzed) until no more acids are present in the organic layer. The solution is dried over Na2SO4 and the

dichloromethane is distilled off under ordinary pressure (and is saved for reuse) the rest of the volatiles areevaporated in vacuo, and the crude phenyl-2-propanone is vacuum distilled at 25 mmHg, bp 120-140°C. Theyield about 30ml (70%).

Potassium Acetate/Copper Sulfate3c

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 is introduced 2000 ml anhydrous acetic anhydride in 4000 ml flask. The mixture isrefluxed 24 h. After cooling 500 ml of solvent (CCl4, CHCl3, CH2Cl2) is added and the mixture is poured to a flask

containing 2000 ml ice-water. After separation of layers upper layer is removed and lower layer is three timesdecanted with water, separated, dried (Na2SO4, CaCl2), and distilled. The solvent is distilled off and

fractionation column is placed on the top of the flask. Remaining acetic acid and acetic anhydride is thenremoved, pure product is collected at 100°C/15mmHg. Yield 70-90 g (52-67%).

Pyridine Method5

A mixture of phenylacetic acid (13.6 g, 0.1 mol), acetic anhydride (50 ml) and pyridine (50 ml) was refluxed sixhours (in the beginning carbon dioxide evolution was vigorous. After removal of the solvent the residue wastaken up in toluene and washed with 10% sodium hydroxide. Removal of the solvent left a residue witging 12g,which on fractional vacuum distillation gave 7.5 g (56%) phenyl-2-propanone, bp 30-64°C/0.1mmHg.

Lead Acetate Method6

Place 1000g phenylacetic acid and 3000ganhydrous (or trihydrate) lead acetate in adistillation apparatus and heat. First anamount of water will distill, and next phenyl-2-propanone in this destructive distillation, whichrequires liberal application of heat. Thedistillate will separate into two layers. The

organic layer is separated and redistilled to give pure phenyl-2-propanone, bp 105°C/10 mmHg or 216°C atatmospherical pressure.

A considerable improvement to this method has been made by Xtaldoc on a large scale.

The Lead(II)Acetate can be substituted with Calcium(II)Acetate, making the synthesis more environmentallyfriendly.

Methyllithium addition to Phenylacetic Acid27

In a 100ml rb flask equipped with a side tube for a gasinlet capillary, a reflux condenser protected by a sodiumhydroxide drying tube and magnetic stirring was placed0.026 mole (3.5 g) of phenylacetic acid dissolved in 50ml of ether, and the air was then expelled with a rapidstream of dry nitrogen. After 2-3 minutes the gasstream was slowed down, just to create sufficientbubbles for stirring the solution during the experiment.

When all air had been expelled 0.055 mole of an ethereal solution of methyllithium was added through thecondenser. A vivid reaction took place, the ether refluxed, and a white precipitate was formed (lithium salt of theacid). After the addition of all the methyllithium the precipitate partly dissolved and a weakly opalescent solutionwas obtained. If necessary, the solution was then refluxed for 10-30 minutes to complete the reaction. After thesolution had reached room temperature, water was slowly added. The excess of methyllithium was thusdestroyed and lithium hydroxide was formed from the intermediate dilithium salt.

The alkaline water layer, which contained the lithium salt of unreacted acid, was removed in a separatoryfunnel, and the ethereal layer washed three times with half its volume of water. The ether solution was thendried over magnesium sulphate, filtered and the ether driven off, first at ordinary pressure and then at aspiratorvacuum to give 2.65g (76%) of phenylacetone, usually pure enough for most purposes.

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Titanium Tetrachloride Method7

To a stirred solution of 2-nitropropene (0.1mol, 8.7g) in dry CH2Cl2 (300ml) was added

benzene (0.5 mol, 39g) at roomtemperature. Titanium tetrachloride (0.1mol, 19g) was then added dropwise into themixture with stirring at the same temperature. After being stirred for 60 min (or when the starting materialcompletely disappears on TLC), water (150 ml) was added and the resultant heterogenous mixture was stirredat reflux for 2h. The organic phase was separated, the aqueous phase extracted with CH2Cl2, and the pooled

organic extracts washed 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

A solution of 2-nitropropene (300 mg) in benzene (30 equivalents) was added to a well-stirred solution ofCF3SO3H (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. The reaction mixture was immediately (after 1 minute)poured into large excess dry methanol (100 mL) cooled to -78°C with vigorous stirring. After being warmed toambient temperature (10-15 min), the yellow solution was diluted with water (150 mL), neutralized withpowdered NaHCO3 and saturated with NaCl. The solution was extracted with CH2Cl2, dried over Na2SO4, and

concentrated, and the residue was flash chromatographed (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.

P H E N Y L - 2 - P R O P A N O N E F R O M P H E N Y L - 2 - N I T R O P R O P E N E8

Sodium Borohydride/Nef Reaction

In this preparation, phenyl-2-nitropropene is reduced tophenyl-2-nitropropane withNaBH4 in methanol, followed by

hydrolysis of the nitro groupwith hydrogen peroxide andpotassium carbonate, a variety of the Nef reaction. The preparation is a one-pot synthesis, without isolation ofthe intermediate. This synthesis is not suitable for ring-substituted phenyl-2-nitropropenes, as the side chaintends to be oxidized when electron-donating substituents are present on the ring.

16.3g (0.1 mole) phenyl-2-nitropropene was dissolved in 200ml methanol in a 250ml Erlenmeyer flask situatedon a magnetic stirrer, and chilled to 0°C with an ice/salt bath. Then, with good stirring, 7.6g (0.2 mole) of NaBH4

was added a little at the time, and the temperature was not allowed to to rise above 15°C. When thegeneration of heat had subsided, the ice/salt- bath was removed and the solution was stirred at roomtemperature for two hours. At the end of this period, the flask was once again placed in an ice/salt bath and thesolution was allowed to cool to 0°C again. 100 ml of 30% H2O2 was then added, together with 30 grams of

anhydrous potassium carbonate, and the solution was left to stir for 18-24 hours at room temp. During theaddition of H2O2/K2CO3 a white, sticky precipitate forms, which can be a bit too thick for a weak magnetic stirrer

to handle, so the mass can be stirred with a glass rod now and then during the first two hours, after which theprecipitate will be much looser and no match for any mag-stirrer.

The next day, the solution is slowly acidified with 2M HCl with good stirring, care being taken for the evolution ofheat and CO2. About 300 ml of acid is needed. When the pH of the solution turned acid, the color became

significantly more yellow, but the acidity was confirmed with pH paper. All of the precipitate was also be gone atthis point. The solution was extracted with 3x100ml CH2Cl2, and the pooled organic extracts washed with 100ml

2M NaOH and 200ml H2O. The organic phase was dried over MgSO4, filtered with suction, and the solvent

removed under vacuum to give a clear yellow oil. After distillation of said oil at aspirator vacuum, the yield wasaround 60-70% of phenyl-2-propanone (P2P) as a light yellow oil.

Reduction with Iron Powder13

If phenyl-2-nitropropene is reduced byiron powder in an acidic medium (suchas acetic acid or aqueous hydrochloricacid) the nitroalkene is reduced to theoxime, which is then hydrolyzed by theacid into the desired phenyl-2-propanone.

Phenyl-2-nitropropene (10 g, 61 mmol) was dissolved in 75 ml HOAc and slowly dripped into a refluxing slurry ofFe powder (32 g, 0.57 mol) in 140 ml HOAc. The mixture turned brownish and foamy, and the mixture wasrefluxed on low heat for 1.5 h. The reaction mixture was poured into 2000ml water, and was extracted with3x100 ml CH2Cl2. The combined extracts was washed with 2x150 ml H2O and dried over MgSO4. The solvent

was distilled off, and the residue distilled under vacuum to give phenyl-2-propanone in 75% yield.

Reduction with Chromous Chloride18

Another method for reducing phenyl-2-nitropropene to phenyl-2-propanone in 80% yield is to useChromium(II)chloride as the reducing agent.

P H E N Y L - 2 - P R O P A N O N E F R O M C H L O R O A C E T O N E 9

41 grams (0.31 mole) of anhydrous

aluminum chloride and 100 ml of anhydrousbenzene (free from thiophene) were put in a500ml three-necked flask which wasequipped with a mercury-sealed stirrer, areflux water condenser and a small additionfunnel. The top of the condenser wasconnected to a sulfuric acid trap and thistrap was connected to a gas absorption bottle. The mixture was stirred and heated to refluxing on a steambath and 13.9 g (0.15 mole) of chloroacetone was allowed drop in slowly during a period of 30 minutes. Afterrefluxing for 5 hours, the solution was practically black. After cooling to room temperature, the reaction mixturewas decomposed by slowly adding water through the condenser, stirring during the addition. When no morehydrogen chloride was evolved, 20 ml of water and 20 ml of concentrated hydrochloric acid was added. Thebenzene layer was separated and the aqueous layer extracted with four 25 ml portions of benzene. All of thebenzene solutions were combined and filtered. The benzene was distilled off, and the remaining viscous oil wasdistilled under reduced pressure. Nine grams of liquid boiling below 123°C/20-22mmHg was obtained.Approximately 10g of high-boiling material was left in the distilling flask. Phenyl-2-Propanone was recoveredfrom the distillate by making the bisulfite addition product, filtering, decomposing the addition product withsodium carbonate solution, and steam distilled as long as any oil distilled over. The distillate was extracted withether, the ether dried over anhydrous MgSO4 and the ether distilled on a steam bath. The phenyl-2-Propanone

was distilled under reduced pressure, bp 108-114°C/20-22mmHg. Yield 6.5 g (32%).

P H E N Y L - 2 - P R O P A N O N E F R O M E P H E D R I N E D E R I V A T I V E S 1 0

When ephedrine and related compounds are heated in strong aqueous acid, they are dehydrated to theenamine, which spontaneously can rearrange to the isomeric imine (Schiff Base), which then can be hydrolyzedinto phenyl-2-propanone and an amine salt. As all the steps are reversible processes, the reaction equilibrium isdriven towards the desired product by continuously removing the formed phenyl-2-propanone by the aid ofsteam distillation.

Ephedrine derivatives that can be used in this procedure include Ephedrine, Pseudoephedrine, Norephedrineand Norpseudoephedrine (Phenylpropanolamine). Many other metal salts can be used instead of the zincchloride, for details, see the translation of the original patents.

1025g 75% sulfuric acid was mixed with 1g ZnCl2, and 192g (1.16 mol) Ephedrine or Pseudoephedrine freebase

was dissolved at a temperature of 50-100°C, and the reaction mixture was heated further to 145-150°C. At125°C steam is passed through the solution to facilitate mixing of the contents. At 145°C the stream of steam isincreased, and during 2.5-3 hours the phenylacetone is steam distilled from the reaction mixture. The the crudephenyl-2-propanone, which is free from propiophenone, is isolated by toluene extraction of the distillate. Afterdistillation through a short vigreaux column, 130g (82%) of phenyl-2-propanone is isolated in a purity of 99.8%.

E L E C T R O S Y N T H E S I S O F P 2 P F R O M B E N Z Y L C H L O R I D E 4

Synthesis of phenyl-2-propanone from benzyl chloride (79 mmol) and acetic anhydride (686 mmol) by electrolysisof the reaction mixture. The anode is made of magnesium or aluminium, the cathode of nickel, the solvent is DMF(110g) and the supporting electrolyte is tetrabutylammonium fluoroborate (2 g, 6 mmol). After the electrolysisusing a current of 1A at a temperature of 0°C (2.2 faradays per mole of benzyl chloride), the remaining benzylchloride, the toluene which isa byproduct of the reduction

of benzyl chloride, andphenyl-2-propanone, both infree form and in the form of itsenol acetate, are present inthe solution. After the DMFhas been evaporated off andthe residue has beenhydrolysed with hot dilute HCl, phenyl-2-propanone is isolated by extraction with ether in 64% yield.

Another procedure33, using a lead cathode and a carbon anode, DMF as the solvent and a tetrabutylammoniumtosylate electrolyte gives a 73% yield of phenyl-2-propanone after hydrolysis of the resulting enol ester.

M E T A L L I C N I C K E L - M E D I A T E D S Y N T H E S I S O F P 2 P F R O M B E N Z Y L

C H L O R I D E A N D A C E T Y L C H L O R I D E 2 8 , 2 9

Preparation of Metallic Nickel

A 50-mL two-neck flask was equipped with a magnetic stirrer, a rubber septum, and a condenser topped withargon inlet and outlet to oil pump. Lithium metal was cut under mineral oil. One piece of lithium with a shiningmetal surface was rinsed in hexane and transferred into a glass tube with a stopcock and a rubber septumwhich had been filled with argon. The glass tube was evacuated to evaporate the hexane, filled with argon, andweighed. 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 placed in the flask through the side neck. The flask was evacuated and filled with argon two orthree times. The use of a glovebox or -bag is not required if contact of the lithium with air is kept to a minimum.Then, glyme (25-30 mL) was added through the septum with a syringe, and the mixture was stirred for 12 h.During the reduction the surface of lithium became pink. After the lithium metal was consumed completely, thestirring was stopped; metallic nickel which had adhered to the walls of the flask was scraped off with the stirrerand a magnet. The nickel precipitated as a bulky black powder in a clear colorless solution after standing. Theseptum on the side neck was replaced with an addition funnel, and a mixture of appropriate reagents in glyme(10 mL) was then added 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), andnaphthalene (0.122 g, 0.95 mmol), was heated to reflux. A mixture of benzyl chloride (1.0 g, 7.9 mmol) andacetyl chloride (0.65 g, 8.3 mmol) in glyme (10 mL) was added dropwise for 30 min. Additional heating wascontinued for 15 min, and the red-brown reaction mixture was cooled to room temperature, poured into aseparatory funnel containing hydrochloric acid solution (37%, 100 mL), and extracted with chloroform twice. Thechloroform solution was washed with water, and the aqueous phase was extracted with additional chloroform.The combined extracts were dried over anhydrous sodium sulfate and concentrated. The crude oil was purifiedby silica gel chromatography. It was eluted with hexane followed by chloroform to give phenyl-2-propanone

(0.72 g, 68%), bp 95-96°C (11 mmHg); IR (neat) 1710 cm-1 (C=O).

P H E N Y L - 2 - P R O P A N O N E B Y R E A R R A N G E M E N T O F 2 - P H E N Y L P R O P A N A L 1 1

2-Phenylpropanal can be rearrangedwith either mercuric chloride (HgCl2) or

sulfuric acid (H2SO4) to form the

isomeric phenyl-2-Propanone (P2P). 2-Phenyl-propanal (hydratropic aldehyde)is an unwatched industrial chemicalwhich is used in the perfume industry.2-phenylpropanal can also be madefrom alpha-methylstyrene.

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

There are other ways of performing this rearrangement, 2-phenylpropanal is isomerized to phenyl-2-propanonein up to 87% yield by passing its vapor over an iron zeolite catalyst bed at 500°C, followed by condensation of

the vapors and redistilling the P2P12.

Even if the method below which uses mercuric chloride is higher yielding than the one using cold sulfuric acid, Iwould definitely reccommend the one with sulfuric acid, as it is much cheaper to use, and is not disastrous foryour health or the environment. 60g of mercuric chloride contains 45 grams of mercury, enough to poison amedium-sized lake if released into the environment, and if you happen to ingest it yourself, it will accumulate inyour body.

It is not possible to effectively separate 2-phenylpropanal (bp 222°C/760mmHg) from phenyl-2-propanone (bp214°C/760mmHg) through simple distillation and certainly not via vacuum distillation as the boiling points aretoo close. Fractional distillation could theoretically be used to separate them, but the size of the column thatwould have to be used makes that option impractical. A good idea for separating a mixture of the two is tooxidize the mixture with a mild oxidant which won't affect the P2P, but which will oxidize the aldehyde to 2-phenylpropionic acid. The acid can then be separated from the ketone by dissolving the mixture in a non-polarsolvent and washing the solution with dilute sodium hydroxide. The P2P stays in the organic layer, which is thendried over MgSO4, the solvent removed under vacuum and the residue vacuum distilled to give pure P2P.

Method A

30g of 2-phenylpropanal is heated together with a mixture of 60g mercuric chloride (HgCl2, 1 eq.) and 450ml

75% ethanol in a pressure-safe sealed glass container for 4.5h at 100°C in a boiling water bath, during whichtime a precipitate forms. Water is added, and the solution is steam-distilled (during which operation theprecipitate redissolves). The distillate is extracted with ether, dried, and the solvent is evaporated. The oilyresidue is then vacuum distilled with a fractionating column to collect the phenyl-2-propanone in a yield of 80%or more, bp 92-101°C at 14mmHg.

When 0.1 equivalents of HgCl2 was used, only 10% phenyl-2-propanone was formed, the rest consisted of

unchanged aldehyde.

Method B

9 g of 2-phenylpropanal is slowly added with good stirring during 35 minutes to 40ml concentrated sulfuric acid,while the temperature of the reaction mixture is kept at -16°C. After all the 2-phenylpropanal has been added,the mixture is allowed to stand at the same temperature for another 15 minutes, and then the mixture ispoured onto crushed ice (100-150g is probably a suitable amount). When the ice has melted, the organics areextracted from the water phase by 3x50ml diethyl ether, the pooled organic phases dried over MgSO4, the

ether distilled off and finally the residue is vacuum distilled (bp 91-96°C at 11 mmHg) to give 5.6g (62%) ofphenyl-2-propanone.

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If acetone is reacted with a strong base, which is able to deprotonate one of the relatively acidic alpha protonsof the ketone, acetone enolate is formed in quantitative yield. Such strong bases include sodium amide, lithiumdiisopropylamide and several alkoxides, for example potassium tert-butoxide.

If this enolate of acetone is allowed to react with a halobenzene(preferably iodobenzene, but bromobenzene should also work) in DMSOunder rigidly anhydrous conditions, the two species will combine to formphenyl- 2-propanone.

There has been no known actual attempts at this synthesis using theenolate of acetone and a halobenzene in DMSO (but it has been done in

liquid

ammonia), but other ketone enolates, suchas pinacolone has been extensively studiedin this medium. There are no theoreticalobstacles at all to why it would not work inthe production of phenyl-2-propanone. Theyields in the reactions range between 50and 98%. The reaction can be catalyzed by

iron salts, oxygen or UV light.

For a more in-depth discussion of this synthesis, read Drone #342's Enolate Phenylacetone Synthesis FAQ 1.0

F R E E - R A D I C A L A L K Y L A T I O N O F B E N Z E N E W I T H A C E T O N E C A T A L Y Z E D

B Y M A N G A N E S E ( I I I ) A C E T A T E 1 7

Phenyl-2-Propanone can be made in a single step by a free-radical reaction between benzene and acetone. Thereaction relies upon the special oxidative powers of manganese(III)acetate, a compound easily prepared frompotassium permanganate. The yield is relatively low, and requires high dilution of the reactants, but this can beimproved, and the reaction is also applicable for other substituted benzenes, as can be seen in thecomprehensive Manganese(III)acetate catalyzed aromatic acetonylation document on this site.

A mixture of Manganese(III)acetatedihydrate (13.4g, 50 mmol), benzene(150ml), acetone (150ml) and glacial aceticacid (250ml) was refluxed under an inertatmosphere (argon, helium or nitrogen) untilthe dark brown color ofmanganese(III)acetate changed to the palepink of manganese(II)acetate (about 90 min). The reaction mixture was partitioned between 400ml ether and250ml water. The ether layer was separated and washed with 250ml water and with 2x250ml 5% Na2CO3 to

remove any remaining acetic acid. The ether was then dried over anhydrous Na2SO4 (or MgSO4), the solvent

evaporated and the residue fractionately distilled to recover unreacted benzene, and to give phenyl-2-propanone in 40% yield (1.34g) based on the reacted manganese(III)acetate, which is the limiting reagent inthis reaction.

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M E T H Y L S T Y R E N E W I T H T H A L L I U M ( I I I ) N I T R A T E 2 3

Warning: Thallium salts are exceedingly toxic, and may be lethal upon ingestion! Handle with gloves only!

A solution of Thallium(III)Nitrate (39g, 100 mmol) in100ml methanol is added to a solution of alpha-methylstyrene (11.82g, 100mmol) in 50ml methanol atroom temperature with stirring, and there is animmediate precipitation of Thallium(I)Nitrate, and afterstanding for 15 minutes, the precipitate is filtered off,washed with a little methanol, and the filtrate is shakenfor 5 min with 1M H2SO4 to hydrolyze the formed

Phenyl-2-Propanone dimethyl acetal. The solution is extracted with ether, dried over MgSO4 and the solvent

distilled off, and the residue vacuum distilled to give 10.9g Phenyl-2-Propanone (81% yield).

Thallium(III)Nitrate

50g Thallium(III)Oxide (Tl2O3) is dissolved in 150ml warm, concentrated nitric acid and cooling the pale yellow

solution to 0°C. The colorless crystals of Thallium(III)Nitrate trihydrate are filtered, washed with a little dilute

nitric acid and dried in vacuo over phsphorus pentoxide. Thallium(III)Nitrate (mol wt 390) is stable indefinitely ifstored in tightly sealed bottles. The salt is readily soluble in methanol and dilute mineral acids.

alpha-Methylstyrene can also be treated with Bromine and Sulfuric Acid to yield P2P.

P H E N Y L - 2 - P R O P A N O N E F R O M B E N Z A L D E H Y D E A N D A P H O S P H O N I U M

Y L I D E ( W I T T I G R E A C T I O N ) 1 5

The phosphonium salt was prepared by dissolving triphenyl phosphine (76.4g, 0.29 mol) and alpha-chloroethyl

methyl ether16 (28.4g, 0.30 mol) in 125 mL benzene. After standing for 40 h the mixture was filtered andwashed with ether giving a white solid (112g, 88%) consisting of the crude phosphonium salt containing onemolar equivalient of benzene crystallization. This salt is slightly hygroscopic on exposure in air but can be storedindefinitely in a sealed container. The ylid resulting from treatment of the phosphonium salt with base wasfound to be very unstable at room tempature, the characteristic red color dissappearing within a few seconds.Accordingly, the preparation and reaction of this ylid was best carried out at -40°C.

The phosphonium salt (33 mmol) was suspended in 40 mL of glyme at -40°C under nitrogen. Potassium tert-butoxide (33 mmol) in 15 mL of glyme was added with stirring over 5 minutes. At this point a solution ofbenzaldehyde (30 mmol) in 5 mL of glyme was added over five minutes. The mixture was allowed to warm toroom temp over 1h and was then directly distilled, to give pure phenyl-2-propanone enol methyl ether).

Phenyl-2-propanone was conveniently prepared from the enol ether by mixing with one equivalent of water with0.5% HCl and enough methanol to effect solution. The solution was heated to boiling and the solvent was thenevaporated to give relatively pure phenyl-2-propanone in 88% overall yield.

P H E N Y L - 2 - P R O P A N O N E B Y A R Y L A T I O N O F P O T A S S I U M

A C E T Y L A C E T O N A T E 2 1

To a stirred solution of bromobenzene (31.4g, 200 mmol) in DMF(1 liter) was added cuprous iodide (32.4 g, 167 mmol) andpotassium acetylacetonate hemihydrate (125g, 834 mmol;Aldrich). The mixture was stirred and heated at 100°C for 24 hr,cooled, stirred with 2M sodium hydroxide (250 ml) for 1 hr andextracted with toluene (2x500 ml). The combined extracts werewashed with water, 1M hydrochloric acid and satd. aq. sodiumbicarbonate, dried over magnesium sulphate and concentratedin vacuo to leave a dark brown oil, which after purification gave phenyl-2-propanone in 65% yield.

P H E N Y L - 2 - P R O P A N O N E B Y H E C K A R Y L A T I O N 2 2

To a stirred solution of bromobenzene (60 mmol),isopropenyl acetate (9g, 90 mmol) and dichloro-bis-(tri-o-tolylphosphine)palladium (0.47g, 0.67 mmol) indry toluene (30 ml), under nitrogen, was addedtributyltin methoxide (25.9 ml, 90 mmol; Aldrich).The mixture was stirred and heated at 100°C for 5hr, cooled and the solvent evaporated in vacuo. Theresidue was chromatographed on silica gel, toafford the phenyl-2-propanone in 67% yield.

P H E N Y L - 2 - P R O P A N O N E F R O M B E N Z Y L C Y A N I D E A N D

T R I M E T H Y L A L U M I N U M 2 5

Trimethylaluminium (30ml of a 2M solution in toluene) wasadded to a solution of benzyl cyanide (2.34g, 20 mmol) in20ml of toluene at -78°C and the mixture was understirring allowed to slowly warm up to room temperatureand refluxed for 12h. After being cooled to 0°C, thesolution was poured over crushed ice and made acidicwith 6M HCl. Ethyl acetate was added and the mixturewas vigorously stirred for one hour. The organic layerwas washed with aqueous NaHCO3, brine and dried over MgSO4. Removal of the solvent gave 2.75g of crude

phenyl-2-propanone as an oil, which can be purified by vacuum distillation or column chromatography.

P H E N Y L - 2 - P R O P A N O N E F R O M P H E N Y L A C E T A L D E H Y D E A N D D I M E T H Y L

C A D M I U M

Dimethyl Cadmium

2 MeMgI + CdCl2 => Me2Cd + 2 MgICl

To 500 ml. 3-neck rb. DRY FLASK attach a reflux condenser. Attach 125ml sep. funnel, add 31.3 ml. methyl iodideeither freshly prepared or dried overnight with calcium chloride. Add 60 ml. anhydrous diethyl ether to sep.funnel, replace stopper.

Add 12.5 grams Magnesium turnings to flask. Add 75 ml anhydrous ether to flask. Allow aprox. 10 ml. of halideether solution to enter flask. If cloudiness does not become apparent in 1 or 2 min stop. Do not add more! Takea glass rod about 12 inches in length and score with a 3 corner file 2 inches from one end using pliers and a ragto protect your hands break away the 2 inch piece. using the remaing 10 inch piece gently poke at themagnesium turnings to expose fresh metal.

If reaction starts, add halide dropwise as quickly as the reflux column can handle. Be prepared to stop and coolwith ice water bath if needed. When all the halide has been added and the reaction is no longer refluxing, add31.2 grams of anhydrous cadmium chloride in small portions through side neck restoppering after each addition.

After all the Cadmium chloride has been added, the flask will have a tannish brown solid mass inside. This is thedimethyl cadmium, keep it covered and protected from air. Proceed immediately to next part if at all possible.

Notes: Avoid breathing the cadmium chloride dust (it needs to be finely ground after drying) avoid contact withthe methyl iodide or ether solution of methyl iodide avoid breathing any vapours of the metal conversion

reaction (it smells like garlic if you must know).

Phenyl-2-Propanone

To a clean dry sep. funnel add 64 ml. freshlydistilled phenylacetaldehyde (Note 1) and 50 ml.anhydrous ether. Add dropwise thealdehyde/ether solution to the dimethyl cadmiumswirling occasionally to break up the clumps. Beprepared to stop addition and cool if needed.When reflux has subsided do not heat. Quicklypour into a 1000 ml. beaker containing 100 ml. distilled water 10 ml conc. HCl and 100 cc. of chipped ice.Neutralize with sat. sodium bicarb untill fizzing stops. Separate, and extract water layer with 2x50 ml portions oftechnical grade ether. Distill under reduced pressure to strip off excess ether. Test with bisulfite any product notforming addition is phenyl-2-propanol (very small amount) can be saved for later oxidation. Hydrolyse additionproduct and distill if desired. bp. 100 at 13 mm. Yield 50-55 ml, ~85% of P2P.

Note 1: The phenylacetaldehyde will polymerise on standing. This polymer is degraded to the monomer ondistillation. For this preparation it also needs to be as dry as possible.

P H E N Y L - 2 - P R O P A N O N E F R O M P H E N Y L A C E T Y L C H L O R I D E A N D

D I M E T H Y L C A D M I U M 3 2

A mixture of 40 ml. of anhydrous ether and 6.1 grams (0.25 mole) of magnesium was stirred under reflux while35.5 grams (0.25 mole) of methyl iodide in 140 ml. of anhydrous ether was added over a 3-hour period; stirringunder reflux was continued for an additional hour. The reaction mixture was cooled with an ice bath and 22.4grams (0.134 mole) of powdered anhydrous cadmium chloride was added over a 5- to 10-minute period,warmed to room temperature, and refluxed on a steam cone for 1 hour. Ether was removed by distillation on asteam bath. To theresidue was added 100 ml. of anhydrous benzene and the distillation was continued untilabout 50 ml. more of distillate was collected. Again 100 ml of anhydrous benzene was added, the flask wascooled in an ice bath, and 30.9 grams (0.2 mole) of phenylacetyl chloride in 75 ml of anhydrous benzene wasadded with stirring over a period of approximately 10 minutes. The reaction mixture was warmed to roomtemperature and refluxed with stirring on a steam cone for 1 hour. The flask was again cooled in an ice bathand the reaction mixture decomposed by the addition of a solution of 25 grams of ammonium chloride in 200 mlof cold water. The organic phase was separated, washed, and dried over anhydrous sodium sulfate. Thebenzene was removed by flash distillation and the ketone distilled under reduced pressure. There was thusobtained 15.5 grams (58%) of 1-phenyl-2-propanone, bp 74-76°C/3 mmHg).

P H E N Y L - 2 - P R O P A N O N E B Y G R I G N A R D A D D I T I O N T O A C E T I C

A N H Y D R I D E 2 6

In a 500-mL three-necked flask, situated in a dry ice/acetone slush in a Dewar flask, there was added a solutionof acetic anhydride (40g, 2.55 mol) in diethyl ether (100ml), 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 dryice/acetone). To this was added an etheral solution of benzylmagnesium chloride, prepared from benzyl chloride(25.5g, 0.2 mol) and magnesium shavings (4.9g, 0.2 mol). After the addition after one hour was finished, thereaction mixture was allowed to stir at dry ice temperature for 2-3 hours, the cooling bath removed and thereaction quenched by the careful addition of saturated aqueous ammonium chloride. The aqueous layer was

separated, the organic phase washed with 10% sodium carbonate solution until the washes were no longeracidic 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 fractionately distilled to yield phenyl-2-propanone (14g,52%), bp 214-215°C/760mmHg (100-101°C/13mmHg).

P H E N Y L - 2 - P R O P A N O N E B Y G R I G N A R D A D D I T I O N T O N I T R I L E S 1 9 , 2 4

127g benzyl chloride was dissolved in 250mL Et2O, to this was added 27g Mg turnings in portions, an iodine

crystal being added after the first portion to initiate Grignard rxn. A thick white precipitate built up and cloggedup some Mg, but after all was added, there was excess unclogged Mg which would not react. [NOTE: Thisclogged-up material didn't react fully w/the MeCN, and so was decomposed to toluene, so try to avoid it!].Submersionof 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 rxn mixture was cooled in an ice-salt bath. A soln. of 62gacetonitrile in 100mL Et2O was added slowly while stirring w/a thermometer. The reaction temperature rose to

30°C. After completion of addition, the mixture was refluxed gently, stirred thoroughly, then left to cool to roomtemp. 500mL 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 final product would be higher if reaction mixture was first poured onto ice, thenacidified.] After all effervescence had stopped, the organic layer was separated. NaCl was added to the aqueouslayer, which was then extracted w/Et2O [NOTE: I think a lot of product 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 42g crude phenyl-2-propanone as a clear orange oil. Vacuum distillation of thisoil afforded pure phenyl-2-propanone (bp 91-96°C at 11 mmHg).

The intermediate phenyl-2-propanone imine magnesium salt can also be prepared from methylmagnesium iodideand benzyl cyanide. Both are hydrolyzed to phenyl-2-propanone with dilute hydrochloric acid. The imine salt canalso be reduced directly to amphetamine by sodium borohydride in methanol in high yield.

Simplification of the above procedure, by Poodle:

In a dream, 0.2 mol benzylmagesiumchloride grignard reagent were prepared by standard methods indiethylether (Total reaction volume: 200ml). Reaction initiated by heating the mixture to 60°C for a shortperiode of time. About 2 moles of acetonitrile (100ml) was mixed with 100 ml of anhydrous diethylether andcooled in ice/water. The benzylmagnesium chloride solution was added the acetonitrile over a periode of 10minutes, using constant swirling of the reaction mixture. A white percipitate was formed, corresponding to aintermediate complex, not soluble in ether or acetonitrile. This complex was isolated by filtration through abuchner, and washed twice with water-free ether to remove any unwanted remains of acetonitrile or benzylchloride. The white complex was brie fly dried, but as it began to turn yellow, no chances was taken and 15 mldistilled water was added, then another 10 ml (The complex reacted immediatly with the water, giving heat andcausing remaining ether to boil, the solution turned yellow/orange with oily orange bubbles.) The solution wasexposed for a vacuum to remove any remaining ether in the solution. Upon using the vaccum, ether wasremoved and the solution separated into two layers with an orange oil on top and a water layer containingsalts and undissolved salts. The oily layer was separated and gave 21 ml of possible P2P, about 75-80% of thetheoretical 26 ml. The ketone was frozen at -20, responding to that temperature by forming a solid, astheoretically expected by a substance having a melting point at -16.

This method could be of interest for producing P2P from acetonitrile, as it greatly simplifies the procedure byeliminating any need for extensive extraction of the ketone.

Phenyl-2-Propanone from Benzylchloride (via dibenzyl cadmium)20,30,31

2 PhCH2MgCl + CdCl2 → (PhCH2)2Cd + 2 MgCl2

(PhCH2)2Cd + 2 CH3COCl → 2 PhCH2COCH3 + CdO

Benzylmagnesium chloride was prepared from a solution of 0.2 mol benzyl chloride in 100ml anhydrous etherand 0.2 mol magnesium turnings (Org. Synth. Coll. Vol 1, p. 471). The clear dark solution was filtered undernitrogen through a glass wool plug. The solution of the grignard reagent was diluted with ether so that theconcentration was no greater than 0.2 mol per 300ml and then cooled in an ice-bath. Anhydrous cadmiumchloride (0.16 mol) was added with vigorous stirring over 10-15 min. Stirring was continued with cooling for 2h.

A solution of 0.1 mol acetyl chloride in 3 volumes anhydrous ether was added to the cold benzyl cadmiumreagent over 5 min. It was necessary to use a 2:1 molar ratio of the cadmium reagent to acid chloride, if theratio was less a considerable amount of acid was found in the product. The mixture was stirred in an ice-bathfor 8h, and hydrolyzed with 20% H2SO4. The ether layer was separated and the aqueous phase extracted twice

with ether. The combined ether solutions were washed with water and 10% sodium bicarbonate, and wasallowed to stand without drying overight. The ether solution was then extracted with 4x25ml 10% sodiumbicarbonate, and the combined aqueous extracts were extracted twice with ether, and all the pooled etherextracts were washed with water and dried over sodium sulfate. The ether was distilled off, and the residuevacuum distilled to give phenyl-2-propanone in 50-70% yield (calculated on the acid chloride), (bp 91-96°C at 11mmHg).

The thermal stability of dibenzyl cadmium is low, so keep it on ice during handling. Using benzyl cadmiumchloride or dibenzyl cadmium gave little difference in yield.

R E F E R E N C E S

1. Org. Syn. Coll. Vol. 2, p 487-489

2. Org. Syn. Coll. Vol. 2, p 391-392

3.

a. Magidson and Garkusha, Zh. Obsh. Khimii, 11(4) 339 (1941); Chem. Abs. 5868 (1941)

b. Chem. Ber. 68, 2112 (1935)

c. Juraj Kizlink, Chemicke Listy 84(9), 993-4 (1990)

4. US Pat 4,629,541

5. [ Reference Lost ]

6. A. I. Vogel, Practical Organic Chemistry, 5th Ed, p. 612-613.

7. Tet. Lett. 29(24), 2977-2978 (1988)

8. R. Ballini, Synthesis 723-726 (1994)

9. J. Amer. Chem. Soc. 62, 1622 (1940)

10. German Patents 3,026,698 and 3,200,232

11. Danilov and Danilova, Chem. Ber. 60, 1050 (1927)

12. US Patent 4,694,107

13. Alexander Shulgin, Pihkal #109

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23. A. McKillop, Oxidative Rearrangement of Olefins with Thallium(III)nitrate, Tet. Lett. 60, 5275-5280 (1970),

A. H. Frye, Oxidation of Olefinic Compounds with Solutions of Thallium(III) Salts, US Pat 3,452,047

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