Synthesis of P2P

This file is a part of the Rhodium site archive.This Aug 2004 static snapshot is hosted by Erowid as of May 2005 and is not being updated. > > Back to Rhodium Archive Index > > [WWW.RHODIUM .WS] [] [CHEM ISTRY ARCHIV E] Search SYNTHESIS OF PHENYL-2-PR OPANONE (P2P) BY R H ODI U M TABLE OF CONTENTS Table of Contents Introduction P2P from Benzyl Cyanide P2P from Phenylacetic Acid Friedel-Crafts Alkylation of Benzene with 2-Nitropropane Reduction of Phenyl-2-Nitropropene Friedel-Crafts Alkylation of Benzene with Chloroacetone Hydrolysis of Ephedrine Derivatives Electrochemical Coupling of Benzyl Chloride and Acetic Anhydride Nickel-mediated Coupling of Benzyl Chloride and Acetyl Chloride Semipinacol Rearrangement of Phenyl-2-Propanal P2P from Bromobenzene/Acetone Enolate Radical Alkylation of Benzene with Acetone, catalyzed by Mn 3+ Oxythallation of alpha-methylstyrene Wittig reaction of Benzaldehyde Cu(I)-catalyzed Arylation of Potassium Acetylacetonate Pd-catalyzed Arylation of Isopropenyl Acetate Alkylation of Benzyl cyanide with Trimethylaluminium P2P from Phenylacetaldehyde and Dimethyl Cadmium P2P from Phenylacetyl Chloride and Dimethyl Cadmium P2P via Grignard Addition to Acetic Anhydride P2P via Grignard Addition to Benzyl Cyanide References 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 s ynthesizing 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. 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 and discarded. and the nitrile precipitated by adding slowly. is separated and the acid layer extracted with 600ml of ether. 90 ml of glacial acetic acid.3 moles of dry product) is added slowly. and the solution heated on the steam bath for two hours before standing overnight. The mixture is thoroughly shaken. the condenser closed with a calcium chloride tube. The oil and ether layers are washed successively with 100ml of water. and kept at this temperature for two hours. cooled in a freezing mixture to -10°C. The moist cake weighing about 300g corresponds to 188-206g (5964%) of dry colorless alpha-phenylacetoacetonitrile. 1750ml of water added rapidly. with vigorous shaking. Phenyl-2-Propanone2 350 ml of concentrated sulfuric acid is placed in a 3000ml flask and cooled to -10°C. The ether is removed from the filtrates. after cooling.5168 PHENYL-2-PR OPANONE alpha-Phenylacetoacetonitrile1 FROM BENZYL CYANIDE A solution of sodium ethoxide is prepared from 60 g.6 mol) clean sodium and 700 ml of absolute alcohol (dried over calcium oxide or sodium) in a 2000 ml roundbottomed flask equipped with a reflux condenser. The filter cake is practically colorless and corresponds 250-275g of dry sodium salt. The ketone forms a layer and. The solution is cooled to 0°C. the temp being kept below 20°C (If pure dry alpha-phenylacetoacetonitrile is used. mp 87-89°C. and the residue distilled from a modified Claisen flask with a 25 cm fractionating side arm. The sodium salt still wet with ether is dissolved in 1. The total first crop of moist alpha-phenylacetoacetonitrile obtained according to the procedure above (corresponding to 188-206g or 1. After all is added the flask is warmed on the steam bath until solution is complete and then for five minutes longer. (2. washed with ether. The sodium sulfate is collected on a filter. with occasional shaking. A somewhat higher yield has been obtained by a different variation of this synthesis.2-1. The fraction boiling at 110-112°C at 24 mmHg is collected. the ether combined with the oil and dried over 20g of anhydrous sodium sulfate. The sodium salt is collected on a 6 inch Buchner funnel and washed four times on the funnel with 250 ml portions of ether. and the flask placed on a vigorously boiling water bath and heated for two hours. . The combined filtrates are placed in the freezing mixture until they can be worked up as indicated below.Density: 1. while the temperature is kept below 10°C. it is important that acetic anhydride is present in the reaction mixture in a large molar excess over the phenylacetic acid. the solution cooled to 0°C. If the ratio is too small. PHENYL-2-PR OPANONE FROM PHENYLACETIC ACID In this reaction. it weighs 125-150g (77-86% of the theoretical amount). half its weight of water should be added to the sulfuric acid or charring will take place on the steam bath). with shaking. originating from Russia. To the hot solution added a mixture of 234g (2 moles) of pure benzyl cyanide 264g (3 moles) of dry ethyl acetate (dried by refluxing over P 2O 5 for 30min followed by distillation). the phenylacetone will condense with itself to form useless Dibenzyl Ketone.3 liters of distilled water at room temperature. The precipitate separated by suction filtration and washed four times on the funnel with 250 ml portions of water.0057 g/ml (20°C) Refractive Index: 1. or 69-76% of the calculated mount. The next morning the mixture is stirred with a wooden rod to break lumps. Potassium Acetate/Copper Sulfate3c To a mixture of 136 g (1. acetic anhydride (50 ml) and pyridine (50 ml) was refluxed six hours (in the beginning carbon dioxide evolution was vigorous. Pyridine Method5 A mixture of phenylacetic acid (13. Yield 70-90 g (52-67%). CaCl2). 500 ml acetic anhydride and acetic acid are distilled off. the crude product is extracted with 2x250ml 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. and next phenyl-2propanone in this destructive distillation. The mixture is refluxed 24 h. After removal of the solvent the residue was taken up in toluene and washed with 10% sodium hydroxide.1 mol) anhydrous cupric sulphate is introduced 2000 ml anhydrous acetic anhydride in 4000 ml flask.3% 20 h 50. The solvent is distilled off and fractionation column is placed on the top of the flask. purify and reuse). CH2Cl2) is added and the mixture is poured to a flask containing 2000 ml ice-water. First an amount of water will distill. which on fractional vacuum distillation gave 7.5 g (56%) phenyl-2-propanone. Heating of the reaction mixture to 145-150°C on an oil bath provides sufficiently energetic evolution of carbon dioxide.0% 20 h 33.8% 20 h 51.6 11. The solvent is stripped off under vacuum and by vacuum distilling at 125-135°C/30-32 mmHg the crude product is obtained.0% 60 g 1000 g 60 g 100 g 100 g 100 g 600 g 600 g 600 g 600 g . bp 30-64°C/0. Removal of the solvent left a residue witging 12g. and 16 g (0. The PAA 60 g 60 g 60 g 60 g AA 600 g 600 g 600 g 600 g AA:PAA NaOAc Time Yield 10 10 10 10 16. dried (Na 2SO 4. After cooling 500 ml of solvent (CCl4. 70 g sodium or potassium acetate. Phenyl-2-Propanone Ketoxime was obtained in 88-90% yield. pure product is collected at 100°C/15mmHg. Acetic Anhydride (AA) and Sodium Acetate (NaOAc) is put in to a large round-bottomed flask equipped with a reflux condenser fitted with a drying tube.0% 20 h 56. CHCl3. which was distilled at 154-156°C/30mmHg. The reflux setup is rearranged for distillation and excess solvent is removed (acetic acid and acetic anhydride.0 mol) phenylacetic acid. the rest is mixed with 1000 ml water after cooling down. 25 g anhydrous sodium acetate and 850 ml acetic anhydride are refluxed with stirring under moisture protection for 40 h.6 g. and the crude phenyl-2-propanone is vacuum distilled at 25 mmHg. which requires liberal application of heat.1mmHg.5 6 2 6 30 g 30 g 30 g 30 g 30 g 90 g 50 g 50 g 500 g 5h 0% 8 h 33. bp 120-140°C. The yield about 30ml (70%). To the residue there is added 400ml water and the mixture is extracted with 3x100mL dichloromethane (or chloroform).0% 12 h 46. The distillate will separate into two layers. Lead Acetate Method6 Place 1000g phenylacetic acid and 3000g anhydrous (or trihydrate) lead acetate in a distillation apparatus and heat. The solution is dried over Na 2SO 4 and the dichloromethane is distilled off under ordinary pressure (and is saved for reuse) the rest of the volatiles are evaporated in vacuo. separated. 0. Sodium Acetate Method (alternative) 3b 50 g phenylacetic acid. Formation of the ketone is controlled by mixing an aliquot of the reaction mixture with excess of water and ammonium hydroxide until weakly alkaline – upon heating to boiling the oily layer must not disappear.5% 20 h 49.1 mol).6% 20 h 51. A second distillation gives 50-55% yield of product boiling at 210-215°C at atmospherical pressure.Sodium Acetate Method (alternative) 3b The Phenylacetic Acid (PAA). After separation of layers upper layer is removed and lower layer is three times decanted with water. and distilled. Remaining acetic acid and acetic anhydride is then removed. After the addition of all the methyllithium the precipitate partly dissolved and a weakly opalescent solution was obtained. making the synthesis more environmentally friendly.1 mol.65g (76%) of phenylacetone. first at ordinary pressure and then at aspirator vacuum to give 2. as a colorless oil. 19g) was then added dropwise into the mixture with stirring at the same temperature.026 mole (3. After being warmed to ambient temperature (10-15 min). The organic phase was separated. just to create sufficient bubbles for stirring the solution during the experiment. The 2. Titanium tetrachloride (0.5-153. The solution was extracted with CH2Cl2. 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 stirred for 60 min (or when the starting material completely disappears on TLC). Triflic Acid Method14 A solution of 2-nitropropene (300 mg) in benzene (30 equivalents) was added to a well-stirred solution of CF3SO 3H (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.7g) in dry CH2Cl2 (300ml) was added benzene (0. A vivid reaction took place. and the air was then expelled with a rapid stream of dry nitrogen. usually pure enough for most purposes. 70% of theory). bp 105°C/10 mmHg or 216°C at atmospherical pressure. the yellow solution was diluted with water (150 mL). If necessary. which contained the lithium salt of unreacted acid. . 392 mg (85%). a reflux condenser protected by a sodium hydroxide drying tube and magnetic stirring was placed 0. and concentrated. dried over Na 2SO 4. Evaporation of the solvent followed by vacuum distillation (bp 100-101°C at 14mmHg) afforded Phenyl-2-propanone (ca 9g.5 g) of phenylacetic acid dissolved in 50 ml of ether. The ether solution was then dried over magnesium sulphate. and the pooled organic extracts washed with 1 M Na 2CO 3 solution and dried over MgSO 4. 8. recrystallized from methanol. The Lead(II)Acetate can be substituted with Calcium(II)Acetate. eluting with CH2Cl2:n -hexane 12:7) to give pure phenyl-2-propanone.055 mole of an ethereal solution of methyllithium was added through the condenser. water was slowly added.5°C. had mp 152. the aqueous phase extracted with CH2Cl2. was removed in a separatory funnel. neutralized with powdered NaHCO 3 and saturated with NaCl. The excess of methyllithium was thus destroyed and lithium hydroxide was formed from the intermediate dilithium salt. and the ethereal layer washed three times with half its volume of water. PHENYL-2-PR OPANONE Titanium Tetrachloride Method7 BY NITR OALKYLATION OF BENZENE To a stirred solution of 2-nitropropene (0. Methyllithium addition to Phenylacetic Acid27 In a 100ml rb flask equipped with a side tube for a gas inlet capillary. and a white precipitate was formed (lithium salt of the acid). The alkaline water layer.1 mol. A considerable improvement to this method has been made by Xtaldoc on a large scale. After the solution had reached room temperature. the solution was then refluxed for 10-30 minutes to complete the reaction. and the residue was flash chromatographed (on SiO 2. 39g) at room temperature.organic layer is separated and redistilled to give pure phenyl-2-propanone.4 dinitrophenylhydrazone derivative. water (150 ml) was added and the resultant heterogenous mixture was stirred at reflux for 2h. After 2-3 minutes the gas stream was slowed down.5 mol. When all air had been expelled 0. the ether refluxed. filtered and the ether driven off. The next day.1 mole) phenyl-2-nitropropene was dissolved in 200ml methanol in a 250ml Erlenmeyer flask situated on a magnetic stirrer. 7.31 mole) of FROM CHLOROACETONE9 anhydrous . followed by hydrolysis of the nitro group with hydrogen peroxide and potassium carbonate. At the end of this period. During the addition of H2O 2/K2CO 3 a white. sticky precipitate forms. 61 mmol) was dissolved in 75 ml HOAc and slowly dripped into a refluxing slurry of Fe powder (32 g. Phenyl-2-nitropropene (10 g. and the solvent removed under vacuum to give a clear yellow oil. Reduction with Chromous Chloride18 Another method for reducing phenyl-2-nitropropene Chromium(II)chloride as the reducing agent. The preparation is a one-pot synthesis. When the pH of the solution turned acid. When the generation of heat had subsided.3g (0. but the acidity was confirmed with pH paper. a variety of the Nef reaction. after which the precipitate will be much looser and no match for any mag-stirrer. Reduction with Iron Powder13 If phenyl-2-nitropropene is reduced by iron powder in an acidic medium (such as acetic acid or aqueous hydrochloric acid) the nitroalkene is reduced to the oxime. which can be a bit too thick for a weak magnetic stirrer to handle. 100 ml of 30% H2O 2 was then added. together with 30 grams of anhydrous potassium carbonate. The solution was extracted with 3x100ml CH2Cl2.5 h. the solution is slowly acidified with 2M HCl with good stirring.2 mole) of NaBH4 was added a little at the time.6g (0. and the temperature was not allowed to to rise above 15°C. The solvent was distilled off. All of the precipitate was also be gone at this point. This synthesis is not suitable for ring-substituted phenyl-2-nitropropenes. 16. About 300 ml of acid is needed. to phenyl-2-propanone in 80% yield is to use PHENYL-2-PR OPANONE 41 grams (0. the ice/salt. and chilled to 0°C with an ice/salt bath. phenyl-2nitropropene is reduced to phenyl-2-nitropropane with NaBH4 in methanol. After distillation of said oil at aspirator vacuum. and the solution was left to stir for 18-24 hours at room temp. The organic phase was dried over MgSO 4. The mixture turned brownish and foamy. Then. The combined extracts was washed with 2x150 ml H2O and dried over MgSO 4. without isolation of the intermediate. and the residue distilled under vacuum to give phenyl-2-propanone in 75% yield. with good stirring. care being taken for the evolution of heat and CO 2. the flask was once again placed in an ice/salt bath and the solution was allowed to cool to 0°C again. filtered with suction. 0. The reaction mixture was poured into 2000ml water. and the pooled organic extracts washed with 100ml 2M NaOH and 200ml H2O. which is then hydrolyzed by the acid into the desired phenyl-2propanone.PHENYL-2-PR OPANONE Sodium Borohydride/Nef Reaction FROM PHENYL-2-NITR OPR OPENE8 In this preparation. and the mixture was refluxed on low heat for 1.57 mol) in 140 ml HOAc.bath was removed and the solution was stirred at room temperature for two hours. the color became significantly more yellow. and was extracted with 3x100 ml CH2Cl2. so the mass can be stirred with a glass rod now and then during the first two hours. as the side chain tends to be oxidized when electron-donating substituents are present on the ring. the yield was around 60-70% of phenyl-2-propanone (P2P) as a light yellow oil. and the remaining viscous oil was distilled under reduced pressure.16 mol) Ephedrine or Pseudoephedrine freebase was dissolved at a temperature of 50-100°C. 1025g 75% sulfuric acid was mixed with 1g ZnCl2. and 192g (1. 20 ml of water and 20 ml of concentrated hydrochloric acid was added. the reaction equilibrium is driven towards the desired product by continuously removing the formed phenyl-2-propanone by the aid of steam distillation.5-3 hours the phenylacetone is steam distilled from the reaction mixture. the solution was practically black. decomposing the addition product with sodium carbonate solution. The mixture was stirred and heated to refluxing on a steam bath and 13. which is free from propiophenone. ELECTR OSYNTHESIS OF P2P FROM BENZYL CHLOR IDE4 Synthesis of phenyl-2-propanone from benzyl chloride (79 mmol) and acetic anhydride (686 mmol) by electrolysis of the reaction mixture. The benzene was distilled off. and the reaction mixture was heated further to 145-150°C. which then can be hydrolyzed into phenyl-2-propanone and an amine salt. for details. bp 108-114°C/20-22mmHg. a reflux water condenser and a small addition funnel.5 g (32%). All of the benzene solutions were combined and filtered. Norephedrine and Norpseudoephedrine (Phenylpropanolamine). the solvent is DMF (110g) and the supporting electrolyte is tetrabutylammonium fluoroborate (2 g. The the crude phenyl-2-propanone. they are dehydrated to the enamine. After the electrolysis using a current of 1A at a temperature of 0°C (2. After refluxing for 5 hours. stirring during the addition.2 faradays per mole of benzyl chloride). the reaction mixture was decomposed by slowly adding water through the condenser. As all the steps are reversible processes. see the translation of the original patents. 130g (82%) of phenyl-2-propanone is isolated in a purity of 99.15 mole) of chloroacetone was allowed drop in slowly during a period of 30 minutes. which spontaneously can rearrange to the isomeric imine (Schiff Base). Many other metal salts can be used instead of the zinc chloride. and steam distilled as long as any oil distilled over. the cathode of nickel. 6 mmol). the remaining benzyl chloride. PHENYL-2-PR OPANONE FROM EPHEDRINE DERIVATIVES10 When ephedrine and related compounds are heated in strong aqueous acid. filtering. The phenyl-2-Propanone was distilled under reduced pressure.9 g (0. Phenyl-2-Propanone was recovered from the distillate by making the bisulfite addition product. When no more hydrogen chloride was evolved. The benzene layer was separated and the aqueous layer extracted with four 25 ml portions of benzene. After distillation through a short vigreaux column.8%. is isolated by toluene extraction of the distillate. Nine grams of liquid boiling below 123°C/20-22mmHg was obtained. At 145°C the stream of steam is increased. After cooling to room temperature. and during 2. Approximately 10g of high-boiling material was left in the distilling flask. Ephedrine derivatives that can be used in this procedure include Ephedrine. The distillate was extracted with ether. the ether dried over anhydrous MgSO 4 and the ether distilled on a steam bath. the toluene which is a byproduct of the reduction . Yield 6.aluminum chloride and 100 ml of anhydrous benzene (free from thiophene) were put in a 500ml three-necked flask which was equipped with a mercury-sealed stirrer. The top of the condenser was connected to a sulfuric acid trap and this trap was connected to a gas absorption bottle. Pseudoephedrine. At 125°C steam is passed through the solution to facilitate mixing of the contents. The anode is made of magnesium or aluminium. 97 mmol). IR (neat) 1710 cm-1 (C=O). phenyl-2-propanone is isolated by extraction with ether in 64% yield. It was eluted with hexane followed by chloroform to give phenyl-2-propanone (0. and a condenser topped with argon inlet and outlet to oil pump. lithium (2.3 mmol) in glyme (10 mL) was added dropwise for 30 min.29 Preparation of Metallic Nickel OF P2P FROM BENZYL A 50-mL two-neck flask was equipped with a magnetic stirrer. and weighed. METALLIC NICKEL-MEDIATED SYNTHESIS CHLOR IDE AND ACETYL CHLOR IDE28. was heated to reflux. 2-phenylpropanal can also be made from alpha-methylstyrene. poured into a separatory funnel containing hydrochloric acid solution (37%. glyme (25-30 mL) was added through the septum with a syringe.0 equiv. and the mixture was stirred for 12 h. lithium (0. Reaction of Benzyl Chloride with Acetyl Chloride in the Presence of Metallic Nickel Metallic nickel in glyme (25 mL). Then. 7. PHENYL-2-PR OPANONE BY REARRANGEMENT OF 2-PHENYLPR OPANAL11 2-Phenylpropanal can be rearranged with either mercuric chloride (HgCl2) or sulfuric acid (H2SO 4) to form the isomeric phenyl-2-Propanone (P2P). The septum on the side neck was replaced with an addition funnel. and extracted with chloroform twice. a rubber septum.1 equiv.9 mmol). 100 mL).3 mmol) were placed in the flask through the side neck. Another procedure 33. A mixture of benzyl chloride (1.of benzyl chloride.122 g. The flask was evacuated and filled with argon two or three times. The glass tube was evacuated to evaporate the hexane. and naphthalene (0. The chloroform solution was washed with water. The combined extracts were dried over anhydrous sodium sulfate and concentrated. Additional heating was continued for 15 min. and phenyl-2-propanone. metallic nickel which had adhered to the walls of the flask was scraped off with the stirrer and a magnet.65 g. 21-30 mmol). filled with argon. After the DMF has been evaporated off and the residue has been hydrolysed with hot dilute HCl. 21. The crude oil was purified by silica gel chromatography.152 g. The nickel precipitated as a bulky black powder in a clear colorless solution after standing. and naphthalene (0.95 mmol). During the reduction the surface of lithium became pink.72 g. 0. using a lead cathode and a carbon anode. and the red-brown reaction mixture was cooled to room temperature. 2Phenyl-propanal (hydratropic aldehyde) is an unwatched industrial chemical which is used in the perfume industry. are present in the solution. 8. Lithium metal was cut under mineral oil. . the stirring was stopped. 0. both in free form and in the form of its enol acetate.0 g. One piece of lithium with a shining metal surface was rinsed in hexane and transferred into a glass tube with a stopcock and a rubber septum which had been filled with argon. Nickel halide (1.9 mmol) and acetyl chloride (0. 68%). The use of a glovebox or -bag is not required if contact of the lithium with air is kept to a minimum. 9-13 mmol). prepared from nickel iodide (2. After the lithium metal was consumed completely. bp 95-96°C (11 mmHg). and a mixture of appropriate reagents in glyme (10 mL) was then added to the nickel. and the aqueous phase was extracted with additional chloroform.3 equiv. DMF as the solvent and a tetrabutylammonium tosylate electrolyte gives a 73% yield of phenyl-2-propanone after hydrolysis of the resulting enol ester.91. enough to poison a medium-sized lake if released into the environment. while the temperature of the reaction mixture is kept at -16°C. and if you happen to ingest it yourself. Method A 30g of 2-phenylpropanal is heated together with a mixture of 60g mercuric chloride (HgCl2. and the solution is steam-distilled (during which operation the precipitate redissolves). the rest consisted of unchanged aldehyde. I would definitely reccommend the one with sulfuric acid. Such strong bases include sodium amide. If this enolate of acetone is allowed to react with a halobenzene (preferably iodobenzene.The CAS number for 2-phenyl-propanal is [93-53-8]. alpha-methyl benzeneacetaldehyde and alpha-methyl phenylacetaldehyde. which is able to deprotonate one of the relatively acidic alpha protons of the ketone.6g (62%) of phenyl-2-propanone. When 0. and is not disastrous for your health or the environment. 2Phenylpropionaldehyde. After all the 2-phenylpropanal has been added. only 10% phenyl-2-propanone was formed. Fractional distillation could theoretically be used to separate them. but which will oxidize the aldehyde to 2phenylpropionic acid. the ether distilled off and finally the residue is vacuum distilled (bp 91-96°C at 11 mmHg) to give 5. The acid can then be separated from the ketone by dissolving the mixture in a non-polar solvent and washing the solution with dilute sodium hydroxide. and the solvent is evaporated. Even if the method below which uses mercuric chloride is higher yielding than the one using cold sulfuric acid.5h at 100°C in a boiling water bath. 222°C/760mmHg. Water is added. the mixture is allowed to stand at the same temperature for another 15 minutes. The distillate is extracted with ether. the two species will combine to form phenyl. Cumenealdehyde. dried. the solvent removed under vacuum and the residue vacuum distilled to give pure P2P. it will accumulate in your body.2-propanone. 2-phenylpropanal is isomerized to phenyl-2-propanone in 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 P2P 12. PHENYL-2-PR OPANONE FROM ACETONE ENOLATE If acetone is reacted with a strong base. Boiling point 92-94°C/12mmHg. bp 92-101°C at 14mmHg. which is then dried over MgSO 4. as it is much cheaper to use. There are other ways of performing this rearrangement. but bromobenzene should also work) in DMSO under rigidly anhydrous conditions.) and 450ml 75% ethanol in a pressure-safe sealed glass container for 4. The P2P stays in the organic layer. acetone enolate is formed in quantitative yield. 60g of mercuric chloride contains 45 grams of mercury. A good idea for separating a mixture of the two is to oxidize the mixture with a mild oxidant which won't affect the P2P. It is not possible to effectively separate 2-phenylpropanal (bp 222°C/760mmHg) from phenyl-2-propanone (bp 214°C/760mmHg) through simple distillation and certainly not via vacuum distillation as the boiling points are too close. 1 eq. the pooled organic phases dried over MgSO 4. Method B 9 g of 2-phenylpropanal is slowly added with good stirring during 35 minutes to 40ml concentrated sulfuric acid. The oily residue is then vacuum distilled with a fractionating column to collect the phenyl-2-propanone in a yield of 80% or more. and then the mixture is poured onto crushed ice (100-150g is probably a suitable amount).1 equivalents of HgCl2 was used. There has been no known actual attempts at this synthesis using the enolate of acetone and a halobenzene in DMSO (but it has been done in liquid . for example potassium tert-butoxide. the organics are extracted from the water phase by 3x50ml diethyl ether. When the ice has melted. during which time a precipitate forms. and synonyms for it include Hydratropic aldehyde. lithium diisopropylamide and several alkoxides. but the size of the column that would have to be used makes that option impractical. ammonia). The ether was then dried over anhydrous Na 2SO 4 (or MgSO 4). but other ketone enolates. The solution is extracted with ether. 100 mmol) in 100ml methanol is added to a solution of alphamethylstyrene (11.34g) based on the reacted manganese(III)acetate. such as pinacolone has been extensively studied in this medium. The reaction can be catalyzed by For a more in-depth discussion of this synthesis. There are no theoretical obstacles at all to why it would not work in the production of phenyl-2-propanone. washed with a little methanol. and after standing for 15 minutes. read Drone #342's Enolate Phenylacetone Synthesis FAQ 1. The yield is relatively low.9g Phenyl-2-Propanone (81% yield). A mixture of Manganese(III)acetate dihydrate (13. dried over MgSO 4 and the solvent distilled off. The yields in the reactions range between 50 and 98%. but this can be improved. The reaction mixture was partitioned between 400ml ether and 250ml water. and the residue vacuum distilled to give 10. helium or nitrogen) until the dark brown color of manganese(III)acetate changed to the pale pink of manganese(II)acetate (about 90 min). Thallium(III)Nitrate 50g Thallium(III)Oxide (Tl2O 3) is dissolved in 150ml warm. and the filtrate is shaken for 5 min with 1M H2SO 4 to hydrolyze the formed Phenyl-2-Propanone dimethyl acetal. oxygen or UV light.iron salts. and requires high dilution of the reactants. The ether layer was separated and washed with 250ml water and with 2x250ml 5% Na 2CO 3 to remove any remaining acetic acid. PHENYL-2-PR OPANONE METHYLSTYR ENE WITH OXYTHALLATION OF ALPH ATHALLIUM(III)NITRATE23 BY Warning: Thallium salts are exceedingly toxic. benzene (150ml).82g. a compound easily prepared from potassium permanganate. as can be seen in the comprehensive Manganese(III)acetate catalyzed aromatic acetonylation document on this site. 100mmol) in 50ml methanol at room temperature with stirring. and there is an immediate precipitation of Thallium(I)Nitrate. and to give phenyl-2propanone in 40% yield (1. which is the limiting reagent in this reaction. 50 mmol). and the reaction is also applicable for other substituted benzenes. acetone (150ml) and glacial acetic acid (250ml) was refluxed under an inert atmosphere (argon.0 FR EE-RADICAL ALKYLATION OF BENZENE BY MANGANESE(III)ACETATE17 WITH ACETONE CATALYZED Phenyl-2-Propanone can be made in a single step by a free-radical reaction between benzene and acetone. The reaction relies upon the special oxidative powers of manganese(III)acetate. The colorless crystals of Thallium(III)Nitrate trihydrate are filtered. the solvent evaporated and the residue fractionately distilled to recover unreacted benzene.4g. washed with a little dilute . concentrated nitric acid and cooling the pale yellow solution to 0°C. and may be lethal upon ingestion! Handle with gloves only! A solution of Thallium(III)Nitrate (39g. the precipitate is filtered off. Accordingly. alpha-Methylstyrene can also be treated with Bromine and Sulfuric Acid to yield P2P. The mixture was allowed to warm to room temp over 1h and was then directly distilled. Potassium tertbutoxide (33 mmol) in 15 mL of glyme was added with stirring over 5 minutes.4g. 167 mmol) and potassium acetylacetonate hemihydrate (125g. stirred with 2M sodium hydroxide (250 ml) for 1 hr and extracted with toluene (2x500 ml). The combined extracts were washed with water. 1M hydrochloric acid and satd. Aldrich).4 g. 200 mmol) in DMF (1 liter) was added cuprous iodide (32. 834 mmol.29 mol) and alpha-chloroethyl methyl ether16 (28. The phosphonium salt (33 mmol) was suspended in 40 mL of glyme at -40°C under nitrogen. 0. . At this point a solution of benzaldehyde (30 mmol) in 5 mL of glyme was added over five minutes. 88%) consisting of the crude phosphonium salt containing one molar equivalient of benzene crystallization. dried over magnesium sulphate and concentrated in vacuo to leave a dark brown oil. The mixture was stirred and heated at 100°C for 24 hr.nitric acid and dried in vacuo over phsphorus pentoxide. the preparation and reaction of this ylid was best carried out at -40°C. PHENYL-2-PR OPANONE FR OM BENZALDEHYDE Y LIDE (WITTIG REACTION)15 AND A PHOSPHONIUM The phosphonium salt was prepared by dissolving triphenyl phosphine (76. This salt is slightly hygroscopic on exposure in air but can be stored indefinitely in a sealed container. The solution was heated to boiling and the solvent was then evaporated to give relatively pure phenyl-2-propanone in 88% overall yield. PHENYL-2-PR OPANONE ACETYLACETONATE21 BY AR YLATION OF POTASSIUM To a stirred solution of bromobenzene (31. which after purification gave phenyl-2-propanone in 65% yield.5% HCl and enough methanol to effect solution. The salt is readily soluble in methanol and dilute mineral acids. Phenyl-2-propanone was conveniently prepared from the enol ether by mixing with one equivalent of water with 0. The ylid resulting from treatment of the phosphonium salt with base was found to be very unstable at room tempature. 0. cooled.4g. Thallium(III)Nitrate (mol wt 390) is stable indefinitely if stored in tightly sealed bottles. sodium bicarbonate.30 mol) in 125 mL benzene. the characteristic red color dissappearing within a few seconds. to give pure phenyl-2-propanone enol methyl ether). aq. After standing for 40 h the mixture was filtered and washed with ether giving a white solid (112g.4g. 20 mmol) in 20ml of toluene at -78°C and the mixture was under stirring allowed to slowly warm up to room temperature and refluxed for 12h. brine and dried over MgSO 4. was added tributyltin methoxide (25. 0. 10 ml. cooled and the solvent evaporated in vacuo. Removal of the solvent gave 2. 90 mmol. isopropenyl acetate (9g. under nitrogen. The mixture was stirred and heated at 100°C for 5 hr. The organic layer was washed with aqueous NaHCO 3. When all the halide has been added and the reaction is no longer refluxing. If cloudiness does not become apparent in 1 or 2 min stop.2 grams of anhydrous cadmium chloride in small portions through side neck restoppering after each addition. add halide dropwise as quickly as the reflux column can handle. which can be purified by vacuum distillation or column chromatography. Do not add more! Take a glass rod about 12 inches in length and score with a 3 corner file 2 inches from one end using pliers and a rag to protect your hands break away the 2 inch piece. 3-neck rb. funnel. add 31. PHENYL-2-PR OPANONE TR IMETHYLALUMINUM25 FROM BENZYL CYANIDE AND Trimethylaluminium (30ml of a 2M solution in toluene) was added to a solution of benzyl cyanide (2. DRY FLASK attach a reflux condenser. Add 12. 90 mmol) and dichloro-bis (tri-o-tolylphosphine)palladium (0. to afford the phenyl-2-propanone in 67% yield.3 ml. of halide ether solution to enter flask. Notes: Avoid breathing the cadmium chloride dust (it needs to be finely ground after drying) avoid contact with the methyl iodide or ether solution of methyl iodide avoid breathing any vapours of the metal conversion . Add 60 ml. PHENYL-2-PR OPANONE CADMIUM Dimethyl Cadmium FROM PHENYLACETALDEHYDE AND DIMETHYL 2 MeMgI + CdCl2 => Me 2Cd + 2 MgICl To 500 ml. Be prepared to stop and cool with ice water bath if needed. Attach 125ml sep. the flask will have a tannish brown solid mass inside. Ethyl acetate was added and the mixture was vigorously stirred for one hour.75g of crude phenyl-2-propanone as an oil. funnel.PHENYL-2-PR OPANONE BY HECK AR YLATION22 To a stirred solution of bromobenzene (60 mmol). After all the Cadmium chloride has been added. methyl iodide either freshly prepared or dried overnight with calcium chloride. replace stopper. The residue was chromatographed on silica gel. Allow aprox. After being cooled to 0°C.67 mmol) in dry toluene (30 ml).34g. This is the dimethyl cadmium. the solution was poured over crushed ice and made acidic with 6M HCl. add 31.9 ml. Add 75 ml anhydrous ether to flask. using the remaing 10 inch piece gently poke at the magnesium turnings to expose fresh metal. If reaction starts.47g. Aldrich). keep it covered and protected from air.5 grams Magnesium turnings to flask. Proceed immediately to next part if at all possible. anhydrous diethyl ether to sep. reaction (it smells like garlic if you must know). Be prepared to stop addition and cool if needed. more of distillate was collected. Ether was removed by distillation on a steam bath. there was added a solution of acetic anhydride (40g. Note 1: The phenylacetaldehyde will polymerise on standing. Test with bisulfite any product not forming addition is phenyl-2-propanol (very small amount) can be saved for later oxidation. sodium bicarb untill fizzing stops. and 30. Again 100 ml of anhydrous benzene was added. the cooling bath removed and the reaction quenched by the careful addition of saturated aqueous ammonium chloride. The aqueous layer was . the flask was cooled in an ice bath. anhydrous ether.1 grams (0. Yield 50-55 ml. For this preparation it also needs to be as dry as possible. bp 74-76°C/3 mmHg). freshly distilled phenylacetaldehyde (Note 1 ) and 50 ml.4 grams (0. The reaction mixture was cooled with an ice bath and 22. Distill under reduced pressure to strip off excess ether. To theresidue was added 100 ml. There was thus obtained 15. and the flask was equipped with a magnetic stirrer. the reaction mixture was allowed to stir at dry ice temperature for 2-3 hours.25 mole) of magnesium was stirred under reflux while 35.55 mol) in diethyl ether (100ml). and dried over anhydrous sodium sulfate. situated in a dry ice/acetone slush in a Dewar flask. When reflux has subsided do not heat. washed. bp. and extract water layer with 2x50 ml portions of technical grade ether. warmed to room temperature. a thermometer and an addition funnel (modified so that the added liquid was cooled externally by dry ice/acetone). Add dropwise the aldehyde/ether solution to the dimethyl cadmium swirling occasionally to break up the clumps. 2.5 grams (58%) of 1-phenyl-2-propanone.2 mole) of phenylacetyl chloride in 75 ml of anhydrous benzene was added with stirring over a period of approximately 10 minutes. The flask was again cooled in an ice bath and the reaction mixture decomposed by the addition of a solution of 25 grams of ammonium chloride in 200 ml of cold water. This polymer is degraded to the monomer on distillation.2 mol) and magnesium shavings (4.134 mole) of powdered anhydrous cadmium chloride was added over a 5. 0. HCl and 100 cc.to 10-minute period.25 mole) of methyl iodide in 140 ml.9 grams (0. of anhydrous ether was added over a 3-hour period. funnel add 64 ml. 100 at 13 mm. beaker containing 100 ml. ~85% of P2P. 0. The organic phase was separated. and refluxed on a steam cone for 1 hour.5g. PHENYL-2-PR OPANONE DIMETHYL CADMIUM32 FROM PHENYLACETYL CHLOR IDE AND A mixture of 40 ml. Separate. Quickly pour into a 1000 ml. The reaction mixture was warmed to room temperature and refluxed with stirring on a steam cone for 1 hour.9g. of chipped ice. distilled water 10 ml conc. PHENYL-2-PR OPANONE ANHYDR IDE26 BY GRIGNARD ADDITION TO ACETIC In a 500-mL three-necked flask. Phenyl-2-Propanone To a clean dry sep. After the addition after one hour was finished. stirring under reflux was continued for an additional hour. To this was added an etheral solution of benzylmagnesium chloride. prepared from benzyl chloride (25. The benzene was removed by flash distillation and the ketone distilled under reduced pressure.2 mol). Hydrolyse addition product and distill if desired.5 grams (0. of anhydrous ether and 6. of anhydrous benzene and the distillation was continued until about 50 ml. Neutralize with sat. 52%). no chances was taken and 15 ml distilled water was added. then acidified. . the ether evaporated on a water bath and the residue fractionately distilled to yield phenyl-2-propanone (14g. Both are hydrolyzed to phenyl-2-propanone with dilute hydrochloric acid. After all Mg was added. This complex was isolated by filtration through a buchner. an iodine crystal being added after the first portion to initiate Grignard rxn. Et2O and a small amount of toluene were evaporated to give 42g crude phenyl-2-propanone as a clear orange oil. giving heat and causing remaining ether to boil. PHENYL-2-PR OPANONE BY GRIGNARD ADDITION TO NITRILES19. dried over MgSO 4. Upon using the vaccum. as it greatly simplifies the procedure by eliminating any need for extensive extraction of the ketone. then left to cool to room temp. the rxn mixture was cooled in an ice-salt bath. A white percipitate was formed. The white complex was brie fly dried.] After all effervescence had stopped. the organic phase washed with 10% sodium carbonate solution until the washes were no longer acidic to universal pH paper.2 mol benzylmagesiumchloride grignard reagent were prepared by standard methods in diethylether (Total reaction volume: 200ml). The benzylmagnesium chloride solution was added the acetonitrile over a periode of 10 minutes. Reaction initiated by heating the mixture to 60°C for a short periode of time. but after all was added. the organic layer was separated. Vacuum distillation of this oil afforded pure phenyl-2-propanone (bp 91-96°C at 11 mmHg). and so was decomposed to toluene. of 62g acetonitrile in 100mL Et2O was added slowly while stirring w/a thermometer. The combined Et2O layers were washed with H2O. it was still very orange even after adding NaCl and extracting with Et2O (which was a lighter shade of orange than the aq. there was excess unclogged Mg which would not react. and no further reaction occurred. After completion of addition. ether was removed and the solution separated into two layers with an orange oil on top and a water layer containing salts and undissolved salts. not soluble in ether or acetonitrile. by Poodle: In a dream. The imine salt can also be reduced directly to amphetamine by sodium borohydride in methanol in high yield. 500mL 10% HCl was added slowly under stirring. A thick white precipitate built up and clogged up some Mg. The oily layer was separated and gave 21 ml of possible P2P. The intermediate phenyl-2-propanone imine magnesium salt can also be prepared from methylmagnesium iodide and benzyl cyanide. stirred thoroughly. I think the purity of final product would be higher if reaction mixture was first poured onto ice. The reaction temperature rose to 30°C. but as it began to turn yellow. bp 214-215°C/760mmHg (100-101°C/13mmHg). The ketone was frozen at -20. 0.Submersion of the flask in cold H2O was used as necessary during addition to prevent excessive boiling of the Et2O. [NOTE: This seemed to cause the Et2O layer to take on a reddish tint. using constant swirling of the reaction mixture. the solution turned yellow/orange with oily orange bubbles. A soln.24 127g benzyl chloride was dissolved in 250mL Et2O. about 75-80% of the theoretical 26 ml. responding to that temperature by forming a solid. to this was added 27g Mg turnings in portions. and washed twice with water-free ether to remove any unwanted remains of acetonitrile or benzyl chloride. then another 10 ml (The complex reacted immediatly with the water. About 2 moles of acetonitrile (100ml) was mixed with 100 ml of anhydrous diethylether and cooled in ice/water. NaCl was added to the aqueous layer. layer!)]. so try to avoid it!]. as theoretically expected by a substance having a melting point at -16. Simplification of the above procedure. followed by 50 ml brine. The organic phase was dried over MgSO 4. [NOTE: This clogged-up material didn't react fully w/the MeCN.separated. corresponding to a intermediate complex. the mixture was refluxed gently. This method could be of interest for producing P2P from acetonitrile. which was then extracted w/Et2O [NOTE: I think a lot of product was left behind in this aqueous layer.) The solution was exposed for a vacuum to remove any remaining ether in the solution. filtered. 68. 45. Lett. Lett. Coll. Ber. The thermal stability of dibenzyl cadmium is low. Ann.. Chem. Shudo. Chem.16 mol) was added with vigorous stirring over 10-15 min. 57. 269 (1884) 17. Vol. 155-158 (1980) 20. (bp 91-96°C at 11 mmHg).2 mol per 300ml and then cooled in an ice-bath. p. 242 (1984) 23. 2. Soc. 1622 (1940) 10. Syn.1 mol acetyl chloride in 3 volumes anhydrous ether was added to the cold benzyl cadmium reagent over 5 min. J. Coll. T. A. The mixture was stirred in an ice-bath for 8h. Chem. Am. McKillop. 21. Lett. 49. Tet. The clear dark solution was filtered under nitrogen through a glass wool plug. Tet. Chem. Ballini. Lett. Coulsen. It was necessary to use a 2:1 molar ratio of the cadmium reagent to acid chloride. 5th Ed. Org. and was allowed to stand without drying overight. Tetrahedron 46. The ether was distilled off. Shudo. Soc. Tet. and hydrolyzed with 20% H2SO 4.31 2 PhCH2MgCl + CdCl2 → (PhCH2)2Cd + 2 MgCl2 (PhCH2)2Cd + 2 CH3COCl → 2 PhCH2COCH3 + CdO Benzylmagnesium chloride was prepared from a solution of 0. K.Phenyl-2-Propanone from Benzylchloride (via dibenzyl cadmium) 20. T. Chem. Zh. Ohwada. and all the pooled ether extracts were washed with water and dried over sodium sulfate. German Patents 3. The ether solution was then extracted with 4x25ml 10% sodium bicarbonate. 5275-5280 (1970) . Obsh. if the ratio was less a considerable amount of acid was found in the product.30. Magidson and Garkusha. 612-613.541 5. Khimii.629. Jap. Alexander Shulgin. 2112 (1935) c. 2. 1603-1607 (1984) 18. US Patent 4. Chem. Stirring was continued with cooling for 2h. and the combined aqueous extracts were extracted twice with ether. . K. Lett. 7. Practical Organic Chemistry.2 mol magnesium turnings (Org. J. 3777 (1985) 19. Okabe. Vol. [ Reference Lost ] 6. REFERENCES 1. The ether layer was separated and the aqueous phase extracted twice with ether. 7539-7555 (1990) 15. p 487-489 2. 2977-2978 (1988) 8. The combined ether solutions were washed with water and 10% sodium bicarbonate. Amer. Oxidative Rearrangement of Olefins with Thallium(III)nitrate. p. Chem. Juraj Kizlink.200. Syn. Danilov and Danilova. Org. Coll.026. Pihkal #109 14. and the residue vacuum distilled to give phenyl-2-propanone in 50-70% yield (calculated on the acid chloride). Org. Ohwada. p 391-392 3. 62. 54. R. Ber.. 82. 1050 (1927) 12.. K. Synthesis 723-726 (1994) 9. 11(4) 339 (1941) . so keep it on ice during handling. Vol 1. Soc. I.232 11. Chem. T.. Synth.. 3323-3326 (1964) 16. T. Abs. 225. D. Ohta. Tet. K. Anhydrous cadmium chloride (0. The solution of the grignard reagent was diluted with ether so that the concentration was no greater than 0. 5868 (1941) b.694. Tet.107 13. 29(24). 733 (1989) b. Okabe. Chemicke Listy 84(9). Lett. Using benzyl cadmium chloride or dibenzyl cadmium gave little difference in yield. 26. J. Chem. A solution of 0. J. A new Synthesis of Methyl Ketones .2 mol benzyl chloride in 100ml anhydrous ether and 0. 60. 60. 1975 (1960) 21. Chem.698 and 3. Vogel. R.. a. a. 471). 597-600 (1982) 22. Org. US Pat 4. A. 993-4 (1990) 4. Bull. Ohta. T.780 J. 782-790 (1952) J. 24.R. Chem.452. Electroreductive Acylation of Benzyl Chlorides with Acid Anhydrides . Org. 2451-2452 (1983) J. I. 30. Rec. Amer. Hirashima and J. 741 (1939) H. Oxidation of Olefinic Compounds with Solutions of Thallium(III) Salts . Lett. Chem. F. H. Engineering Data 15(1). Nelson. Chem. Chim. Chem. T.047 J. J. Soc. Alkyl Benzyl Ketones and Hydantoin Derivatives . 28. . 29. 32. Scand. Gilman.639. 27. Sund and H. 200-201 (1970) 33. US Pat 3. Shiokawa. 1373-1381 (1985) Tet. Chemistry Letters 2005-2008 (1991) 24. Soc..H. Nishiguchi. 6. Henze. Trav. 67. 26. 154 (1945) Acta Chem. 518-530 (1936) E. Frye. 50.A. 3369-3370 (1972) US Pat 5. J. Am. 25. 61. 37. Chem. 31. Oki. Org. 55.