Cyrax
(Hive Bee)
01-10-02 18:39
No 254821
      P2P from phenylacetylchloride
(Rated as: good read)
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I know it, this is not the most easy method to make P2P (you first have to prepare phenylacetylchloride from the acid), but because it is an original reaction, I have decided to post it smile.

First, we acylate the acid chloride with the magnesiumethoxy derivate of diethyl malonate.  Then, we do a hydrolysis and decarboxylation of the 2 ester groups to get the methyl ketone.

Procedure:
In a 500 ml three-necked flask equipped with a mercury sealed stirrer, dropping funnel, and reflux condenser protected by a drying tube, was placed 5.35 g (0.22 mole) of magnesium.  5 ml of absolute EtOH and 0.4 ml of CCl4 were added.
The reaction, which started immediately, was allowed to proceed for a few minutes and 75 ml of absolute ether was then added cautiously.  The resulting mixture was placed on a steam bath and a solution of 35.2 g (0.22 mole) of diethyl malonate, 20 ml of absolute ethanol and 25 ml of absolute Et2O was added at such a rate that rapid refluxing was maintained, heat being applied when necessary.
The mixture was refluxed for 3 hours, or until the magnesium had dissolved.  To the clear solution was added with vigorous stirring (in certain cases a viscous mixture was formed and unless it was stirred vigorously, lower yields were obtained) an etheral solution of 0.20 mole of phenylacetylchloride and the mixture refluxed for 30 minutes.  The reaction mixture was cooled and acidified with dillute sulfuric acid.  The ether phase, with which an ether extract of the aqueous phase was combined, was washed with water and the solvent distilled.
To the crude diethyl malonate was added a solution of 60 ml of glacial acetic acid, 7.5 ml of concentrated sulfuric acid and 40 ml of wather, and the mixture refluxed for 4 or 5 hours until the decarboxylation was complete.
The reaction mixture was chilled in an ice-bath, made alkaline with 20 % NaOH solution, and extracted with several portions of ether.  The combined etheral extracts were washed with water, dried with sodium sulfate followed by drierite, and the solvent distilled.
The residue containing the ketone was distilled in vacuo (97-98.5 C / 13 mm Hg) or recrystallized.

Yield: 71 %

Ref.: JACS (1946) vol 68 p 1386

I remember that there exists a reaction between an alkyllithium and a lithium salt of a carboxylic acid, but I can't find a refference (I haven't searched very hard at the moment).  This should yield the ketone. Can someone help me to find a ref.?  Thx
I was thinking about
 MeLi + Ph-CH2-COOLi --> P2P
 
 
 
 
    halfapint
(Ubiquitous Precursor Medal Winner)
01-10-02 19:13
No 254839
      Re: P2P from phenylacetylchloride  Bookmark   

Wonder if they couldn't drop just one solvent out of that blend. Maybee two, two less solvents would suit me just fine. Oh, just grumbling. It's basically an etherial reflux, with a minority of ethanol as a reagent. The .4 ml carbon tet doesn't count, I guess it's catalytic? And the acetic and sulfuric in the next step are reagents too, I expect. Well, it's an anhydrous reaction, but I doubt it's so drasticly sensitive to water as the Grignard. Looks good to me.

turning science fact into <<science fiction>>
 
 
 
 
    Cyrax
(Hive Bee)
01-10-02 21:08
No 254876
      Re: P2P from phenylacetylchloride
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In Vogel's Textbook of practical organic chemistry (5th edition) p 621 - 622, they do a similar reaction to get cyclohexyl methyl ketone.

Procedure:
 Place 10.7 g (0.44 mole) of magnesium turning in a 1-liter three-necked RBF, equipped with a sealed stirring unit, a dropping funnel and a double surface reflux condenser each protected with a CaCl2 guard-tube.  Add in one portion a mixture of absolute ethanol and 1 ml of CCl4.  Allow the reaction, which commences almost immediately, to proceed for about 5 minutes and then add carefully 150 ml of sodium-dried ether.  Site the flask in a warm-water bath and allow the reaction mixture to reflux gently while a solution of 70 g (0.44 mol) of diethyl malonate in 50 ml of dry ether is added with stirring.  On completion of the addition, heat the mixture under reflux for about 3 hours or until all the magnesium has reacted.  Then add with vigorous stirring  solution of 58 g (0.4 mol) of cyclohexylcarbonyl chloride in 50 ml of dry ether.  Heat the reaction mixture under reflux for 2 hours and then cool and acidify with 50 ml of dilute sulfuric aced.  Separate the ether layer and extract the residual aqueous solution sith two 50 ml portions of ether.  Wash the combined ether extracts with water and evaporate the solvent on a rotary evaporator.  To the residue add a solution of 120 ml of glacial acetic acid, 15 ml of concentrated sulphuric acid and 80 ml of water and heat under reflux for 5 hours.  Cool the reaction mixture, basify careful by addition of 100 ml of 20 % NaOH solution and extract the solution with four 50 ml portions of ether.  Dry the combined ether extracts over Na2SO4 and remove the ether on a rotary evaporator.  Distill the crude product at atmospheric pressure through a short fractionating column.  The yield of cyclohexyl methyl ketone of bp 178-180 C is 35 g (70 %)

I suggest you stick to the given procedures (anhydrous conditions and the CCl4 seem to be important, although I don't know what the function of CCl4 is in this reaction).  Watch out: CCl4 is BAD for your health.  If you do the reaction like I said, you should get a yield of 70 % without problems.
 
 
 
 
    Cyrax
(Hive Bee)
01-15-02 19:35
No 256749
      Re: P2P from phenylacetylchloride
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This is an optimized procedure for the Willgerodt reaction.  Ref: JACS (1946) vol 68 p 2025

"Acetophenone (25 g, 0.208 mole), 37.5 g of sulfur (1.17 gram atomic weights), 50 ml (0.76 mole) of concentrated ammonium hydroxide (15 M), and 30 ml of pyridine were sealed in a 22 mm o.d. hard glas (not Pyrex) bomb tube and heated to 157 +/- 6 for approximately four and one-half hours.  The tube was allowed to cool to room temperature and opened (no residual pressure).  The reaction mixture was transferred to an evaporating dish and evaporated to dryness on a water-bath.  The dry residue of sulfur and reaction product was leached with a total of about 500 ml of boiling water in several portions.  The clarified filtrate was cooled, whereupon 20 g of phenylacetamide, m.p. 156 - 158 cor., separated from the solution.  Concentration of the filtrate yielded a second crop of 2.7 g of amide.  The filtrate from the second crop was evaporated to dryness and extracted with ether, yielding an additional 0.32 g of amide and 1.2 g of phenylacetic acid.  The combined yields of phenylacetamide and phenylacetic acid amounted to 85.8 %.  The acid, after crystallization from water, melted at 76.3 - 77.3 cor."

What the hell means 'cor.'?
Now, you just have to hydrolyse the amide to the acid.

The next article is JACS (1946) vol 68 p 2029.  Here, they get phenylacetamide from styrene and from phenylacetylene.

"A mixture of 21.7 g of styrene, 37.5 g. of powdered sulfur, 50 ml of concentrated ammonium hydroxide and 30 ml of pyridine was heated in a sealed glass tube at 165 C for four hours.  The mixture was worked up as previously described for the preparative reaction with acetophenone (cfr. supra wink).  Two crops amounting to 16.1 g of amide, m.p. 158.6 - 160 , were obtained and an additional 2.0 g of amide and phenylacetic acid brought the total yield to 64 %."

You can also start from phenylacetylene (more expensive).

"A mixture of 12.0 g of phenylacetylene, 18.9 g of powdered sulfur, 30 ml of concentrated ammonium hydroxide (15 M), and 18 ml of pyridine was heated in a sealed glass tube at 160 +/- 5 for four hours.  Phenylacetamide was isolated as previously described for the preparative reaction with acetophenone; the first crop of recrystallized product amounted to 7.9 g of glistening, colorless plates m.p. 157 - 158.5 cor.  Additional crops brought the total yield to 11.24 g (72 %)."
 
 
 
 
    Rhodium
(Chief Bee)
01-15-02 19:40
No 256750
      Re: P2P from phenylacetylchloride  Bookmark   

What the hell means 'cor.'?

That the temperature is "corrected". They have not just checked the thermometer when the compound melted, they have alsio calibrated the mp apparatus against some known standard.