Stramonium
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Darzen Condensation Difficulties - any tips?
After several failed attempts at a Darzen Condensation help is needed. Originally the procedure in [1] was used but after several failed attempts, a
new solvent system was tried (detailed below) which again failed.
BACKGROUND:
Attempts at the synthesis of alfa-methyl-beta-p-fluorophenylglycidic esters have been unsuccessful. A procedure was devised whereby the reaction was
carried out in dry toluene rather than methanol as specified in [1] and the methyl chloroester was substituted with the ethyl ester. After the
condensation was "complete", the mixture was very viscous (appeared to be a white precipitate) and upon hydrolysis in aqueous sodium hydroxide and
acidification, failed to decarboxylate to the desired p-fluorophenyl-2-propanone. Below is the procedure (Adapted from [1] with the beforemention
changes) that was followed:
To a well stirred solution of the benzaldehyde (1 mol) in dry toluene, cooled in an ice bath, was added 1.1mol of ethyl 2-chloropropionate. Slowly,
over 15min, 1.5mol sodium methoxide (98%, dry powder) suspended in dry toluene was added to the aldehyde/chloroester mixture ensuring that the
temperature remained below 10*C. 30 min after the final addition of the sodium methoxide, the mixture was removed from the ice bath and allowed to
stir at room temperature for 6hrs. The toluene mixture was added 1mol of NaOH as 10% aqueous solution and allowed to stir at 50*C for 5hrs. The
aqueous phase was seperated and acidified to pH 3 with hydrochloric acid and allowed to stir at 80*C for 3 hrs. The yellow oil that seperated was
collected (dissolved if solution was basified).The oil failed to form a bisulfite adduct and had a boiling point almost identical to 2-chloropropionic
acid. The reactions were carried out using 50-100mmol of the aldehyde.
QUESTIONS:
It appears that the condensation is failing. Why?
Does anyone know if ethyl 2-chloropropionate can be substituted for the methyl ester when NaOMe is used as the base? I have only ever seen NaOEt used
with the ethyl ester in literature but the original post from which the procedure was adapted lists the two as interchangable when NaOMe is used.
Similarly, is there any reason not to conduct this condensation in toluene? The unsuccessful attempt in methanol left me thinking that toluene may
prevent hydrolysis of the ethyl 2-chloropropionate prior to its condensation with the aldehyde but the modified reaction was still unsuccessful.
Anyone who has successfully synthesised a substituted phenylglycidic ester is asked to share their method.
Likewise any comments on possible reasons for failure are very appreciated.
Thanks in advance!
REFERENCES:
[1] Procedure as posted by Barium at The H*ve (Post No 379632) .
"I´ve made quite a few phenylacetones with this method now, and finally I´ve got a nice overall method.
1 mol of your favourite benzaldehyde
1.1 mol methyl or ethyl 2-chloropropionate
1.5 mol sodium methoxide, preferebly as the commercially avalible and dirt cheap 30% soln in MeOH.
Toluene, about 200-250 ml/mol benzaldehyde. Make sure the toluene is dry.
Add the toluene, benzaldehyde and haloester to a rb flask equipped with a mag stirbar, thermometer and a addition funnel. With cooling, add the sodium
methoxide solution dropwise at a rate which keeps the reaction temperature between 10 to 15°C. When the addition is over allow the mixture to stir at
room temp for one hour. The toluene solution of the glycidic ester is now poured into 1 mol NaOH, as a 5% aqueous solution, and the mixture heated to
70-75°C for 60 minutes to hydrolyze the glycidic ester. The toluene layer is then separated from the aqueous layer. The sodium salt of the glycidic
acid can now be isolated by concentration of the aqueous solution to about one third of the original volume and cooling to 10°C, filtration and
washing with cold MeOH affords the salt in a quite pure form.The phenylacetone is generated by heating the previous alkaline solution of the sodium
salt of the glycidic acid to 90°C, and acidifying to pH 5.5 with either acetic acid or hydrochloric acid. A vigourous evolution of carbon dioxide
starts immediately upon addition of acid. The slightly acidic solution is kept at 90°C for approximately one hour, or about 10 minutes after the
carbon dioxide evolution has ceased. The solution is then cooled to room temperature, the pH raised to 8, and the ketone extracted with ether"
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not_important
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Given that there is a bunch of ionic type going-ons in the Darzen, I'd wonder about running it in such a non-polar solvent as toluene. It would seem
that doing so means the reaction is going to depend on the halo-ester and the aldehyde to do any needed solvation. Note that your quoted ref is using
NaOMe as a 30% solution in MeOH, not the dry NaOMe, so the reference is running in mixed toluene-MeOH.
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leu
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When these reactions are carried out using bases such as sodium methoxide they must be conducted under totally anhydrous conditions, even the humidity
in the atmosphere can cause problems  An inert atmosphere has be used to solve this
issue in some published articles. Some more reference information can be obtained from:
http://people.bu.edu/jaylowe/Named%20reactions/D/Darzen/Darz...
Aromatic hydrocarbons have been used as solvents successfully. You may find some helpful tips in these articles, as well as many important facts about
the mechanism, technique and course of the reaction:
[Edited on 1-11-2006 by leu]
Attachment: Darzens.zip (245kB)
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Chemistry is our Covalent Bond
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