Sciencemadness Discussion Board

Ethyl Phenylcyanoacetate Synthesis troubles

SuperOxide - 1-4-2022 at 15:06

Recently, I've taken an interest in the synthesis of ethyl phenylcyanoacetate. The prep I'm following is from Orgsyn, and it seems like a pretty detailed procedure.
I gave it a shot last week, and initially it looked pretty promising. But when I distilled off all of the ether, I had ~7.4 g left of the crude product (still containing ether), which was 10x less than the yield of the pure product from the Orgsyn procedure (I was doing it on the same yield).

I plan on trying it again, but the diethyl carbonate is pretty expensive so I would like to see if someone else can point out something I may have done wrong. I've saved my notes to a PDF and attached, and also uploaded some pictures to Imgur here
Attachment: Ethyl Phenylcyanoacetate Synthesis (.5M) Notes.pdf (262kB)
This file has been downloaded 286 times

Just for reference, here's the procedure from Orgsyn:
Quote:
Sodium ethoxide is prepared from 12.0 g. (0.52 g. atom) of sodium and 300 ml. of anhydrous ethanol in a 1-l. three-necked round-bottomed flask fitted with a reflux condenser carrying a calcium chloride tube. After the sodium has dissolved completely, the condenser is arranged for distillation under reduced pressure and the excess ethanol is removed by heating the flask on a steam bath while the system is maintained at the pressure obtained with an ordinary aspirator (Note 1).

As rapidly as possible, after removal of the ethanol, the flask is fitted with a rubber-sealed stirrer, a dropping funnel, a distilling head containing a thermometer, and a condenser arranged for distillation into a flask protected by a calcium chloride tube. There are then added 300 ml. (292 g., 2.5 moles) of dry diethyl carbonate, 80 ml. of dry toluene, and 58.5 g. (0.50 mole) of phenylacetonitrile (Note 2). The flask is heated, with good stirring, and the cake of sodium ethoxide soon dissolves. When distillation has started, dry toluene is added dropwise at about the same rate that the distillate is collected. Approximately 200–250 ml. of toluene should be added in a period of 2 hours (Note 3) while stirring and distillation are continued.

The mixture is cooled and transferred to a 1-l. beaker. After addition of 300 ml. of cold water, the aqueous phase is acidified with 35–40 ml. of acetic acid. The layers are separated and the water solution is extracted with three 75-ml. portions of ether. The organic solutions are combined, washed with 100 ml. of water, and dried over anhydrous magnesium sulfate. The low-boiling solvents are removed by distillation at atmospheric pressure, and the residue is distilled under reduced pressure through a short (15-cm.) Vigreux column. After a 1–5 g. forerun, the product is collected at 125–135°/3–5 mm. (Note 4). The yield is 66–74 g. (70–78%).


I think where I may have gone wrong was maybe during the workup, or right before it. I highly doubt it's related to the purity/dryness of any of the reagents, as I made sure the alcohol, toluene, benzyl cyanide and diethyl carbonate were very pure and scrupulously dry.

It wasn't clear in the Orgsyn procedure if I was supposed to let the reaction mixture distill til it was dry (or nearly dry), or if I was supposed to leave a certain amount of toluene in there. When it mentions to "pour out" the contents into a 1L beaker I get the impression that it should still have some toluene left. I got a little distracted and basically distilled almost all of it off.

Some changes I think I could make:

  1. Not let the toluene level get so low before calling it quits
  2. After the ether extraction, test adding some ammonia to a small sample to see if anything interesting happens (I found that mentioned here on page two.

Any input is appreciated. Thanks!

UC235 - 1-4-2022 at 18:06

The toluene is being used to azeotropically remove ethanol and push the reaction forward. The liquid level in the flask shouldn't drop at all during the reaction if you're adding fast enough. Initial distillate should be the binary azeotrope, mostly, bp 76.7C. It seems likely that diethyl carbonate and ethanol also form an azeotrope (the methyl ester and methanol do) so you may have lost reactant that way.

I see you're using sieves for drying. Are they 3A? And did you activate them freshly yourself.

In the imgur album you say "mostly dry" with the ethoxide. Maybe not dry enough.

Potentially overheated by distilling most of the toluene off.

Did you check that the aqueous layer was actually acidic? Also if left wet for any decent amount of time before acidifying, I'd expect hydrolysis.

EDIT: I don't know, and maybe don't want to know what you're making this for, but would ethyl phenylmalonate be able to substitute? http://orgsyn.org/Content/pdfs/procedures/cv2p0288.pdf Procedure looks more robust except for the whole not killing yourself with CO part.

[Edited on 2-4-2022 by UC235]

SuperOxide - 1-4-2022 at 19:22

Quote: Originally posted by UC235  
The toluene is being used to azeotropically remove ethanol and push the reaction forward. The liquid level in the flask shouldn't drop at all during the reaction if you're adding fast enough. Initial distillate should be the binary azeotrope, mostly, bp 76.7C. It seems likely that diethyl carbonate and ethanol also form an azeotrope (the methyl ester and methanol do) so you may have lost reactant that way.

Right, I get that the ethanol and toluene distill over as an azeotrope, but I also think that the DEC is expected to distill over as well. I figured that was one of the reasons behind the large excess (along with trying to push the reaction forward). Only .5M of BnCN is used while 2.5M of DEC is used.
Quote: Originally posted by UC235  
I see you're using sieves for drying. Are they 3A? And did you activate them freshly yourself.
Yes, I did very recently activate them, and they're good quality sieves too.
Quote: Originally posted by UC235  
In the imgur album you say "mostly dry" with the ethoxide. Maybe not dry enough.
I don't say "mostly dry", I say "mostly solid" because not all of the EtOH had left the NaOEt. I know the EtOH is as dry as I can possibly get it (dried with sodium, distilled, kept over freshly activated sieves). And I don't think the residual EtOH is a big deal because it gets removed along with the EtOH that gets formed when then NaOEt reacts.
Quote: Originally posted by UC235  
Potentially overheated by distilling most of the toluene off.
Yes, I totally agree with you. >_< I got distracted playing with my dog, lol. Damnit.

Quote: Originally posted by UC235  
Did you check that the aqueous layer was actually acidic? Also if left wet for any decent amount of time before acidifying, I'd expect hydrolysis.

So when I let it cool down, and it was pretty damn dry (I saw no liquid, but its possible some toluene was absorbed into some of the solids). I added the 300mL of water, which went basic (obviously for the residual NaOEt left over) and separated from the toluene. I then separated the aqueous layer and acidified it to a pH of ~2 using AcOH. I may have waited a few hours before adding the AcOH (multi tasking), but I don't think that would have given it enough time to hydrolyze.

Illegal Parkinson - 7-11-2024 at 00:31

Frederick Dr Leonard, CH369764 (163 to Geigy).

Methyl 3-amino-2-phenylpropanoate
[99092-02-1]

The new compounds of formula I are fast-acting stimulants of the central nervous system. They can be administered orally or parenterally and are not very toxic. They are suitable for treating mental depression, a result of nervous exhaustion, chronic fatigue and drug therapies.

Catalytic hydrogenation of Ethyl phenylcyanoacetate [4553-07-5]