Sciencemadness Discussion Board

Methylenation of catechol with dichloromethane

theAngryLittleBunny - 9-8-2017 at 10:20

Usually, for a methylenation reaction, you need diiodomethane, but this differcult to obtain, expensive, and since it's like 95% iodine, you need A LOT of it. But I found a methode on Erowid which uses dichloromethane instead.

https://erowid.org/archive/rhodium/chemistry/methylenation.h...

I've tried it, and it REALLY WORKS O.o. The only drawback is that is uses dimethylsulfoxide as a solvent, which might be differcult to obtain, but still much easier then diiodomethane. They promise a yield of 95%, which sounds a bit unrealistic. But I adopted the methode in a very sloppy way with a small scale, and still got 50% yield, so you might get there if you do it properly.

First, I mixed 22g of catechol, 17g of NaOH and 17mL of water in a beaker with cooling, then I added 40mL of dimethyl sulfoxide. It heats up again, I let it sit for an hour and after that it was a wet solid. Next, I put 20mL of dichloromethane into 50mL of dimethylsulfoxide and heated it to a reflux (dichloromethane seems to have a much higher boiling point in dimethylsulfoxid). Then I addad the catechol NaOH mix over 30 min into the hot DCM solution, and just let it sit for a night. In the next morning, I just added about 100mL of water and distilled the methylenedioxo benzene as an azeotrop with water at 98°C.

The use of such huge amounts of dimethylsulfoxide is neccessary in order to keep the concentration of catechol in the reaction mix low, if the concentration is high, more methyleme groups will attach between two catechol rings, but maybe you could just add more catechol NaOH to the solvent after destillation and reuse it that way.

Anyway, this methode seemed to be almost too good to be true, so I just felt like I had to confirm here that it really works.

Crowfjord - 9-8-2017 at 11:13

Nice. I probably would have used even more DMSO, the amounts you used were not all that dilute. That may have contributed to the somewhat low yield. Then again, 50% is still pretty good considering the simplicity of the procedure and materials. Cyclonight also did a similar reaction a few years ago, with protocatechualdehyde instead of catechol.

Assured Fish - 9-8-2017 at 14:10

Yes this is called the williamson reaction, it is well known that it works with all halides including chloride, bromide and iodides (excluding fluoride). Its a fairly robust reaction and can be carried out in any polar aprotic solvent including DMSO DMF and probably even acetone.
It also works quite well in an aqueous solution in the presence of a phase transfer catalyst provided you keep compatibility in mind.

https://en.wikipedia.org/wiki/Williamson_ether_synthesis

I should also add that the distillate that you collected with steam distillation of methylenedioxy benzene is not an azeotrope.
It is just a mixture of two immicible liquids that when agitated and heated generate there own vapor pressures however when both components are heated together within the same system, the overall vapor pressure increases, thus you are able to boil 2 immicible components at a much lower boiling point than what they would boil at alone.
this of coarse requires a fair bit of agitation to work properly.

[Edited on 10-8-2017 by Assured Fish]

[Edited on 10-8-2017 by Assured Fish]

DJF90 - 10-8-2017 at 04:53

Quote: Originally posted by theAngryLittleBunny  
But I adopted the methode in a very sloppy way with a small scale, and still got 50% yield, so you might get there if you do it properly.

First, I mixed 22g of catechol...


Makes me laugh when people say small scale and then proceed to describe several grams, especially on a first run through.
Quote: Originally posted by theAngryLittleBunny  
The use of such huge amounts of dimethylsulfoxide is neccessary in order to keep the concentration of catechol in the reaction mix low

Huge amounts of DMSO? Where?? 90 mL for 22g of substrate is pretty concentrated (~4vol). I'll let you work out the molar concentration before you retract your statement...
Quote: Originally posted by theAngryLittleBunny  

Anyway, this methode seemed to be almost too good to be true, so I just felt like I had to confirm here that it really works.


Ephesian also reported this method with a full experimental write-up five years ago: http://www.sciencemadness.org/talk/viewthread.php?tid=21927

[Edited on 10-8-2017 by DJF90]

cubalibre - 10-8-2017 at 12:38

DJF90 , it's a bit off-topic but do you know of any good review dealing with systematic evaluation of reaction concentrations in organic chemistry?
I've the feeling that most publications just use what worked with similar substrates/reactions.
Seldomly I see actual experimental design data.

Is there a mol percentage that you start with when running new reactions?
Be it from intuition, experience or actual facts.
Or do you always run a series and check results using DoE/PCA whatever in industry/academia?

DJF90 - 14-8-2017 at 10:39

Quote: Originally posted by cubalibre  
I've the feeling that most publications just use what worked with similar substrates/reactions.


As a practicing med-chemist, when doing a "new reaction", the first course of action is to check the literature for conditions using a similar substrate (or the exact substrate if it has been done before). These might be tweaked slightly to account for substrate differences (e.g. if you're using a amine salt rather than the freebase, you might include an (additional?) equivalent of base (iPr2NEt, Cs2CO3, NaOAc etc.) to compensate) or availability of solvents or reagents (e.g. NaBH(OAc)3 in place of NaBH3CN). The choice of appropriate modifications is largely drawn from experience or intuition, at least personally.
Quote: Originally posted by cubalibre  
Is there a mol percentage that you start with when running new reactions?
Be it from intuition, experience or actual facts.
Or do you always run a series and check results using DoE/PCA whatever in industry/academia?


I wouldn't expect concentration to be screened in DoE unless it was expected to be a significant factor (e.g. for radical reactions or macrocyclisations).

Generally, during a routine day in the lab, I'll be looking at about 30 volumes of solvent (thats 30 mL per gram of substrate). Sometimes its more (up to 100 volumes if I'm working with < 20 mg or so; minimises handling/transferance losses), sometimes less (2 to 5 vol if its a well defined process on "larger" scale).

A few years back, when I was a process chemist, the guideline was a maximum process volume (thats the total volume that needs to be accomodated at any single point in time) of 30 volumes or less. We'd process a kilo or so in 20L flasks, running multiple batches for a several-step synthesis to obtain a kilo or two of final product at the end.

Small reaction modification suggestion to increase yields

boilingstone2 - 14-8-2017 at 21:18

The Finklestein reaction exploits the difference in solubility of sodium iodide and sodium chloride in organic solvents. Sodium iodide is reacted with an alkyl chloride in an organic solvent to form the alkyl iodide and sodium chloride. This occurs because sodium chloride precipitates out of the organic solvent, thus shifting the equilibrium of the reaction towards the alkyl iodide. Could this be used to improve the yield of your reaction? In your posted procedure, it would appear the sodium iodide would be regenerated after the diiodomethane created in-situ reacts to form the ether. This sodium iodide could then react to form more diiodomethane, precipitate further sodium chloride, creating more ether, and such the cycle could continue. A quick google search shows that diiodomethane is a product in the scope of the Finklestien reaction, so my guess is it's likely sodium iodide could act as a kind of catalyst for this reaction?

gravityzero - 18-8-2017 at 09:43

Quote: Originally posted by Crowfjord  
Nice. I probably would have used even more DMSO, the amounts you used were not all that dilute. That may have contributed to the somewhat low yield. Then again, 50% is still pretty good considering the simplicity of the procedure and materials. Cyclonight also did a similar reaction a few years ago, with protocatechualdehyde instead of catechol.


If anyone is interested in Cyclonight's writeup with original pictures. A archive PDF was created some time back. Glad the pictures were saved, since they are no longer on the forum.

Attachment: Prototocatechualdehyde Methylenation.pdf (560kB)
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