Sciencemadness Discussion Board

Prototocatechualdehyde methylenation. Photo-essay.

CycloKnight - 30-1-2014 at 06:51

What follows is a slight variation of the commonly referenced catechol methylenation procedure, easily found copied and pasted all over the internet. This variation would theoretically produce heliotropin (used in perfumery).
I couldn't find any experimental data to confirm whether this synthesis actually works or not. So lets find out.

Chemicals used:
138g protocatechualdehyde
120 ml 50% NaOH aqueous solution (91g NaOH, 91g dH2O)
500 ml dimethylsulfoxide (DMSO)
120ml (160g) dichloromethane (DCM).

Equipment used:
1L RBF & condenser (for methylenation), stirrer hotplate with oil bath
500 ml RBF (for addition mixture), stirrer mantle
500 ml mixing beaker
3L RBF & heater for steam distillation
Suitable large container for collecting distillate (I used 2L beaker)
Converted steam cooker & aquarium tubing for steam distillation (with short glass tube & cork)
Funnel/cork/glass tubing for reactant addition (though not essential)
1 L separating funnel (for dichloromethane extractions of steam distillate)

No inert atmosphere was used for this experiment.

300 ml of DMSO is added to the 1L RBF, then 120ml dichloromethane is added. Reflux condenser added with cooling water flowing, oil bath heated to 125-130 deg C.

Whilst the bath is heating, the addition mixture is prepared. 120 ml 50% NaOH, 138 g protocatechualdehyde and 200 ml DMSO are combined in a 500 ml beaker (with stir bar), there is some heat evolution and the mixture is stirred on the hot plate for a few minutes to fully dissolve the protocatechualdehyde and any residual NaOH. Once dissolved, the mixture is poured into the 500 ml RBF (rinsed down the funnel with a little extra DMSO), and then transferred to the 500 ml stirrer mantle for heating and stirring. Mixture was kept hot but without boiling. No temperature measurement was used for the addition mixture.

Methylenation solution on left, addition mixture on right.


Once the DMSO/DCM mixture was nicely refluxing (oil bath at round 125 deg C), 15 more minutes were allowed for the addition mixture to stir before addition was started.

Orange addition funnel was connected to a small glass tube, this makes addition much easier, much easier than addition via the condenser.
The drop of addition liquid held in position by capillary force, prevents DCM vapor from exiting the funnel - this works quite well and I can contend this is far easier than using an eyedropper (pipettes tend to melt at this temp), which is very impractical on this scale.


Addition commenced (with vigorous magnetic stirring)


Wearing a rubber glove for heat protection, the hot 500 ml RBF was literally poured into the small addition funnel. A few minutes were allowed in between funnel additions.
This waiting time is necessary because the reaction causes DCM to boil vigorously, it could easily overwhelm the condenser if the additions are not spaced apart (also, according to literature sources, reactant dilution is necessary to improve yields).
In total about 40 minutes were required to complete the addition. The reaction (with vigorous stirring and good reflux) was continued for another 90 minutes, before turning the heat off and allowing to cool (with stirring).

Once cool, the mixture was transferred to a larger container suitable for steam distillation. I had a 3L RBF at hand, so used that. About half a litre of water was added prior to steam distilling.

3L RBF has been set up for distillation (using double surface condenser for good rate of steam condensation), and brought to boiling temperature, and now steam is being added via a small glass tube that is submerged nearly to the bottom of the RBF (though only partly visible in the photo below).



Steam distillate, distilling over quite rich in reaction product:


About 2 gallons of water were put through the reaction mixture (using a pressure cooker as steam source) and condensed.
Once cooled, much of the product crystallises in the water, and is easily removed by filtration. The heliotropin laden water is kept for solvent extraction later. It still contains a few grams per litre.

Glass sintered filter funnel (after filtering a small amount of cooled steam distillate).


2L beaker


Filtering the product


The total dried crystals yield was around 34 grams.
The filtered water was extracted with about 30 ml DCM per litre.

The combined DCM extracts were combined, and added to a 500 ml RBF for distillation (using the large double surface condenser).
Once the DCM was mostly distilled off, the condenser was changed for a small liebig condenser, and set up for vacuum distillation.
I was expecting multiple fractions, however the still head (under full vacuum) rapidly rose to 140 deg C and slowly rose to 143 by the end of the distillation. So I only ended up collecting one single fraction,







Product rapidly crystallising in receiver






Product crystallising in the condenser


Vacuum distillation yielded 26 grams,far more than i was expecting. There was some product still in the steam distilled water when it was discarded (as it still had a strong smell of vanilla/piperonal). If I'd known it held up so much product, I'd have carried out at least 3 x 30 ml DCM extractions per litre.
Also, I stopped the steam distillation when the distillate stopped appearing milky/turbid. However, the last litre, although not milky in appearance, still produced lots of crystals, so I feel I stopped the steam distillation too soon.

The total combined yield was 60 grams, of a product which appears indiscernible (in terms of color, taste, smell, texture and melting point) to another small sample of heliotropin that I've compared it with.
Assuming this product is pure heliotropin/piperonal, then this equates to an overall molar yield of 40 %. Not too bad, but clearly there is still room for improvement.

Attachment: methylenation of catechols.pdf (348kB)
This file has been downloaded 1006 times

[Edited on 30-1-2014 by CycloKnight]

Boffis - 30-1-2014 at 10:25

Nice write up Cycloknight!

Did you try dissolving salt in the steam distillate before extraction? It sometimes helps increase the efficiency of the extraction with weakly polar organics.

CycloKnight - 30-1-2014 at 10:53

Thanks, no I didn't add salt but that sounds like a good suggestion - I'll give it a try next time !

zig - 31-1-2014 at 00:08

Excellent write-up cycloknight, love the pics. I'll bet your lab reeked of sunshine and rainbows after that!

Apparantly aromatherapists believe heliotropin has anti anxiolytic properties. Did you find your concerns and consternations all blissfully washed away in the wake of your experiment!?:D

Edit: How in gods name is protocatechualdehyde pronounced?

[Edited on 31-1-2014 by zig]

CycloKnight - 31-1-2014 at 07:59

Yes, sunshine and rainbows indeed, interesting medicine this. :)

A note regarding this methylenation I should add, the reaction is rather sensitive to reagent temperatures and concentrations.
A previous run wouldn't reach the 125 deg C bath temperature without the refluxing DCM overwhelming the condenser, so I left it at that. Turns out I'd added a little more DCM than needed (I was trying to compensate for some DCM vapor that had boiled away by adding a little extra). The reaction was a complete failure, virtually nothing steam distilled from it, so worth keeping in mind that the stated reaction temperature must be attained.

Rich_Insane - 4-2-2014 at 14:08

Pardon me if this question is a bit tangential, but do you think that the high temperature (hence why DMSO was used, I presume) was very important here?

Would using a different methylene halide (i.e. CH2I2 or CH2Br2) speed up the reaction? If I recall correctly, this is just a nucleophilic substitution repeated twice to form the methylenedioxy bridge, and I believe iodine/bromine would be very good leaving groups.

Anyways, good job! This is a really nice writeup.

stoichiometric_steve - 18-2-2014 at 13:28

Using CH2I2 and doing this reaction with hydroxyde and a phase transfer catalyst in a two-phase system will probably even yield much higher.

Electra - 18-2-2014 at 17:56

Quote: Originally posted by stoichiometric_steve  
Using CH2I2 and doing this reaction with hydroxyde and a phase transfer catalyst in a two-phase system will probably even yield much higher.


You beat me to it!

Not only would the yield be higher, but the reaction would occur much more rapidly and the need for DMSO would be eliminated. Theoretically only leaving in the solution Sodium Hydroxide, Sodium Chloride, water, and the PTC, and upon cooling allowing for a quick and easy filtration of the product. Since the product is not soluble in water, and nearly all of the reactant products are, separation is very easy. If excess DCM were used it could just be boiled off before filtering.

[Edited on 19-2-2014 by Electra]

zig - 19-2-2014 at 22:29

Quote: Originally posted by stoichiometric_steve  
Using CH2I2 and doing this reaction with hydroxyde and a phase transfer catalyst in a two-phase system will probably even yield much higher.
Quote: Originally posted by Electra  

Not only would the yield be higher, but the reaction would occur much more rapidly


Why is that? Got any good links on the subject?

As far as choosing a PTC, would one be looking for something like a crown ether (15-5 for Na+, if memory serves) or a water soluble salt? I guess I'm unsure of which reactant needs to be ferried where.

Electra - 4-3-2014 at 13:21

Quote: Originally posted by zig  
Quote: Originally posted by stoichiometric_steve  
Using CH2I2 and doing this reaction with hydroxyde and a phase transfer catalyst in a two-phase system will probably even yield much higher.
Quote: Originally posted by Electra  

Not only would the yield be higher, but the reaction would occur much more rapidly


Why is that? Got any good links on the subject?

As far as choosing a PTC, would one be looking for something like a crown ether (15-5 for Na+, if memory serves) or a water soluble salt? I guess I'm unsure of which reactant needs to be ferried where.


CTAB is tried and true for this reaction and is one of the most widely used industrial surfactants due to its use in soap.

It is neither a crown ether nor water soluble.

The phenolic/catechol material (to be methylenated) is slightly acidic and thus attaches to the sodium hydroxide, forming a water soluble ion of sorts. CTAB would then "ferry" the ion into the organic phase so that it can react easily with the organic substrage (methylene halide). It's a basic SN2 reaction catalyzed by the base NaOH. The base deprotonates the hydroxyl groups on the phenol and upon contact with the methylene halide a substitution can occur. The speed/ease at which the substitution precedes depends on how easily the halides can leave the methylene halide, which basic halogen leaving group rules apply.

The Rhodium Archives has many articles on the use of PTC in methylenation reactions.