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 1152 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.

CycloKnight - 6-9-2018 at 07:24

Here are the images since the original image links are no longer supported by the image hosting site.

Attachment: Prototocatechualdehyde Methylenation.pdf (560kB)
This file has been downloaded 55 times

nimgoldman - 6-9-2018 at 09:05

Thanks for the peer-review.

Do you think this will work on 4-allylcatechol (obtained by demethylation of eugenol) ?

I am currently leaning more towards KF-catalysed methylenation in DMF merely because the method in newer, but the DMSO approach might have advantages.

I will try both methods but now I am working on eugenol demethylation via pyridine.HCl to obtain the catechol and all I got is awful sticky sludge, but at least it looks demethylated as the smell of eugenol is gone.

Attaching the picture of demethylated product, crashed from toluene, supposedly 4-allylcatechol loaded with impurities. I am afraid this has to be purified before attempting methylenation.

IMG_20180828_013146.jpg - 122kB

[Edited on 6-9-2018 by nimgoldman]

CycloKnight - 6-9-2018 at 11:24

A few years ago I spent months attempting eugenol demethylation to 4-allylcatechol, using various formulations employing HBr, followed by methylenation in DMSO, before eventually running out of time.
HBr is just so simple to prepare, it would be ideal if it could be made to work for this particularly fickle demethylation. I tried various solvents, varying concentrations, temperatures, reaction times, etc. The extremely high dilution needed seemed to make this route somewhat prohibitive without a dedicated recirculating product extraction system. The results were very poor, but I haven't give up on that yet.
The main problem of course was avoiding the polymerised gunk. I didn't use an inert atmosphere but I now have an argon source for the next attempt.

Now that I have some time put aside for this, I'll be revisiting this process very shortly, and for purification the plan is to try crystallising in petroleum ether before taking it any further.

I've prepared a quantity of elemental bromine, and am keen to carry out a few millimole scale trial runs using an aluminium bromide complex that is effective at demethylating vanillin to protocatechualdehyde. It'll likely be a waste of time on eugenol, but maybe worth a try anyway. If its a total failure, even at higher dilution, then ho hum, at least I can cross it off the to-do list.

Attachment: Process for the manufacture of protocatechualdehyde.pdf (394kB)
This file has been downloaded 43 times

nimgoldman - 7-9-2018 at 05:17

Quote: Originally posted by CycloKnight  
Now that I have some time put aside for this, I'll be revisiting this process very shortly, and for purification the plan is to try crystallising in petroleum ether before taking it any further.


I am now in the process of experimenting with eugenol, also invested huge bulk of time so far - please don't take my motivation away :)

The Py.HCl demethylation looks promising though I will try direct heat input instead of MW. I read another patent on how to optimize the process. None of the authors mention inert atmosphere. I am new to this kind of reaction so it's just try and fail...

My first attempt was very crude, the eugenol could be impure (should have used freshly distilled) and the ether extract should have been washed properly before evaporation. But polymerisation is most probably the cause of resulting gunk and avoiding air and moisture is always a good idea. Are there other possible factors for polymerization? Time? Heat?

I have read about polymerization risks only regarding to methylenation, not regarding to o-demethylation of methyl aryl ethers, such as catechol, allylcatechol etc.

Quote: Originally posted by CycloKnight  
and for purification the plan is to try crystallising in petroleum ether before taking it any further.

I've prepared a quantity of elemental bromine, and am keen to carry out a few millimole scale trial runs using an aluminium bromide complex that is effective at demethylating vanillin to protocatechualdehyde. It'll likely be a waste of time on eugenol, but maybe worth a try anyway. If its a total failure, even at higher dilution, then ho hum, at least I can cross it off the to-do list.


Well it cannot be told whether it is waste of time until all the promising methods have been tried. I haven't found any information that it's not doable or why it should be too hard (actually I read vanillin is harder to demethylate). I found several demethylation reactions and several methylenation ones. The target is safrole, which can be easily identified by smell and various reagents.

Why the choice of pet ether for purification? Catechol is purified by crystallization from benzene or toluene, then further purified by sublimation in vacuo. I think this will be similar for the allylpyrocatechol.

BTW I have also the heliotropin (piperonal) synthesis project (there is an overlap so we can help each other later if you like), but my current approach is oxidative cleavage of piperine with ozone.

Just like in the linked paper, I use HAILEA Ozone Steriliser, that will bubble O3 through a solution of piperine in acetone. The resulting product should be a mixture or piperine and piperonal. The separation of the said compounds is another exercise.

The paper also describes heliotropin synthesis starting from vanillin. Demethylation is done with AlCl3 or AlBr3 and methylenation by methylene chloride in NMP (n-methyl-2-pyrrolidone), which is an aprotic solvent - probably can be substitued by DMSO or DMF.

Kudos to you for the Br2 production. I am attempting HBr(g) according to one patent, to obtain HBr in GAA or HBr(aq.) with concentration above azeotropic.

Sorry for leading your thread a bit off track with the demethylation stuff. I also hope this does not look like "cookery" since we are dealing with precursors. All this is of course done on microscale with the intention of studying these interesting aromatic compounds and reviewing existing processes.

[Edited on 7-9-2018 by nimgoldman]

CycloKnight - 8-9-2018 at 16:29

Piperine in acetone sounds like a nifty approach to piperonal, I have a number of tesla coils I've built, 2 of which (solid state dual resonant tesla coils, computer controlled) generate half a million volts - I'd imagine any of them could be adapted to power one heck of an ozone generator.

Can't go wrong using pure eugenol, I vac distilled mine and currently have about 1.5L vac distilled and a few hundred ml of sodium eugenolate purified oil. Obviously, that was made by reacting vac distilled eugenol with NaOH, solvent washed before reverting it back to the oil. The aim was to eliminate impurities that might be causing problems, but actually I never noticed any difference between that and the vacuum distilled oil, so never used much of it.

As for the polymerisation, naturally the problem is worse with increased concentration. I recall higher reaction temperatures generating tar faster but there was too much eugenol being used, so it was more concentrated that it should've been. On one occasion, after removing the oil after an attempted 48% HBr demethylation run, I observed the whole lot appearing to polymerise into a gooey mass in a matter of second, before I could get it to the methylenation apparatus.

The final product I made did have a strong smoky odour (as its often described) and appeared to quickly degrade when not kept in the freezer. I didn't isolate the pure product, but the mixture was very viscous at room temperature. I recall having problems separating the product from the impurities, so later on I acquired the petroleum ether since its described as a recrystallisation solvent. Something new to try soon.
I tried separating the final product by vacuum distilling, and collected the higher boiling point fraction and assumed that to be the product (mixed with a proportion of eugenol still) but it wasn't pure enough to crystallise.

------------------------------------------------------------------------------
Physical properties of 4-allylcatechol
Alternate names: 3,4-dihydroxyallylbenzene, 4-allylpyrocatechol, 2-Hydroxychavicol.
Melting point: 46-48.5°C
Boiling point: 123-124°C/1mmHg, 141-144°C/7mmHg, 147-149°C/10mmHg, 155-157°C/13mmHg, 156-158°C/16mmHg. 289.2/760 mmHg.
Solubility (H2O): 25 g/l at 26°C.
Recrystallization solvents: Benzene, petroleum ether, diethyl ether.
Density: 1.148 g/cc
Flash point: 141.7 deg C.
Molecular weight: 150.177 amu.
------------------------------------------------------------------------------


These are images from those experiments back in 2014.

48% HBr/eugenol after a several hour demethylation attempt.


Final product mixture


Same sample the next day if left at ambient temperature



Quote:
All this is of course done on microscale with the intention of studying these interesting aromatic compounds and reviewing existing processes.


If a viable eugenol route can be found then it may one day prevent safrole containing trees from being eradicated in the rainforests. Helping to save the rainforest(s), sounds good to me.


[Edited on 9-9-2018 by CycloKnight]

nimgoldman - 9-9-2018 at 14:00

Thanks for the properties table and the pics.

Here is one interesting paper from 2015:

Transformation of Eugenol and Safrole into Hydroxychavicol

They successfuly isolated eugenol (no more purification beyond the traditional A/B extraction) and even provided GCMS data for the oil and the isolate. Their eugenol was 83% pure, contaminated mostly with caryophyllene and humulene. But since they successfuly synthesized 4-allylcatechol from it, the impurities are probably not a problem.

Demethylation has been done with AlCl3 and DCM in DMS (not DMSO). The allylcatechol have been isolated by flash column chromatography.

Two issues are the yield was around 30% (pretty low) and they used flash column chromatography to purify the allylcatechol.

I will try the pyridine.HCl method with purified eugenol under argon to see if there are any improvements.

As for the safrole - unfortunately over 90% of safrole is produced for pesticide, fragrance and chemical industries (approx. 20 000 tons a year according to Wiki) so illicit drug manufacture could be only a small part of it.

But anyway I am looking for a green method for producing safrole at small scale for whatever lab applications, as the source chemicals are easily available locally, including the clove oil (very cheap even at retail price - imported from India).

If the product will look good, I will continue with the base-catalysed methylenation reactions in aprotic solvents including the one you presented.

zed - 14-9-2018 at 14:03

I have read that de-methylation of Eugenol by HX, in whatever form, is not easy. But, NaOH may be more effective.

Excepting that, NaOH will probably isomer-ise the Allyl side chain to Propenyl.

The demethylation of Vanillin by HX is generally more successful, but easier still is that of Ethyl Vanillin by H2SO4.

Sadly, for this synthetic pathway, the world provides an abundance of Eugenol, whilst I have never heard of an Ethyl vs Methyl, version of Eugenol. But, I am going to check on it.

OK, I checked around. If it exists, it is not an easy find.

[Edited on 14-9-2018 by zed]

[Edited on 14-9-2018 by zed]

Loptr - 14-9-2018 at 16:07

Quote: Originally posted by zed  
I have read that de-methylation of Eugenol by HX, in whatever form, is not easy. But, NaOH may be more effective.

Excepting that, NaOH will probably isomer-ise the Allyl side chain to Propenyl.

The demethylation of Vanillin by HX is generally more successful, but easier still is that of Ethyl Vanillin by H2SO4.

Sadly, for this synthetic pathway, the world provides an abundance of Eugenol, whilst I have never heard of an Ethyl vs Methyl, version of Eugenol. But, I am going to check on it.

OK, I checked around. If it exists, it is not an easy find.

[Edited on 14-9-2018 by zed]

[Edited on 14-9-2018 by zed]


Some might be interested in that isomerized compound.

Propenyl Guaethol - 15-9-2018 at 13:03

Quote: Originally posted by Loptr  
Quote: Originally posted by zed  
I have read that de-methylation of Eugenol by HX, in whatever form, is not easy. But, NaOH may be more effective.

Excepting that, NaOH will probably isomer-ise the Allyl side chain to Propenyl.

The demethylation of Vanillin by HX is generally more successful, but easier still is that of Ethyl Vanillin by H2SO4.

Sadly, for this synthetic pathway, the world provides an abundance of Eugenol, whilst I have never heard of an Ethyl vs Methyl, version of Eugenol. But, I am going to check on it.

OK, I checked around. If it exists, it is not an easy find.

[Edited on 14-9-2018 by zed]

[Edited on 14-9-2018 by zed]


Some might be interested in that isomerized compound.


Not sure if a base would cleave the ethoxy due to the production process of the chemical.
US2663741
US2663741
I'm not sure if this process would work on eugenol or isoeugenol.

[Edited on 15-9-2018 by Propenyl Guaethol]

mackolol - 16-9-2018 at 00:28

Wouldn't the yield be higher if less quantity of aldehyde is used? Erowid says that this method of methylenation done with catechol yields 95,4% but molar equivalent of protocatechualdehyde can be too much as this molecule is bigger and maybe harder to react. For me yield should be much higher .