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Author: Subject: Demethylation of Vanillin and Eugenol
CycloKnight
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[*] posted on 18-9-2018 at 03:25
Demethylation of Vanillin and Eugenol


Further to recent discussions in the Protocatechualdehyde Methylenation thread, I thought it pertinent to start a separate thread specifically for demethylation discussion. All feedback and contributions welcome.

I'll start with yesterday's vanillin demethylation to protocatechualdehyde attempt. Based on US patent 2975214, see attached file.
This uses bromine and aluminum to form a complex with the aromatic solvent (toluene or xylene work well, among certain others). Said complex is used to to demethylate the aryl ether (in this case vanillin), in situ.
Because elemental bromine is being used, overhead forced ventilation (or equivalent) is essential. I'm using a diy fume hood.

The reagent ratios used here are the same as per the patent, only rescaled to 0.0083. So instead of 600g bromine, this will use 5g bromine. All other reagents scaled accordingly.

General setup:


0.56 g Aluminum


5 g Bromine


Ice bath under RBF. Bromine addition to 25 ml toluene with 0.56 g aluminum already added, with good stirring. RBF glass stopper is loosened for pressure equalization during addition.
Temperature maintained at around 20 deg C. Whilst the reaction is exothermic, it was still very easy to maintain the temperature on this scale.
Addition was complete in about 2 minutes, then stirring was continued for another 50 minutes (until heat ceased to be evolved) to form the Al Br ArH complex with the toluene (complex is detailed in the patent). Xylene works fine also if toluene isn't available.
Patent doesn't mention reaction times, but I've found through experiment that its important to get the Al reacted before continuing with the next step. The finer the aluminum the better. Reaction rate is controlled by Br addition rate.



1.26 g vanillin crystals


Vanillin addition. Vanillin would not dissolve in 10 ml toluene, so ended up having to wash with extra toluene. In hindsight, I should have just added the vanillin in powder form, one scoop at a time to the RBF. Fumes aren't a problem at this stage, just a little HBr fuming. During addition temperature is maintained between 15 and 20 deg C. Some heat is released during this step, but it was easy to to control the temperature.


As per the patent, this mixture was maintained between 15 and 20 deg C, stirred for 1 hour. This is the demethylation reaction, methyl bromide is evolved.



Then afterwards heating applied and gradually brought up to about 90 deg C (patent calls for 100 deg C, but this seems to work). Then was stirred for another 20 minutes or so at 90 C, then allowed to cool.

Reaction complete and cooled to ambient temperature. Ready for workup.


Reaction mix is poured into a beaker with 83g ice and 2ml of 35% HCl (aq), with good stirring.


The purple mix soon changed to light amber when combined with the water. This due to the AlBr2 (attached to where the methyl used to be) decomposing in contact with the water, and then forming the protocatechualdehyde.

I'm not clear on why the patent calls for so much ice, I had to gently apply heat to melt the ice, not particularly exothermic.




Separate the two phases, naturally the toluene layer is on top.


Aqueous phase is extracted with dichloromethane (though the patent calls for diethyl ether, and then to evaporate the ether to yield oily protocatchualdehye)


The organic phase (toluene) is then extracted with 3 portions of 9 ml 5% NaOH solution. This pulls the majority of product.

Then those 3 extracts are combined, and acidified by adding several ml of 35% HCl, the solution color changes to a light brown solution as the protocatchualdehyde precipitates out. This was then covered with cling film and put in the freezer overnight.

Next morning.




0.55 grams crude protocatechualdehyde. This does not include the DCM extractions, since they haven't been worked up yet.


In conclusion, compared with the eugenol variation of this process (which I've already attempted nearly a dozen times on this same scale), this is a walk in the park. The patent appears to work, as claimed.
No emulsions, the phases separate immediately without any fuss, and altogether quite friendly. I'm sure this could easily be scaled up to any size within reason, the main downside obviously is it involves working with bromine.

Additionally, according to the patent most of the inorganic bromine can be recovered from the aqueous phase by acidifying and either oxidizing or gassing with chlorine. The patent claims that between the methyl bromide and inorganic bromide, the total recoverable bromine is 88-92% per cycle.

Attachment: Process for manufacture of protocatechuic aldehyde US2975214.pdf (394kB)
This file has been downloaded 404 times

[Edited on 18-9-2018 by CycloKnight]
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[*] posted on 18-9-2018 at 05:03


Nice to see you working on a sensible scale. You say the reaction was complete but provide no details as to how this was determined (TLC?)? You also provide no data to support your claim that the isolated solids were indeed the desired product, and that it was clean (melting point, TLC)?

I don't mean to demotivate, but merely to stimulate the use of good scientific principles.
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CycloKnight
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[*] posted on 18-9-2018 at 05:15


As for the eugenol variation, the reaction proceeds rather similarly until the workup, except the eugenol addition is much easier without the solids to contend with.
However, the aqueous/organic phase separation is very slow, there is some tar & aluminum sludge that sticks to the separating funnel walls which is a nuisance.

For the product extraction from the organic phase, when using 5% NaOH as for protocatechualdehyde, the product instantly turns to dark red sticky goop. Irreversibly so. Using K2CO3 instead, avoids the red goop, but final yields are nowhere near as high as with vanillin (protocatechualdehyde) I still haven't yet established whether its the product that's polymerizing with the NaOH, or whether its an impurity that's complicating this step. Steam distillation perhaps?

The extracted product might be the target hyroxychavicol (4-allylcatechol) but haven't positively identified it, and may not be able to isolate enough without first scaling up somewhat beyond 5 g bromine. One could only imagine an allyl protecting group for the eugenol making life a whole lot easier.



[Edited on 18-9-2018 by CycloKnight]
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[*] posted on 18-9-2018 at 06:47


Nice write-up.
Thanks for posting this up.
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CycloKnight
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[*] posted on 18-9-2018 at 09:32


Quote: Originally posted by DJF90  
You say the reaction was complete but provide no details as to how this was determined (TLC?)? You also provide no data to support your claim that the isolated solids were indeed the desired product, and that it was clean (melting point, TLC)?


No definitive claims at this stage, this is just a trial run for the scaled up runs later. I can't say whether the product is pure or not. No doubt there remains an element of faith still, however as the thread progresses we will find out whether the product is the target compound or not. All a work in progress.
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[*] posted on 18-9-2018 at 13:21


Pretty cool. I've been thinking about giving this a try for making dopamine. I wonder about the effect of increasing the amount of aluminum without increasing the amount of bromine.



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[*] posted on 18-9-2018 at 15:02


Have you seen the paper for AlI3/tetrabutylammonium? Xylene or toluene should substitute nicely for benzene.

Synthesis 1985; 1985(4): 437-439
DOI: 10.1055/s-1985-31235
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[*] posted on 18-9-2018 at 17:37


Quote:

For the product extraction from the organic phase, when using 5% NaOH as for protocatechualdehyde, the product instantly turns to dark red sticky goop. Irreversibly so. Using K2CO3 instead, avoids the red goop, but final yields are nowhere near as high as with vanillin (protocatechualdehyde) I still haven't yet established whether its the product that's polymerizing with the NaOH, or whether its an impurity that's complicating this step. Steam distillation perhaps?

The extracted product might be the target hyroxychavicol (4-allylcatechol) but haven't positively identified it, and may not be able to isolate enough without first scaling up somewhat beyond 5 g bromine. One could only imagine an allyl protecting group for the eugenol making life a whole lot easier.

Polymerization seems likely, the eugenol/AlCl3 reaction is notoriously difficult to work-up or perform, with tars being the major product of most attempts. A different strategy must be chosen for the extraction of the final product.

Protocatechualdehyde should polymerize less because the aldehyde draws electron density from the ring and adds a quinone-like enolized resonance structure. However this same resonance structure makes methylenation of protocatechualdehyde more difficult than other catechols.

Quote:
Using K2CO3 instead, avoids the red goop, but final yields are nowhere near as high as with vanillin (protocatechualdehyde)


For catechol, pKa1 = 9.45; pKa2 = 12.8. If we assume that the dianion of catechol is what causes the trouble -- because it is easily oxidized to a semiquinone radical -- then our goal should be to deprotonate the catechol one time, so it becomes water soluble, but not two times, to prevent oxidation and polymerization. Potassium carbonate does exactly that: carbonic acid's pKa2 is 10.3, which is enough to deprotonate catechol once but not twice.

The problem with K2CO3 is that it tends to reduce the solubility of organic compounds in water:

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

One possibility is instead to use milk of magnesia, which also has a pH of around 10.5, but which does not tend to salt-out organic compounds. The obvious disadvantage is that Mg(OH)2 is a heterogeneous base, so you cannot "wash" a solid residue with a magnesium hydroxide suspension.

Another possibility is to use an amine base, such as pyrrolidine (pKaH+ = 11.3), isopropylamine (pKaH+ = 10.7), diisopropylamine (pKaH+ = 11), methylamine (pKaH+ = 10.6), with ammonia being not preferable due to the negative effect of NH4+ on solubility. Which amine I leave up to you, but most small aliphatic amines qualify; aromatic amines tend to be weaker and less soluble, so they are not suitable.

Still another possibility is to use lithium or sodium carbonate, which have a slightly weaker salting-out effect than K2CO3.




[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 19-9-2018 at 07:57


Check out the workup in this patent.
CN107473916A
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clearly_not_atara
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[*] posted on 19-9-2018 at 08:07


"The addition of aluminum iodide (2.242g, 5.5mmol) to a IOOml eggplant-shaped flask, acetonitrile (40ml), potassium tert-butoxide (1.237g, ll.Ommol) and eugenol (0.819g, 5.0mmol) and heated to 80 ° C, stirring was stopped after 18 hours, cool to room temperature acidified by addition of 2mol / L dilute hydrochloric acid (IOml) eggplant type flask, and extracted with ethyl acetate (50ml X 3), the combined organic phases, washed first with saturated aqueous sodium thiosulfate (IOml), then saturated brine (IOml), dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated on a rotary evaporator, the residue was purified by flash column chromatography (eluent ethyl acetate / petroleum ether = 1: 4, volume ratio) to give 0.733 g crude 4-allyl-catechol, 4-allyl-catechol take crude (0.709 g) under reduced pressure sublimation oil Li to afford 4-allyl catechol 〇.681g (white waxy solid, 93% yield)."
There are methods on the forum for synthesizing acetonitrile and metal alkoxides, but hopefully you can buy them.

[Edited on 19-9-2018 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 19-9-2018 at 11:40


clearly_not_atara All very helpful, thanks. I hadn't properly considered that the K2CO3 might have been hindering the extraction.
Whilst there was a large amount of red tar with the NaOH extraction(s), it was far more than the total recovered product when using K2CO3 instead. The numbers didn't add up, that was why I was suspicious that possibly another impurity was involved with forming the tar.

I might revisit the eugenol variation in the next few days, run on a larger scale, sampling the product mixture and applying different work up strategies. Can't do any harm.

Yesterday I ran another vanillin demethylation attempt based on 50 g bromine, 12.6 g vanillin. I ran this one hotter towards the end and then accidentally overheated to about 120 deg C for a short while, but during the workup today I didn't note any obvious signs of degradation/tar. Solution is sparkling with crystals now, should find out the yield tomorrow.

Myr - I haven't read it yet but will check it out later when i get a chance, thanks for the suggestion.
Propenyl Guaethol, good find, the workup procedure may come in handy later.




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[*] posted on 19-9-2018 at 13:02


Might the OrgSyn preparation of catechol from guaiacol be useful here?

https://www.sciencemadness.org/whisper/viewthread.php?tid=29...




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[*] posted on 19-9-2018 at 13:33


Quote: Originally posted by myr  
Have you seen the paper for AlI3/tetrabutylammonium? Xylene or toluene should substitute nicely for benzene.

Synthesis 1985; 1985(4): 437-439
DOI: 10.1055/s-1985-31235


They used almost double the stoichiometric amount of aluminum. Using some extra aluminum sure beats halogenating the solvent....





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[*] posted on 19-9-2018 at 18:57


Quote: Originally posted by Magpie  
Might the OrgSyn preparation of catechol from guaiacol be useful here?

https://www.sciencemadness.org/whisper/viewthread.php?tid=29...
I think you might get 4-(2-bromopropyl)-catechol and/or a polymer. The bifunctional phenol/bromoalkane might polymerize upon basic workup.

For vanillin, HBr is known to work.




[Edited on 04-20-1969 by clearly_not_atara]
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CycloKnight
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[*] posted on 20-9-2018 at 02:00


One of my acidified aqueous solution extracts from the eugenol trials (5g bromine/0.56 g Al/1.36 g eugenol) was put in the corner of my work area several days ago with no lid and forgotten about.





Quite distinctive needles.
I'll put this aside for any future testing.
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[*] posted on 20-9-2018 at 09:10


Quote: Originally posted by clearly_not_atara  

For vanillin, HBr is known to work.


The guaiacol to catechol synthesis uses HBr, not Br2.




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[*] posted on 20-9-2018 at 13:57


I never said otherwise. 4-(2-bromopropyl)-catechol is the product of adding HBr to the double bond in eugenol. Whether the intermediate carbocation (if formed) would undergo other reactions is anyone's guess.



[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 20-9-2018 at 14:42


Quote: Originally posted by clearly_not_atara  
I never said otherwise. 4-(2-bromopropyl)-catechol is the product of adding HBr to the double bond in eugenol. Whether the intermediate carbocation (if formed) would undergo other reactions is anyone's guess.


Oh yeah... you could bring back a double bond with KOH I guess, but it might be in a different spot.




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[*] posted on 20-9-2018 at 16:55


I wonder what Pearl and Beyer of the JACS article thought about the patent they're mentioned by...maybe their AlBr3 was made by them that same way, just didn't explicitly say so...

Protocatechualdehyde.
A solution of 15.2 g. (0.1 mole) of vanillin in 45 ml. of nitrobenzene at 15° was treated with a solution of 53.4 g. (0.2 mole) of anhydrous aluminum bromide in 60 ml. of nitrobenzene at 10°. The gel which formed was stirred with 125 ml. of nitrobenzene, warmed on the steam-bath to 95°, and allowed to stand at room temperature for 30 minutes. The dark mixture was cooled and poured into 1 L of water containing a little hydrochloric acid. This mixture was extracted with ether, and the ether was extracted with 5% NaOH solution. The alkaline solution was washed with ether, acidified with dilute sulfuric acid, and extracted with ether. The ether was dried and distilled, leaving 12.8 g. (93%) of oily protocatechualdehyde which crystallized on cooling. Recrystallization from toluene gave colorless needles melting at 151-152° and not depressing a mixed melting point with authentic protocatechualdehyde.

JACS 75, 2630 (1953)




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[*] posted on 20-9-2018 at 19:24


I am trying eugenol demethylation using pyridine hydrochloride (Py.HCl).

This article studies demethylation rate at constant temperature, depending on time:

Schmid, Christopher R., et al. "Demethylation of 4-methoxyphenylbutyric acid using molten pyridinium hydrochloride on multikilogram scale." Organic process research & development 8.4 (2004): 670-673.

One problem with Py.HCl demethylation is large excess of it is needed and possibly a PTC. The above paper, however, shows that almost complete demethylation is possible in 5 hours at 190 °C with just 1.5 molar excess of Py.HCl and 1-2 hours with 4 molar excess.

They measured 4-Methoxyphenylbutyric Acid but I guess any methyl aryl ether will work.

I am waiting for an argon pressure regulator and then prepare Py.HCl, distill my eugenol and conduct the demethylation under inert atmosphere in a stoppered flask.

The reaction will be quenched with cold water and extracted with ether. The ether extract will be washed several times with water, dried and evaporated to hopefully yield hydroxychavicol (allylcatechol).
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[*] posted on 22-9-2018 at 20:42


Sexy colours! Nice work. We tried lots of ways to do this with vanillin and in the end the best result was using pyridine hydrochloride (still not a great yield, but might be better if we could get the reagent more dry - it's *insanely* hygroscopic). This method looks worth a try though.



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[*] posted on 23-9-2018 at 01:51


Chemplayer! I re-watched your attempt at vanillin demethylation with pyridine HCl. I wonder if the pyridine HCl could be dried with a Dean-Stark setup using toluene. Otherwise, I you could bubble HCl gas in pyridine.

Any new videos coming next?
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[*] posted on 23-9-2018 at 02:42


Reaction and decomposition temperatures are both much higher than boiling temperature of water, so by the time reaction starts most of the water is gone no matter how much there was on the begginning.
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[*] posted on 23-9-2018 at 06:27


It doesn't work like that. You still have to use anhydrous DMF (BP: 153 °C) and DMSO (BP: 189 °C) for reactions that fail in the presence of water. The water doesn't just boil off completely.

Same for ionic liquids (IL). Pyridine hydrochloride could be considered an ionic "liquid", melting at only 145 °C which is quite low for an ionic compound. The definition of an IL is arbitrary and varies a lot. A typical procedure for drying ILs is heating for several days at 100 °C under high vacuum.

I know you said "most" of the water is gone, my point is you cannot consider something dry by just heating it in the open above 100 °C.
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[*] posted on 23-9-2018 at 06:42


Pyridine hydrochloride turns from white crystals into slush in front of your eyes in under 10 seconds! It's the most extreme I've seen. Of course, it's just speculation that it's the water content which caused the low yield, but the toluene solvent and Dean-Stark trap is an excellent idea for a re-try.



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