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Author: Subject: 4-Allylcatechol Methylenation
CycloKnight
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[*] posted on 13-2-2019 at 13:38
4-Allylcatechol Methylenation


A 4-allylcatechol methylenation reaction was attempted using the results from my latest eugenol demethylation procedure using aryl (AlBr2)HBr complex as demethylating reagent, which I believe is now yielding 4-allylcatechol at around 50% yield based on eugenol, give or take.

The methylenation method is similar to the method I used for protocatechualdehyde methylenation to piperonal I posted here in 2014, which itself was based on the procedure referenced in "The Methylenation of Catechols"
W. Bonthrone and J. W. Cornforth
J. Chem. Soc. (C), 1202-1204 (1969)

There are four main differences with the approach I'll be using here.
1) I'll be using potassium carbonate as base instead of hydroxide (I've tried using sodium hydroxide twice previously, with almost no yield and complete loss of 4-allylcatechol feedstock).
2) Instead of using an oil bath I'll be using a stirrer mantle and regulating the solution temperature by controlling the dichloromethane reflux, by adding or removing dichloromethane as needed. The reaction temperature being carefully monitored to maintain 125 - 130 C at all times.
3) Vigorous overhead stirring will be used here since there is some phase separation.
4) The base & 4-allylcatechol will not be premixed beforehand, they will be added separately, a squirt at a time down the leibig condenser, using two separate glass pipettes.

Also since 4-allylcatechol is oxygen sensitive and with the longer reaction time, argon atmosphere will be used.




Reagent ratios:
250 ml DMSO
55 ml dichloromethane

73.5 g K2CO3 (in 73.5 g dH2O)
68 g crude 4-allylcatechol crystal mass

Procedure
25 ml DCM (dichloromethane) is added to the DMSO in the 500 ml RBF, this is just enough to allow a good reflux at 125-130 C. The remaining 20 ml will be added as needed to maintain reaction temperature within the target range. Approximately 1 ml DCM will reduce the reaction temperature by a degree C, so it will be replaced as its slowly consumed by the reaction.

With solution temperature measurement and condenser fitted in place, heating and vigorous overhead stirring is turned on and allowed to reach reflux.

4-AC, DCM & K2CO3 addition solution.



The 4-AC is dark coloured due to some air exposure, all of my 4-AC samples/solutions rapidly turn pink, violet then blue (when anhydrous) when exposed to air. In the presence of moisture it would instead turn brown and eventually black. The 4-AC will be melted by gentle heating prior to addition.

With the refluxing RBF solution at 125 C (refluxing at ~2 drips/second), and the mantle on constant 80% heating, the addition is started with a few ml of the K2CO3, followed with about a ml of the 4-AC. Repeating a few times, then allowing to stir for 10 minutes, before continuing. Going slow, 3 hours was given for the addition, stirring until all DCM has been added, and with another 2 hours stirring after addition.

At about 90 minutes into the addition, a strong root beer odour was noted from the addition pipette(s).

Pipette addition was as far down the condenser as possible, to ensure the DCM reflux carries the reactants into the reaction mixture instead of accumulating solids in the condenser.


Nearing the end of the addition now.


The black marker lines represent the level before addition was started, to help judge the addition proportions.

Last of the 4-AC crystals, will be melted by gentle external heating with a hot air gun before addition with the pipette.


5 hrs in, reaction mixture is dark brown.


The whole reaction mixture was combined with tap water and steam distilled.
Pressure cooker was used to supply the steam.


The first product to come over was a little leftover dichloromethane, and then lots of free oil on the sides and sinking to the bottom.





A total of 1.7 L of condensate was collected, and 33 g of free oil (inside amber bottle). No solvent extraction was carried out on any of the condensate. Steam distillation was stopped at this point because there was a lot of waxy crystalline non-volatiles coming over and accumulating in the condenser, so it was assumed the target product was mostly distilled.


The 33 g of oil was then vacuum distilled.



First fraction, collected up to 116 C. Vacuum distillation was stopped to test the oil to decide when to change receivers. Pure root beer oil.


Second fraction, collected up to 125 C. Only 3 ml collected, possibly iso.


Third fraction collected from 125 C to 147 C when solids began accumulating in the condenser. Distillation was stopped at this point. Temperature increased rapidly after the second fraction, to 147 C, so am confident a clean fraction separation was achieved.

Fraction in receivers one and two were combined,
total isolated yield was 15.46 g of 5-allyl-1,3-benzodioxol. Seems quite pure but haven't confirmed purity yet.
The purity of the 4-AC was unknown so it remains impossible to calculate the exact molar yield.









[Edited on 14-2-2019 by CycloKnight]
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monolithic
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[*] posted on 13-2-2019 at 20:13


Another interesting write-up, thank you for your contributions. :) Just curious, have you taken a look at the paper I posted in your other thread, regarding eugneol demethylation with aluminum isopropoxide?
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DavidJR
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[*] posted on 14-2-2019 at 05:41


Errrrrrrrrr.... this looks a bit dodgy. It's only a hydroamination away from being MDMA.
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CycloKnight
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[*] posted on 14-2-2019 at 06:33


Allowing for impurities in the 4-AC, I'd estimate molar yield to be somewhere in the 25-30% region.
The reason for adding the base and 4-AC separately, is because when mixed (even with DMSO added) there is some phase separation, and the 4-AC low melting point (~49 C) makes it easy to melt and add in liquid in form without having to dissolve (as is needed with protocatechualdehyde).

The reason for avoiding the oil bath is because the oil is messy, and I've found from previous experiments that my DCM reflux method seems to work as well, but this will be tested later with more highly refined 4-AC. I've had purer 4-AC, but I'm afraid a lot of it was destroyed. Its sacrifice was not in vain however, as it has somewhat expanded my knowledge of what doesn't work as far as 4-AC methylenations go.

For the reactant concentrations used in this run, the reaction temperature increases by about a degree every 10 minutes, indicating about a ml of dichloromethane being consumed. It perhaps comes as no surprise that this is considerably slower than the hydroxide equivalent in DMSO (with protocatechualdehyde). Its important to maintain as high a dilution as is practicable, to maximize yields and minimize side products. So next time a suggestion might be to pace the 4-AC addition with the dichloromethane consumption. This would lengthen the reaction time somewhat, however.

Monolithic, I have - it looks interesting! There are a few demethylation routes that look to hold promise but tbh I've been that busy formulating this bromine method (optimizing rxn conditions, bromide recovery, etc) that I haven't yet tested any other routes since working on this one. This 4-AC method requires two days (with reagents in hand), one day to form the demethylating reagent, run the eugenol demethylation and hot hydrolysis. The second day to do the workup, involving solvent removal under vacuum (about 2 hrs) and the vacuum distillation collecting the 4-AC fraction.

I haven't quite finished the final writeup on the method yet but when I do I'll post the update on the eugenol demethylation thread.
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CycloKnight
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[*] posted on 14-2-2019 at 07:20


As an aside, this thread was intended in the interest and spirit of chemistry discussion only. Not interested in discussing any theoretical misuse of this (albeit synthetically replicated) wonderful naturally occurring substance and traditional root beer flavouring. I have it growing in my greenhouse, piper auritum. I posted a thread about it a while back.
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[*] posted on 14-2-2019 at 07:36


Quote: Originally posted by DavidJR  
Errrrrrrrrr.... this looks a bit dodgy. It's only a hydroamination away from being MDMA.


You're not the only one to think this. Spirit of chemistry discussion is all very well, and I'm sure CycloKnight is completely above board - he had a "knock on the door" a little while back - but I fear what our non-registered readers can make of this.




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CycloKnight
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[*] posted on 14-2-2019 at 07:54


Again, all very theoretical misuse. I see what you're saying but there are already far easier routes the non-registered users could use for such endeavours and with far higher yields. I'd be far more concerned about what they can do with benzaldehyde, available now on ebay for $50 per litre. I see nothing to fear here.
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[*] posted on 14-2-2019 at 12:32


Really nice work! I wonder why NaOH was such a problem. Possibly the anion is not so stable -- if the benzylic carbon is deprotonated, I could imagine an isomerization all the way to this:

quinone_methide.png - 5kB

Quote: Originally posted by DavidJR  
Errrrrrrrrr.... this looks a bit dodgy. It's only a hydroamination away from being MDMA.

Quick, describe an accessible Markovnikov hydroamination catalyst for unactivated terminal alkenes. You know, a little simpler than 2-dicyclopentylphosphino-2'-dimethylaminobiphenyl bis-1,5-cyclooctadiene rhodium (I) tetrafluoroborate.



[Edited on 14-2-2019 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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DavidJR
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[*] posted on 14-2-2019 at 12:39


Quote: Originally posted by clearly_not_atara  

Quote: Originally posted by DavidJR  
Errrrrrrrrr.... this looks a bit dodgy. It's only a hydroamination away from being MDMA.

Quick, describe an accessible Markovnikov hydroamination catalyst for unactivated terminal alkenes. You know, a little simpler than 2-dicyclopentylphosphino-2'-dimethylaminobiphenyl bis-1,5-cyclooctadiene rhodium (I) tetrafluoroborate.


Ok you got me, the easier way is to hydrobrominate first.

[Edited on 14-2-2019 by DavidJR]
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[*] posted on 14-2-2019 at 12:56


Can we please (again) stop the discussion about what should or should not be allowed to discuss on this forum? Again, I will quote Polverone.

Quote: Originally posted by Polverone  
It's probably spitting into the wind but I would like to remind everyone that the legal restrictions (or lack thereof) on possessing/manufacturing a substance has never been a reason for me to shut down discussions here. Hence the large, flourishing Energetic Materials section. I would actually enjoy more discussion of novel psychoactive substances here, or novel routes to popular materials. Much how I enjoy new substances or synthetic routes to energetic materials when they're discussed in the EM section. The USA has some of the most overbearing synthetic drug laws but some of the most permissive free speech laws in the world, so there is no risk to the forum or myself from discussing any chemistry here no matter how great the legal penalties might be if you get caught trying to implement said chemistry in your own home.

I don't like low-effort threads started by people who are apparently just looking for a quick way to get high or get rich. Nor do I like low-effort threads started by people who just want to make a big, impressive explosion without too much work. But I am never going to lock a thread just because it might be a felony to do the chemistry where I live, or where some other members live. Everything is fine to write about and some members may be more risk-tolerant or lucky enough to live in less legally uptight jurisdictions. The legal considerations, like the personal safety risks, are the responsibility and choice of the individual contemplating doing some chemistry.

So please, feel free to discuss synthetic routes to this ketamine metabolite or any other interesting molecule that crosses your mind.


Source

If anyone here thinks further discussion is necessary I propose you set up a new topic. Either we change the original idea of SM and change the rules on this forum, or people who don't like it either capitulate or leave.



[Edited on 14-2-2019 by Tsjerk]
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DavidJR
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[*] posted on 14-2-2019 at 13:16


Quote: Originally posted by Tsjerk  
Can we please (again) stop the discussion about what should or should not be allowed to discuss on this forum? Again, I will quote Polverone.

Quote: Originally posted by Polverone  
It's probably spitting into the wind but I would like to remind everyone that the legal restrictions (or lack thereof) on possessing/manufacturing a substance has never been a reason for me to shut down discussions here. Hence the large, flourishing Energetic Materials section. I would actually enjoy more discussion of novel psychoactive substances here, or novel routes to popular materials. Much how I enjoy new substances or synthetic routes to energetic materials when they're discussed in the EM section. The USA has some of the most overbearing synthetic drug laws but some of the most permissive free speech laws in the world, so there is no risk to the forum or myself from discussing any chemistry here no matter how great the legal penalties might be if you get caught trying to implement said chemistry in your own home.

I don't like low-effort threads started by people who are apparently just looking for a quick way to get high or get rich. Nor do I like low-effort threads started by people who just want to make a big, impressive explosion without too much work. But I am never going to lock a thread just because it might be a felony to do the chemistry where I live, or where some other members live. Everything is fine to write about and some members may be more risk-tolerant or lucky enough to live in less legally uptight jurisdictions. The legal considerations, like the personal safety risks, are the responsibility and choice of the individual contemplating doing some chemistry.

So please, feel free to discuss synthetic routes to this ketamine metabolite or any other interesting molecule that crosses your mind.


Source

If anyone here thinks further discussion is necessary I propose you set up a new topic. Either we change the original idea of SM and change the rules on this forum, or people who don't like it either capitulate or leave.


Actually, I guess that is a reasonable approach to take. I was just a bit concerned about how it might appear to outside observers. The chemistry is, indeed, interesting.

Perhaps I should post about my modafinil synthesis (which I will add is legal where I am)...
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Tsjerk
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[*] posted on 14-2-2019 at 13:24


Maybe a mod/admin could split all the mdma/benzaldehyde/Polverone/modafinil discussion to a separate thread, doing more honor to the really nice chemistry this thread should be about?

@DavidJR; I would love to see your modafinil synthesis!
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Tsjerk
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[*] posted on 14-2-2019 at 13:33


Quote: Originally posted by DavidJR  
(which I will add is legal where I am)...


Polverone clearly states in the quote above it doesn't matter whether or not it is legal in your jurisdiction. Nobody here could even tell whether or not it was because we don't know where you are.
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CycloKnight
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[*] posted on 15-2-2019 at 08:40


Quote: Originally posted by clearly_not_atara  
I wonder why NaOH was such a problem. Possibly the anion is not so stable -- if the benzylic carbon is deprotonated, I could imagine an isomerization all the way to this: <snip>


I'm curious also, if there was any tar generated then I certainly didn't notice it. I did observe of a lot of waxy crystalline product which appeared similar to what is also produced using the K2CO3 method (but as a side product) from early on in the steam distillation, indicating there was little methylenated product. I'd estimate there were just a few drops of methylenated product, from 58 g of 4-AC. Any more experiments with NaOH will be on the mmol scale.
It seems that the 4-AC didn't polymerise or get degraded, but only yielded a different main product, which would tie in with what you're suggesting.

Interestingly, the run with the 4-AC & NaOH was possibly going to be the SM post, so took lots of images.
Distilling the final fraction during the workup. The secondary still head saves a lot of agro by avoiding the condenser altogether (receiver just gets swivelled downwards when ready to collect the last fraction).




Fully crystallised.


Melted in preparation for the methylenation (purple caused by oxygen exposure)


Just a shame it didn't work with NaOH. When I get time to prepare more, I'll aim to use similar quality 4-AC and repeat the methylenation experiment.

[Edited on 16-2-2019 by CycloKnight]
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