PapaFranku4647
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Seeking Advice on Demethylation of Methoxy-Substituted Compounds
Hi everyone,
I'm looking into methods for demethylating methoxy-substituted compounds and was hoping to get some input from those with hands-on experience.
Specifically, I'm interested in converting melatonin to n-acetylserotonin. I've come across a few sources suggesting that Boron Tribromide (BBr₃)
can be effective for this transformation, but I’ve also heard that it can be quite a pain to actually handle.
Has anyone successfully carried out a demethylation of these kinds of compounds using BBr₃ or something similar? Any insights, tips, or literature
recommendations would be greatly appreciated.
Thanks in advance for your help!
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bnull
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Take a look at procedures 8 and 10 (p.376) from Greene's Protective Groups in Organic Synthesis, 4th edition. I'm including other procedures in case
there's something else you want to try.
Attachment: Cleavage of methyl aryl ethers from Greene's Protective Groups (4th ed.).pdf (123kB)
This file has been downloaded 55 times
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PapaFranku4647
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Quote: Originally posted by bnull  | Take a look at procedures 8 and 10 (p.376) from Greene's Protective Groups in Organic Synthesis, 4th edition. I'm including other procedures in case
there's something else you want to try.
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Thanks for the literature! I'm frustrated because all these methods involve reagents that are difficult to acquire and equally challenging to work
with. What do you think would be the easiest way to achieve something like this in a home lab, both in terms of obtaining the chemicals and using
them, even if it means sacrificing efficiency?
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bnull
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It depends. Is it for human consumption?
Edit: Typo.
[Edited on 22-2-2025 by bnull]
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PapaFranku4647
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No, it's part of a two-step procedure in a project I'm doing. The project involves converting melatonin to serotonin.
The first step is the demethylation of melatonin to N‑acetylserotonin, and the second step is the deacetylation of N‑acetylserotonin to serotonin.
I'm currently in the research phase. This project will serve as a proof of concept for a video (think of it like what NileRed or Chemdelic does with
projects, such as "Turning sleeping pills into serotonin to bring joy to my life," or another catchy title)
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bnull
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Yeast would probably be the cheapest and most accessible. I remember reading about demethylation using enzymes from yeast (good old Saccharomyces
cerevisiae?) or bacteria. Don't ask me where, I didn't save that info.
Again, take a look at those other procedures; there are at least other 3 that are feasible in a home lab with reasonable (in terms of price and
handling) reagents. Ceric ammonium nitrate/sodium dithionite, for example, although it may work only with para-dimethoxy aromatics, who knows.
By the way, how are you going to verify it is serotonin?
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PapaFranku4647
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| Quote: Originally posted by bnull | Yeast would probably be the cheapest and most accessible. I remember reading about demethylation using enzymes from yeast (good old Saccharomyces
cerevisiae?) or bacteria. Don't ask me where, I didn't save that info.
Again, take a look at those other procedures; there are at least other 3 that are feasible in a home lab with reasonable (in terms of price and
handling) reagents. Ceric ammonium nitrate/sodium dithionite, for example, although it may work only with para-dimethoxy aromatics, who knows.
By the way, how are you going to verify it is serotonin? |
I'm planning to verify it using a melting point test since the melting points for melatonin (117°C) and serotonin (167°C) are quite different.
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bnull
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I have the impression I saw something about a substitution involving an ether and an alcohol, more specifically an alkyl aryl ether and an alkyl
alcohol, the products being a phenol and an aliphatic ether:Ar−OMe+R−OH→Ar−OH+R−OMe.
The aliphatic ether, being more volatile than
the phenol, would be easily removed from solution. I'll see if I can find it again.
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PapaFranku4647
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| Quote: Originally posted by bnull | | I have the impression I saw something about a substitution involving an ether and an alcohol, more specifically an alkyl aryl ether and an alkyl
alcohol, the products being a phenol and an aliphatic ether:Ar−OMe+R−OH→Ar−OH+R−OMe.
The aliphatic ether, being more volatile than
the phenol, would be easily removed from solution. I'll see if I can find it again. |
That sounds pretty good actually. Would this be a nucleophilic substitution mechanism? This sounds much more accessible than some other methods.
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Texium
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I'm skeptical of the alcohol method being effective. If that worked, we should see methyls falling off of methoxy-substituted arenes when refluxing in
methanol or ethanol... which definitely doesn't happen.
On the other hand, if you want to figure out how to make sodium methanethiolate, it's a very effective (but smelly) reagent for demethylating aryl
methyl ethers:
Attachment: Sodium methanethiolate.pdf (68kB)
This file has been downloaded 38 times
[Edited on 2-26-2025 by Texium]
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bnull
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Me too. I just glimpsed the abstract and filed it for later as usual. It probably required some non-OTC catalyst. It was a reference given by a
reference given by March's or Greene's. Too sick to remember or to comb my search history now.
Anyway. March's Advanced Organic Chemistry, 7th ed., section 10-49 (Formation of Alkyl Halides from Ethers), page 504:
| Quote: |
Ethers can be cleaved by heating with concentrated HI or HBr. Hydrogen chloride is seldom successful, and HBr reacts more slowly than HI, but is often
a superior reagent, since it causes fewer side reactions. Phase-transfer catalysis has also been used, and 47% HBr in ionic liquids has proven
effective. Dialkyl ethers and alkyl aryl ethers can be cleaved. In the latter case, the alkyl–oxygen bond is the one broken. As in Reaction 10-48,
the actual leaving group is not OR'-, but -OHR'. Although alkyl aryl ethers always cleave so as to give an alkyl halide
and a phenol, there is no general rule for dialkyl ethers. |
Attachment: more_ether_cleavage.pdf (227kB)
This file has been downloaded 28 times
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Lionel Spanner
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According to DOI 10.1021/ol0349965, IBX can be used for demethylation of methyl phenyl ethers at room temperature in THF - like ceric ammonium
nitrate, it results in a quinone, which can be then be reduced with sodium dithionite.
Apparently it works less well with electron-poor rings, and it can also be quite hit and miss, depending on the nature of the substrate. If there are
benzylic alcohols present, or allyl alcohols conjugated to an aromatic ring (e.g. cinnamic alcohol) it will oxidise them to aldehydes instead.
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PapaFranku4647
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I think I'm actually going to use 47% HBr. It's much more obtainable (sulfuric acid + bromine salt) and it doesn't seem nearly as bad to work with as
BBr3. It also seems, from literature, that it is quite effective at cleaving aryl methyl ethers.
Here are some examples of HBr O-Demethylation in patents:
http://commonorganicchemistry.com/Rxn_Pages/O_Demethylation/...
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Texium
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In your case, HBr may be ideal. If your goal wasn't to make serotonin, you'd have to worry about hydrolysis of the amide, but since you want that to
happen anyway, use an excess and heat it strongly, and maybe you can get to it in one pot!
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Dope Amine
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Phosphoric acid + NaBr is a better way to make HBr/acetic acid because it won't make Br2.
Add to a RBF glacial acetic acid, and a 1:1 molar ratio of NaBr and H3PO4. Attach air condenser (Vigreux column) and then
attach to the top of the air condenser a barbed tubing adapter with tubing running to a mineral oil bubbler. Heat to 115°C for 6 hours. NaBr will
start dissolving as temp increases and then color will start to change to yellow at about 80°C.
Strangely I didn't observe any increase in pressure during the entire reaction and I've actually done the reaction with a stopper on the condenser,
but the mineral oil bubbler is still recommended for safety and protection from moisture.
After 6 hours turn off the heat. Once the rm has reached room temperature (or maybe refrigerator temperature if you want) the previously chunky NaBr
will have been replaced by fine NaH2PO4. Decant off your HBr/AcOH solution.
To demethylate aryl methyl ethers use 1 molar equivalent of boric acid to achieve the conversion under more gentle reaction conditions (less heat,
less byproducts).
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