Adas
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Alkylation questions
Hello SM,
I have a few questions, I've been doing a few experiments and I'm not sure what's going on so maybe you could clarify.
Let's start with the simple one. I dissolved phenethylamine HCl in ethanol and wanted to N-ethylate it. I made an HCl generator and dissolved HCl gas
in the ethanolic solution, then boiled the solution for a few minutes. This was then poured onto a heater to dry and there was a clear smell of EtCl
and HCl. The problem is, I have no way to test whether the reaction worked. Basically it behaves pretty much like normal PEA HCl.
Do you think that boiling an ethanolic solution of PEA HCl and EtCl causes alkylation? Most people I've asked are pretty sure it works very well. I
assume the quartenary salt was created.
Another one is a bit tricky. I was trying to make DET (diethyl tryptamine) from tryptophan. As you know, decarboxylating tryptophan is tricky and
produces many side-products, so I've decided that I would alkylate it first. I used the same method as above, so I should theoretically be left with
fully N-ethylated tryptophan chloride (quartenary salt).
Then I wanted to decarboxylate it, and assumed that it could be done in NaOH solution. Firstly the ethanol would leave (tertiary amine would be
created), and then it would decarboxylate. But I was left with mixed results. When I first tried boiling it with NaOH, the solution was clear and
smelled of tryptamines. The other time, when NaOH dissolved in the alkylated Trp solution, it became milky. After a bit of heating, it started
behaving like a lava lamp. The white percipitate melted together and became brownish. After even more heating, it dissolved completely.
This leads me to think that the carboxylic group was esterified for some reason, the oil was the freebase ester, which was de-esterified by the NaOH
and sodium salt of the diethyl-Trp was dissolved in the solution. No decarboxylation after that. Is it normal that the Trp was esterified? And how
could I decarboxylate the product (diethyl-Trp sodium salt)? My friend suggested a non-polar solvent, but that would require the free form, not the
sodium salt, and that would be tricky to get, you know.
Also, could melatonin be alkylated that way? It's an amide but something tells me it should work.
Any help is appreciated.
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Crowfjord
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It is doubtful that any useful amount of ethyl chloride was formed merely from reaction of ethanol with HCl. Synthesis of alkyl chlorides from
primary, non-benzylic alcohols requires catalysis by zinc chloride. Further, even if a fair amount of ethyl chloride had been produced, it would not
have reacted with the amine, as protonated amines are not particularly nucleophilic. That, and alkyl chlorides react fairly slowly in alkylations at
ambient temperature and pressure.
In your tryptophan experiment, you probably did esterify some tryptophan. With the sodium hydroxide treatment, the ester probably hydrolysed,
polymerized, oxidized, etc.
If you want to try alkylations, I would suggest making ethyl bromide (search the board or Rhodium). Add this to a neutral solution of your amine, or
better yet, use a non-nucleophilic base.
If you want tryptamine derivatives, decarboxylate tryptophan first. It is not very hard, there are some good threads on sciencemadness on the subject.
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Adas
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Quote: Originally posted by Crowfjord  | | Further, even if a fair amount of ethyl chloride had been produced, it would not have reacted with the amine, as protonated amines are not
particularly nucleophilic. That, and alkyl chlorides react fairly slowly in alkylations at ambient temperature and pressure. |
The EtCl smell was strong. But even salts must be nucleophilic enough to react with EtCl. Everywhere you look people report that their main problem
with alkylations is the formation of quartenary salt. Which means they were alkylating a salt already. Second thing - it didn't react at ambient
temperature. As I said, I boiled it for several minutes while holding some pressure in the test tube.
Tryptophan decarboxylation requires xylene which I do not have. I've tried toluene but not only it didn't work, but the toluene was literally
EXPLODING in the flask even on low heat. It was really scary. And as I said, lots of side products is created in the process (ketimines etc.).
Anyways, thanks for your answer.
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turd
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| Quote: Originally posted by Adas | | Everywhere you look people report that their main problem with alkylations is the formation of quartenary salt. Which means they were alkylating a
salt already. |
This makes no sense. The quat is a salt, but the tertiary amine is not a salt.
NR<sub>3</sub> + RX --> NR<sub>4</sub><sup>+</sup> + X<sup>-</sup>
If you carefully read the various TiHKAL entries you will find that Shulgin always uses a (sterically hindered) base.
| Quote: | | I've tried toluene but not only it didn't work, but the toluene was literally EXPLODING in the flask even on low heat. It was really scary.
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I fear even the boiling point of xylene is too low for a decent reaction rate. Forget about toluene. Toluene was certainly not exploding (huh?).
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Bot0nist
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Bumping, I'm sure.
U.T.F.S.E. and learn the joys of autodidacticism!
Don't judge each day only by the harvest you reap, but also by the seeds you sow.
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Adas
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Turd, I meant for example when you want to di-alkylate something. After the first alkylation it's already a salt but the alkylation tends to proceed
further. Sterically hindered base? What for?
Toluene was exploding. Like local overheating, you know. That kind of stuff. That's why I think that the amino group must be protected first.
Bot0nist, what are you sure about? Care to explain what your post was supposed to mean?
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Luderlasse
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| Quote: Originally posted by Adas | Turd, I meant for example when you want to di-alkylate something. After the first alkylation it's already a salt but the alkylation tends to proceed
further. Sterically hindered base? What for?
Toluene was exploding. Like local overheating, you know. That kind of stuff. That's why I think that the amino group must be protected first.
Bot0nist, what are you sure about? Care to explain what your post was supposed to mean? |
No its not a salt after first alkylation, only the alkylation of the tertiary amine results in a quartinary salt.
The sterically hindered base is useful because otherwise alkylation of your base will occur. DIPEA is commonly used for this.
Your toluene was not exploding, what occurred is sometimes called bumping. It can be prevented by magnetic stirring or boiling stones.
[Edited on 26-6-2015 by Luderlasse]
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turd
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And to add to this: The whole point of adding a base is to remove the HX formed by the alkylation reaction.
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Adas
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| Quote: Originally posted by Luderlasse |
No its not a salt after first alkylation, only the alkylation of the tertiary amine results in a quartinary salt.
The sterically hindered base is useful because otherwise alkylation of your base will occur. DIPEA is commonly used for this.
Your toluene was not exploding, what occurred is sometimes called bumping. It can be prevented by magnetic stirring or boiling stones.
[Edited on 26-6-2015 by Luderlasse] |
Oh so, for example, N-ethylphenethylamine hydrochloride is NOT A SALT? :O And the formation of a quartenary salt is probably the least of my problems.
Easily removed with NaOH.  Thanks for the suggestion anyway.
You call it bumping, I call it exploding. That's all. But boiling stones did not prevent it. It was weird as hell, never saw a liquid bump like that
before.
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Crowfjord
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The way I understood your first post, you had an ethanolic solution of amine, to which you then added HCl. If ethyl chloride formed, the amine salt
probably formed first. If you had added ethyl chloride to a neutral solution of amine, then some alkylation would occur because some amine would get
alkylated, while remaining amine would still be in base form to scavenge the formed HCl, allowing more alkylation to occur. It is in this way that
over alkylation happens. Since you started out with an acidic solution, though, I think it is unlikely that much, if any N-alkylation occurred in that
mix.
[Edited on 26-6-2015 by Crowfjord]
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Adas
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And I finally thought I have figured out a good way to do alkylations... I will try it once more though, with NH4Cl. If it's alkylated, it smells very
differently from ammonia.
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zed
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You mentioned N-Alkylating your Tryptamine, and then decarboxylating it. This might or might not, be easy. Such decarboxylations usually take place
through an imine intermediate. A di-alkylated tryptamine, cannot form an imine.
Not to say it cannot work. Just that it cannot work the way this decarboxylation usually works......via ketone catalyzed, imine formation, and
subsequent moderate temperature, thermal decarboxylation.
[Edited on 27-6-2015 by zed]
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