Pumukli - 11-8-2024 at 06:01
Dear fellow amateurs,
I'm curious whether acylating amides (actually substituted N-acyl-anilines) with acyl-chlorides in the presence of AlCl3 (usual Friedel-Crafts way) is
possible?
Well, beyond the mere possibility, whether such route would be a good one?
My fear (maybe unsubstantiated) is that in the presence of AlCl3 some sort of "acyl wandering" would occur and would lead to mixed products:
Ar-N-Ac + RCOCl + AlCl3 -> RCO-Ar-N-Ac + Ac-Ar-N-COR + Ac-Ar-N-Ac + RCO-Ar-N-COR + possibly other crap
I could not find anything meaningful about this type of reaction while searching on the net, but I'd rather not waste precious acyl-chloride(s) and
AlCl3 to find out.
Could anyone cite a relevant article (or better: have personal experience with such reaction)?
Boffis - 12-8-2024 at 08:48
I seem to remember asking this question before and not getting any helpful responses but it must be said there are several similar reaction that would
suggest it is likely. Methylaniline rearranges to toluidines (o and p) under the influence of "metal halides" (the Reilly-Hinkinbottom reaction) and
acylated phenols rearrange to hydroxy acylbenzenes (Fries reaction).
It would be an interesting experiment to simply warm acetanilide with AlCl3 and see what happens. I am not sure how the liberated amine group will
stand up to the harsh reagents though. This may be the problem since its an obvious extension of the reactions cited above. I also wondered if the
Reilly-Hinkinbottom reaction would work with dialkylanilines; I don't know what the mechanism is and I guess it depends on whether or not the free
amine hydrogen is necessary for the reaction or not. And this is all before you add the acyl chloride.
Pumukli - 12-8-2024 at 12:11
Thanks Boffis!
I found this:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619038/
It is something similar but starts from a substituted trifluoro-acetamide. And they report that acyl-wandering does occur but not from the N. :-)
I don't know if trifluoro-acetamides can be used as models to simple acetamides though. They may posses some special properties that simple acetamides
don't and one can easily be mislead by the supposed analogous behaviour.
Oh no! According to this article 10.1002/1615-4169(20010129)343:1<71::AID-ADSC71>3.0.CO;2-J my idea is doomed!
Simple acetyl is not strong enough to decrease the basicity of N-H bond in the amide group for this reaction to work with AlCl3. Special, strongly
electron withdrawing groups are required (trifluoro-acetic as above or exotic ones as in this second article.)
AvBaeyer - 12-8-2024 at 19:23
The answer to Pumukli's question appears to be yes - acetanilides can be ring acylated under Friedel-Crafts-like conditions. However, the Lewis acid
is not AlCl3 which is shown not to work. More "exotic" catalysts are required. A relevant reference is:
doi.org/10.1002/1615-4169(20010129)343:1<71::AID-ADSC71>3.0.CO;2-J
Catalytic Friedel-Crafts Acylation of Aniline Derivatives
Shū Kobayashi, Ichiro Komoto, Jun-ichi Matsuo
Advanced Synthesis and Catalysis, 343, 71-74 (2001)
The article is available on SciHub.
I found it on Google: "friedel crafts reaction with n-acylated aniline"
Have a good read,
AvB