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Author: Subject: Extension of the Eschweiler-Clarke alkylation
njl
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[*] posted on 2-2-2020 at 11:03
Extension of the Eschweiler-Clarke alkylation


Why can't the EC alkylation be performed with longer main-chain acids? The procedure calls for Formic acid and ends with the methylation of an amine, but why can't something like Acetic/Propanoic/etc. be used in play of Formic acid?
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UC235
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[*] posted on 2-2-2020 at 11:30


The formic acid serves as reducing agent and is oxidized to CO2 in the process. Longer chain acids are incapable of donating the necessary hydride equivalent and are redox-inactive.
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njl
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[*] posted on 2-2-2020 at 11:52


Thanks. Why exactly can't longer acids be oxidized?

Edit: I don't suppose the addition of something like NaBH4 would allow the reaction to proceed with longer chain acids?

[Edited on 2-2-2020 by njl]
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DavidJR
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[*] posted on 3-2-2020 at 06:47


What are you trying to achieve? The methyl groups being added to the amine come from the formaldehyde, not the formic acid...
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njl
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[*] posted on 4-2-2020 at 06:46


I was just under the impression that the methyl groups came from the acid. Looking back that was a silly mistake, so my bad. My question still stands though, although now with longer aldehydes. The reason I ask is because I can't find anything about substituting the formaldehyde with longer chains, but I don't know why substitutions would drastically affect the reaction (I'm assuming substitutions won't work, just because I can't find anything that takes advantage of the reaction with longer aldehydes).
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4-2-2020 at 09:47
DavidJR
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[*] posted on 5-2-2020 at 07:34


I don't see why it wouldn't work with, e.g. acetaldehyde, but I haven't tried it.
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clearly_not_atara
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[*] posted on 5-2-2020 at 08:52


It does not work with aldehydes other than formaldehyde, due to acidic aldol condensations.

It does not work with acids other than formic, because the formyl CH donates the required electrons and other acids have alkyl chains in this place.




[Edited on 04-20-1969 by clearly_not_atara]
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Metacelsus
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[*] posted on 5-2-2020 at 09:52


Hmm, what about something non-enolizable, like benzaldehyde? Formic acid + benzaldehyde + amine might give a benzylamine.

In the case where the amine is ammonia, this is the Leuckart reaction. See here: https://pubs.acs.org/doi/abs/10.1021/jo01188a006

There are examples of using formic acid as a transfer hydrogenation reagent to reduce imines in presence of a catalyst (eg. https://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b00889). I'm not sure it would work without the catalyst, though.

[Edited on 2020-2-5 by Metacelsus]




As below, so above.
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