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Author: Subject: Eschweiler-Clarke Procedure
UKnowNotWatUDo
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[*] posted on 10-3-2011 at 11:58
Eschweiler-Clarke Procedure


Anyone have a good procedure for an Eschweiler-Clarke methylation?Things like reaction temps/times. What kind of molar ratios should the formic acid/formaldehyde be in relative to the amine. Does it proceed smoother whether the amine is in the base or protonated form or does it not matter? Any information, especially first hand experience, would be greatly appreciated.
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antibody
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[*] posted on 10-3-2011 at 13:53


et voila!

http://www.erowid.org/archive/rhodium/pdf/eschweiler-clarke....
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sentinel097
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[*] posted on 5-8-2011 at 20:47


Does the Eschweiler-Clarke reaction apply to simple amides as well as amines? I can't imagine why it wouldn't, but what do I know?
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UKnowNotWatUDo
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[*] posted on 5-8-2011 at 20:58


I know it is possible, yes. I don't have the article in front of me at the moment but there are several examples of it succeeding with amides. However there are also many more examples of it failing I'm afraid.
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[*] posted on 6-8-2011 at 02:19


The reaction is done simply by heating a primary or secondary amine with slight excess of formaldehyde in 85% formic acid as solvent and reagent at 100 C until the CO2 effervescence slows down (generally it takes no more than a couple of hours).

There are thousands of examples in the literature, so it would be pointless to give an example, but there is one focused on pedagogic aspects in J. Chem. Educ. (DOI: 10.1021/ed045p118).
By UTFSE, other references can be found on this forum.
Quote: Originally posted by UKnowNotWatUDo  
I know it is possible, yes. I don't have the article in front of me at the moment but there are several examples of it succeeding with amides. However there are also many more examples of it failing I'm afraid.

I never saw anything of this kind mentioned in any of the review articles on the topic, so please find those references. I can imagine that N-deformylative Eschweiler methylations of N-alkylformamides to give tertiary amines might be possible under some conditions, but I never saw an Eschweiler N-methylation of an amide to give an N-methylamide. I can't imagine why it would work, but what do I know?




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[*] posted on 6-8-2011 at 04:32


Quote: Originally posted by Nicodem  
I never saw anything of this kind mentioned in any of the review articles on the topic, so please find those references. I can imagine that N-deformylative Eschweiler methylations of N-alkylformamides to give tertiary amines might be possible under some conditions, but I never saw an Eschweiler N-methylation of an amide to give an N-methylamide.


Me either.

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I can't imagine why it would work, but what do I know?


I'm sure thats not strictly true Nicodem ;)


[Edited on 6-8-2011 by DJF90]
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sentinel097
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[*] posted on 6-8-2011 at 13:33


Just to be abundantly clear, you're saying that methylation of primary amides isn't possible, that it may be possible on secondary amides, or that it's simply not possible to stop the methylation of a primary amide at the secondary amide stage? The latter makes perfect sense given my limited knowledge of the reaction, but I don't see why one little oxygen atom with no direct attachment to the reacting group would inhibit it's reactivity.

[Edited on 6-8-2011 by sentinel097]
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[*] posted on 6-8-2011 at 15:00


Quote: Originally posted by sentinel097  
Just to be abundantly clear, you're saying that methylation of primary amides isn't possible, that it may be possible on secondary amides, or that it's simply not possible to stop the methylation of a primary amide at the secondary amide stage?

I'm saying nothing of that. I said I never saw a single example of an Eschweiler-Clarke type of N-methylation of any amide whatsoever. That's why I made a call for a reference.
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I don't see why one little oxygen atom with no direct attachment to the reacting group would inhibit it's reactivity.

In organic chemistry the reactivity is all about some "atom with no direct attachment to the reacting group".
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[*] posted on 6-8-2011 at 18:57


Of course, that's what I thought you meant. Assuming my understanding of probability theory is more solid than my ability to comprehend the countless ramifications of organic chemistry, I think it's safe to say that someone must have tried it at some point, so the lack of reported results would indicate beyond a reasonable doubt that the likelihood of it working is rather slim. In contrast, the likelihood of any attempts to verify this hypothesis resulting in wasted reagents is dramatically greater. These things are never simple, are they?
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[*] posted on 6-8-2011 at 22:07


Ah, my bad. I was remembering the article sightly wrong. It described the N-alkylation of amides using formaldehyde and was compared to the eschweiler-clarke procedure, however the hydrogen source was molecular hydrogen and they utilized a Pd/C catalyst. Sorry sentinel097 for any confusion I may have caused you.

Never the less if your interest lies in N-alkylation of an amide the article may prove useful to you still. Google "Extension of the eschweiler-clarke procedure to the N-alkylation of amides" and you will find it.
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[*] posted on 7-8-2011 at 14:53


Ah, much obliged. So it's possible, but not simple by any means. I rest my case.
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[*] posted on 7-8-2011 at 14:55


Quote: Originally posted by UKnowNotWatUDo  


Never the less if your interest lies in N-alkylation of an amide the article may prove useful to you still. Google "Extension of the eschweiler-clarke procedure to the N-alkylation of amides" and you will find it.


Extension of the eschweiler-clarke procedure to the N-alkylation of amides
Fabienne Fache, Laurent Jacquot, Marc Lemaire
Tetrahedron Letters,
1994, Volume 35, Issue 20, Pages 3313-3314
doi:10.1016/S0040-4039(00)76894-8
http://www.sciencedirect.com.pbidi.unam.mx:8080/science/arti...

...make your request for it at the Reference section...solo




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ThatchemistKid
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[*] posted on 9-8-2011 at 08:38


The electron density around an amide nitrogen is nothing like that around an amine nitrogen's... amides are generally not very nucleophilic and usually have to be deprotonated to react.
the amide carbonyl bond has partial double bond character and the electron density is shifted a bit more towards the carbonyl carbon in the case of the amide instead of pushed towards the nitrogen in the case of the amine...that is why it will not react (atleast to my knowledge) in this reaction.

[Edited on 9-8-2011 by ThatchemistKid]

[Edited on 9-8-2011 by ThatchemistKid]

oh and one more thing that one little oxygen atom not attached to the nitrogen is a big deal in this case it is causing carbon next to the nitrogen to have low electron density ..diminished MO lobes and it is having a field affect on the nitrogens electron density sucking it away and because of the lone pairs on the nitrogen and the double bond of the oxygen to the carbon this atom has a couple resonance structures that are major contributers ...funny what one little oxygen atom can do while not being attached to the nitrogen.

[Edited on 9-8-2011 by ThatchemistKid]
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