Sciencemadness Discussion Board

Eschweiler-Clarke for Ethyl or Propyl groups

fajahadita - 21-1-2007 at 22:41

Does anyone think that ethyl or propyl groups could be added to a primary amine to form a tertiary without forming quarternary salts by using a modified version of this reaction??

Assuming the imine is still formed by the formic acid do you think it's possible to replace formaldehyde with ethanal or propanal to form ethyl or propyl groups??

Furch - 21-1-2007 at 23:12

I don't see a difference between this reaction and other reductive aminations? It's just that the Eschweiler-Clarke uses formic acid as the reducing agent, instead of Al, NaBH4 or the like...

The question is whether formic acid will reduce the ethyl-imine and the propyl-imine, and my guess is that it will. It's just a hunch, so go look it up somewhere to confirm it.


- Furch

Nicodem - 22-1-2007 at 12:43

The Eschweiler-Clarke reaction using aldehydes/ketones other than formaldehyde becomes called the Leuckart reaction or the Leuckart-Wallach reaction. Due to the lower reactivity of non-formaldehyde carbonyl compounds, it requires temperatures as high as 150-180°C while the Eschweiler-Clarke reaction proceeds at bellow 100°C already. The Leuckart reaction with aldehydes containing alpha-hydrogens generally gives crap. It does however work on many ketones, very often even if they contain alpha-hydrogens. It works best with a mixture of formamide with some formic acid or else ammonium formate for aminations equivalent to reductive aminations with NH3. With alkyl amines in formic acid it also works but less effectively since it is preferable to use a great excess of the amine for better yield (which becomes quite difficult with large amines).

solo - 22-1-2007 at 13:21

Here is a nice method ,save one needs a closed vessel to do this reaction however I wonder if the alkylation of the amine will change the izomerization and also if it will affect OH groups ....although in the study there was an amine alcohol and it seems to have survived.......solo

--------------------------------------------------------------------------------------

A SOLVENT-FREE AND FORMALIN-FREE ESCHWEILER-CLARKE METHYLATION FOR AMINES
Thomas Rosenau,1 Antje Potthast,1 Ju¨ rgen Ro¨ hrling, Andreas Hofinger,1 Herbert Sixta,2 and Paul Kosma
SYNTHETIC COMMUNICATIONS, 32(3), 457–465 (2002)


Abstract
Primary and secondary amines are N-methylated by a mixture
of paraformaldehyde and oxalic acid dihydrate in good to
excellent yields. The reaction proceeds without involvement
of organic solvents and toxic formalin. Reaction temperatures
of 100 C are required for the decomposition of oxalic acid
into the intermediate formic acid which acts as the actual
reductant. The reaction conditions have been optimized, and
the mechanism has been elucidated by means of deuteration
experiments.

Attachment: A Solvent-Free and Formalin-Free Eschweiler-Clarke Methylation for Amines.pdf (137kB)
This file has been downloaded 6204 times

Nicodem - 30-3-2007 at 01:49

Quote:
Originally posted by Nicodem
The Leuckart reaction with aldehydes containing alpha-hydrogens generally gives crap.

I must correct myself in that this generality is not as wide as I thought. Some aldehydes with alpha-hydrogen(s) do give moderate to good yields in the Leuckart reaction as long as the amines used are secondary (see attachment).

The Behavior of Aliphatic Aldehydes in the Leuckart-Wallach Reaction.
Peter L. de Benneville, Jane H. Macartney
J. Am. Chem. Soc., 72, (1950) 3073-3075.

Attachment: The Behavior of Aliphatic Aldehydes in the Leuckart-Wallach Reaction.pdf (346kB)
This file has been downloaded 1815 times

solvent free Eschweiller-Clarke

chemrox - 30-3-2007 at 19:40

I shouldn't comment after so quick a read but I wanted to ask, is the main reason for using oxalic acid in place of formic to be "greener?" Because, as Solo points out, higher temps are need to break up the oxalic to generate the formic you still need.

The other question was, and this may be a really dumb one, besides unsaturated rings systems as in the case of benzaldehyde, what aldehydes don't have alpha hydrogen?

not_important - 30-3-2007 at 20:34

Quote:
Originally posted by chemrox
I shouldn't comment after so quick a read but I wanted to ask, is the main reason for using oxalic acid in place of formic to be "greener?" Because, as Solo points out, higher temps are need to break up the oxalic to generate the formic you still need.


The main point is no free formaldehyde, the source of CH2 to become CH3, and a somewhat unpleasant material.

Concentrated formic acid is a drag to keep around, it slowly decomposes into water and carbon monoxide. Bottles of it have been known to explode as a result of the pressure buildup, so now they generally have a pressure release vent in the cap. Formic acid is not as pleasant to measure out as oxalic acid is, same goes for formalin vs paraformaldehyde.

The 100 C temperature isn't that different than needed anyway.
Quote:
The other question was, and this may be a really dumb one, besides unsaturated rings systems as in the case of benzaldehyde, what aldehydes don't have alpha hydrogen?


Take acetaldehyde, look at the methyl group. Replace each hydrogen there with a methyl group, so you get (CH3)3C-CHO

chemrox - 31-3-2007 at 00:35

Quote:
Concentrated formic acid is a drag to keep around, it slowly decomposes into water and carbon monoxide. Bottles of it have been known to explode as a result of the pressure buildup, so now they generally have a pressure release vent in the cap.


how should I store mine?
Quote:

Take acetaldehyde, look at the methyl group. Replace each hydrogen there with a methyl group, so you get (CH3)3C-CHO


OIC yeah it was a dumb question-thanks for straightening me out

not_important - 31-3-2007 at 01:11

Quote:
Originally posted by chemrox
how should I store mine?


How concentrated? Bought or made?
Purchased formic acid is likely to have a pressure relief cap. Acid with a strength of 90% or less doesn't appear to be a problem; the reports talk about 98% and above. I imagine that keeping the formic acid cool will reduce the decomposition rate.

more info:

http://info.anu.edu.au/hr/OHS/Hazard_Alerts/_Formic_Acid_Exp...
Quote:
OIC yeah it was a dumb question-thanks for straightening me out


"Where are my car keys", waving about the hand holding the car keys.

Sometimes you need to step back from a problem, or set it aside, to see the answer.

chemrox - 31-3-2007 at 07:21

my formic is commercial and is unopened so far .. cool storage away from the lab is possible .. I like the car key analogy ;^)

postart - 7-1-2011 at 18:48

Quote: Originally posted by Furch  
I don't see a difference between this reaction and other reductive aminations? It's just that the Eschweiler-Clarke uses formic acid as the reducing agent, instead of Al, NaBH4 or the like...


- Furch


I thaught the Eschweiler-Clarke was for N-methylation are you saying that it can be used to reduce ketones to amines? Sherly Im misunderstanding your statement?

postart - 9-1-2011 at 15:50

Has anyone ever heard of oxalic acid being used as a hydride donor for imine formation for reductive amination? Theoretically the oxalic acid could dissociate giving two hydrides. One mole oxalic acid for two moles of ketone with an excess of the amine. Does this sound feasable? I couldn't find any references of this ever being done.

UnintentionalChaos - 9-1-2011 at 20:12

Quote: Originally posted by postart  
Has anyone ever heard of oxalic acid being used as a hydride donor for imine formation for reductive amination? Theoretically the oxalic acid could dissociate giving two hydrides. One mole oxalic acid for two moles of ketone with an excess of the amine. Does this sound feasable? I couldn't find any references of this ever being done.


This is not a long thread. If you had bothered to read to the fourth post (Which surely would have taken you all night), you would have found a reference using oxalic acid.

postart - 9-1-2011 at 20:30

Its a reference of methylation for amines not reductive amination of ketones. Of course its the same mechanism.
[Edited on 10-1-2011 by postart]

[Edited on 10-1-2011 by postart]

postart - 16-1-2011 at 19:47

I was wondering while looking at this thread about making drugs.

research. don't double post.

[Edited on 29-1-2011 by Ramiel]