Sciencemadness Discussion Board

Primary Amine Methylation

solo - 21-12-2006 at 11:29

In the methylation of a primary amine* if there happens to be an OH reactive group in the aromatic amine (primary amino alcohol) will the methylation with oxalic acid and paraformaldehyde at 100 C or other methods, affect the OH group .................solo

Thomas Rosenau,1 Antje Potthast,1 Ju¨ rgen Ro¨ hrling,1 Andreas Hofinger,1 Herbert Sixta,2 and Paul Kosma1,
SYNTHETIC COMMUNICATIONS, 32(3), 457–465 (2002)

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.

other references

The Action of Formaldehyde on Amines and Amino Acids'
Journal of the American Chemical Society 0002-7863, vol: 55 1933 p:4571

Simple aliphatic amines are smoothly methylated to the corresponding tertiary amines by warming in formic acid solution with formaldehyde.Dibenzylamine, under these conditions, is mainly converted into methyldibenzylamine, but at the same time yields some benzaldehyde and a more volatile base (probably dimethylbenzylamine).
Tetra-alkyl-diaminomethanes,o n warming with formic acid, are converted into equimolar quantities of the corresponding dialkylamine and methyldialkylamine. Hexamethylenetetramine reacts with warm formic
acid yielding mainly ammonia and trimethylamine, with smaller amounts of mono- and dimethylamines; only three-quarters of the methylene carbon reappears as methyl in the final mixture.
Only about two-thirds of the anticipated amount of carbon dioxide, calculated on the assumption that the formic acid is the sole hydrogen donor, is obtained in these reactions; apparently some of the formaldehyde also contributes hydrogen.
Amino acids react with formaldehyde in warm formic or acetic acid with detachment of some of the nitrogen in the form of volatile bases. Dimethyl derivatives were isolated from the reaction in formic acid with glycine, P-aminopropionic acid, a-aminoisobutyric acid and a-amino-aphenylbutyric acid. Other amino acids yielded breakdown and condensation of various degrees of complexity. Benzaldehyde was
isolated from a-aminophenylacetic acid, propiophenone from a-amino-aphenylbutyric acid, and a-(4-phenyl-2,3-diketopyrrolidyl)-/3-phenylpropionic acid from phenylalanine. Mechanisms by which these products may be formed are suggested.

Download both articles here,....

[Edited on 22-12-2006 by solo]

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XxDaTxX - 21-12-2006 at 18:34

"(primary amino alcohol) ... will the methylation affect the OH group"

They got 93% yield of the tertiary amine using 2-aminoethanol without affecting the alcohol, however, I suspect you are not interested in tertiary product no? ... or perhaps you meant a reactive phenol moiety?

....or PERHAPS we should talk of DCM wax interactions .... hahahhaa

[Edited on 22-12-2006 by XxDaTxX]

solo - 21-12-2006 at 20:52

Thanks for pointing that out as I didn't notice it ............regardless of wheather it's a primary or a secondary amine the reaction of methylation doesn't seem to effect the OH group.....however one thing was discovered with this neat study , that is methylation without solvents in quantitative yields without affecting the OH groups...............solo

[Edited on 22-12-2006 by solo]

not_important - 21-12-2006 at 23:20

I did some digging around when I ran into the oxalic+paraformaldehyde, and someone I know informed me that an associate of theirs had a grad student try a few other amines (sorry, that is getting to be a bit indirect). Alcohols did dehydrate to some extent if they were prone to that anyway. The other thing that happened was the formation of a 6-member ring as a side product in a case where there were 3 alkyl carbons between the O of OH and N of amine; the COH2 ended up bridging the O and N as a methylene.

And, no, I don't know the exact compounds that gave the side reactions. But I was told that the seem to be fairly special case examples.

Another concern might be in cases with a fairly active aromatic ring the formldahyde might react with the ring, likely leading to condensation products.

solo - 22-12-2006 at 04:54

Nothing like a test to verify the claims of this study since it doesn't take much to find out . however the resutls may be very helpful to some who find this study helpful in their reactions...................solo