[veljanovski]

Hi to all Chemist out there

I can't synthesise an Amid properly.

My reaction:

Methyl ester + Amine (primer) = Amide (T=120°C No Solvent)

I've tried different Molecules with this Funktional Groups but nothing is working.

Anyone with an Idea what am I doing wrong?

Pleas help. Is for an scientific Project that need to be done quickly.

Thanks

Dragan


 

[HP]

Try higher temperture if possible or t + pressure(be mention that amidation is a reversible reaction)..Have you tried microwave assisted synthesis 

[veljanovski]

Hi

I've already tried higher Temperature but my Reactants are not stable enough for that.

I never tried Pressure though, but I'm working with very small amount and the Methanol as byproduct  is probably already gone because I can't see it in NMR (T=120°C). I think that the balance is probably on the side of the Products with that.

Thanks

Dragan

[HP]

Well if methanol is gone then amide must be present In general amidation of methyl or ethyl esters is easily (at lower temperatures  much quick and without catalist) than heat amidation of amines with carboxylic acids (in fact corresponding salts with the amine). Its probably because methanol and ethanol have lower b.p than water and easily removed from the equilibria... Working with small quant is not as in lab or industrial scale because of mass, heat and difusion transporting processes which are different. I recomend you to analyze your starting and reaction products with IR spectroscopy. If amidation occur then the ester group absorbance at about 1730-1740sm-1 must shift to 1630-1650 sm-1 which will indicate Amide I bond formation, also Amide II at around 1580sm-1 or comb Amide at 1520sm-1 will occur. 1-2 mg of your product spred between two KBr platelets will be fine for this analyze 

[firassh2000]

try to use few drop of HCl

[HP]

Ading HCl will lead to amonium salt formation by the amine reaction:
R-NH2 + HCl (may be you mean 36% aq sol)--> R-NH3+ Cl-
Also possible hydrolisis of Me-ester bonds to free carboxylic acid..
I dont think acid bedia will help amidation as knowing acid catalist hydrolisis of amides. May be ading some catalitic amounts of dehydrating agents like 85% H3PO4 or even conc H2SO4 may help some  Its interesting if try using polyphosphate acid catalist (easily prepare by partual hidrolysis of P2O5) or some strong anionic resin as easily removed later...But i dont know if all these tricks are useable in working in microscale synthesis as mentioned by veljanovski

[lavoisier]

Hi veljanovski,
I have carried out this reaction on a small scale with 7M methanolic ammonia, at room temperature and without using any pressure device. It IS very slow (days), but it works, as March or other OrgChem books say. I've also used other amines, as MeNH2 and EtNH2, even in water/MeOH, without observing any hydrolysis of the methyl ester.
You may need to use an excess of amine - if you can, of course - to speed up the process.

If you can't, a good way round could be hydrolysing the methyl ester with, say, NaOH in water/THF and then couple the free acid and the amine with any coupling reagent you like.

For the rest:
1. the equilibrium constant is favourable, i.e. the amide is more stable than the ester; just look at the very harsh conditions needed to hydrolyse an amide...; and to my knowledge you can't do this with an alcohol.
2. I guess an acidic catalyst is not likely to help, especially if you use aliphatic amines, because they will just mop up the acid, making it unavailable to protonate the ester (besides, I think a different mechanism operates here)
3. I don't really understand how you analyse your reaction mixture. You say you use NMR and don't see MeOH; but do you see the ester methyl group or not? And what about the residue coming from your amine? Do you see it in the product or not? I would advise you to spend some time evaluating how good your analytical methods are before you state that a reaction doesn't work.

[HP]

I share your opinion lavoisier about possible analitical mistake or wrong product NMR data interpretation...One become clear - reaction of amidation Me-ester with amine is kinetically and entropic more favorite than amidation of free carboxylic acids with amines where reaction is two steps: first carboxylic acid ammonium salt formation and next dehydration with amide bond formation (dehydration of the formed amide to nitrile is possible in some cases as side reaction in melts at high temperatures or if using strong dehydrating agents like P2O5). I still insist that microwaves could further optimize this process to one-minute one