Sciencemadness Discussion Board

How sensitive is an imine to hydrolysis to an amine?

German - 1-6-2021 at 00:14

I have a molecule with a primary amine and a secondary amine. I want to turn the primary into an amide but leave the secondary alone. One option I am looking at is treating the molecule with benzaldehyde which will turn the primary to an imine, but leave the secondary amine alone. At that point I can BOC protect the secondary, perform hydrolysis to get the imine back to an amine, and then turn the amine into an amide with say acetic anhydride. But my concern is hydrolysis on the imine to get it back to an amine. Although BOC should not come off in basic conditions I have found with my molecule BOC does come off in strongly basic conditions with heat (like above 60c possibly less). Strangely though I can keep the BOC on in even 2% HCl.

So my question is exactly how sensitive is an imine to hydrolysis? Can I just stir in some water at room temp and get my amine back? Or we are talking some strong acid/base with heat?

Thank you.

zed - 1-6-2021 at 02:25

Got a picture?

clearly_not_atara - 1-6-2021 at 08:00

You run the risk of your chloroformate attacking the imine anyway. They can dealkylate amines after all.

Imine stability varies, with aliphatic ketones < aliphatic aldehydes < benzaldehydes < furfural < dinitrobenzaldehyde with benzaldehyde imines often needing a little coaxing to cleave. Using bisulfite traps the aldehyde, driving the equilibrium towards the reactants.

Instead of all this circuitry, you might be able to take advantage of the higher reactivity of the primary amine and just react the unmodified diamine with the methyl ester of your acyl moiety. With appropriate stoichiometry (1-1.1:1) and rxn time (20-100 hours at rt) you should get the desired monoacyl with much less hassle modulo a few recrystallizations.

Jenks - 1-6-2021 at 08:43

Quote: Originally posted by clearly_not_atara  
Instead of all this circuitry, you might be able to take advantage of the higher reactivity of the primary amine and just react the unmodified diamine with the methyl ester of your acyl moiety. With appropriate stoichiometry (1-1.1:1) and rxn time (20-100 hours at rt) you should get the desired monoacyl with much less hassle modulo a few recrystallizations.

Isn't the secondary amine more nucleophilic due to the (likely) electron-donating nature of the second substituent? Which is why it is hard to monoalkylate an amine without it reacting further? However, depending on what the substituents are, steric hindrance may make the secondary amine less reactive, particularly if a more bulky anhydride could be employed.

I started searching for a better way, but found a paper describing exactly what German suggests. Maybe that paper, if it can be accessed, would describe the exact conditions needed to hydrolyze the benzaldehyde imine.

[Edited on 1-6-2021 by Jenks]

German - 1-6-2021 at 20:20

^^^^ Hey thanks. That paper gave me my answer. They actually converted back to the amine during workup! They just based with lye during workup and then extracted to organic layer. So I guess it is pretty damn easy.