Carbonyl Addition

Amines are good nucleophiles. We've already seen how they might attack a compound with a good leaving group. Amines may also attack a carbonyl group whose carbon is electron-deficient. The product of the reaction is an imine with a C=N double bond.

Imine formation: acetone and methylamine, with acid catalysis, give the N-methylimine of acetone and water

What is the reaction mechanism? Seeing it in motion is very instructive, but it may be rather complex to follow.

The mechanism of the formation of an imine through the attack of an amine to a carbonyl is named addition-elimination.

Let's break it down into its different steps.

Animation of the orbitals of the ketone carbonyl group

Step 1: Protonation of the carbonyl and attack by N

Protonation of the carbonyl and attack of methylamine on the carbonyl carbon, more electrophilic in the protonated resonance form

Animation: methylamine approaches the protonated carbonyl

Acid catalysis produces the protonation of some ketone molecules. These few protonated ketones have their carbon electrophilicity enhanced. The nucleophilic addition of the amine nitrogen is thus highly facilitated. The former carbonyl carbon changes from planar sp² to tetrahedral sp³.

Step 2: Proton transfer

The protonated tetrahedral intermediate gives a proton to another methylamine molecule, forming the geminal amino alcohol (carbinolamine)

Animation: tetrahedral intermediate protonated on nitrogen

The protonated tetrahedral intermediates give up one proton to the amine molecules that didn't react yet, producing a geminal amino alcohol or carbinolamine (geminal = both functions bonded to the same carbon), an intermediate that is not usually isolated.

Step 3: Protonation of the OH

Protonation of the OH group of the amino alcohol, which becomes a good leaving group (water)

Part of the aminoalcohol molecules undergo protonation on the OH, which is weakly basic, leading to an intermediate with an excellent leaving group: water.

Step 4: Loss of water

Loss of water: the nitrogen lone pair expels water and the iminium ion is formed

Animation: amino alcohol protonated on oxygen

The weakened C-O bond, due to the protonation, heterolytically breaks up leading to an intermediate iminium ion. The former carbonyl carbon, that changed from sp² to sp³, recovers the sp² hybridization.

Step 5: Final deprotonation

Excess methylamine deprotonates the iminium ion and the imine is obtained

Animation: iminium ion with the new C=N double bond

The excess of amine deprotonates the iminium salt, yielding the final imine.

Unfortunately, the overall reaction is not thermodynamically favored in many cases. Therefore, it is necessary to shift all the equilibria by removing the produced water with either a drying agent (molecular sieves, etc.) or a Dean-Stark apparatus.

Energy diagram (kcal/mol) of the formation of the imine from acetone and methylamine: reactants −56.8; protonated ketone 117.6; protonated tetrahedral intermediate 91.0; carbinolamine −58.8; protonated carbinolamine 136.6; iminium ion 88.5; imine and water −56.7