Reductive amination: the mechanism, step by step
The amine and the carbonyl condense to a C=N, and the reducing agent then delivers a hydride to that carbon. The order matters: nothing reduces the carbonyl itself.
The pathway runs in 4 steps. What sits between them is a real structure: it is what the reaction passes through, and on a bad day it is what you isolate instead of the product.
Below is the sequence as it is taught. On the platform it is drawn on whatever structures you supply, with the curly arrows resolved to the actual atoms involved rather than to a general case with R groups on it.
The steps
The amine adds to the carbonyl
The nitrogen shares its pair of electrons with the carbon of the C=O group, and the double bond's electrons move up onto the oxygen.
Addition of the amine lone pair into the carbonyl π*, giving a zwitterion.
The proton moves from nitrogen to oxygen
The spare hydrogen on the nitrogen hops across to the oxygen, leaving a hydroxyl and a neutral nitrogen.
Proton transfer giving the neutral hemiaminal, in practice through the solvent.
Water leaves and the C=N forms
The nitrogen pushes its electrons into the bond to carbon, making a double bond, and water is forced off.
Loss of water to give the imine. This is the species the reducing agent acts on, and it is far more easily reduced than the carbonyl it came from.
The reducing agent delivers a hydride
The reducing agent hands a hydrogen, with both its electrons, to the carbon of the C=N. The nitrogen takes the electrons of the double bond, and an amine is left.
Hydride addition to the C=N. The reagent is chosen to be mild enough to leave an unactivated carbonyl alone, which is why the condensation has to happen first.
What this drawing assumes
- The reducing agent is chosen so that it reduces the C=N and leaves the C=O alone. Drawing the hydride arriving after the condensation is not a simplification, it is the whole point of the method.
- The proton transfers between nitrogen and oxygen are collected into one step.
Other pathways this class runs by
- With a secondary amine the species reduced is an iminium rather than a neutral imine, and it is reduced faster still.
- Run stepwise, the imine can be isolated first and reduced separately; done in one pot, it never accumulates.
Run it on your own structures
Enter the reactants and the product you expect. If the transformation is one the engine can perform and this pathway reaches that product from those structures, it is drawn on them — with the arrows on the right atoms and the intermediates you would actually pass through. If it does not reach the product, you are told that instead of being shown a drawing that does not apply.
Other mechanisms
Nucleophilic acyl substitution
The nucleophile adds to the carbonyl, the carbon holds four groups for a moment, and the leaving group is pushed out as the double bond comes back.
Bimolecular nucleophilic substitution
One step. The nucleophile comes in on the opposite side from the leaving group, and the carbon turns inside out as the exchange happens.
Imine formation
The amine adds to the carbonyl, the resulting alcohol-amine loses water, and a carbon–nitrogen double bond is left.
Diels-Alder cycloaddition
One step. Six electrons move round a ring at once, two new single bonds form at the ends and the double bond ends up in the middle.
Bimolecular elimination
One step. The base takes a hydrogen from one carbon while the leaving group departs from the next, and a double bond forms between them.
Unimolecular nucleophilic substitution
The leaving group goes first, on its own, leaving a flat carbon with a positive charge. Whatever is around then attacks it from either side.