Nucleophilic acyl substitution: the mechanism, step by step
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.
The pathway runs in 3 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 nucleophile attacks the carbonyl carbon
The nitrogen has a pair of electrons it is willing to share. It reaches the carbon of the C=O group, and the electrons of the double bond move onto the oxygen to make room.
A lone pair on the nucleophile adds into the π* of the carbonyl. The carbon goes from three groups to four, the oxygen takes a negative charge and the nucleophile a positive one.
The carbonyl comes back and the leaving group goes
The oxygen pushes its electrons back down to remake the double bond, and that forces the chloride off the other side.
The alkoxide collapses: the oxygen lone pair reforms the π bond and the C–leaving-group bond breaks heterolytically, the pair leaving with the departing atom.
A base takes the proton
The atom that attacked is still carrying a positive charge and a spare hydrogen. Something basic in the flask takes that hydrogen away, and the neutral product is left.
Proton transfer from the cationic nucleophile to any base present — a second equivalent of the nucleophile, an added base, or the group that just left.
What this drawing assumes
- Addition and elimination are drawn as two steps. Whether the tetrahedral species is a true intermediate or only a transition state depends on the substrate, and for an acyl chloride it is short-lived.
- Proton transfers are drawn as their own step and are fast compared with the two that make and break the bonds to carbon.
Other pathways this class runs by
- A strongly acidic medium protonates the carbonyl oxygen first, which makes the carbon more electrophilic; the order of the middle two steps is then reversed.
- With a poor leaving group and a strong nucleophile the addition can become rate-limiting rather than the collapse.
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
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.
Organometallic addition to a carbonyl
The carbon attached to the metal is nucleophilic. It adds to the carbonyl, and the alkoxide that results is protonated when the reaction is worked up.