Nucleophilic acyl substitution

Carbonyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. This reaction can be accelerated by acidic conditions, which make the carbonyl more electrophilic, or basic conditions, which provide a more anionic and therefore more reactive nucleophile. The tetrahedral intermediate itself can be an alcohol or alkoxide, depending on the pH of the reaction. The tetrahedral intermediate of an acyl compound contains a substituent attached to the central carbon that can act as a leaving group. After the tetrahedral intermediate forms, it collapses, recreating the carbonyl C=O bond and ejecting the leaving group in an elimination reaction. As a result of this two-step addition/elimination process, the nucleophile takes the place of the leaving group on the carbonyl compound by way of an intermediate state that does not contain a carbonyl. Both steps are reversible and as a result, nucleophilic acyl substitution reactions are equilibrium processes. Because the equilibrium will favor the product containing the best nucleophile, the leaving group must be a comparatively poor nucleophile in order for a reaction to be practical. Under acidic conditions, the carbonyl group of the acyl compound 1 is protonated, which activates it towards nucleophilic attack. In the second step, the protonated carbonyl (2) is attacked by a nucleophile (H−Z) to give tetrahedral intermediate 3. Proton transfer from the nucleophile (Z) to the leaving group (X) gives 4, which then collapses to eject the protonated leaving group (H−X), giving protonated carbonyl compound 5. The loss of a proton gives the substitution product, 6. Because the last step involves the loss of a proton, nucleophilic acyl substitution reactions are considered catalytic in acid. Also note that under acidic conditions, a nucleophile will typically exist in its protonated form (i.e. H−Z instead of Z−). Under basic conditions, a nucleophile (Nuc) attacks the carbonyl group of the acyl compound 1 to give tetrahedral alkoxide intermediate 2. The intermediate collapses and expels the leaving group (X) to give the substitution product 3. While nucleophilic acyl substitution reactions can be base-catalyzed, the reaction will not occur if the leaving group is a weaker base than the nucleophile (i.e. the leaving group must have a higher pKa than the nucleophile). Unlike acid-catalyzed processes, both the nucleophile and the leaving group exist as anions under basic conditions. This mechanism is supported by isotope labeling experiments. When ethyl propionate with an oxygen-18-labeled ethoxy group is treated with sodium hydroxide (NaOH), the oxygen-18 label is completely absent from propionic acid and is found exclusively in the ethanol.