What is Nucleophilic Acyl Substitution?

Nucleophiles are electron-rich species that are capable of donating electrons to an electrophile. They have a lone pair of electrons that attack electron-deficient sites in a molecule, thereby forming a new bond. Nucleophilic acyl substitution is a substitution reaction in which a nucleophile displaces a leaving group (LG) bonded to the central carbon of an acyl compound (RCO-LG) ^[1-8].

List of Acyl Compounds

The acyl compounds are carboxylic acid (RCO-OH) derivatives such as the following:

• Acyl halide (RCO-X)
• Acid anhydride (R(CO)O(CO)R’)
• Thioester (RCO-OSR’)
• Ester (RCO-OR’)
• Amide (RCO-NR’₂)

Reactivity Order of the Acyl Compounds

Here is the order of reactivity of the acyl compound.

Acyl halide > acid anhydride > thioester > ester = carboxylic acid > amide > carboxylate

List of Nucleophiles

Here are some nucleophiles that add to the carbonyl (C=O) group.

Oxygen-centered: H₂O, ROH, and OH^–

Nitrogen-centered: R₂NH, RNH-NH₂, and HO-NH₂

Carbon-centered: R₃C-MgX, (R₃C)₂Cu-Li, and R₃C-Li

Others: LiAlH₄, NaBH₄, X^–, and HSO₃^–

Example of Nucleophilic Acyl Substitution

Fischer esterification of benzoic acid (C₆H₅COOH) with methanol (CH₃OH) in the presence of sulfuric acid (H₂SO₄) gives methyl benzoate (C₆H₅COOCH₃) is an example of nucleophilic acyl substitution ^[8-10].

C₆H₅COOH + CH₃OH → C₆H₅COOCH₃ + H₂O

Mechanisms of Nucleophilic Acyl Substitution ^[1-7]

The mechanism of nucleophilic acyl substitution begins with a nucleophilic attack on an electrophilic carbonyl carbon, forming an intermediate known as tetrahedral alkoxide. Next, the negative charge on the alkoxide transfers to the leaving group. The second step involves eliminating the leaving group, allowing the C=O carbonyl bond to reform and create a new acyl compound.