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Nucleophilic Acyl Substitution

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].

Nucleophilic Acyl Substitution

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].


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.

Nucleophilic Acyl Substitution Mechanism

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