Nucleophilic acyl substitution

Nucleophilic acyl substitution describes the substitution reaction involving nucleophiles and acyl compounds. Acyl compounds are carboxylic acid derivatives including esters, amides and acid halides. Nucleophiles include anionic reagents such as alkoxide compounds and enolates or species of high basicity, such as amines.^[1]

Reaction mechanism

Nucleophilic acyl substitution with nucleophile (Nu) and leaving group (L)

The reaction of a nucleophile with a polar carbonyl group such as a ketone or an aldehyde results in nucleophilic addition with a tetrahedral alkoxide as primary reaction product. However, in acyl compounds the carbonyl group is bonded to a substituent that can act as a leaving group. Upon attack of the nucleophile at the carbonyl group, as before, a tetrahedral intermediate is formed with the nucleophile, the leaving group and the oxygen anion attached to the central carbon atom. The alkoxy group can now revert back to the carbonyl group and at the same time expel the leaving group. The nucleophile has taken the position previously occupied by the leaving group.

This mechanism is supported by isotope labeling experiments. The ¹⁸O labeled ethoxy oxygen atom in ethyl propionate (leaving group = EtO) winds up exclusively in the ethanol product in a reaction with NaOH ^[2].

Acyl substitution is basically a two-step nucleophilic addition and elimination reaction. Both reaction steps are reversible reactions. The relative strength of both nucleophilic species determines the reaction outcome, but in practical reactions the leaving group is by far the poorest nucleophile.

Carboxylic acids as well as the related esters and amides are often insufficiently reactive to undergo nucleophilic substitution. The carboxylic acid is often activated by conversion to the acyl chloride using thionyl chloride.

Reactions

Many condensation reactions are nucleophilic acyl substitutions. Carboxylic acids react with chlorine donors such as thionyl chloride or phosphorus trichloride to acid chlorides, with alcohols to esters in esterfication and carboxylic acids selfcondense to acid anhydrides. With amines they form amides. Esters react with Grignard reagents in a nucleophilic acyl substitution, leading to ketones, followed by a nucleophilic addition, leading to tertiary alcohols. Esters also react with Enolate nucleophiles. For example ethyl acetate reacts with acetone to acetylacetone.

The Baker-Venkataraman rearrangement is a nucleophilic acyl substitution used in the synthesis of flavones. In the Weinreb ketone synthesis ketones are synthesized from carboxylic acid precursors. An unusual intramolecular acyl substitution is the Chan rearrangement.

See also

• The substitution reactions in organic chemistry are nucleophilic acyl substitution, nucleophilic aliphatic substitution and nucleophilic aromatic substitution.

References

1. ^ John McMurry. Organic Chemistry (2nd Ed. ed.). ISBN 0-534-07968-7. 
2. ^ Attributed to D.N. Kursanov (1899) McMurry

External links

• Reaction of ethyl acetate with acetone in Organic Syntheses Coll. Vol. 3, p.16; Vol. 20, p.6 Article