Core Concepts
In this article, we will explore the reaction mechanism of nucleophilic acyl substitutions.
Related Articles
- Nucleophilic Substitution Reaction
- What is a Nucleophile?
- Carboxylic Acid Derivatives and their Reactions
- Carboxylic Acid Functional Group
What is Nucleophilic Acyl Substitution?
Nucleophilic acyl substitution is the replacement of the heteroatom of the carboxylic acid derivative’s leaving group with a nucleophile. This type of reaction is used primarily when converting one carboxylic acid derivative species to another less reactive derivative. The replacing nucleophile in these reactions may be an alcohol, amine, carboxylic acid, or water.
Mechanism
Nucleophilic acyl substitution contains three steps: proton transfer (protonation or deprotonation), bond breakage, and bond formation. Bond breakage is used to describe the loss of the leaving group, and bond formation is used to describe nucleophilic attack.
The order of the steps for substitution is determined by the catalyst. If the reaction is acid catalyzed, protonation will occur first, followed by bond formation, proton transfer, and bond breakage. If not acid catalyzed, bond formation is the first step. Because this reaction is multi-step, each unique step may occur more than once (e.g., multiple proton transfers). See below for the general step-by-step acid-catalyzed mechanism.
Determining Reactivity
While it would be nice to know all carboxylic acid derivatives undergo substitution with all nucleophiles, reactivity follows a strict lineage. An acyl chloride is the most reactive species, reacting with all reactants previously mentioned (alcohol, amine, carboxylic acid, or water).
The second most reactive species is an acyl anhydride, which forms via the reaction of an acyl chloride with a carboxylic acid. An acyl anhydride does not react with a carboxylic acid because the leaving group is equivalent to the nucleophile. However, an acyl anhydride can react with an alcohol, an amine, or water.
The third most reactive species is an ester, formed via the reaction of an acyl anhydride with alcohol. An ester can react with water to form a carboxylic acid, or an amine to form an amide. An amide is the second least reactive species (or fourth most reactive) and only reacts with water to form a carboxylic acid.
Below is a visual order of reactivity, from most reactive to least reactive.
Reaction Summary
Acyl chloride:
- + carboxylic acid -> acyl anhydride
- + alcohol -> ester
- + amine -> amide
- + water -> carboxylic acid
Acyl anhydride
- + alcohol -> ester
- + amine -> amide
- + water -> carboxylic acid
Ester
- + amine -> amide
- + water -> carboxylic acid
Amide
- + water -> carboxylic acid
To make more sense of what reacts and what doesn’t, it may be helpful to draw a reaction map. Below is an example.
Organometallic and Gilman Reagents
Carboxylic acid derivatives can also form alcohols and ketones via reaction with organometallic and Gilman reagents, respectively. In these substitution reactions, the R groups of the reagents are the added nucleophiles.
Three derivatives react with organometallic (Grignard and Organolithium) reagents – acyl chloride, acyl anhydride, and ester. The selected derivative reacts with 2 equivalents of the reagent to form a tertiary alcohol.
Only one derivative undergoes nucleophilic acyl substitution with a Gilman reagent – acyl chloride. As previously noted, acyl chloride forms a ketone during reaction with a Gilman reagent.
