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Nucleophilic Acyl Substitution

Nucleophilic Acyl substitution is a fundamental chemical reaction that involves the replacement of an acyl group in a molecule. This reaction plays a crucial role in organic synthesis and pharmaceutical research, enabling the formation of esters, amides, and other important functional groups.

Acyl substitution reactions occur when an acyl compound reacts with a nucleophile, resulting in the substitution of the acyl group with the nucleophile. Common starting materials for these reactions include acyl chlorides and esters.

Under basic conditions, amides can also undergo acyl substitution. Understanding the mechanisms and applications of acyl substitution reactions is essential for designing efficient synthetic routes and developing new drugs.

Reaction Process

During nucleophilic acyl substitution, a nucleophile replaces a leaving group attached to an acyl carbon atom.

The leaving group can be a halogen (such as chlorine) or another functional group. The nucleophile attacks the carbon atom, forming a new bond while simultaneously displacing the leaving group.

Notable Exception

There is one notable exception to this reaction process. Anhydrides, and esters, the reaction proceeds smoothly with a nucleophile attacking the carbonyl carbon directly.

However, in amides, due to resonance stabilization from the nitrogen lone pair electrons delocalizing into the carbonyl oxygen atom (inductive electron withdrawal), they are less reactive toward nucleophilic attack.

Conditions and Examples

The success of nucleophilic acyl substitution reactions depends on several factors such as temperature, solvent choice, and reactant concentrations. For example:

  • Higher temperatures generally increase reaction rates.

  • Polar solvents like water or alcohol are often used.

  • Acidic or basic conditions may be employed depending on the specific reaction requirements.


  1. In the synthesis of aspirin (acetylsalicylic acid), salicylic acid undergoes nucleophilic acyl substitution with acetic anhydride.

  2. Another example is the conversion of ethanoic acid (acetic acid) to ethyl acetate through reaction with ethanol.

Nucleophilic acyl substitution offers great versatility in organic synthesis by allowing the introduction of various functional groups into molecules. It is a powerful tool for chemists to create new compounds with desired properties.

Mechanism of Nucleophilic Acyl Substitution

The mechanism of nucleophilic acyl substitution involves a series of steps that result in the replacement of one group by another on an acyl carbon atom.

This reaction is commonly seen in organic chemistry and has various applications in the synthesis of pharmaceuticals, polymers, and other important compounds.

Nucleophilic Attack on the Carbonyl Carbon

In the first step of the mechanism, a nucleophile attacks the carbonyl carbon atom, which is positively polarized due to its high electronegativity.

The nucleophile can be either a charged species or a carbon-based nucleophile. This attack results in the formation of a tetrahedral intermediate.

Leaving Group Departure

Following the nucleophilic attack, the leaving group attached to the carbonyl carbon departs from the molecule.

This departure creates a negative charge on an adjacent atom, such as oxygen or nitrogen. The leaving group can be different depending on the reaction conditions and substrate.

Rearrangement of Tetrahedral Intermediate

The tetrahedral intermediate formed undergoes rearrangement to yield the final product. This rearrangement can involve various mechanistic steps such as migration of substituents within the molecule or ring-opening reactions in aromatic systems.

The nature and position of substituents greatly influence this rearrangement process.

Factors Influencing Reaction Rate and Outcome

Several factors influence the rate and outcome of nucleophilic acyl substitution reactions. Steric hindrance around the reacting center can hinder or promote reaction rates depending on its effect on nucleophile access.

Electronic effects also play a crucial role; electron-withdrawing groups increase reactivity while electron-donating groups decrease it.

Types of Nucleophilic Acyl Substitution Reactions

Nucleophilic acyl substitution reactions are a fundamental concept in organic chemistry. There are several types of these reactions that chemists commonly encounter.

Understanding the characteristics and requirements of each type is crucial for successful implementation.

Nucleophilic Addition Elimination (SN2)

One type of nucleophilic acyl substitution reaction is known as nucleophilic addition elimination, or SN2. In this reaction, the nucleophile attacks the carbonyl carbon while simultaneously pushing out the leaving group.

The rate-determining step involves a concerted mechanism, where the bond formation and bond breaking occur simultaneously.


  • SN2 reactions proceed with inversion of stereochemistry.

  • They typically occur in one step, resulting in a single transition state.


  • SN2 reactions can be hindered by steric hindrance around the carbonyl carbon.

  • They require a strong nucleophile to facilitate attack on the electrophilic carbon.

Nucleophilic Addition Elimination (SN1)

Another type of nucleophilic acyl substitution reaction is nucleophilic addition elimination, or SN1. Unlike SN2 reactions, which involve a concerted mechanism, SN1 reactions proceed through a two-step process.

First, the leaving group departs to form an intermediate carbocation. Then, the nucleophile attacks the carbocation to complete the reaction.


  • SN1 reactions can tolerate steric hindrance around the carbonyl carbon.

  • They often exhibit racemization due to the rapid interconversion of enantiomers during intermediate formation.


  • The reaction rate depends on both substrate concentration and solvent polarity.

  • Side reactions such as rearrangements may occur due to stability differences in carbocations.

Intramolecular Acylation Reactions

Intramolecular acylation reactions involve a cyclic structure where an internal nucleophile attacks an adjacent acyl group. These reactions often occur in ring systems and can lead to the formation of lactones or lactams, depending on the nature of the nucleophile.

Key Information:

  • Intramolecular acylation reactions proceed through a cyclization step.

  • They are commonly used for the synthesis of cyclic compounds.

Reactivity Trends in Nucleophilic Acyl Substitution

Reactivity trends in nucleophilic acyl substitution reactions depend on various factors that influence the rate of the reaction.

These factors include the leaving group ability, electrophilicity of the carbonyl carbon, and steric hindrance around it.

Leaving Group Ability and Reactivity

The reactivity of acyl derivatives in nucleophilic acyl substitution reactions is influenced by the stability of the leaving group.

Leaving groups with higher stability tends to enhance reactivity, as they are more willing to dissociate from the carbonyl compound. On the other hand, less stable leaving groups can hinder reactivity.

Electrophilicity of Carbonyl Carbon

The electrophilicity of the carbonyl carbon also affects the relative reactivities of different acyl derivatives. A more electrophilic carbonyl carbon will react more readily with a nucleophile, leading to a faster reaction rate.

This electrophilic character is influenced by various factors such as electron-withdrawing or donating groups attached to the carbonyl compound.

Steric Hindrance

Steric hindrance around the carbonyl carbon can impact reactivity trends as well. Bulky substituents near the carbonyl carbon can hinder nucleophilic attack and slow down the reaction rate due to steric repulsion between atoms.

Understanding these reactivity trends is crucial for predicting and explaining various types of nucleophilic acyl substitution reactions. It allows chemists to make informed decisions about reaction conditions and select appropriate reagents for specific transformations.

Interconversion of Acid Derivatives in Acyl Substitution

Acid derivatives, such as esters, amides, and anhydrides, can undergo interconversion through acyl substitution reactions. These conversions play a crucial role in organic synthesis as they allow chemists to access a wide range of functional groups.

Careful selection of reagents and reaction conditions is key to controlling the outcome of these transformations. By choosing the appropriate combination, chemists can achieve specific substitutions and manipulate the structure of acid derivatives.

Here are some important points to understand about the interconversion of acid derivatives in acyl substitution:

Acid Derivatives and their Importance

  • Acid derivatives refer to compounds derived from carboxylic acids, including esters, amides, and anhydrides.

  • These derivatives are valuable intermediates in organic synthesis due to their ability to be transformed into various functional groups.

  • Through acyl substitution reactions, chemists can modify the structure and properties of acid derivatives to create desired products.

Control over Substitution Reactions

  • The outcome of acyl substitution reactions depends on factors such as reagent choice, reaction temperature, and solvent.

  • For example, using a nucleophilic reagent like an alcohol or ammonia leads to esterification or amidation respectively.

  • On the other hand, employing a strong base like hydroxide ions results in basic hydrolysis that converts acid derivatives into carboxylic acids.

Specific Examples

  • One common reaction involving acid derivatives is the conversion of acid halides (acyl chlorides) into esters using alcohols as nucleophiles.

  • Another example is the transformation of acid anhydrides into carboxylic acids through hydrolysis with water or alcohol.

By understanding how different combinations of reagents and conditions influence acyl substitution reactions, chemists can strategically design synthetic routes for accessing specific functional groups.

This flexibility allows for the creation of diverse organic compounds with various applications.


We started by understanding nucleophilic acyl substitution, its applications, and the mechanism behind it. Then, we delved into different types of nucleophilic acyl substitution reactions and discussed reactivity trends in these reactions.

Finally, we examined the interconversion of acid derivatives in acyl substitution.

By now, you have gained a comprehensive understanding of acyl substitution and its importance in organic chemistry. The knowledge you have acquired can be applied to various scenarios where acyl substitution plays a crucial role.

Whether you are studying or working in the field of chemistry, these insights will undoubtedly prove valuable.


What are some common nucleophiles used in nucleophilic acyl substitution?

Some common nucleophiles used in nucleophilic acyl substitution include hydroxide ion (OH-), alkoxide ions (RO-), primary amines (RNH2), thiolate ions (RS-), and carboxylic acid derivatives such as esters or amides.

How does steric hindrance affect the reactivity of nucleophilic acyl substitutions?

Steric hindrance refers to bulky substituents around the reacting carbon atom in an acid derivative molecule. It can hinder the approach of a nucleophile, reducing the reaction rate and making it more difficult for a reaction to occur.

Can you provide an example of an intramolecular nucleophilic acyl substitution reaction?

Certainly! An example of an intramolecular nucleophilic acyl substitution is the cyclization of a β-ketoester to form a cyclic β-diketone. In this reaction, the carbonyl oxygen acts as a nucleophile and attacks the adjacent electrophilic carbon atom, resulting in ring formation.

What are some applications of acyl substitution reactions in organic synthesis?

Acyl substitution reactions find wide applications in organic synthesis. They are commonly used for the preparation of carboxylic acids, esters, amides, and other important functional groups. These reactions also play a vital role in pharmaceutical synthesis and natural product isolation.

How does temperature affect the rate of nucleophilic acyl substitution reactions?

In general, increasing the temperature enhances the rate of nucleophilic acyl substitution reactions by providing more kinetic energy to reactant molecules. However, excessively high temperatures can lead to undesired side reactions or decomposition of reactive intermediates. It is crucial to optimize the reaction conditions for each specific case.