Nucleophilic Acyl Substitution

What is Nucleophilic Acyl Substitution?

Nucleophilic acyl substitution is a type of substitution reaction involving an acyl group and a nucleophile. In nucleophilic acyl substitution, a nucleophile displaces the leaving group, resulting in a carbonyl compound.

• The resulting product in nucleophilic acyl substitution is a carbonyl compound with a nucleophile.

Acyl derivative reacts with various nucleophiles; thus, nucleophilic acyl substitution synthesises many products.

Table of Content

• Reaction Mechanism
• Acid-catalysed Nucleophilic Acyl Substitution
• Base-catalysed Nucleophilic Acyl Substitution
• Reactivity Trends
• Reaction of Acid Halides
• Reaction of Anhydrides
• Reaction of Esters
• Reaction of Amides
• Frequently Asked Questions – FAQs

Reaction Mechanism

Nucleophilic acyl substitution can proceed in two conditions, i.e. acidic and basic conditions.

• The acidic conditions make carbonyl more electrophilic, while the basic conditions make the nucleophile more anionic, thus accelerating the rate of reaction.

Acidic Mechanism

Under acidic conditions,

• Step 1: Carbonyl group of the acyl compound 1 is protonated, activating it towards the nucleophilic attack.
• Step 2: The pronated carbonyl 2 is attacked by a nucleophile forming tetrahedral intermediate 3.
• Step 3: Proton is transferred from nucleophile Z to the leaving group X giving 4 as an intermediate structure.
• Step 4: Intermediate structure 4 then eject protonated leaving group HX, forming protonated carbonyl compound 5.
• Step 5: Protonated carbonyl compound 5 loses a proton, forming the resulting substitution product.

As the proton is lost in the last step, thus it is called acid-catalysed nucleophilic acyl substitution. And under acidic conditions, nucleophiles will exist in their protonated form, i.e. HZ.

Basic Mechanism

Under basic conditions,

• Step 1: Nucleophile attacks the carbonyl group of acyl compound 1 to give a tetrahedral alkoxide intermediate 2.
• Step 1: The nucleophile and intermediate expel the leaving group to give the share substitution product 3.

Note: For the reaction to proceed, nucleophiles should be more substantial base than the leaving group, or we can say that nucleophiles must have lower pK_a than the leaving group.

Reactivity Trends of Acyl Derivatives

There are five main types of acyl derivatives.

• Acid Halide
• Anhydrides
• Esters
• Amides
• Carboxylate ions

Acid Halide is most reactive towards nucleophilic acyl substitution, followed by anhydrides, esters, amides and carboxylate ions. Carboxylate ions are unreactive towards nucleophilic acyl substitution as they don’t have any leaving group.

Reactivity trends of acyl derivatives

• Leaving group ability to detach itself from the acyl compound. Strong bases are poor leaving groups. Thus, species with strong conjugate acid like HCl would be an excellent leaving group, while a species with weak conjugate acid like acetic acid will be a poor leaving group. Thus, chloride ion is a better leaving group than acetate ion.

Thus we can say that the reactivity of the acyl compound increases with a decrease in the basicity of leaving group.

• Resonance also plays an essential role in affecting the reactivity of acyl derivatives towards nucleophilic substitution reactions.
• Amide exists in two resonance stabilised forms.
• Both of them have a significant contribution to the overall structure.
• The amide bond between carbonyl and nitrogen have a significant double bond character.
• A tetrahedral intermediate is formed when a nucleophile attacks a resonance-stabilised amide group.
• Amide loses its extra stability.
• Thus, amide does not react efficiently.

This clearly explains why amide derivatives are least reactive towards nucleophilic substitution.

• Esters experience less resonance stabilisation; thus, the formation of tetrahedral intermediate is energetically favourable.
• Anhydrides experience even less resonance stabilisation; thus, the formation of tetrahedral intermediate is energetically favourable.
• Acid halides experience the most negligible resonance stabilisation; thus, the formation of tetrahedral intermediate is energetically favourable.

This clearly explains why acid halide derivatives are most reactive towards nucleophilic substitution followed by anhydride, ester and amides.

Reaction of Acid Halides

• Acid halides are the most reactive acyl derivatives.
• Acid halides react with carboxylic acid to form anhydrides.
• A nucleophilic substitution reaction can easily convert acid halides into other acyl derivatives.

Mechanism:

Step 1: Carboxylic acid attacks on acid chloride, forming a tetrahedral intermediate 2.

Step 2: Tetrahedral intermediate collapses, ejects chloride ions and forms oxonium ion species.

Step 3: Deprotonatin takes place, resulting in anhydride and HCl.

• Acid Halides react with a Grignard reagent to form tertiary alcohol.

Reaction of Anhydrides

• The reaction of an acid halide and anhydride are pretty similar.
• Anhydride can be converted into any acyl derivatives except acid halide.
• Anhydride is used in Schotten–Baumann-reaction to synthesise esters and amides from alcohols and amines.
• Water hydrolyse amine to its corresponding acid.
• Anhydride reacts with carbon nucleophiles to form ketones and tertiary alcohols.
• Anhydride also participates in Friedel craft acylation.
• Reactivity of anhydrides can be increased by using a catalytic amount of N,N-dimethylaminopyridine, or DMAP.
• Reactivity of anhydrides can also be increased by using pyridine.

Mechanism:

Step 1: DMAP attacks the anhydride to form a tetrahedral intermediate.

Step 2: Tetrahedral intermediate collapses and ejects a carboxylate ion to amide.

Step 3: Nucleophie attacks tetrahedral amide intermediate.

Step 4: Tetrahedral intermediate collapses and expels pyridine group to form the resulting substitution product.

Note: Aromaticity is restored.

Note: DMAP amide intermediate is more activated towards nucleophilic attack than the anhydride as dimethylaminopyridine is a better leaving group than carboxylate.

Reaction of Ester

• Esters are less reactive than acid halides and anhydrides.
• Esters react with ammonia and primary and secondary amines to give amides.
• Esters can be converted into other esters by transesterification.
• Transesterification can be both acid- and base-catalysed.
• The basic hydrolysis of esters is known as saponification.

Reaction of Amides

• Amides are less reactive and do not participate in most reactions.
• Amides are stable towards the water.
• Amides can be hydrolysed to carboxylic acids in the presence of acid or base.
• Primary and secondary amides do not react favourably with carbon nucleophiles. In contrast, tertiary amides react with carbon nucleophiles to form ketones.

Mechanism

Step 1: Phenyl lithium attacks the carbonyl group of DMF, forming a tetrahedral intermediate.

Step 2: Dimethylamide anion, a poor leaving group, does not leave, and thus nucleophiles could not attack.

Step 3: Under acidic conditions, alkoxide and amines are protonated.

Step 4: A neutral molecule of dimethylamine and proton is lost, resulting in benzaldehyde.