Chapter 25: Nucleophilic Acyl Substitution

What is nucleophilic acyl substitution, and what are its main steps?

A nucleophile replaces a leaving group attached to a carbonyl carbon.

Mechanism:

1. Nucleophilic attack on the carbonyl carbon.

2. Formation of a tetrahedral intermediate.

3. Elimination of the leaving group, reforming C=O.

What is the reactivity order of carboxylic acid derivatives toward nucleophilic acyl substitution?

Acid chloride > Acid anhydride > Ester > Amide.

• More electrophilic carbonyls react more readily.

• Weaker bases are better leaving groups.

• Amides are least reactive because of strong nitrogen resonance donation.

Why do carboxylic acid derivatives undergo addition–elimination instead of simple addition?

They contain a leaving group that can be expelled when the tetrahedral intermediate collapses and reforms the carbonyl.

How do you name carboxylic acids and carboxylate salts?

Carboxylic acid: Change -e → -oic acid.

Carboxylate: Change -oic acid → -oate.

Number the carboxyl carbon as C1.

Examples:

• CH₃CH₂COOH → Propanoic acid

• CH₃CH₂COO⁻ Na⁺ → Sodium propanoate

How do you name esters?

Name the alkyl group attached to oxygen first, then the carboxylate portion ending in -oate.

Example: CH₃CH₂COOCH₃ → Methyl propanoate.

How do you name acid chlorides and anhydrides?

Acid chlorides: Change -oic acid → -oyl chloride.
Anhydrides: Replace acid with anhydride; for mixed anhydrides, list both acid names alphabetically.

Examples:

• CH₃CH₂COCl → Propanoyl chloride

• (CH₃CO)₂O → Acetic anhydride

How do you name amides and nitriles?

Amides: Change -e → -amide; nitrogen substituents use N-.

Nitriles: Change -e → -nitrile, counting the nitrile carbon as C1.

Ring-attached nitriles use -carbonitrile.

Examples:

• CH₃CONHCH₃ → N-Methylethanamide

• CH₃CH₂CN → Propanenitrile

What products form when an acid chloride reacts with different nucleophiles?

H₂O → Carboxylic acid

ROH → Ester

NH₃ or amine → Amide

R₂CuLi → Ketone

How can an ester be converted into an amide?

React the ester with NH₃ or an appropriate primary or secondary amine, replacing the OR group with a nitrogen-containing group.

What is transesterification, and what conditions are used?

Conversion of one ester into another by exchanging the OR group.

• Acidic: H⁺ and excess alcohol.

• Basic: Matching alkoxide and excess corresponding alcohol.

• Excess alcohol helps drive the equilibrium toward the desired ester.

What is saponification, and what products does it form?

Base-promoted ester hydrolysis.

• Reagents: NaOH, H₂O.

• Products: Carboxylate salt + alcohol.

• Acidic workup (H⁺) converts the carboxylate into a carboxylic acid.

What happens when an amide undergoes hydrolysis?

The amide is converted into a carboxylic acid or carboxylate under heated acidic or basic conditions.

• Acidic: H⁺, H₂O, heat.

• Basic: NaOH, H₂O, heat.

How are carboxylic acids synthesized using Grignard reagents?

Convert an alkyl or aryl halide into a Grignard reagent using Mg in ether.

React with CO₂.

Perform acidic workup (H⁺).

Product: Carboxylic acid containing one additional carbon.

How are carboxylic acids converted into acid chlorides?

Use SOCl₂ (thionyl chloride).

Reaction: RCOOH → RCOCl.

How are acid anhydrides formed from carboxylic acids?

Dehydration using P₂O₅ and heat.

Two carboxylic acid groups combine with loss of water to form an anhydride. Suitable dicarboxylic acids can form cyclic anhydrides.

What is Fischer esterification, and what is its mechanism?

A carboxylic acid reacts with an alcohol under acidic conditions to produce an ester.

Mechanism:

1. Protonation of the carbonyl oxygen.

2. Alcohol attacks the carbonyl.

3. Proton transfers.

4. Water leaves.

5. Deprotonation forms the ester.

How are amides synthesized directly from carboxylic acids?

Carboxylic acid + NH₃, heat → Primary amide (through an ammonium carboxylate intermediate).

Carboxylic acid + amine + DCC → Amide under milder conditions.

What is DCC, and why is it useful in amide synthesis?

DCC (dicyclohexylcarbodiimide) activates carboxylic acids by creating a better leaving group.

This allows amide formation under milder conditions and produces a urea byproduct.

What happens when a nitrile is completely reduced?

It forms a primary amine through an imine intermediate.

General transformation:

R–C≡N → R–CH₂NH₂

What happens when a nitrile undergoes acidic hydrolysis?

It forms a carboxylic acid.

Reagents: H⁺, H₂O, heat.

How can a nitrile be selectively reduced to an aldehyde?

1. DIBAL-H

2. H₂O workup

Product: R–CHO.

What happens when a nitrile reacts with a Grignard reagent?

A ketone forms after hydrolysis.

Reagents:

1. RMgX

2. H₂O workup

The Grignard reagent adds an R group to the nitrile carbon, creating an imine-derived intermediate that hydrolyzes to a ketone.

How do you predict whether one carboxylic acid derivative can be converted into another?

Compare their reactivities.

Conversions from more reactive to less reactive derivatives are generally easier:

Acid chloride → Anhydride → Ester → Amide.

Reverse conversions usually require activation or special reagents.

What are the key reagents for converting carboxylic acids into different derivatives?

Acid chloride: SOCl₂

Anhydride: P₂O₅, heat

Ester: ROH, H⁺

Amide: Amine + DCC, or NH₃ + heat

What are the most important mechanisms to know from Chapter 25?

• Nucleophilic acyl substitution

• Saponification

• Fischer esterification

• Amide formation using DCC

• Nitrile hydrolysis

Know where the nucleophile attacks, how the tetrahedral intermediate forms, and when proton transfers or leaving-group elimination occur.