Chapter 21 -Carboxylic Acid Derivatives

Acid Chloride to anhydride

Starting

• Acid Chloride ( Cl - C (=O) - R)

Reagent

• carboxylic Acid

End product Anhydride ( R - CO - O - CO - R)

Mechanism

1. Addition of the reagent : the Oxygen from the carboxylic attacks to acid chloride → the double bond oxy of the acid chloride becomes a singe bond

A Tetrahedral intermediate forms

2. Chloride (Cl⁻) leaves, restoring the C=O double bond

3. The Cl removes a proton (H⁺) → forms the anhydride product

Acid Chloride to Ester

Starting

• Acid Chloride

Reagents

• Alcohol

• Pyridine

Mechanism

1. the alcohol attacks the acid chloride forming tetrahedral. ( the double bond with O of acid chloride becomes a single bond)

2. the Cl Leaves causing the double bond with oxygen to be restored

3. The Pyridine comes in and take a hydrogen from R - OH

Acid chloride to Amide

Starting

• Acid chloride (R-C(=O)-Cl)

Reagent

• Amine (R₂N-H) — can be ammonia, primary amine (1°), or secondary amine (2°)

Mechanism

Step 1: Addition of nucleophile

• The amine's nitrogen attacks the carbonyl carbon

• Forms tetrahedral intermediate

Step 2:

• Chloride ion (Cl⁻) leaves

• Restores the C=O double bond

Step 3: Loss of a proton

• Another Amine removes a proton from the nitrogen

• Forms the amide product

Product types:

• Ammonia (NH₃) → primary amide (1°)

• Primary amine (RNH₂) → secondary amide (2°)

• Secondary amine (R₂NH) → tertiary amide (3°)

Anhydride to Ester

Starting:

• Anhydride ( R - CO - O - CO - R)

Reagent:

• Alcohol ( R-OH)

Mechanism

1. Alcohol Attacks one carbonyl group of the anhydride forming a tetrahedral intermediate

2. The other acid salt (carboxylate salt) ( O - C=O - R) acts a leaving group

3. The acid group that left takes a hydrogen from the R - OH

End product:

• Ester

• Acid

Anhydride to amide

Starting

• Anhydride

Reagent:

• Amine ( can be can be ammonia, primary amine (1°), or secondary amine (2°)

Mechanism

1. the amine attacks the carbon forming a tetrahedral

2. the acid group ( O - C=O - R) acts a leaving group

3. The same acid takes the Hydrogen from the amine

End product

• Amide

• Acid

Product types:

• Ammonia (NH₃) → primary amide (1°)

• Primary amine (RNH₂) → secondary amide (2°)

• Secondary amine (R₂NH) → tertiary amide (3°)

Ester to amide ( Ammonolysis)

Starting

• ester ( R - CO - OR)

Reagent :

• NH₃ Or 1° Amine (R - NH₂)

MUST BE AMONIA OR 1° AMINE

Mechanism

1. the amine attacks the carbon of the ester

2. a tetrahedral intermediate is formed

3. the OR acts asa leaving group and breaks the bond with carbon

4. The same OR takes a hydrogen from the Nitrogen in amine

End Product

• Amide

• Alcohol

Hydrolysis of acid chlorides and Anhydrides

Starting

• Acid chloride or Anhydrides

ReagentL

• Water (H₂O)

Mechanics

• water comes in attacks the carbon from acid chloride adding H- O -H

• the Chloride (Cl) leaves

• Another water comes in a removed a hydrogen from H-O-H

End product

• carboxylic acid

• H₃O⁺

With Anhydrides → 2 carboxylic acid

Hydrolysis of Amides

Starting :

• Amide → R–C(=O)–NHR′

Reagent:

• H₃ O⁺ ( or strong acid H₂SO₄)

• H₂O

Mechanism

Part 1:

1. the Amide Oxygen attacks the H⁺ (acid) taking a hydrogen making (OH)

2. water comes in and attacks the carbon of the amides cause the double bond with oxygen and carbon to become single bonded

3. Another water comes in and takes a hydrogen from the H-O-H

Part 2:

1. Another Acid (H⁺) comes in and the Nitrogen (NH₂) attacks it taking a Hydrogen making (NH₃)

2. The NH₃ Leaves restoring the double bond with carbon and oxygen

3. the NH₃ takes the Hydrogen from the O

End Product:

• carboxylic acid

• NH₄

Hydrolysis of Nitriles

Starting:

• Nitriles ( R–C≡N)

Reagent :

• OH , H₂O → basic

• H⁺ , H₂O → Acidic

End product

under acidic condition = Carboxylic acid

Basic condition = Carboxylate ion

Reduction of Esters, carboxylic acid, acid halide to 1 Alcohols

Starting

• Ester: R-C(=O)-O-R

• Carboxylic Acid : R-C(=O)-OH

• Acid chlorides R-C(=O)-Cl

Reagent:

• LiALH₄

• LAH

• H₃O⁺

Mechanism

1. the Carbon of the starting reagent attacks the LiAlh₄ taking a hydrogen from the reagent , the double with Oxygen becomes singular

2. A tetrahedral intermediate is formed R - C- O- OR

3. The OR leaves and he double bond is restored → forming an aldehyde

4. Another LiALH₄ comes in and the carbon of the aldehyde attacks it taking a Hydrogen breaking the double bond

5. Acid comes in and the Oxygen takes a hydrogen forming a primary alcohol

Reduction of Acyl Halides to Aldehydes

Starting :

• Acyl Halides ( R - C ( = O) - X)

Reagent

• LiALH ( O- t -BU)₃

End product

• aldehyde

Reduction to aldehydes with DIABL

Starting

• Esters R - C (=O) - OR

Reagent

• DIABL or DIBAL -H

• (i-Bu)₂ALH

End product

• aldehydes

Reduction of amide to an amine

Starting:

• Amide ( R - C ( = O ) - NH₂

Reagent:

• LiALH₄

• H₂O

End product

• amine

R - CH₂ - NH₂

R - CH₂ - NH - R

Reduction of Nitriles to primary Amines

Starting:

• Nitriles R–C≡N

Reagent:

• LAH or LiALH₄

• H₂O

Mechanism

1. One of the hydride ions (H⁻) from LiAlH₄ attacks the electrophilic carbon of the nitrile triple bond. This adds hydrogen to the carbon.

2. A second hydride attacks. Now you have two H atoms added to the carbon

3. When the water comes in it give two more hydrogen to nitrogen making the Al leave

End product primary amines

Gringard reagent → to alcohol

Starting

• Ester

• Acid chloride

Reagent

• R - MgX (comes in 2x)

• H₃O ⁺

Mechanism

1. the grignard attacks the starting product giving a R group

2. a tetrahedral intermediate is formed where the double bond of O is single bonded

3. The OR group leaves forming a Ketone

4. Another R - mgX comes in and attack the ketone give an R group

FInal product

2 or 3 Alcohol depending on the R group

DIfferent Acid chloride reaction

Friedel crafts acylation

Starting

• acid chloride

• Benzene ring

Reagent

• AlCL₃

• H₂O

FInal product

• Ketone

Anhydride Synthesis

Starting

• Acid Chloride

• Carboxylate

• Carboxylic Acid

Reagent :

• pyridine

Reaction of Anhydrides

Acetic Formic Anhydride

Starting

• Acetic Formic Anhydride CH₃-C(=O)-O-C(=O)-H)

Reagent

• R - OH

• R - NH₂

End

• Ester

• Amide

• Carboxylic Acid

lactone formation

Starting :

• hydroxy acid (a molecule with both -OH and -COOH groups)

Reagents:

5-6 membered rings: Form easily with just H⁺

7+ membered rings: Needs H⁺ And Benzene

End product:

• Lactrones : cyclic esters formed from hydroxy acids

Reactions of Amides

Formation of Lactams

Starting :

• An amino acid (a molecule with both -NH₂ and -COOH groups

Reagent

• Heat

End product

Lactam → cyclic amide

Mechanism of B-Lactam Acylation

Starting material:

• β-propiolactam (a 4-membered ring lactam with a C=O)

Reagent:

• Nuc: (a nucleophile — could be water, an amine, an alcohol, etc.)

• Water

Mechanism

1. the Nuc attacks the Carbon with the double bonde with Oxygen

2. The bond breaks between N and C

3. Water comes in and donates a Hydrogen to the Nitrogen (protonation)

End product

Open-chain amide with a protonated amine group → acylated product

Thioesters formation

Starting

• Carboxylic Acid

Reagent

• Thiol ( R - SH)

Mechanism

1. Thiol attacks the carbonyl carbon

2. Oxygen gets protonated to make water (a good leaving group)

Mechanism of Action of Acetyl CoA:

Starting :

• Acetyl CoA (acetyl coenzyme A) CH₃-C(=O)-S-CoA

Reagent:

Nuc: (a nucleophile — could be an -OH, -NH₂, -SH, or another nucleophile)

Mechanism

1. Nucleophile attacks the carbonyl carbon of acetyl CoA → forms a tetrahedral intermediate

2. CoA leaves as the leaving group

3. Acylated product forms — the nucleophile now has an acetyl group attached

End product

• acylated product (CH₃-C(=O)-Nuc)

• Plus free coenzyme A (CoA-SH)