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Carboxylic Acid Derivatives: Complete Reactions Guide

There are five major groups of carboxylic acid derivatives.

They are: acid chloride, anhydride, ester, amide and nitrile.


carboxylic acid derivatives
carboxylic acid derivatives

Carboxylic acid derivatives also differ in their reactivity towards a nucleophile. Acid Chlorides are most reactive followed by anhydride, ester, and amide.


carboxylic acid derivatives reactivity chart
carboxylic acid derivatives reactivity chart

GENERAL MECHANISM


We can think of the group next to the carbonyl (C=O) group as the leaving group (or future leaving group). For example: Cl for acid chloride, OR for ester and so on. This group will be replaced by the nucleophile that is reacting with the molecule.


This general concept will be applicable to most reactions. You will see a lot of reactions in this chapter but the good news is that they are all similar in the nucleophile replacing the leaving group.


Carboxylic acid derivatives reaction mechanism in basic and acidic conditions
Carboxylic acid derivatives reaction mechanism in basic and acidic conditions


ACID CHLORIDE REACTIONS

Acid chlorides are most reactive and can be converted into carboxylic acids, anhydrides, esters, and amides. Again, we can just think of Cl as the leaving group and the nucleophile replacing it.


1. Acid Chloride To Carboxylic Acid Conversion


Reagent: H2O


Product: Replace Cl with OH

acid chlorides conversion to carboxylic acid with mechanism
acid chlorides conversion to carboxylic acid with mechanism

2. Acid Chloride To Ester Conversion


Reagent: ROH

Product: Replace Cl with OR


acid chloride to ester conversion

3. Acid Chloride To Anhydride Conversion

Reagent: RCOO- ( salt of carboxylic acid)

Product: Replace Cl with OCOR

Acid Chloride To Anhydride reaction
Acid Chloride To Anhydride reaction


4. Reaction of Acid Chloride with Organometallic Reagents ( Grignard or Organolithium)


Reagent: 1. 2RMgX or 2RLi 2. H2O, HCl

Product: Get rid of Cl. Turn =O into OH, and add two R groups (from RMgX) to the carbon with OH

For this reaction two equivalents of grignard or organolithium reagent are needed. The first equivalent attacks C=O pushing electrons up to the oxygen. In the next step electrons from the oxygen go down to make a double bond and kicking off Cl. The reaction does not stop here! Instead, another equivalent of Grignard or organolithium attacks the c=O pushing electrons up the oxygen. Finally, we use water or acid in the second step to protonate O- to become OH.

Reaction of Acid Chloride with Organometallic Reagents ( Grignard or Organolithium)
Reaction of Acid Chloride with Organometallic Reagents ( Grignard or Organolithium)

5. Acid Chloride To Amide Conversion


Acid chloride can also be converted to an amide by reaction with NH3 (ammonia) or primary or secondary amine. This reaction is fast and irreversible.


Reagent: NH3, RNH2 (primary amine) or R2NH (secondary amine)

Product: Replace Cl with NH2, NHR or NR2.


Acid Chloride To Amide Conversion
Acid Chloride To Amide Conversion

6. Acid Chloride To Ketone Conversion


Reagent: 1.R2CuLi 2. H2O

Product: Replace Cl with R from Gilman Reagent

Acid Chloride and Gilman reagent ( diorganocopper) reaction
Acid Chloride and Gilman reagent ( diorganocopper) reaction



ANHYDRIDE REACTIONS

Anhydrides are very similar to acid chlorides in their reactions. Let's take a look:


1. Anhydride to Carboxylic Acid Conversion

This is a reaction of anhydride with water.


Reagent: H2O

Product: Replace OCOR with OH

 Anhydride to Carboxylic Acid Conversion
Anhydride to Carboxylic Acid Conversion

2. Anhydride to Ester Conversion

This is a reaction of anhydride with alcohol


Reagent: ROH

Product: Replace OCOR with OR

Anhydride to Ester Conversion
Anhydride to Ester Conversion

3. Anhydride to Amide Conversion

This is a reaction of anhydride with ammonia or amines.


Reagent: NH2, RNH2 or R2NH

Product: replace OCOR with NH2 or NHR or NR2.

Anhydride to Amide Conversion
Anhydride to Amide Conversion

ESTER REACTIONS


1. Ester to Carboxylic Acid Conversion


Reagent: H2O, H3O+ or 1.OH-, H2O 2.H3O+

Product: Replace OR with OH

Ester to Carboxylic Acid Conversion
Ester to Carboxylic Acid Conversion

Mechanisms

Mechanism Of Ester Hydrolysis In Acid
Mechanism Of Ester Hydrolysis In Acid

Mechanism Of Ester Hydrolysis In Base
Mechanism Of Ester Hydrolysis In Base

2. Ester to Another Ester Conversion (Transesterification)


Reagent: R'OH with H+

Product: Replace OR with OR'

transesterification reaction
transesterification reaction

3. Ester to Alcohol Conversion: Reaction Of Ester with Grignard or Organolithium Reagents.

Reagent: 1. 2 equivalents of RMgX or RLi 2. H2O, HCl

Product: Get rid of OR on the ester, and turn =O into OH. Add two R groups from the organometallic reagent to the carbon with OH.


Reaction of Ester with Grignard or Organolithium Reagent
Reaction of Ester with Grignard or Organolithium Reagent

Mechanism of ester reaction with Grignard reagent
Mechanism of ester reaction with Grignard reagent


4. Ester To Amide Conversion


AMIDE REACTIONS



1. Amide to Carboxylic Acid Conversion

Amides are less reactive than other carboxylic acid derivatives and require more rigorous conditions for hydrolysis.


Reagent: HCl, H2O heat OR NaOH, H2O, heat

Product: replace NH2 or NHR with OH