Carboxylation of Grignard Reagents

Reaction type:  Oxidative Insertion then Nucleophilic Addition

Summary:

• Magnesium can insert into C-X bonds (X = Br, I)  in ether or THF to give Grignard reagents.
• Grignard reagents react with CO₂ (which can be viewed as a C=O compound) to give the carboxylic acid after acid work-up.
• Note that the carbon skeleton is extended by 1 C atom during this reaction.
• Remember that Grignard reagents also react with -OH, -NH, -SH and C=O groups.

Preparation of Carboxylic Acid Derivatives

	acyl chlorides
	acid anhydrides
	esters
	amides
	carboxylates

Reaction type:  Nucleophilic Acyl Substitution

Overview

• In principle, all carboxylic acids derivatives can be made from the parent carboxylic acid see above.
• In practice, there may be better methods, e.g. amides are more readily prepared from the more reactive acyl chlorides.
• However, appreciating the relationship between these groups is important and useful.

For example, an ester to the acid plus the alcohol:

 

Preparation of Acyl Chlorides

Summary

• Acyl chlorides are prepared by treating the carboxylic acid with thionyl chloride, SOCl₂, in the presence of a base.
• Acyl chlorides are by far the most commonly encountered of the acyl halides.
• This reaction is discussed in more detail in Chapter 20.

• Reaction of Alcohols with SOCl₂

Preparation of Acid Anhydrides

Summary

• Symmetrical anhydrides can be are prepared by heating the carboxylic acid
• Symmetrical anhydrides are by far the most commonly encountered, e.g. acetic anhydride.
• This reaction will be discussed in more detail in Chapter 20.

Preparation of Esters

Summary

• This reaction is also known as the Fischer esterification.
• Esters are obtained by refluxing the parent carboxylic acid with the appropriate alcohol with an acid catalyst.
• The equilibrium can be driven to completion by using an excess of either the alcohol or the carboxylic acid, or by removing the water as it forms.
• Alcohol reactivity order :  CH₃OH > 1^o > 2^o > 3^o (steric effects)
• Esters can also be made from other carboxylic acid derivatives, especially acyl halides and anhydrides, by reacting them with the appropriate alcohol in the presence of a weak base (see chapter 20)
• If a compound contains both hydroxy- and carboxylic acid groups, then cyclic esters or lactones can form via an intramolecular reaction. Reactions that form 5- or 6-membered rings are particularly favorable.

MECHANISM FOR REACTION FOR ACID catalyzed ESTERIFICATION
Step 1: An acid/base reaction. Protonation of the carbonyl makes it more electrophilic.
Step 2: The alcohol O functions as the nucleophile attacking the electrophilic C in the C=O, with the electrons moving towards the oxonium ion, creating the tetrahedral intermediate.
Step 3: An acid/base reaction. Deprotonate the alcoholic oxygen.
Step 4: An acid/base reaction. Need to make an -OH leave, it doesn't matter which one, so convert it into a good leaving group by protonation.
Step 5: Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral water molecule.
Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the ester product.

Preparation of Amides

Summary

• In general, it is not easy to prepare amides directly from the parent carboxylic acid.
• The acid will protonate the amine preventing further reaction since the carboxylate is a poor electrophile and the ammonium ion is not nucleophilic.

• It is much easier to convert the carboxylic acid to the more reactive acyl chloride first.

Related Reactions

• Preparation of Acyl Chlorides
• Preparation of Esters

Reduction of Carboxylic Acids

Reaction usually in Et₂O or THF followed by H₃O⁺ work-ups

Summary

• Carboxylic acids are less reactive to reduction by hydride than aldehydes, ketones or esters.
• Carboxylic acids are reduced to primary alcohols.
• As a result of their low reactivity, carboxylic acids can only be reduced by LiAlH₄ and NOT by the less reactive  NaBH₄

• Reaction of RLi and RMgX with esters
• Reaction of RLi and RMgX with carbon dioxide
• Reduction of Aldehydes and Ketones
• Reduction of Esters

a-Halogenation (Hell-Volhard-Zelinsky reaction)

• Reagents most commonly : Br₂ and either PCl₃, PBr₃ or red phosphorous in catalytic amounts.
• Carboxylic acids can be halogenated at the C adjacent to the carboxyl group.
• This reaction depends on the enol type character of carbonyl compounds.
• The product of the reaction, an a-bromocarboxylic acid can be converted via substitution reactions to a-hydroxy- or a-amino carboxylic acids.

• a-Halogenation of Aldehydes and Ketones

Decarboxylation

Summary

• Loss of carbon dioxide is called decarboxylation.
• Simple carboxylic acids rarely undergo decarboxylation.
• Carboxylic acids with a carbonyl group at the 3- (or b-) position readily undergo thermal decarboxylation, e.g. derivatives of malonic acid.

• The reaction proceeds via a cyclic transition state giving an enol intermediate that tautomerizes to the carbonyl.

DECARBOXYLATION
Step 1: Remember curly arrows flow.... Start at the protonation of the carbonyl, break the O-H bond and form the p bond, break the C-C and make the C=C. Note the concerted nature of this reaction and the cyclic transition state.
Step 2: Tautomerization of the enol of the carboxylic acid leads to the acid product (not shown here).