Preparations of Carboxylic Acids
(overview)
 
 

Carbonation of Grignards
Hydrolysis of Nitriles
Oxidation of 1o Alcohols
Oxidation of Aldehydes
Oxidation of Alkyl Benzenes

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

Summary

• Grignard reagents react with dry ice (solid CO₂)  followed by aqueous acid work-up to give carboxylic acids.
• CO₂ can be thought of as a being a dicarbonyl compound :  O=C=O
• Note that the carboxylic acid contains one extra C atom compared to the original halide from which the Grignard reagent was prepared.

• Reaction of RLi and RMgX with esters
• Reaction of RLi and RMgX with epoxides
• Reaction of RLi and RMgX with carbon dioxide
• Hydride Reductions of Aldehydes and Ketones
• Hydride Reductions of Esters

NUCLEOPHILIC ADDITION OF RMgX TO CARBON DIOXIDE
Step 1: The nucleophilic C in the Grignard reagent adds to the electrophilic C in the polar carbonyl group, electrons from the C=O move to the electronegative O creating an intermediate magnesium carboxylate complex.
Step 2: This is the  work-up step, a simple acid/base reaction. Protonation of the carboxylate oxygen creates the carboxylic acid product from the intermediate complex.

 Hydrolysis of Nitriles

Reaction type : Nucleophilic Substitution then Nucleophilic Addition then  Nucleophilic Acyl Substitution !

Summary

• 1^o and 2^o alkyl halides (X = Cl, Br, I) or tosylates undergo S_N2 substitution with cyanide salts to give nitriles.
• Nitriles can be hydrolyzed to carboxylic acids without the isolation of the amide intermediate.
• Note that the carbon skeleton is extended by 1 C atom during this reaction sequence.
• Although aromatic nitriles cannot be prepared via the S_N2 reaction, they too can be converted to the aromatic carboxylic acid by hydrolysis.

Summary

• Primary alcohols, RCH₂OH, can be oxidized to carboxylic acids, RCO₂H, under aqueous conditions.
• Typical reagents are based on aqueous Cr (VI):

chromic acid, H₂CrO₄, chromate salts, e.g. Na₂CrO₄, dichromate salts, e.g. K₂Cr₂O₇
• The oxidation goes first to the aldehyde then the carboxylic acid.
• R can be alkyl or aryl.

Related Reactions

• Oxidations of Alcohols

Summary

• Aldehydes, RCHO, can be oxidized to carboxylic acids, RCO₂H, under aqueous conditions.
• Typical reagents are based on aqueous Cr (VI):

chromic acid, H₂CrO₄, chromate salts, e.g. Na₂CrO₄, dichromate salts, e.g. K₂Cr₂O₇
• The oxidation actually proceeds on the hydrate, RCH(OH)₂, formed by the reaction of water with the aldehyde.
• R can be alkyl or aryl.

Related Reactions

• Oxidations of Primary Alcohols
• Oxidations of Alcohols

Oxidation of Alkyl Benzenes
(review of Chapter 11)

Summary:

• When treated under strong oxidizing conditions, benzylic-H are oxidized all the way to the carboxylic acid.
• Common reagents : Hot, acidic KMnO₄
• The alkyl substituent can be methyl-, 1^o or 2^o alkyl.
• 3^o alkyl are not oxidized because they lack a benzylic-H.
• Simple alkane C-H can not be oxidized in this manner.
• This, therefore gives a potential route to aromatic carboxylic acids.

Question
Why don't 3^o alkyl aromatic substituents get oxidized ?