Nucleophilic Acyl Substitution - Reactions of Acyl Derivatives - Carboxylic Acids

Carboxylic Acids

Carboxylic acids are not especially reactive towards nucleophilic substitution, though they can be converted to other acyl derivatives. Converting a carboxylic acid to an amide is possible, but not straightforward. Instead of acting as a nucleophile, an amine will react as a base in the presence of a carboxylic acid to give the ammonium carboxylate salt. Heating the salt to above 100 °C will drive off water and lead to the formation of the amide. This method of synthesizing amides is industrially important, and has laboratory applications as well. In the presence of a strong acid catalyst, carboxylic acids can condense to form acid anhydrides. The condensation produces water, however, which can hydrolyze the anhydride back to the starting carboxylic acids. Thus, the formation of the anhydride via condensation is an equilibrium process.

Under acid-catalyzed conditions, carboxylic acids will react with alcohols to form esters via the Fischer esterification reaction, which is also an equilibrium process. Alternatively, diazomethane can be used to convert an acid to an ester. While esterification reactions with diazomethane often give quantitative yields, diazomethane is only useful for forming methyl esters.

Thionyl chloride can be used to convert carboxylic acids to their corresponding acid chlorides. First, carboxylic acid 1 attacks thionyl chloride, and chloride ion leaves. The resulting oxonium ion 2 is activated towards nucleophilic attack and has a good leaving group, setting it apart from a normal carboxylic acid. In the next step, 2 is attacked by chloride ion to give tetrahedral intermediate 3, a chlorosulfite. The tetrahedral intermediate collapses with the loss of sulfur dioxide and chloride ion, giving protonated acid chloride 4. Chloride ion can remove the proton on the carbonyl group, giving the acid chloride 5 with a loss of HCl.

Phosphorus(III) chloride (PCl₃) and phosphorus(IV) chloride (PCl₅) will also convert carboxylic acids to acid chlorides, by a similar mechanism. One equivalent of PCl₃ can react with three equivalents of acid, producing one equivalent of H₃PO₃, or phosphorus acid, in addition to the desired acid chloride. PCl₅ reacts with carboxylic acids in a 1:1 ratio, and produces phosphorus(V) oxychloride, POCl₃, as a byproduct.

Carboxylic acids react with Grignard reagents and organolithiums to form ketones. The first equivalent of nucleophile acts as a base and deprotonates the acid. A second equivalent will attack the carbonyl group to create a geminal alkoxide dianion, which is protonated upon workup to give the hydrate of a ketone. Because most ketone hydrates are unstable relative to their corresponding ketones, the equilibrium between the two is shifted heavily in favor of the ketone. For example, the equilibrium constant for the formation of acetone hydrate from acetone is only 0.002.