Carboxylic acids unreactivity towards nucleophiles

Relative reactivities of carboxylic acid derivatives toward nucleophilic acyl substitution. A more reactive derivative may be converted to a less reactive derivative by treatment with an appropriate reagent. Treatment of a carboxylic acid with thionyl chloride converts the carboxylic acid to the more reactive acid chloride. Carboxylic acids are about as reactive as esters under acidic conditions, but are converted to the unreactive carboxylate anions under basic conditions. 

Why carboxylic acids are unreactive towards nucleophilic substitution. 

Chemically speaking these dioxygenases have to carry out a difficult task as they catalyze the mono-hydroxylation of substrates that are often unreactive towards nucleophilic, electrophilic and free radical reagents. In this respect they resemble the mono-oxygenases (8) with the important difference that the other atom of oxygen is not reduced to water, but is incorporated into the new carboxyl group which arises from the a-keto acid on oxidative decarboxylation (eq. 63) (2). 

The most unreactive carboxylic acid derivatives, esters and amides, usually require some form of catalysis to activate the carbonyl to nucleophilic attack. Acid catalysis for amide hydrolysis is quite effective. Since amides are so unreactive toward nucleophilic attack, specific-acid catalysis is most commonly observed. Here, full protonation of the amide carbonyl is necessary to activate the species enough that nucleophilic attack is possible (Figure 10.19 A). With acidic conditions up to about 80% acid (requiring values see Section 5.2.5),... 

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