Organic Chemistry MCAT Practice Exam

Which of the following carboxylic acid derivatives is the most reactive?

1. Amide

2. Ester

3. Acid Anhydride

4. Acid Halide

The correct answer is: Acid Halide

Carboxylic acid derivatives vary in their reactivity due to the nature of their leaving groups and the stability of the resulting species after nucleophilic attack. Acid halides are particularly reactive because they have a good leaving group (the halide ion) and an electrophilic carbonyl carbon that is highly susceptible to nucleophilic attack. In the case of acid halides, the carbonyl carbon is electrophilic due to the strong electronegative nature of the halogen, which pulls electron density away from the carbon. This makes the carbon much more positive and attractive to nucleophiles, facilitating faster reactions. Additionally, when the nucleophile attacks, the leaving group is a stable halide ion, which further drives the reaction forward. In contrast, amides have a nitrogen in the leaving group position, which is a relatively poor leaving group because of its stronger bond with carbon and the resonance stabilization it provides to the carbonyl. Esters have a similar situation, but the leaving group (alkoxide) is still less stable than a halide. Acid anhydrides have moderate reactivity, being more reactive than esters and amides but less reactive than acid halides, as they result in a carboxylic acid upon hydrolysis