Reactivity tracks how easily the leaving group departs from the tetrahedral intermediate. Chloride (from acyl chloride) is the best leaving group — it is the conjugate base of a strong acid. Carboxylate (from an anhydride) is next. Alkoxide (from an ester) and hydroxide (from a carboxylic acid) are comparable. Amide nitrogen donates its lone pair into the carbonyl, reducing electrophilicity and making nitrogen a very poor leaving group — so amides are the least reactive.
Question 2 True / False
Carboxylic acids are more acidic than alcohols primarily because the oxygen in carboxylic acids is more electronegative than the oxygen in alcohols.
TTrue
FFalse
Answer: False
Both functional groups contain oxygen atoms with similar electronegativity — the key difference is resonance. When a carboxylic acid loses a proton, the resulting carboxylate anion delocalizes the negative charge equally across both oxygens through resonance. This charge delocalization strongly stabilizes the conjugate base, making the acid much stronger (pKa ≈ 5) compared to alcohols, where the alkoxide anion has no resonance stabilization and bears the full charge on a single oxygen (pKa ≈ 16).
Question 3 Short Answer
Explain why it is possible to convert an ester directly to an amide, but converting an amide directly to an ester under mild conditions is not practical.
Think about your answer, then reveal below.
Model answer: An ester is more reactive than an amide toward nucleophilic substitution. Treating an ester with an amine (a nucleophile) displaces the alkoxide leaving group to form the amide — this works because alkoxide is a better leaving group than amide nitrogen. Reversing the reaction requires making the amide nitrogen leave, but nitrogen is a very poor leaving group because it donates its lone pair into the carbonyl, and amide hydrolysis requires forcing conditions (strong acid/base, heat). Mild conditions do not provide enough energy to overcome amide stability.
The reactivity hierarchy dictates the direction of these interconversions. You can always move 'down' the reactivity ladder (from more to less reactive) under mild conditions, because a better leaving group is being replaced by a worse one. Moving 'up' the ladder requires activating the less reactive compound first — typically by converting the amide to an acyl chloride using a reagent like thionyl chloride, then reacting the acyl chloride with the alcohol.