For nucleophilic reactions at the carbonyl carbon which of the following do you think is the most reactive in this type of reaction?Question 8

The reactivity of carbonyl compounds toward nucleophilic attack depends largely on two factors:

• Electrophilicity of the carbonyl carbon
• Leaving group ability of the substituent attached to the carbonyl

1. Acid Chlorides

Most reactive

Acid chlorides have a highly electrophilic carbon due to the strong electron-withdrawing chlorine. Also, Cl⁻ is an excellent leaving group, making acid chlorides extremely reactive toward nucleophiles.

2. Carboxylic Acids

Moderately reactive

The -OH group is less electron-withdrawing than Cl, and although it’s not a great leaving group, the acid proton makes the molecule susceptible to activation (e.g., protonation), enabling nucleophilic substitution in acidic media.

3. Esters

Less reactive than carboxylic acids

Esters have an -OR group which is slightly electron-donating through resonance. This stabilizes the carbonyl and reduces the electrophilicity of the carbon. The alkoxide (-OR⁻) is a poorer leaving group than Cl⁻.

4. Ketones

Even less reactive

Ketones undergo nucleophilic addition rather than substitution. There is no leaving group. The carbonyl carbon is less electrophilic due to electron-donating alkyl groups attached to it.

5. Amides

Least reactive

Amides are stabilized by resonance between the lone pair on nitrogen and the carbonyl carbon. This greatly reduces electrophilicity. Also, the amide nitrogen is a poor leaving group (NH₂⁻ is highly basic and unstable).