Carboxylic Acid Derivatives: Reactivity Order and Nucleophilic Acyl Substitution

Carboxylic acid derivatives are compounds in which the OH of a carboxylic acid is replaced by another group: a halide (acid chloride), a carboxylate (anhydride), an alkoxy group (ester) or an amine (amide). They share one reaction type, nucleophilic acyl substitution, and one ranking of reactivity.

Reactivity order

Acid chloride > anhydride > ester (about equal to carboxylic acid) > amide

Reactivity tracks how good the leaving group is and how electrophilic the carbonyl carbon is.

The resonance point explains why amides are the least reactive and why peptide bonds are stable enough to build proteins, as discussed in the protein structure note. Leaving group quality follows the same acid strength logic as the pKa note: weaker base means better leaving group.

The mechanism: addition, then elimination

Unlike SN2, this is a two-step process through a tetrahedral intermediate.

1. Addition. The nucleophile attacks the carbonyl carbon. The C=O pi bond breaks and the oxygen becomes negative, giving a tetrahedral intermediate. The carbon changes from sp² to sp³.
2. Elimination. The C=O reforms and the leaving group departs.

The net result is that the leaving group is swapped for the nucleophile. Compare this with the single-step backside attack in the SN1/SN2 note. Acyl substitution occurs at a planar carbonyl carbon, so there is no backside inversion.

Interconversion rule

You can convert a more reactive derivative into a less reactive one directly, but not the reverse without extra activation.

• Acid chloride + alcohol gives an ester.
• Acid chloride + amine gives an amide.
• Anhydride + amine gives an amide plus a carboxylic acid.
• Ester + amine can give an amide, but slowly.
• Amide to ester or acid usually needs harsh conditions such as strong acid or base and heat.

Hydrolysis

Hydrolysis gives the carboxylic acid (or carboxylate in base) and the leaving group. Base-promoted ester hydrolysis is called saponification. It is effectively irreversible because the carboxylate product is deprotonated and no longer electrophilic. Acid-catalyzed ester hydrolysis is reversible, and Le Chatelier's principle controls the yield.

Spotting them by IR

The C=O stretch sits at different positions: acid chlorides near 1800 cm^-1, anhydrides show two peaks near 1800 and 1750, esters near 1735, and amides lower, about 1650, because of resonance. The IR and NMR note covers the method.

Common traps

• Reversing the reactivity order. Amides are the least reactive.
• Calling it SN2. It goes through a tetrahedral intermediate, not a single concerted step.
• Forgetting the nucleophile must be able to displace a worse leaving group.

One-minute recap

Acid chloride > anhydride > ester > amide, set by leaving group ability and resonance donation. Nucleophilic acyl substitution is addition to the carbonyl followed by elimination of the leaving group, and reactive derivatives convert easily into less reactive ones.