Nucleophilic Acyl Substitution

Many of the same kinds of nucleophiles that add to aldehyde and ketone carbonyls will attack the carbonyl of an acid (acyl) derivative like an acid chloride, and yield substitution products. This substitution occurs in two steps, rather than a direct S_N2, because:

The filled-empty interaction is between the filled p on the nucleophile and the empty p* orbital of the carbonyl, whereas in the S_N2 case, the empty orbital is the s* of the C-X bond

Just like nucleophilic addition, nucleophilic acyl substitution comes in two flavors:

Uncatalyzed

Whereas the majority of these reactions will occur for all leaving groups with all nucleophiles, the reaction represented by the last nucleophile (the Claisen condensation) only occurs with esters.

Acid-Catalyzed

Catalysis by toluenesulfonic acid is shown, but a drop of sulfuric acid works well also. Just as in the nucleophilic addition case, protonation enhances the polarization of the p* orbital toward carbon.

Claisen condensation occurs only with esters.

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