Nucleophilic Acyl Substitution
Reactions of Carboxylic Acid Derivatives: Chlorides, Anhydrides, Esters, and Amides.
By chemca Team • Updated Jan 2026
Carboxylic acid derivatives contain an acyl group ($R-CO-$) bonded to a leaving group ($L$). Unlike aldehydes and ketones (which undergo addition), these derivatives undergo substitution, where the leaving group is replaced by a nucleophile.
1. General Mechanism (Addition-Elimination)
Two-Step Process
- Addition (Rate Determining): The nucleophile ($Nu^-$) attacks the carbonyl carbon to form a tetrahedral alkoxide intermediate.
- Elimination: The lone pair on oxygen pushes back to reform the carbonyl double bond, expelling the leaving group ($L^-$).
$$ R-CO-L + Nu^- \rightleftharpoons \underset{\text{Tetrahedral Intermediate}}{R-C(O^-)(Nu)L} \rightarrow R-CO-Nu + L^- $$
2. Relative Reactivity of Derivatives
Leaving Group Ability
The reactivity depends on the basicity of the leaving group. Weaker bases are better leaving groups.
| Derivative | Structure | Leaving Group ($L^-$) | Basicity of L |
|---|---|---|---|
| Acid Chloride | $R-CO-Cl$ | $Cl^-$ (Chloride) | Weakest Base (Best LG) |
| Acid Anhydride | $(RCO)_2O$ | $RCOO^-$ (Carboxylate) | Weak Base |
| Ester | $R-CO-OR'$ | $R'O^-$ (Alkoxide) | Strong Base |
| Amide | $R-CO-NH_2$ | $NH_2^-$ (Amide) | Strongest Base (Worst LG) |
Reactivity Order: Acid Chloride > Anhydride > Ester > Amide
Conversion Rule: A more reactive derivative can be easily converted into a less reactive one (e.g., Chloride $\to$ Ester). The reverse is difficult and often requires special conditions.
3. Reactions of Acid Chlorides & Anhydrides
Versatile Intermediates
Acid chlorides and anhydrides react vigorously with nucleophiles.
1. Hydrolysis (Reaction with Water):
$$ R-COCl + H_2O \rightarrow R-COOH + HCl $$
2. Alcoholysis (Reaction with Alcohol):
$$ R-COCl + R'OH \xrightarrow{\text{Pyridine}} R-COOR' + HCl $$
Pyridine neutralizes the HCl formed.
3. Aminolysis (Reaction with Ammonia/Amines):
$$ R-COCl + 2NH_3 \rightarrow R-CONH_2 + NH_4Cl $$
4. Reactions of Esters
Fischer Esterification & Hydrolysis
A. Fischer Esterification (Formation):
Reversible reaction between Acid and Alcohol catalyzed by acid ($H_2SO_4$).
$$ RCOOH + R'OH \xrightleftharpoons{H^+} RCOOR' + H_2O $$
B. Acidic Hydrolysis (Reverse of Esterification):
$$ RCOOR' + H_2O \xrightleftharpoons{H^+} RCOOH + R'OH $$
C. Saponification (Alkaline Hydrolysis):
Irreversible reaction with base (NaOH). Yields Salt of Acid (Soap) and Alcohol.
$$ RCOOR' + NaOH \rightarrow RCOO^-Na^+ + R'OH $$
D. Transesterification:
Reaction of an ester with an alcohol to exchange the alkoxy group.
$$ RCOOR' + R''OH \xrightleftharpoons{H^+} RCOOR'' + R'OH $$
Knowledge Check
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