Amide Formation

Acid Chloride to Amide (NH3, RNH2, R2NH)

Exam Answer

Show mechanismTry your substrate
Reagents
NH3 or amines (often with base)
Major outcome
RCOCl to amide (RCONH2 / RCONHR / RCONR2)
Selectivity
Fast nucleophilic acyl substitution; moisture-sensitive starting material

Common traps

  • Excess amine scavenges HCl and keeps the nucleophile unprotonated
  • Water contamination gives carboxylic acid (or salt)
  • Tertiary amines can act as base but cannot form amides

Acid chlorides acylate amines rapidly to give amides via nucleophilic acyl substitution. Using NH₃, RNH₂, or R₂NH yields primary, secondary, or tertiary amides, respectively. Each acylation generates HCl, so you run with excess amine (nucleophile + base) or with an added base/HCl scavenger (pyridine, Et₃N, or aqueous NaHCO₃/Na₂CO₃ under Schotten–Baumann biphasic conditions).

Quick Summary

Reagents/conditions: Acid chloride + amine (2 eq) or 1 eq amine + base (1–2 eq); 0 °C → rt; dry solvent or Schotten–Baumann (biphasic base).
Outcome: NH₃ → 1° amide; RNH₂ → 2° amide; R₂NH → 3° amide.
Notes: Base/excess amine traps HCl (ammonium/pyridinium/Et₃NH⁺Cl⁻); keeps nucleophile free.


Mechanism — 4 Steps (Closed-Shell Nucleophilic Acyl Substitution)

  1. Amine attack (tetrahedral intermediate): Amine lone pair (NH₃/RNH₂/R₂NH) attacks the acyl carbon; C=O π shifts to oxygen → O⁻/N⁺ tetrahedral adduct.
    Amine attack on acid chloride forming tetrahedral intermediate
  2. Collapse; chloride leaves: O⁻ re-forms C=O; Cl⁻ departs to give an N‑acylammonium (protonated amide).
    Collapse of tetrahedral intermediate; chloride leaves
  3. Deprotonation to neutral amide: Base (excess amine, pyridine, Et₃N, or carbonate) removes N–H, yielding the neutral amide and ammonium/pyridinium chloride.
    Pyridine removes an N–H proton from the protonated amide; chloride is a spectator
  4. Product frame: Amide product (a secondary amide is pictured); the corresponding ammonium/pyridinium/Et₃NH⁺Cl⁻ salt is omitted. Neutral secondary amide product; salt byproduct omitted

Mechanistic Checklist (Exam Focus)

  • Show tetrahedral addition → collapse; Cl⁻ is the leaving group.
  • Include deprotonation/base step; otherwise amine becomes RNH₃⁺Cl⁻ and stalls.
  • Map outcomes by amine class: NH₃ → 1°, RNH₂ → 2°, R₂NH → 3° amide; 3° amines can act as bases or acyl-transfer catalysts, but do not directly furnish neutral amides.
  • Moisture competes (hydrolysis); Schotten–Baumann uses basic water to neutralize HCl continuously.
  • Anilines are slower; still acylate due to acid chloride reactivity—use base/longer time.

Worked Examples

Reactant

Benzoyl chloride

Reagent

NH₃ button

NH₃; excess traps HCl.

Ammonia reagent

Product

Benzamide

Benzamide + NH₄Cl (not shown)

Reactant

Cyclohexanecarbonyl chloride

Reagent

Primary amine plus base conditions

EtNH₂ (2 eq or + base)

Ethylamine reagent

Product

N-ethylcyclohexanecarboxamide

Secondary amide

Reactant

p-Nitrobenzoyl chloride

Reagent

Secondary amine plus base conditions

di-n-propylamine + base

Di-n-propylamine reagent

Product

N,N-di-n-propyl-p-nitrobenzamide

Tertiary amide (salt byproduct not shown)


Scope & Limitations

  • Works well: Aliphatic/aromatic acid chlorides with NH₃, primary, or secondary amines. Anilines react but may need stronger base/longer time.
  • Amines as base: 2 eq amine (one nucleophile, one base) is standard; external bases (pyridine/Et₃N/carbonate) keep amine deprotonated.
  • Schotten–Baumann: Biphasic H₂O/organic with NaHCO₃/Na₂CO₃ neutralizes HCl as it forms.
  • Tertiary amines: No N–H is available to form a neutral amide directly. They can serve as bases or form transient acylammonium intermediates during acyl transfer.
  • Competing hydrolysis: Water without base yields carboxylic acid (hydrolysis). Keep dry unless intentionally biphasic/basic.

Amide formation with an acid anhydride

An acid anhydride can replace the acid chloride as the acyl donor. Ethylamine and ethanoic anhydride give N-ethylethanamide, with the other acetyl group becoming ethanoic acid or ethanoate according to the acid–base conditions.

The amine attacks an acyl carbon, forming a tetrahedral intermediate; collapse expels carboxylate, and proton transfer gives the amide. Only one half of the anhydride is incorporated into that amide. Primary and secondary amines can give neutral amides by this route; tertiary amines have no N–H proton and cannot give the analogous neutral amide by simple deprotonation.

ethylamine gives N-ethylethanamide; ethanoic anhydride.
Net organic transformation; reagents and product accounting are described above.

Practical Tips

  • Add acid chloride slowly to cold amine/base to control exotherm and keep nucleophile free.
  • Choose base by goal: excess amine (simple), pyridine (traps HCl, can catalyze), Et₃N (non-nucleophilic), carbonate buffer (Schotten–Baumann).
  • For anilines/poor nucleophiles, avoid aqueous media unless using strong base; consider DMAP or heat if needed.
  • Filter or extract salts (RNH₃⁺Cl⁻, PyH⁺Cl⁻, Et₃NH⁺Cl⁻) during workup; wash organic layer with dilute base.

Exam-Style Summary

RCOCl + NH₃/RNH₂/R₂NH → tetrahedral intermediate → collapse (Cl⁻ leaves) → base deprotonates → RCONH₂/RCONHR/RCONR₂. Use 2 eq amine or amine + base to trap HCl; tertiary amines can serve as bases/catalysts but do not directly give neutral amides.


FAQ

How do I drive acid chloride → amide instead of hydrolysis?
Exclude water or run Schotten–Baumann with base to neutralize HCl; keep amine deprotonated.

Can tertiary amines make amides?
They do not directly give neutral amides because they lack N–H. They can act as bases or form transient acylammonium intermediates during acyl transfer (for example, pyridine).

Why use excess amine?
One equivalent acylates; the second scavenges HCl to maintain nucleophilicity.

Do anilines react?
Yes, but slower; use base/longer time. Acid chlorides are reactive enough to acylate anilines.


Interactive Toolbox

  • Mechanism Solver — Open the mechanism tool for additional practice; no preset or route toggle is verified for this guide.
  • Reaction Solver — Open reaction practice; automatic results for the worked examples above have not been verified.
  • IUPAC Namer — name amide products.

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