Amide Formation

Acid Chloride Reactions: Amide formation from Acid Chlorides using Amines (NH3, R2NH, and RNH2)

Acid Chloride → Amide with Amines (NH₃, RNH₂, R₂NH)

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.
    Base deprotonates N to give neutral amide; chloride captured
  4. Product frame: Amide product (primary/secondary/tertiary) with the corresponding ammonium/pyridinium/Et₃NH⁺Cl⁻ salt.
    Amide product with salt byproduct

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 act only as base.
  • 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

RNH₂ button

EtNH₂ (2 eq or + base)

Ethylamine reagent

Product

N-ethylcyclohexanecarboxamide

Secondary amide

Reactant

p-Nitrobenzoyl chloride

Reagent

R₂NH button

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: Bases only (no N–H); they do not furnish amides.
  • Competing hydrolysis: Water without base yields carboxylic acid (hydrolysis). Keep dry unless intentionally biphasic/basic.

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 are bases only.


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?
No. They lack N–H; they only act as bases (Et₃N, 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 — animate attack → collapse → deprotonation; toggle amine class and base mode (excess amine vs pyridine/Et₃N vs Schotten–Baumann).
  • Reaction Solver — choose acid chloride and amine class to preview amide class and salt byproduct.
  • IUPAC Namer — caption amide products without exposing SMILES.

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