Amide Formation Dcc Coupling

Carboxylic Acid to Amide (DCC Coupling)

Exam Answer

Show mechanismTry your substrate
Reagents
DCC plus amine (often with additive like DMAP)
Major outcome
RCO2H plus amine to amide
Selectivity
Mild coupling avoids acid chloride route

Common traps

  • Acid plus amine alone gives ammonium salt (not amide)
  • Urea byproduct is expected
  • Additives can change rate/selectivity depending on substrate

Dicyclohexylcarbodiimide (DCC) activates a carboxylic acid toward nucleophilic attack by an amine, forging an amide and precipitating dicyclohexylurea (DCU). The key intermediate is the O-acylisourea; without additives it can rearrange to an unreactive N-acylurea, so reactions are usually run at 0–25 °C in dichloromethane or DMF with optional HOBt/HOAt or catalytic DMAP. DCU typically crystallizes, simplifying workup.



Quick Summary

Reagents / conditions RCO₂H (1.0 eq) + R′NH₂ / NH₃ / R′₂NH (1.1–2.0 eq) + DCC (1.0–1.3 eq); optional HOBt/HOAt (0.5–1.0 eq) or DMAP (5–10 mol %); dry CH₂Cl₂ or DMF, 0 °C → rt.
Outcome Secondary amides from RNH₂, primary amides from NH₃, tertiary amides from R₂NH, plus DCU (precipitates in CH₂Cl₂).
Mechanism Carboxylate adds to DCC → O-acylisourea; the amine attacks the acyl carbon → tetrahedral intermediate; collapse expels DCU to give the amide. Additives detour through active esters (HOBt/HOAt) or acyl-DMAP.
Pitfalls N-acylurea (O→N migration) and α-racemization via oxazolone pathways—mitigated by low temperature, prompt aminolysis, and HOBt/HOAt or DMAP.
Amines that work RNH₂ (standard), NH₃ (primary amides), R₂NH (tertiary amides). Tertiary amines (R₃N) lack N–H and only serve as bases/catalysts.


Mechanism — Five RDKit Frames

Step 1 activation: carboxylate adds to DCC to form the O-acylisourea
Step 1 — O-acylisourea formation. Carboxylate O attacks the central carbodiimide carbon while the proton transfers to a DCC nitrogen.
Step 2 amine addition to the activated acyl carbon
Step 2 — Aminolysis. R′NH₂ / NH₃ / R′₂NH attacks the acyl carbon to give a tetrahedral intermediate.
Step 3 proton transfers prepare the isourea fragment to leave
Step 3 — Proton shuttles (solvent/additives) neutralize the amine and stage the isourea fragment as a leaving group.
Step 4 collapse regenerates C=O and expels DCU
Step 4 — Collapse. Electrons drop back to C=O as dicyclohexylurea (DCU) departs, forming the amide.
Product frame showing the amide plus DCU by-product
Step 5 — Product. After collapse, the protonated amide and insoluble dicyclohexylurea (DCU) remain; workup removes the urea to reveal the neutral amide.


Mechanistic Checklist (Exam Focus)

  • Always show the O-acylisourea before the amine attacks—this is not an acid chloride route.
  • Include a tetrahedral intermediate for the aminolysis step; collapse generates the amide plus DCU.
  • Mention N-acylurea formation (O→N migration) and how HOBt/HOAt or DMAP suppress it.
  • For α-stereogenic acids, note the racemization risk via oxazolone and the need for low-T / rapid coupling.
  • Primary and secondary amines (and NH₃) form amides; tertiary amines do not because they lack N–H.
  • DCU precipitation is diagnostic and simplifies workup (filter, wash, extract).


Worked Examples

NH₃ → Primary amide (highlighted NH₂)

Acetic acid + NH₃ + DCC; teal highlight tracks the –NH₂ fragment delivered by ammonia.

Acetic acid reactant
DCC + NH3 reagent button NH3 fragment highlighted
Primary amide with highlighted NH2

Dry conditions prevent hydrolysis of the O-acylisourea.

Cyclohexylmethylamine (RNH₂) → Secondary amide

Benzoic acid + aminomethylcyclohexane; the teal highlight shows the portion of the amine that ends up on the product.

Benzoic acid reactant
DCC + RNH2 reagent button Cyclohexylmethylamine fragment highlighted
Secondary amide with highlighted cyclohexylmethyl portion

Cyclohexylmethylamine delivers a bulky secondary amide in excellent yield.

Dimethylaminoethane (R₂NH) → Tertiary amide

p-Anisic acid + dimethylaminoethane; the product highlight shows the tertiary amine fragment that becomes part of the amide.

p-Anisic acid reactant
DCC + R2NH reagent button Dimethylaminoethane fragment (no highlight)
Tertiary amide with highlighted dimethylamino fragment

HOBt/HOAt or DMAP keeps the O-acylisourea from rearranging before aminolysis.

Trialkylamine (R₃N) → No amide product

DCC cannot form amides with tertiary amines; no N–H is available to transfer.

Acid plus trialkylamine starting point
Mock DCC + R3N reagent button Trialkylamine fragment (no highlight)
No amide — acid remains unchanged

Trialkylamines serve only as bases/catalysts; draw an “✗ No amide” note.



Scope & Limitations

  • Amines: RNH₂ and R₂NH couple efficiently; NH₃ is viable with dry conditions. Tertiary amines do not form amides (no N–H).
  • Acids: Aliphatic, benzylic, and aromatic acids work; sterically hindered acids may require DMAP or alternate carbodiimides (DIC, EDC).
  • Additives: HOBt/HOAt form active esters that suppress N-acylurea and racemization; DMAP accelerates aminolysis, especially for hindered R₂NH.
  • Stereochemistry: α-Chiral acids risk racemization through oxazolone formation—keep cold, react quickly, add HOBt/HOAt.
  • Functional groups: Free alcohols/thiols may compete; protect sensitive sites. Water hydrolyzes O-acylisourea.
  • Operational: DCU is insoluble in CH₂Cl₂ (filter), but more soluble in DMF; cooling can force precipitation.


Practical Tips & Pitfalls

  • Order of addition: Either pre-activate acid + DCC at 0 °C for ~10 min then add amine, or add DCC to a premixed acid/amine. Pick one method and stick with it.
  • Temperature: Start cold (0–5 °C) to limit N-acylurea and racemization; warm to rt only after aminolysis is underway.
  • Additives: Use HOBt/HOAt (0.5–1.0 eq) or DMAP (5–10 mol %) whenever the amine is hindered or the acid is α-chiral.
  • Workup: Filter DCU through celite, rinse with solvent, then proceed to usual aqueous workup. Residual DCU on silica can be minimized by pre-filtration.
  • Safety: DCC is a potent skin sensitizer—gloves and dedicated spatulas only. Dispose of DCU-containing waste appropriately.
  • Moisture: Keep everything dry; water hydrolyzes the O-acylisourea and wastes DCC.


Exam-Style Summary

RCO₂H + DCC → O-acylisourea → amine attack → tetrahedral intermediate → amide + DCU (ppt).
RNH₂ → secondary amide, NH₃ → primary amide, R₂NH → tertiary amide.
Use HOBt/HOAt or DMAP to minimize N-acylurea and racemization; tertiary amines (R₃N) do not couple.



Interactive Toolbox

  • Mechanism Solver — Choose the DCC reagent buttons (NH₃ / RNH₂ / R₂NH) to watch each mechanism variant rendered frame-by-frame.
  • Reaction Solver — Load the same NH₃ / RNH₂ / R₂NH presets to preview the amide outcomes and warnings just like the mechanism view, but in quiz form.
  • IUPAC Namer — Confirm names like “cyclohexyl benzamide” or “N,N-dimethyl p-anisamide” after running the solver.

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