Amide Formation Dcc Coupling

Amide Formation from Carboxylic Acids using DCC (Carbodiimide Coupling)

Amide Formation from Carboxylic Acids using DCC (Carbodiimide Coupling)

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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