Peptide coupling with DCC: practice and mechanism
DCC activates the free COOH group of the Boc amino acid. The NH₂ group of glycine methyl ester attacks: a peptide bond (–CO–NH–) forms. The Boc group and the methyl ester stay.
Example
DCC activates the carboxylic acid (O-acylisourea, a good leaving group). The free amino group of glycine methyl ester attacks, forming the peptide bond and dicyclohexylurea. Boc on the N and the methyl ester on the C stop the building blocks reacting with themselves.
Mechanism step by step
- 1
The carboxylic acid adds to DCC (a carbodiimide): an O-acylisourea forms, an activated ester.
- 2
The NH₂ group of glycine methyl ester attacks the activated carbonyl carbon.
- 3
Dicyclohexylurea (DCU) leaves and precipitates; the peptide bond forms.
Practice tasks
Which product forms, which reagent is needed? After each answer you see the explanation.
Which main product forms?
Typical mistakes
- DCC does not remove the Boc group. That needs a strong acid such as TFA in a separate step.
- The methyl ester survives the coupling; it is exactly what protects the glycine acid group. It is only hydrolysed later with NaOH.
- The N-acylurea is a side reaction when no amine attacks. With the glycine ester the dipeptide forms.
Often confused with: Amide from acyl chloride · Fischer esterification
Frequently asked questions
Why not just heat the acid and amine?
Acid and amine first form a salt (carboxylate and ammonium). Amide formation would then need over 200 °C, at which amino acids racemise and decompose.
What is the racemisation problem?
Activated amino acids can lose the α-H via an oxazolone and racemise. Additives such as HOBt trap the activated ester and reduce this.