Amide coupling: EDC/HOBt template

EDC activates the acid as an O-acylisourea; HOBt intercepts it as the OBt ester, which the amine attacks to give the amide and the water-soluble urea. Key points cover HATU, racemisation and N-acylurea.

Mechanism step by step

Carbodiimide activation: O-acylisourea, then the OBt active ester, then the amide

1. Proton transfer – The acid protonates the carbodiimide N
2. O-Acylisourea – Carboxylate adds to the central carbon
3. OBt active ester – OBt⁻ takes the acyl group; the isourea leaves (it becomes the urea)
4. Aminolysis – The amine takes the acyl group; OBt⁻ (HOBt) is released
5. Deprotonation – Base (or OBt⁻) gives the neutral amide

Key points

• EDC (R³ = Et, R⁴ = (CH₂)₃NMe₂) gives a water-soluble urea, washed out in the work-up; DCC gives insoluble DCU, removed by filtration.
• Without HOBt the O-acylisourea can rearrange (O→N acyl shift) to an unreactive N-acylurea, or cyclise to an oxazolone that racemises α-stereocentres.
• HATU (a HOAt-derived aminium salt) with iPr₂NEt forms the OAt ester directly: faster, with less epimerisation (neighbouring pyridine N).
• Steps 3 and 4 are drawn as one-step acyl transfers for clarity; each goes through a tetrahedral intermediate (addition, then loss of the leaving group).
• Anhydrous HOBt is an explosive hazard; it is sold wetted. Usual order: acid + EDC/HOBt first, then the amine.

Drawn with 159 atoms, 16 arrows, 7 shapes – every one editable in MolDraw.

Sources

• Montalbetti & Falque, Tetrahedron 2005, 61, 10827 Review
• Valeur & Bradley, Chem. Soc. Rev. 2009, 38, 606 Review
• Carpino, J. Am. Chem. Soc. 1993, 115, 4397 Original paper
• Clayden, Greeves & Warren, Organic Chemistry, 2nd ed., OUP 2012 Textbook