Condensation Reagent

Condensation Reagent

Overall Score5
  • Generality
  • Reagent Availabiltiy

General Characteristics

Esters and amides (peptides) can be obtained by condensing carboxylic acids with alcohols and amines under strongly acidic conditions (Fischer method). However, epimerization at the α-position and side reactions are frequently problematic. A simple solution to this problem is to use a condensation reagent. Various reagents are known so far, but they all proceed basically in the same manner. Each has slightly different characteristics.

Standard Reagents with References



  • Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961, 26, 2525. DOI: 10.1021/jo01351a600




<Mukaiyama reagent>

<DMT-MM (Kunishima reagent)>

<HOBt additive>

<Oxyma additive>

  • Subiros-Funosas, R.; Prohens, R.; Barbas, R.; El-Faham, A.; Albericio, F. Chem. Eur. J. 2009, 15, 9394. DOI: 10.1002/chem.200900614


  •  El-Faham, A.; Albericio, F. J. Org. Chem. 2008, 73, 2731. DOI: 10.1021/jo702622c
  •  El-Faham, A.; Funosas, S. R.: Prohens, R.; Albericio, F. Chem. Eur. J. 2009, 15, 9404. DOI: 10.1002/chem.200900615
  •  Subiros-Funosas, R.; Nieto-Rodriguez, L.; Jensen, K. J.; Albericio, F. J. Pept. Sci. 2013, 19, 408. doi:10.1002/psc.2517

<Review of Peptide Coupling Reagent>

<General Review of Chemical Synthesis of Peptides/Prtoeins>


Typical Reaction Mechanism

An example of DCC-mediated condensation:


Typical peptide synthesis involves the elongation at N-terminus. Elongation at the C-terminus is problematic because it involves intramolecular cyclization to give azlactone (and racemization; see below figure). The racemization can be suppressed by using nucleophilic reagents such as HOBT, HOAt, and Oxyma (Cf. J. Am. Chem. Soc. 1964, 86, 2918.).



Amide formation with DMT-MM is oparative under protic(aqueous) conditions.[1]


List of Popular reagents

  • DCC(dicyclohexylcarbodiimide): Most frequently used and practical. However, its toxicity and the difficulty of removing the crystalline urea byproduct are problematic.
  • DIC(diisopropylcarbodiimide): Similar to DCC.
  • EDC(1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; WSCI): Product separation is easy because the urea byproduct is water soluble and easily removed. It’s more expensive than DCC.


  • HATU, HBTU, TATU, TBTU: Hybrid reagents that form HOAt and HOBt in situ. Effective for suppressing epimerization. Expensive. HATU is one of the most reliable reagents for peptide coupling.


  • COMU, HOTU: Hybrid reagents that form a nucleophile called Oxyma. COMU performs better than HATU in some cases. Byproducts are water-soluble and easily removed. COMU generates reactive O-acyl intermediates.


  • BOP-Cl: It is not produced anymore because of its carcinogenic character.
  • PyBOP, BOP, PyBroP: Crystalline solids.


  • DPPA(diphenyl phosphoryl azide, Shioiri Reagent): Advantageous over DCC because the byproducts are easily removed.
  • DMT-MM(2-Chloro-4,6-dimethoxy-1,3,5-triazine + N-methyl morpholine, Kunishima Reagent): Operative under aqueous or alcoholic conditions. Epimerization is surpressed. Excess reagents and byproducts can be removed by HCl aq wash. Very practical.


  • Mukaiyama Reagent


  • Corey-Nicolaou Method, Yamaguchi Macrolactonization, Keck Method: for macrolactonization.
  • Shiina Macrolactonization: more reactive than Yamaguchi Macrolactonization.


  • Mitsuhobu Reaction: Involves stereochemical inversion of alcohols. Useful for various reactions, including macrolactonization.
  • Mukaiyama Quinone method: Operative with tertiary alcohols, involves stereochemical inversion of alcohols.


[1] Kunishima, M., Kawachi, C., Iwasaki, F., Terao, K. Tetrahedron Lett. 1999, 40, 5327. doi:10.1016/S0040-4039(99)00968-5

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