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

<DCC>

Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067. DOI: 10.1021/ja01609a099
Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17, 522. DOI: 10.1002/anie.197805221

<EDC(WSCI)>

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

<BOP>

Castro, B.; Dormoy, J.-R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 16, 1219. doi:10.1016/S0040-4039(00)72100-9

<PyBOP>

Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205. doi:10.1016/S0040-4039(00)94371-5

<HATU, HBTU>

Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 19, 1269. doi:10.1016/0040-4039(78)80103-8
Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927. doi:10.1016/S0040-4039(00)99616-3
Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. DOI: 10.1021/ja00063a082
Carpino, L. A. et al. Angew. Chem. Int. Ed. 2002, 41, 441. [abstract]

Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163. doi:10.1246/cl.1975.1163
Mukaiyama, T. Angew. Chem. Int. Ed. Engl. 1979, 18, 707. DOI: 10.1002/anie.197907073
Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465. doi: 10.1246/cl.1984.1465

<DMT-MM (Kunishima reagent)>

Kunishima, M., Kawachi, C., Iwasaki, F., Terao, K. Tetrahedron Lett. 1999, 40, 5327. doi:10.1016/S0040-4039(99)00968-5
Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, k.; Tani, S. Tetrahedron 2001, 57, 1551. doi:10.1016/S0040-4020(00)01137-6

Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. DOI: 10.1021/ja00063a082

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

<COMU>

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

Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447. doi:10.1016/j.tet.2004.01.020
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. doi:10.1016/j.tet.2005.08.031
Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, DOI: 10.1039/b701677h
El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557. DOI: 10.1021/cr100048w

Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243. DOI: 10.1021/cr950005s
Kent, S. B. H. Chem. Soc. Rev. 2009, 38, 338. DOI: 10.1039/b700141j
Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471. doi:10.1038/nature10702

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.).

Example

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.