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Published on: 5月 1, 2026
This post is related to chemistry issues related to peptide/amide bond formation. Do you have trouble in choosing condensation reaction conditions? It is always an annoying issue to optimize condensation reagents and conditions, especially in peptide synthesis. You would have much better performance If there is a way for selecting an optimal reagent among numerous candidates. But it is still challenging to pick up the reagent for condensation.
Current state-of-the-art amide bond formation approaches are summarized in a couple of reviews.1),2), 3) Condensation of an amine with a carboxylic acid is one of the classical ways and it is still a major and straightforward way to obtain an amide or a peptide.
Generally speaking, coupling of an amine with a carboxylic acid is initiated by activation of the carboxylic acid. There are ways of preparing an acid anhydride or acid halides for forming and amide bonds. However, condensation reagents allow in situ generation of active species. Thus you just need to mix the pair of starting materials, a condensation reagent and some additives if necessary,
Amide/Peptide bond formation reaction with condensation reagents are classified into the categories below according to the type of the active ester:
- O-acylurea (carbodiimides)
- HOBt and related active ester
- Acid halide
- Acid Anhydride
- Triazine
- HOPfp ester
- Others
O-acylurea is generated by reaction with carbodiimides. It is one of the classical but still usable condensation reagents and its history goes back to 1955.4) DCC, DIC, WSCD (EDC) and BDDC are currently used carbodiimide coupling reagents.
HOBt, HOAt and related 1H-benzotriazole reagents generates relatively stable active ester intermediate and its effect on ee of peptide synthesis is relatively low. Thus this class is the most prevalent and applied for automated peptide synthesis.
Condensation reagents in this class have a variety of structures like uronium, aminium, phosphonium, immonium salts. HBTU, HATU, HTCU, TATU, TSTU, TOTU and COMU are the representative exapmles of uranium salts. Other well-known condensation reagents in this class are like PyBOP and PyAOP (phosphonium), CIP and DMC (Imidazolium).
Acid halide and acid anhydride are often avoided in peptide synthesis because they are relatively labile to base-induced epimerization at the a-position. But in situ generation of a highly reactive intermediate enables condensation of unreactive coupling partners. Triazine (cyanuric fluoride and CDMT), Halo-uronium salts (TFFH and DFIH), halo-phosphonium salts (BOP-Cl and PyCIU) are the representative examples and Halo-sulfonium, -dioloxolium, -dithiolium, -thiazolium and -pyridinium salts are also applied in this class.
Triazine-based condensation reagents is represented by DMT-MM and its variations.5),6) The reagents of this class tolerate alcoholic solvents and are known to suppress unwanted side reactions.
HOPfp-based ones are represented by FOMP, FDPP, PyPOP and PFNB. They are generally HOPfp variation of HOBt-based reagents and exhibit higher reactivity in condensation reactions.
So many coupling reagents have been developed but commercially available ones are still scares due to the wide usability or high cost of synthesis. In order for optimizing the condensation reagent, this study would be useful as a benchmark.7)
This paper was published mainly by Pfizer. The authors screened 48 reagents against the coupling of benzoic acid and benzylamine in aqueous media (MeCN/water 1:1) at 20 degrees. According to their research, DIC-HOPO showed high substrate scope and DMT-MM BF4, TPTU-NMI and COMU-collidine are the water-compatible choice for the condensation reagent and additives.
Condensation reaction to for an amide bond is necessary for the synthesis of PepMetics® molecules. We have optimized conditions in a general sense to maximize the throughput in synthesis of target compounds.
Honestly speaking, we sometimes encounter an issue of condensation. Most PepMetics® molecules are easily synthesized with the golden standard. But there are still issues of steric hindrance, electronic nature, reaction speed, unwanted side reaction, epimerization and so on. We would love to accommodate a problem-solving, new method. If you are intensely researching on condensation, we would love to have a discussion.