Solution-Phase Peptide Coupling Reagents

Solution-phase peptide synthesis, also known as Liquid-Phase Peptide Synthesis, LPPS, relies heavily on efficient coupling reagents to facilitate the formation of peptide bonds between amino acids. These reagents activate the carboxyl group of the incoming amino acid, allowing it to react with the amino group of the growing peptide chain. The choice of coupling reagent can significantly impact the efficiency, yield, and purity of the final product.

Carbodiimide-Based Reagents

One of the most widely used classes of coupling reagents in LPPS is carbodiimides, such as dicyclohexylcarbodiimide, DCC, and N,N’-diisopropylcarbodiimide, DIC. These reagents activate the carboxyl group by converting it into an O-acylisourea intermediate, which is then attacked by the amino group of the second amino acid. Carbodiimides are favored for their efficiency and cost-effectiveness in small to medium-scale peptide synthesis.¹

Active Ester-Based Reagents

Another important class of coupling reagents is active ester-based reagents, such as HOBt, 1-hydroxybenzotriazole, and HOAt, 1-hydroxy-7-azabenzotriazole, which are often used in combination with carbodiimides. These additives reduce the risk of racemization and improve overall reaction efficiency. The formation of active esters accelerates the coupling reaction and minimizes side reactions, particularly in sequences prone to racemization.²