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Synthetic Methods

Given the importance of amide bonds, there is a plethora of synthetic methods and strategies available for their synthesis. The most popular industrial methods for amide bond formation rely on the aforementioned acylation method, which account for 16% of all reactions carried out by the pharmaceutical industry; a breakdown of these methods is shown in Table 1.[1]

Table 1: Breakdown of acylation methods for amide bond formation in the pharmaceutical industry [1]


Frequency (%)

Acid Chloride


Coupling reagent


Mixed carbonic anhydrides


Carbonyl Diimidazole




The use of acid chlorides is the most common method for amide bond formation in industry, and in the majority of cases, the procedure involves in situ generation of the acid chloride. Mixed carbonic anhydrides provide a cheap and readily scaled method for N-acylation.[1] In recent years, the use of carbonyl diimidazole (CDI) has grown in popularity as it is moderately priced and also readily scaled and worked up. [1]  The use of acyl chlorides and mixed anhydrides is an economical approach to the synthesis of amides; however, all of these acylation methods use stoichiometric quantities of coupling agents, which make them expensive, wasteful and inefficient.

Amide bond formation using enzymatic catalysis circumvents the poor atom economy associated with coupling agents, as well as the potential hazards related with the use of non-aqueous media chemical approaches.  Methods such as lipase-catalysed amidation of carboxylic acids and the hydrolysis of nitriles catalysed by nitrile hydrolases are clean, efficient and safe routes to the synthesis of primary amides. Equally, the use of peptidases and acylases circumvents the need for protection/deprotection steps, which has a positive impact on the mass intensity of the process.  The use of enzyme catalysed amide bond formation has the advantage of operating under mild reaction conditions and their specificity leads to excellent regio- and stereoselectivity.  Despite the progress made in the area of biocatalytic amide bond formation and some commercial success, enzyme catalysed amide synthesis still suffers from a narrow substrate specificity and material intensive isolation stages, which limit their application.[2]

  1. J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Analysis of the reactions used for the preparation of drug candidate molecules, Org. Biomol. Chem., 2006, 4, 2337-2347.
  2. D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. Johnnie L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Key green chemistry research areas-a perspective from pharmaceutical manufacturers, Green Chem., 2007, 9, 411-420.