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ORGANIC CHEMISTRY
Amide bonds connect the amino acids in proteins and occur in many other useful molecules. An amide-forming reaction that turns the conventional approach on its head offers a practical way of making these bonds.
As the main chemical linkage found in proteins, the amide bond is incredibly important. What's more, amides are found in many synthetic polymers, biologically active naturally occurring compounds and pharmaceutically active small molecules. The usual way in which chemists make amides is by reacting a carboxylic acid group (COOH), which is electron deficient, with an amine group (NHR, where R can be a hydrogen atom or a hydrocarbon group), which is electron rich. On page 1027 of this issue, Johnston and colleagues1 describe a fresh approach to forming amide bonds. In their process, the polarity of the reacting groups is reversed, thus overcoming some of the problems with existing methods.
At first glance, the reaction of a carboxylic acid with an amine to make an amide - known as a condensation reaction because it produces water as a side product - looks simple (Fig. 1a). One might expect the electron-rich amine to attack and add to the electron-deficient acid when the two compounds are combined. In fact, each reactant must be chemically activated for condensation to occur, and this involves several challenges.
First, in the absence of an activating agent, the overall equilibrium of the process favours the starting materials rather than the products. Second, congestion caused by the presence of bulky groups around the amine and the acid can greatly slow the condensation. And last, but not least, the stereo chemistry of the carboxylic acid - the orientation of the groups around the carbon atom to which the acid group is attached, often referred to as handedness - must be maintained.
The last issue is particularly important when constructing peptides from chiral amino acids (those that have handedness). In many cases, the stereochemistry of these amino acids is sensitive -...