The Need for Activated Acyl Compounds

As we have seen, most reactions of carboxylic acids, esters, and related compounds involve, as the first step, nucleophilic attack on the carbonyl carbon atom. Examples are Fischer esterification, saponification and ammonolysis of esters, and the first stage of the reaction of esters with Grignard reagents or lithium aluminum hydride. All of these reactions can be summarized by a single mechanistic equation  

The carbonyl carbon, initially trigonal, is attacked by a nucleophile Nu to form a tetrahedral intermediate (step 1). Loss of a leaving group L (step 2) then regenerates the carbonyl group with its trigonal carbon atom. The net result is the replacement of 

Biochemists look at eq. 10.31 in a slightly different way. They refer to the overall reaction as an acyl transfer. The acyl group is transferred from L in the starting material to Nu in the product. 

In general, esters are less reactive toward nucleophiles than are aldehydes or ketones because the positive charge on the carbonyl carbon in esters can be delocalized to the oxygen atom. Consequently, the ester is more stable and less prone to attack. 

Now let us examine some of the ways in which the carboxyl group can be modified to increase its reactivity toward nucleophiles. 

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