Page - (000040) - in Biomedical Chemistry: Current Trends and Developments

Scheme 1.1.24: General mechanism for an acyl substitution reaction. The first step of this mechanism is shared with nucleophilic addition reactions and consists in the nucleophilic addition to the carbonyl group. The second step is a regeneration of the carbonyl group with elimination of the anion. It is important to note that the whole reaction is reversible unless some product stabilization is provided, such as if the leaving group is a stable anion, which is unlikely to be able to attack the carbonyl again. Acyl phosphates are considered activated analogues of carboxylic acids, as the leaving phosphate is a very stable anion and it is unlikely that a better leaving group is attached to a carbonyl group. This shifts the equilibrium towards product formation. On the other hand, a simple carboxylic acid would have the hydroxyl as leaving group which is a strong nucleophile capable of adding onto the carbonyl again. This is the reason why esters, thioesters and acyl phosphates play a major role in promoting substitution reactions within biological systems. In the laboratory environment it is more common the use of carboxylic acid anhydrides and acyl chlorides or bromides. The resulting anions (carboxylates and halogens, respectively) are very weak bases promoting the completeness of the reaction. Because of that, these compounds are very sensitive to hydrolysis thus rendered useless in biological systems. 1.1.4.6.1 Aspirin ‒ Esterifications and Transesterifications Aspirin, acetylsalicylic acid or, by its systematic name, 2-acetoxybenzoic acid, is a nonsteroidal anti-inflammatory drug that inhibits the formation of prostaglandins and thromboxanes by inactivating cyclooxygenases (COXs). It is synthesized by esterification of salicylic acid with acetic anhydride (Scheme 1.1.25). One of its action pathways