Lactones Fischer esterification

Lactones are made from the Fischer esterification, where the hydroxyl and carboxylic acid groups are present in the same molecule. 

While still useful for large-scale esterification of fairly robust carboxylic acids, Fischer esterification is generally not useful in small-scale reactions because the esterification depends on an acid-catalyzed equilibrium to produce the ester. The equilibrium is usually shifted to the side of the products by adding an excess of one of the reactants—usually the alcohol—and refluxing until equilibrium is established, typically several hours. The reaction is then quenched with base to freeze the equilibrium and the ester product is separated from the excess alcohol and any unreacted acid. This separation is easily accomplished on a large scale where distillation is often used to separate the product from the by-products. For small-scale reactions where distillation is not a viable option, the separation is often difficult or tedious. Consequently Fischer esterification is not widely used for ester formation in small-scale laboratory situations. In contrast, intramolecular Fischer esterification is very effective on a small scale for the closure of hydroxy acids to lactones. Here the equilibrium is driven by tire removal of water and no other reagents are needed. Moreover the closure is favored entropically and proceeds easily. 

Formation of Lactones Simple lactones containing five- and six-membered rings are often more stable than the open-chain hydroxy acids. Such lactones form spontaneously under acidic conditions (via the Fischer esterification). 

Under Fischer esterification conditions, many hydroxycarboxylic acids i intramolecular esters (lactones). ... 

Conversion to esters (Fischer esterification) or lactones (discussed in Section 17.7A) ... 

Lactones can be prepared by oxidation or possibly by a cyclization reaction, such as an intramolecular Fischer esterification, if the lactone is a five- or six-membered ring (called y- gamma- and 8- delta- lactones, respectively). 

FIGURE 17.33 A lactone can be formed via an intramolecular Fischer esterification. 

For carboxylic acids, the success of an addition-elimination reaction depends on the transformation of the carboxyl hydroxyl group into a better leaving group. This conversion is often done through protonation in acid-catalyzed reactions. The best example is Fischer esterification, and its cyclic variation, lactone formation (Fig. 17.33). 

Analytical Approach and Interconversion Under mildly acidic conditions, GHB undergoes an internal condensation via Fischer esterification to produce a stable lactone. This involves two steps cyclization, followed by the elimination of water. The reverse reaction, the hydrolysis of GBL to GHB, can be driven in the presence of a strong base, which is the method used clandestinely to make GHB (Figure 7.29). The reverse reaction can occur in solution when GHB is spiked into a drink, many of which are slightly addic. However, once equilibrium between the add and the lactone form has been reached, no significant losses of GHB appear in typical exhibits over the time frame of days or weeks. ... 

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