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Chapter: Organic Chemistry : Functional Group Synthesis

Derivatives of carboxylic acids are generally made from the carboxylic acid.


Derivatives of carboxylic acids are generally made from the carboxylic acid. The traditional routes to esters are as follows:

1. Acid-catalyzed reaction between an acid and an alcohol (Fischer esterification):

2. Reaction of an acid chloride (or acid anhydride) with an alcohol:

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 the removal of water and no other reagents are needed. Moreover the closure is favored entropically and proceeds easily.

A second very common way to convert carboxylic acids to esters is by the reaction of the corresponding acid chloride with an alcohol. A tertiary amine such as pyridine or triethylamine is used to scavenge the HCl by-product. It has also been found effective to add small amounts of N ,N -dimethyl-4-aminopyridine (DMAP) to the reaction mixture in order to promote efficient product formation. If the acid chloride is readily available, this is a very satisfactory preparation. If the acid chloride is not available, a disadvantage to this method is that a car-boxylic acid must first be converted to the acid chloride, which must be isolated and purified prior to the formation of the ester. If the chlorinating agent is not separated from the acid chloride, the alcohol will also react with the chlorinating agent leading to a mixture of products that may be difficult to separate.

For small-scale esterification reactions (<500 mg), the best methods should occur rapidly under mild conditions and only produce by-products which are easily separated from the reaction products. Under these criteria an extremely efficient way to convert acids to methyl esters is to titrate the carboxylic acid with an ethereal solution of diazomethane. The methyl ester is produced rapidly and quantitatively, and the by-product of the esterification is nitrogen. Although diazomethane is a reactive and explosive compound, solutions of diazomethane can be prepared from readily available reagents and used safely in the laboratory.

A second method to efficiently produce methyl esters of carboxylic acids is to treat the acid with potassium carbonate and methyl iodide. The methyl ester is produced under mild conditions and is easily separated from the reaction by-products. This method is somewhat different in that the ester is formed by a nucleophilic displacement of iodide by the carboxylate ion. Normally carboxy-lates are not thought of as good nucleophiles — and they are not— but methyl iodide is a quite reactive electrophile which matches the poor nucleophilicity of the carboxylate satisfactorily.

Besides the above methods, many other satisfactory ways to convert acids to esters are commonly encountered.

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