Fischer esterification

Fischer esterification is a special type of esterification and the process of forming an ester by refluxing a carboxylic acid and an alcohol in the presence of an acid catalyst. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be a primary or secondary alkyl. Tertiary alcohols are prone to elimination, and phenols are usually too unreactive to give useful yields. Commonly used catalysts for a Fischer esterification include sulfuric acid, tosic acid, and lewis acids such as scandium(III) triflate. For more valuable or sensitive substrates (for example, biomaterials), dicyclohexylcarbodiimide is often used. The reaction is often carried out without a solvent (particularly when a large reagent excess e.g. of MeOH is used) or in a non-polar solvent (e.g. toluene) to facilitate the Dean-Stark method. Typical reaction times vary from 1-10 hours at temperatures of 60-110°C.

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Direct acylations of alcohols with carboxylic acids is preferred over acylations with anhydrides (poor atom economy) or acid chlorides (moisture sensitive). The main disadvantage of direct acylation is the unfavorable chemical equilibrium that must be remedied e.g. by a large excess of one of the reagents, or by the removal of water (for example by Dean-Stark distillation, the use of molecular sieves, or the use of a stoichiometric quantity of concentrated sulfuric acid as the catalyst). In one study ^[1] it is found that Tetrabutylammonium tribromide (TBATB) is a very effective catalyst. For example the acylation of 3-phenyl propanol with glacial acetic acid and TBATB at reflux generates the ester in 15 minutes in a 95% chemical yield without the need to remove water. It is believed that hydrobromic acid released by TBATB protonates the alcohol over the acid making the carboxylate the actual nucleophile in a reversal of the standard esterification mechanism.

Mechanism

The reaction mechanism for this reaction has several steps:

1. Proton transfer from acid catalyst to carbonyl oxygen increases electrophilicity of carbonyl carbon.
2. The carbonyl carbon is then attacked by the nucleophilic oxygen atom of the alcohol leading to the formation of an oxonium ion.
3. Proton transfer from the oxonium ion to a second molecule of the alcohol gives an activated complex
4. Protonation of one of the hydroxyl groups of the activated complex gives a new oxonium ion.
5. Loss of water from this oxonium ion and subsequent deprotonation gives the ester.

A generic mechanism for an acid Fischer esterification is shown below using acetic acid.

An example of an esterification is in the formation of benzocaine.

References

1. ^ Tetrabutylammonium tribromide mediated condensation of carboxylic acids with alcohols Sarala Naik, Veerababurao Kavala, Rangam Gopinath, and Bhisma K. Patel Arkivoc 2006 (i) 119-127 Online Article