Steglich esterification

From Wikipedia, the free encyclopedia Jump to: navigation, search The Steglich esterification is a variation of an esterfication with dicyclohexylcarbodiimide as a coupling reagent and 4-dimethylaminopyridine as a catalyst. The reaction was first described by Wolfgang Steglich in 1978. [1] It is an adaptation of an older method for the formation of amides by means of DCC (dicyclohexylcarbodiimide) and 1-hydroxybenzotriazole (HOBT).[2][3]

This reaction generally takes place at room temperature. A suitable solvent is dichloromethane. Because the reaction is mild, esters can be obtained that are inaccessible through other methods for instance esters of the sensitive 1,4-dihydroxybenzoic acid. A characteristic is the formal uptake of water generated in the reaction by DCC, forming the urea compound dicyclohexylurea (DCU).

Contents

1 Reaction mechanism 2 References 3 Further reading 4 External links

Reaction mechanism
The reaction mechanism is described as follows:

The carboxylic acid reacts with DCC to a O-acyl isourea, which is more reactive than the free acid

The alcohol attacks this intermediate, forming DCU and the corresponding ester

With amines, the reaction proceeds without problems to the corresponding amides because amines are more nucleophilic. If the esterification is slow, a side-reaction occurs, diminishing the final yield or complicating purification of the product. This side-reaction is a 1,3rearrangement of the O-acyl intermediate to a N-acyl urea which is unable to further react with the alcohol To suppress this reaction, DMAP is added, acting as an acyl transfer-reagent in the following manner:

This article incorporates information from the German Wikipedia. 1. ^ B. Neises, W. Steglich (1978). "Simple Method for the Esterification of Carboxylic Acids". Angew. Chem. Int. Ed. 17 (7): 522524. doi:10.1002/anie.197805221.

2. ^ J. C. Sheehan, G. P. Hess (1955). "A New Method of Forming Peptide Bonds". J. Am. Chem. Soc. 77 (4): 10671068. doi:10.1021/ja01609a099. 3. ^ W. Knig, R. Geiger (1970). "Eine neue Methode zur Synthese von Peptiden: Aktivierung der Carboxylgruppe mit Dicyclohexylcarbodiimid unter Zusatz von 1Hydroxy-benzotriazolen". Chem. Ber. 103 (3): 788798. doi:10.1002/cber.19701030319.

Further reading
Organic Chemistry Portal Reactions >> Name Reactions Further Information Literature Related Reactions Fischer Esterification Yamaguchi Esterification Synthesis of esters

Steglich Esterification

The Steglich Esterification is a mild reaction, which allows the conversion of sterically demanding and acid labile substrates. It's one of the convenient methods for the formation of tert-butyl esters because t-BuOH tends to form carbocations and isobutene after a subsequent elimination under the conditions employed in the Fischer Esterification.

Mechanism of the Steglich Esterification

DCC (dicyclohexylcarbodiimide) and the carboxylic acid are able to form an O-acylisourea intermediate, which offers reactivity similar to the corresponding carboxylic acid anhydride:

The alcohol may now add to the activated carboxylic acid to form the stable dicyclohexylurea (DHU) and the ester:

In practice, the reaction with carboxylic acids, DCC and amines leads to amides without problems, while the addition of approximately 5 mol-% DMAP is crucial for the efficient formation of esters.

N-Acylureas, which may be quantitatively isolated in the absence of any nucleophile, are the side products of an acyl migration that takes place slowly. Strong nucleophiles such as amines react readily with the O-acylisourea and therefore need no additives:

A common explanation of the DMAP acceleration suggests that DMAP, as a stronger nucleophile than the alcohol, reacts with the O-acylisourea leading to a reactive amide ("active ester"). This intermediate cannot form intramolecular side products but reacts rapidly with alcohols. DMAP acts as an acyl transfer reagent in this way, and subsequent reaction with the alcohol gives the ester.

Recent Literature

Simple Method for the Esterification of Carboxylic Acids B. Neises, W. Steglich, Angew. Chem. Int. Ed., 1978, 17, 522-524.