Steglich Esterification (original) (raw)

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 theFischer 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.

A Sequential Acyl Thiol-Ene and Thiolactonization Approach for the Synthesis of δ-Thiolactones
R. O. McCourt, E. M. Scanlan, Org. Lett., 2019, 21, 3460-3464.