Doebner reaction

The Doebner reaction or Doebner quinoline synthesis is a name reaction in organic chemistry . It was first described in 1887 by Oskar Gustav Doebner (1850–1907) as the synthesis of acid derivatives of quinoline . In contrast to the synthesis of acid derivatives of quinoline according to Pfitzinger , the synthesis according to Doebner is based on pyruvic acid , an aldehyde and aniline .

Overview reaction

Depending on the starting materials used, pyruvic acid and the aldehyde, the final reaction product is an α, β- unsaturated carboxylic acid (with the structure marked in gray , the α, β- unsaturated carboxylic acid corresponds to the reaction product of the Doebner reaction listed below):

In view of Doebner's implementation with aniline, the product is a derivative of quinoline, more specifically a quinoline-4-carboxylic acid:

Reaction mechanism

The exact mechanism of the reaction is not known, two suggestions are made here. One possibility is the aldol condensation which initially takes place , starting from the enol form of pyruvic acid ( 1 ) and the aldehyde, with the formation of a β, γ -unsaturated α- ketocarboxylic acid ( 2 ). Followed by a Michael addition with aniline, an aniline derivative is formed ( 3 ). After the cyclization on the benzene ring and two proton shifts, the quinoline-4-carboxylic acid ( 4 ) is formed with the elimination of water :

An alternative mechanism describes the formation of Schiff's base starting from the aniline and the aldehyde with elimination of water . The subsequent reaction with the enol form of pyruvic acid ( 1 ) leads to the formation of the aniline derivative ( 3 ) mentioned above and the continuation of the reaction mechanism already described:

Competitive reaction

It can be seen from the literature that the Doebner reaction fails in the case of the reaction of 2-chloro-5-aminopyridine. In this case, the cyclization would take place on the amino group instead of the benzene ring and lead to a derivative of pyrrolidine .

Atomic economy

The atomic efficiency of this reaction can be classified as relatively good. There are no higher molecular by-products and even at the lower molecular level, only water is split off in the course of the reaction. It should be noted at this point to what extent the starting materials are fully implemented. Since the mechanisms presented take place via the enol form of pyruvic acid, which generally does not predominate over the keto form, a residue of the starting material pyruvic acid would be expected. A complete metabolism would therefore not exist, which reduces the efficiency of this reaction.

See also

Alternative syntheses of quinoline derivatives are, for example, the Combes quinoline synthesis , the Conrad-Limpach quinoline synthesis and the Pfitzinger reaction for the synthesis of acid derivatives of quinoline.

Individual evidence

1. ↑ ^{a b c d e f g h} Daniel Zerong Wang: Comprehensive Organic Name Reactions and Reagents . tape 1 . John Wiley & Sons, Inc., John Wiley & Sons, Inc., Hoboken, New Jersey 2009, ISBN 978-0-471-70450-8 , pp. 921-923 , doi : 10.1002 / 9780470638859.conrr197 .
2. ^ Rudolf Pummerer: Doebner. In: New German Biography. Volume 4, Duncker & Humblot, Berlin 1959, ISBN 3-428-00185-0 , pp. 13-14.
3. ^ ^{A b} W. Pfitzinger: Quinoline derivatives from isatic acid. In: Journal for Practical Chemistry. Volume 33, No. 1, 1886, p. 100, doi: 10.1002 / prac.18850330110 .
4. ↑ ^{a b c} Oscar Doebner: About α-alkylcinchoninic acids and α-alkylquinolines. In: Justus Liebig's Annals of Chemistry. Volume 242, No. 3, 1887, pp. 265-388, doi: 10.1002 / jlac.18872420302 .
5. ↑ ^{a b} Martin J. Weiss, Charles R. Hauser: Failure of the Doebner Reaction with 2-Chloro-5- aminopyridine . Synthesis of a Pyrrolidine Derivative. In: Journal of the American Chemical Society. Volume 68, No. 4, 1946, pp. 722-723, doi: 10.1021 / ja01208a513 .