Eschweiler-Clarke methylation

The Eschweiler-Clarke methylation (or simply: Eschweiler-Clarke reaction ) is a name reaction of organic chemistry and named after its developers, the German chemist Wilhelm Eschweiler (1860–1936) and the British biochemist Hans Thacher Clarke (1887–1972) . It can be viewed as a special case of the Leuckart-Wallach reaction with formaldehyde as an alkylating reagent and is used for the methylation of primary or secondary amines .

mechanism

Formaldehyde , which is used in excess together with excess formic acid , serves as the methylation agent . In the first reaction step, the nitrogen of the amine 1 attacks the carbonyl carbon of the formaldehyde nucleophilically. The result is compound 2, which is initially protonated by the formic acid in the oxygen . In two further steps, a water molecule is split off, whereupon the transfer of a hydride ion takes place with the formation of carbon dioxide . The desired methylated amine 6 is formed. The mechanism is identical to that of the Leuckart-Wallach reaction.

The driving force of the reaction is the formation of carbon dioxide. There is no formation of quaternary ammonium salts since the tertiary amines formed can no longer react with formaldehyde to form imines. This is their advantage over methylation with haloalkanes such as methyl iodide . If chiral amines are used, the reaction usually proceeds with retention of the stereo information.

Web links

Reto Müller: Eschweiler-Clarke reaction. Organic Chemistry Portal, accessed March 1, 2014 .

Individual evidence

↑ ^a ^b Wilhelm Eschweiler: Replacement of hydrogen atoms bound to nitrogen by the methyl group with the help of formaldehyde . In: Reports of the German Chemical Society . tape 38 , no. 1 , 1905, pp. 880-882 , doi : 10.1002 / cber.190503801154 .
^ Hans Thacher Clarke, Horace Beaven Gillespie, Stanley Z. Weisshaus: The Action of Formaldehyde on Amines and Amino Acids . In: Journal of the American Chemical Society . tape 55 , no. 11 , 1933, pp. 4571-4587 , doi : 10.1021 / ja01338a041 .
^ Daniel Zerong Wang: Comprehensive Organic Name Reactions and Reagents . tape 1 (3 volumes). John Wiley & Sons , Hoboken 2009, ISBN 978-0-471-70450-8 , pp. 1009 , doi : 10.1002 / 9780470638859 .
^ Eugene Farkas, Cheryl J. Sunman: Chiral Synthesis of Doxpicomine . In: Journal of the American Chemical Society . tape 50 , no. 7 , 1985, pp. 1110-1112 , doi : 10.1021 / jo00207a037 .

[Eschweiler-1] Wilhelm Eschweiler: Replacement of hydrogen atoms bound to nitrogen by the methyl group with the help of formaldehyde . In: Reports of the German Chemical Society . tape 38 , no. 1 , 1905, pp. 880-882 , doi : 10.1002 / cber.190503801154 .

[2] Hans Thacher Clarke, Horace Beaven Gillespie, Stanley Z. Weisshaus: The Action of Formaldehyde on Amines and Amino Acids . In: Journal of the American Chemical Society . tape 55 , no. 11 , 1933, pp. 4571-4587 , doi : 10.1021 / ja01338a041 .

[3] Daniel Zerong Wang: Comprehensive Organic Name Reactions and Reagents . tape 1 (3 volumes). John Wiley & Sons , Hoboken 2009, ISBN 978-0-471-70450-8 , pp. 1009 , doi : 10.1002 / 9780470638859 .

[4] Eugene Farkas, Cheryl J. Sunman: Chiral Synthesis of Doxpicomine . In: Journal of the American Chemical Society . tape 50 , no. 7 , 1985, pp. 1110-1112 , doi : 10.1021 / jo00207a037 .