Arndt-Eistert synthesis

The Arndt-Eistert synthesis is a series of chemical reactions designed to convert a carboxylic acid to a higher carboxylic acid homologue (ie. contains one additional carbon atom) and is considered a homologization process. [cite journal
title = Ein Verfahren zur Überführung von Carbonsäuren in ihre höheren Homologen bzw. deren Derivate
author = Fritz Arndt and Bernd Eistert
journal = Berichte der deutschen chemischen Gesellschaft
volume = 1
issue = 68
pages = 200–208
year = 1935
url =
doi = 10.1002/cber.19350680142 ] [Bachmann, W. E.; Struve, W. S. "Org. React." 1942, "1", 38. (Review)] [Ye, T.; McKervey, M. A. "Chem. Rev." 1994, "94", 1091-1160. (Review, DOI|10.1021/cr00028a010)] Named for the German chemists Fritz Arndt (1885-1969) and Bernd Eistert (1902-1978), Arndt-Eistert synthesis is a popular method of producing beta-amino-acids from alpha-amino-acids. Acid chlorides react with diazomethane to give diazoketones. In the presence of a nucleophile (water) and a metal catalyst (Ag₂O), diazoketones will form the desired acid homologue. [Lee, V.; Newman, M. S. "Org. Syn.", Coll. Vol. 6, p.613 (1988); Vol. 50, p.77 (1970). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0613 Article] )] [Linder, M. R.; Steurer, S.; Podlech, J. "Org. Syn.", Coll. Vol. 10, p.194 (2004); Vol. 79, p.154 (2002). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=v79p0154 Article] )]

While the classic Arndt-Eistert synthesis uses thionyl chloride to convert the starting acid to an acid chloride, any procedure can be used that will generate an acid chloride.

Diazoketones are typically generated as described here, but other methods such as diazo-group transfer can also apply. [Danheiser, R. L.; Miller, R. F.; Brisbois, R. G. "Org. Syn.", Coll. Vol. 9, p.197 (1998); Vol. 73, p.134 (1996). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv9p0197 Article] )]

Since diazomethane is toxic and violently explosive, many safer alternatives have been developed [Alan R. Katritzky; Zhang, S.; Hussein, A. H. M.; Fang, Y.; Steel, P. J. "J. Org. Chem." 2001, "66", 5606. (DOI|10.1021/jo0017640)] , such as the usage of ynolates [Reddy, R. E.; Kowalski, C. J. "Org. Syn.", Coll. Vol. 9, p.426 (1998); Vol. 71, p.146 (1993). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv9p0426 Article] )] or trimethylsilyldiazomethane. [Aoyama, T.; Shiori, T. "Tetrahedron Lett." 1980, "21", 4461-4466.] [Aoyama, T.; Shiori, T. "Chem. Pharm. Bull." 1981, "29", 3248.] [Cesar, J.; Dolenc, M. S. "Tetrahedron Lett." 2001, "42", 7099. (DOI|10.1016/S0040-4039(01)01458-7)]

Reaction mechanism

The key step in the Arndt-Eistert synthesis is the metal-catalyzed Wolff rearrangement of the diazoketone to form a ketene. [Huggett, C.; Arnold, R. T.; Taylor, T. I. "J. Am. Chem. Soc." 1942, "64", 3043. (DOI|10.1021/ja01264a505)]

Heat, light, platinum, silver, and copper salts will also catalyze the Wolff rearrangement to produce the desired acid homologue.

Variations

Newman-Beal modification

The addition of triethylamine to the diazomethane solution will avoid the formation of α-chloromethylketone side-products. [Newman, M. S.; Beal, P.F. "J. Am. Chem. Soc." 1950, "72", 5163. (DOI|10.1021/ja01167a101)]

References

ee also

*Curtius rearrangement
*Kowalski ester homologation
*Lossen rearrangement
*Nierenstein reaction