Arndt-Eistert synthesis

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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.[1][2][3] 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.[4][5]

The Arndt-Eistert synthesis

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.[6]

Since diazomethane is toxic and violently explosive, many safer alternatives have been developed[7], such as the usage of ynolates[8] or trimethylsilyldiazomethane.[9][10][11]

Contents

[edit] Reaction mechanism

The key step in the Arndt-Eistert synthesis is the metal-catalyzed Wolff rearrangement of the diazoketone to form a ketene.[12]

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

[edit] Variations

[edit] Newman-Beal modification

The addition of triethylamine to the diazomethane solution will avoid the formation of α-chloromethylketone side-products.[13]

[edit] References

  1. ^ Fritz Arndt and Bernd Eistert (1935). "Ein Verfahren zur Überführung von Carbonsäuren in ihre höheren Homologen bzw. deren Derivate". Berichte der deutschen chemischen Gesellschaft 1 (68): 200–208. doi:10.1002/cber.19350680142. 
  2. ^ Bachmann, W. E.; Struve, W. S. Org. React. 1942, 1, 38. (Review)
  3. ^ Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091-1160. (Review, doi:10.1021/cr00028a010)
  4. ^ Lee, V.; Newman, M. S. Org. Syn., Coll. Vol. 6, p.613 (1988); Vol. 50, p.77 (1970). (Article)
  5. ^ Linder, M. R.; Steurer, S.; Podlech, J. Org. Syn., Coll. Vol. 10, p.194 (2004); Vol. 79, p.154 (2002). (Article)
  6. ^ Danheiser, R. L.; Miller, R. F.; Brisbois, R. G. Org. Syn., Coll. Vol. 9, p.197 (1998); Vol. 73, p.134 (1996). (Article)
  7. ^ Alan R. Katritzky; Zhang, S.; Hussein, A. H. M.; Fang, Y.; Steel, P. J. J. Org. Chem. 2001, 66, 5606. (doi:10.1021/jo0017640)
  8. ^ Reddy, R. E.; Kowalski, C. J. Org. Syn., Coll. Vol. 9, p.426 (1998); Vol. 71, p.146 (1993). (Article)
  9. ^ Aoyama, T.; Shiori, T. Tetrahedron Lett. 1980, 21, 4461-4466.
  10. ^ Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3248.
  11. ^ Cesar, J.; Dolenc, M. S. Tetrahedron Lett. 2001, 42, 7099. (doi:10.1016/S0040-4039(01)01458-7)
  12. ^ Huggett, C.; Arnold, R. T.; Taylor, T. I. J. Am. Chem. Soc. 1942, 64, 3043. (doi:10.1021/ja01264a505)
  13. ^ Newman, M. S.; Beal, P.F. J. Am. Chem. Soc. 1950, 72, 5163. (doi:10.1021/ja01167a101)

[edit] See also