Arndt–Eistert reaction

In organic chemistry, the Arndt–Eistert reaction is the conversion of a carboxylic acid to its homologue. Named for the German chemists Fritz Arndt (1885–1969) and Bernd Eistert (1902–1978), the method entails treating an acid chlorides with diazomethane. It is a popular method of producing β-amino acids from α-amino acids.^[1]

Arndt-Eistert reaction
Named after	Fritz Arndt, Bernd Eistert
Reaction type	Homologation reaction
Identifiers
Organic Chemistry Portal	arndt-eistert-synthesis
RSC ontology ID	RXNO:0000063

Conditions

Aside from the acid chloride substrate, three reagents are required: diazomethane, water, and a metal catalyst. Each has been well investigated.

The diazomethane is required in excess so as to react with the HCl formed previously.^[2] Not taking diazomethane in excess results in HCl reacting with the diazoketone to form chloromethyl ketone and N₂. Mild conditions allow this reaction to take place while not affecting complex or reducible groups in the reactant-acid.^[3]

The reaction requires the presence of a nucleophile (water). A metal catalyst is required. Usually Ag₂O is chosen but other metals and even light effect the reaction.^[4]

 

Arndt-Eistert reaction with ketene intermediate.

Variants

The preparation of the beta-amino acid from phenylalanine illustrates the Arndt–Eistert synthesis carried out with the Newman–Beal modification, which involves the inclusion of triethylamine in the diazomethane solution. Either triethylamine or a second equivalent of diazomethane will scavenge HCl, avoiding the formation of α-chloromethylketone side-products.^[5][6][7]

Diazomethane is the traditional reagent, but analogues can also be applied.^[8] Diazomethane is toxic and potentially violently explosive, which has led to safer alternative procedures,^[9] For example, diazo(trimethylsilyl)methane has been demonstrated.^[10][11]

Acid anhydrides can be used in place of acid chloride. The reaction yields a 1:1 mixture of the homologated acid and the corresponding methyl ester.^[12]

This method can also be used with primary diazoalkanes, to produce secondary α-diazo ketones. However, there are many limitations. Primary diazoalkanes undergo azo coupling to form azines; thus the reaction conditions must be altered such that acid chloride is added to a solution of diazoalkane and triethylamine at low temperature.^[13][14] In addition, primary diazoalkanes are very reactive, incompatible with acidic functionalities, and will react with activated alkenes including unsaturated carbonyls to give 1,3-dipolar cycloaddition products.

An alternative to the Arndt–Eistert reaction is the Kowalski ester homologation, which also involves the generation of a carbene equivalent but avoids diazomethane.^[15]

Reaction mechanism

The acid chloride suffers attack by diazomethane with loss of HCl. The alpha-diazoketone (RC(O)CHN₂) product undergoes the metal-catalyzed Wolff rearrangement to form a ketene, which hydrates to the acid.^[16][17][4] The rearrangement leaves untouched the stereochemistry at the carbon alpha to the acid chloride.^[6]

 

Historical readings

• Arndt, F.; Eistert, B. (1935). "Ein Verfahren zur Überführung von Carbonsäuren in ihre höheren Homologen bzw. deren Derivate" [A process for the conversion of carboxylic acids into their higher homologs or their derivatives]. Ber. Dtsch. Chem. Ges. (in German). 68 (1): 200–208. doi:10.1002/cber.19350680142.
• Bachmann, W. E.; Struve, W. S. (1942). "The Arndt–Eistert Reaction". Org. React. 1: 38.

See also

• Curtius rearrangement
• Kowalski ester homologation
• Lossen rearrangement
• Nierenstein reaction
• Wolff rearrangement

References

1. Ye, T.; McKervey, M. A. (1994). "Organic Synthesis with α-Diazo Carbonyl Compounds". Chem. Rev. 94 (4): 1091–1160. doi:10.1021/cr00028a010.
2. Lee, V.; Newman, M. S. (1970). "Ethyl 1-Naphthylacetate". Organic Syntheses. 50: 77; Collected Volumes, vol. 6, p. 613.
3. Sanyal, S.N. (2003). Reactions, Rearrangements and Reagents (4 ed.). pp. 86, 87. ISBN 978-81-7709-605-7.
4. Kirmse, W. (2002). "100 Years of the Wolff Rearrangement". Eur. J. Org. Chem. 2002 (14): 2193–2256. doi:10.1002/1099-0690(200207)2002:14<2193::AID-EJOC2193>3.0.CO;2-D.
5. Newman, M. S.; Beal, P. F. (1950). "An Improved Wolff Rearrangement in Homogeneous Medium". J. Am. Chem. Soc. 72 (11): 5163–5165. doi:10.1021/ja01167a101.
6. Linder, M. R.; Steurer, S.; Podlech, J. (2002). "(S)-3-(tert-Butyloxycarbonylamino)-4-phenylbutanoic acid". Organic Syntheses. 79: 154; Collected Volumes, vol. 10, p. 194.
7. Clibbens, D. A. Nierenstein, M. (1915). "CLXV.—The action of diazomethane on some aromatic acyl chlorides". J. Chem. Soc. 107: 1491–1494. doi:10.1039/ct9150701491.{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. Danheiser, R. L.; Miller, R. F.; Brisbois, R. G. (1996). "Detrifluoroacetylative Diazo Group Transfer: (E)-1-Diazo-4-phenyl-3-buten-2-one". Organic Syntheses. 73: 134. doi:10.15227/orgsyn.073.0134.
9. Katritzky, A. R.; Zhang, S.; Hussein, A. H. M.; Fang, Y.; Steel, P. J. (2001). "One-Carbon Homologation of Carboxylic Acids via BtCH₂TMS: A Safe Alternative to the Arndt−Eistert Reaction". J. Org. Chem. 66 (16): 5606–5612. doi:10.1021/jo0017640. PMID 11485491.
10. Aoyama, T.; Shiori, T. (1980). "New Methods and Reagents in Organic Synthesis. 8. Trimethylsilyldiazomethane. A New, Stable, and Safe Reagent for the Classical Arndt-Eistert Synthesis". Tetrahedron Lett. 21 (46): 4461–4462. doi:10.1016/S0040-4039(00)92200-7.
11. Cesar, J.; Dolenc, M. S. (2001). "Trimethylsilyldiazomethane in the Preparation of Diazoketones via Mixed Anhydride and Coupling Reagent Methods: A New Approach to the Arndt–Eistert Synthesis". Tetrahedron Lett. 42 (40): 7099–7102. doi:10.1016/S0040-4039(01)01458-7.
12. Bradley, W. Robinson, R. (1930). "The Action of Diazomethane on Benzoic and Succinic Anhydrides, and a Reply to Malkin and Nierenstein". J. Am. Chem. Soc. 52 (4): 1558–1565. doi:10.1021/ja01367a040.{{cite journal}}: CS1 maint: multiple names: authors list (link)
13. Franzen, V. (1957). "Eine neue Methode zur Darstellung α,β-ungesättiger Ketone. Zerfall der Diazoketone R—CO—CN₂—CH₂—R′". Justus Liebigs Annalen der Chemie. 602: 199. doi:10.1002/jlac.19576020116.
14. Yates, P. Farnum, D. G. Wiley, D. W. (1958). Chem. Ind.: 69. {{cite journal}}: Missing or empty |title= (help)CS1 maint: multiple names: authors list (link)
15. Reddy, R. E.; Kowalski, C. J. (1993). "Ethyl 1-Naphthylacetate: Ester Homologation Via Ynolate Anions". Organic Syntheses. 71: 146. doi:10.15227/orgsyn.071.0146.
16. Huggett, C.; Arnold, R. T.; Taylor, T. I. (1942). "The Mechanism of the Arndt-Eistert Reaction". J. Am. Chem. Soc. 64 (12): 3043. doi:10.1021/ja01264a505.
17. Meier, H.; Zeller, K.-P. (1975). "The Wolff Rearrangement of α-Diazo Carbonyl Compounds". Angew. Chem. Int. Ed. 14 (1): 32–43. doi:10.1002/anie.197500321.