Arndt-Eistert Homologation Reaction

What Is the Arndt-Eistert Reaction?

The Arndt-Eistert reaction is a homologation reaction of carboxylic acids (adding a CH₂) and is a very useful synthetic method for growing carboxylic acid carbon chains. [1] This method involves three steps:

• The first step is to convert the acid into the corresponding acid chloride.
• The second step is the formation of the intermediate α-diazomethyl ketone.
• The third step is the Wolff rearrangement.

The Wolff rearrangement can be carried out in a silver oxide/water system or a silver benzoate/triethylamine system, and the yield is generally good (50%~80%) [2].

Fig 1. Overview of the Arndt-Eistert reaction.

If water is replaced by alcohol (ROH) or amine (RNHR'), the corresponding homologation ester or amide is generated. Other metals (palladium, copper) can also catalyze the decomposition of diazoketones. An alternative method is to directly heat or illuminate the diazoketone in a nucleophilic solvent (H₂O, ROH, RNH₂) without using a catalyst.

Reaction Mechanism of Arndt-Eistert Reaction

The first step is the reaction of carboxylic acid and thionyl chloride to obtain an acid chloride, accompanied by the formation of HCl as a byproduct. Thus, diazomethane needs to be added in two molar ratios, one mole of which reacts with HCl to obtain methyl chloride and nitrogen, and the other mole reacts with the acyl chloride to obtain the intermediate product α-diazomethyl ketone. The role of the catalyst in this reaction is not very clear. α-diazomethyl ketone exists in two configurations, s-(E) and s-(Z), which can be converted into each other through the rotation of the intermediate C-C single bond. Wolff rearrangement occurs preferentially in the s-(Z) configuration. With the loss of a molecule of nitrogen, the diazoketone decomposes into carbene. The carbene is converted into vinyl ketone through [1,2] migration, and finally attacked by a nucleophile to generate the corresponding homologous carboxylic acid derivative [2~4].

Fig 2. The mechanism of the Arndt-Eistert reaction.

Scope of Application and Examples

This reaction has a wide range of applications and can tolerate a wide range of non-protonated functional groups, such as alkyl, aryl and double bonds. Protonated functional groups can react with diazomethane or diazoketone and are therefore not suitable for this reaction.

Unlike α-peptides, oligomers of β-amino acids show a fairly good ability to fold into well-defined secondary structures both in solution and in the solid state. β-amino acid building blocks can be synthesized from α-amino acids via the Arndt-Eistert reaction.

Fig 3. Synthesis of β-amino acid building blocks. [5]

Nicolaou used the Arndt-Eistert reaction to homologate a sterically hindered carboxylic acid when synthesizing a CP molecule. Since the intermediate is not very stable, the preparation of the diazoketone is made from methanesulfonyl chloride rather than thionyl chloride. The diazoketone is then dissolved in DMF:H20 (2:1) containing an excess of AgO and heated to 120°C. The homologated carboxylic acid is obtained in 35% yield in just 1 min.

Fig 4. Synthesis of CP molecule. [6]

The Arndt-Eistert homologation reaction also has some disadvantages, such as the difficulty in operation due to the use of diazomethane and the inability to be used for large-scale preparation. If you want to further improve the yield, you usually have to separate and purify the intermediate α-diazomethyl ketone and use freshly prepared silver benzoate, which increases the difficulty of operation. However, based on the current synthetic methods, the Arndt-Eistert homologation reaction is still very practical, especially for the homologation of tertiary carboxylic acids with large steric hindrance.

Related Products

CAS No.	Structure	Product
142-47-2		Sodium hydrogen glutamate
59564-78-2		1,3-Bisbenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid
56617-44-8		5-Oxo-1-o-tolyl-pyrrolidine-3-carboxylic acid
149-87-1		Dl-pyroglutamic acid
6914-76-7		Cyclopropanecarboxylicacid,1-methyl-
42381-05-5		2-Aminoadamantane-2-carboxylic acid
10242-03-2		6-Nitroindole-3-carboxylic acid
874-61-3		4-Oxocyclohexanecarboxylic Acid
98-89-5		Cyclohexanecarboxylic Acid
65058-23-3		L-a-(2-Thienyl)glycine
123-98-8		Azelaoyl Chloride
31301-45-8		3,5-Dimethylisoxazole-4-carbonyl chloride
25026-34-0		4-Chlorophenylacetyl chloride
7148-74-5		2-Bromopropionyl chloride
59084-16-1		4-Piperidinecarbonylchloride,1-acetyl-
2719-27-9		Cyclohexanecarboxylic acid chloride

References

1. Arndt, F., Eistert, B. Ber. 1935, 688.200.
2. Kimse, W. Eur. J. Org. Chem. 2002, 2193.
3. Bachmann, W. E. Struve, W. S. Org. React. 1942, 1, 38.
4. Huggett, C., Amold, R. T., Taylor, T. L, J. Am. Chem. Soc. 1942, 64.3043.
5. Gademann, K., Erst, M., Hoyer, D., Seebach, D. Angew. Chem., Int. Ed. Engl. 1999, 38, 1223.
6. Nicolaou, K.C., Baran, P. S. Zhong, Y.-L., et al. Angew. Chem., Int. Ed, Engl. 1999, 38, 1669.