Chemical Syntheses of Citric Acid

In the same year, the Grimaux and Adam synthesis provoked immediate reactions of Andreoti [2] and Kekule [3] who in two small notes also dealt with the possibility to prepare citric acid. 

The next total synthesis of citric acid was performed 10 years later by Haller and Held [4] in 1890. 

The wrong chemical composition of the final product in the Haller and Held synthesis, comes probably, as pointed out by Professor Maria Milewska, from the fact that in the nineteenth century compounds were identified by an elementary analysis and melting point only. Both hydroxytricarboxyhc acids are expected to have these parameters very similar. However their spectra are different and by the modem methods, the difference between them should easily be detected. 

In 1897 Lawrence [6] prepared citric acid differently, by the condensation of ethyl oxalylacetate (diethyl a-ketosuccinate) with ethyl bromoacetate in the presence of zinc. The reaction should be considered at the time of publication to be veiy advanced becanse the condensation of ketones or aldehydes with a-halo esters using a metallic zinc to form P-hydroxyesters was introduced only 2 years earlier in 1895 by Reformatsky, and similar reactions are named after him. 

Lawrence regarded that the preparation of citric acid performed by Dimschmann and Pechmarm [7] in 1891 can hardly be considered as a synthesis of citric acid. Their series of reactions included an addition of hydrogen cyanide to ethyl ace-tonedicarboxylate which was following by a hydrolysis of the product. However, they used in experiments ethyl acetonedicarboxylate which was in the first instance prepared from citric acid. These reactions can be presented as (ethyl-y-chloro-P-ketobutyrate ethyl p-ketoglutarate — ethyl p-cyano-p-hydroxyglutarate) 

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