Citric acid, 412 nitriles

The glycerol is converted into the symmetrical, or, i -3 -di-chlor-hydrine. By oxidation this yields the symmetrical, or, 1-3-di-chlor acetone, which by the addition of hydrogen cyanide yields the addition product, that on hydrolysis is converted into a hydroxy acid, viz., di-chlor hydroxy iso-butyric acid. By treatment with potassium cyanide this yields the corresponding di-cyanide, or nitrile of citric acid which on hydrolysis yields citric acid. 

Azepine esters (39) undergo a number of 1,4-additions of nucleophiles as shown in Scheme 6 <90JHC107>. With citric acid the hydroxy derivative (40) is obtained which can be converted to the ketone (41) on oxidation with PDC, and on gel chromatography with methanol the adduct (42) was formed in quantitative yield. Addition of TMS-CN to (39) in the presence of palladium(II) acetate yielded the nitrile (43). 

The chemical operations described in the literature to introduce or into citric acid molecule are based essentially on the Grimaux and Adam synthesis. Labeled citric acid was prepared by Wilcox et al. [35] in the reaction of Na CN with 3-chloro-2-carboxy-2-hydroxybutyric acid and the formed nitrile was hydrolyzed directly with hydrochloric acid. From this solution, citric acid was isolated in the form of calcium citrate and finally converted to the acid. An alternative procedme was proposed by Rothchild and Fields [36] to obtain trimethyl citrate from labeled sodium cyanide and di-chloromethyl glycolate. A more complex synthesis of C labeled citric acid is described by Winkel et al. [39]. They used labeled methyl acetate and acetyl chloride (in the presence of hthium 1,1,1,3,3,3,-hexamethyldisilazide, [(CH3)2Si]2NLi which was dissolved in tetrahydiofuran) to obtain methyl acetoac-etate. It reacts in the presence of lithium diisopropylamide, [(CH3)2CH]2NLi, also dissolved in tetrahydrofuran, with dimethyl carbonate to give dimethyl 1,3-ace-tonedicaiboxylate. It is dicarboxylated by the action of bisulfite and potassium cyanide is converted to 3-cyano-3-hydroxy-l,5 pentanedioate and finally hydrolyzed by hydrochloric acid to citric acid. 

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