Pyridine epimerization, aldonic acids

In the presence of a tertiary amine, in particular pyridine (Sec. 31.6), an equilibrium is established between an aldonic acid and its epimer. This reaction is the basis of the best method for converting an aldose into its epimer, since the only configuration affected is that at C-2. The aldose is oxidized by bromine water to the aldonic acid, which is then treated with pyridine. From the equilibrium mixture thus formed, the epimeric aldonic acid is separated, and reduced (in the form of its lactone) to the epimeric aldose. See, for example, Fig. 34.4. 

A word of caution at this point seems most desirable. In every case where a pure aldonic acid or its derivative has been heated with o-phenyl-enediamine and an excess of hydrochloric acid, only a single benzimidazole has been isolated. It is well known that aldonic acids are epimerized by heating them at temperatures above 100° with organic bases such as pyridine. The heating of an aldonic acid with o-phenylenediamine at 135-150° may also result in appreciable epimerization. Thus, Moore and Link20 reported that from the fusion of xylonic acid with o-phenylenediamine at 150°, in the absence of mineral acids, they could isolate the epimeric lyxo-benzimidazole. Barker, Farrar, and Gulland,21 in a more detailed study, proved conclusively that both D-ribo- and D-arabo-benzimidazoles were formed when the condensation of calcium D-ribonate with o-phenylenediamine was carried out in the presence of less than two molecular equivalents of hydrochloric acid, whereas with an excess of hydrochloric acid only the D-ribo-benzimidazole was obtained. It is important, therefore, in the condensation of o-phenylenediamine with an optically active acid at an elevated temperature that the reaction mixture always be kept on the acid side. 

Here the synthesis led to an o-galaheptose (amorphous) and from it a galaoctose (crystalline) was prepared. Many years later the a-gala-heptose was crystallized. The 8-galaheptose crystallized in Fischer s research, and the epimeric character of the two galaheptoses was made highly probable by his interconversion of their aldonic acids on heating with aqueous pyridine. 

Although monosaccharides undergo complex isomerizations in base (see Section 22.5A), aldonic acids are epimerized specifically at C2 when they are heated with pyridine. Show how you could make use of this reaction in a synthesis of D-mannose from D-glucose. 

The direct action of alkali or pyridine on the sugars is of particular value for the preparation of the ketoses, but the action of pyridine on the aldonic acids is solely an epimerization. The action of hot tertiary amines (particularly aqueous pyridine and quinoline), as well as of alkali, on the aldonic acids and their methylated derivatives results in the establishment of an equilibrium between the two epimeric acids 219). 

Closely related to this reaction is the base-catalyzed epimerization of aldonic acids and their lactones (see Lundt and Madsen, this voL). This reaction is, of course, even older than the LdB-AvE process, and was first used by Emil Fischer [29]. Potassium hydroxide and tertiary amines (pyridine, quinoline) have been used as bases. The reaction is much slower than the epimerization of sugars and requires prolonged heating, but the aldonic acids are much more stable to the action of bases than the sugars, and no side reactions occur. The reaction proceeds even if the hydroxyl group at C-2 is methylated [30]. The kinetics and the mechanism of the interconversion of the aldopentonic acids in potassium hydroxyde solution have been studied this reaction also occurs via the enediol and the removal of H-2 is the rate-determining step [31]. It is of industrial importance, as indicated by numerous patents [32]. 

By heating an aldonic acid in aqueous pyridine or quinoline it is partially converted into the C-2 epimeric add. Thus D-mannonic acid (XV) may be transformed into D-gluconic acid (XVI). 

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