The osazone reaction was developed and used by Emil Fischer to identify aldose sugars differing in configuration only at the alpha-carbon. The upper equation shows the general form of the osazone reaction, which effects an alpha-carbon oxidation with formation of a bis-phenylhydrazone, known as an osazone. Application of the osazone reaction to D-glucose and D-mannose demonstrates that these compounds differ in configuration only at C Chain Shortening and Lengthening 1. These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural connections are given by the dashed blue lines.
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The first step is to react the starting sugar with aqueous cyanide typically NaCN ; the cyanide undergoes nucleophilic addition to the carbonyl group of the sugar while sugars tend to exist mainly as cyclic hemiacetal , they are always in chemical equilibrium with their open-chain aldehyde or ketone forms, and in the case of these aldoses it is that aldehyde form that reacts in this synthesis. The cyanohydrin resulting from this addition is heated in water, which hydrolyzes the cyanide into a carboxylic acid group that quickly reacts with itself to form a more stable lactone.
Now there are two diastereomeric lactones in the reaction mixture. They are separated by chromatography , partition into different solvents, or any of the numerous other separation methods and then the desired lactone is reduced with a sodium amalgam.
As illustrated below, D- arabinose is converted to a mixture of D-glucononitrile and D-mannononitrile, which is then converted to D-gluconolactone and D-mannonolactone, separated, and reduced to D- mannose or D- glucose. Improved version More recently, an improved reduction method has been developed that produces somewhat higher yields of the larger sugars. Instead of conversion of the cyanohydrin to a lactone, the cyanohydrin is reduced with hydrogen with a palladium on barium sulfate catalyst , in water as the solvent.
The cyanohydrin is then reduced to an imine that quickly hydrolyzes under the conditions to an aldehyde--thus the final sugars are produced in just two steps rather than three. Then the final sugars are separated instead of the lactones. The special catalyst is needed to avoid further reduction of the aldehyde group to a hydroxyl group, which would yield an alditol. These catalysts that limit hydrogenation to one step are called poisoned catalysts; Lindlar palladium is another example.
The reactions below illustrate this improved method for the conversion of L-erythrose to L- xylose and L-lyxose. Uses and Problems The Kiliani-Fischer synthesis is usually used for production of sugars that are difficult or impossible to obtain from natural sources; it is an invaluable tool for this purpose.
However it is limited by its low yield, its use of toxic reagents, and the fact that it only works for aldoses; sometimes the starting sugars can also be hard to find. Some unusual ketoses may be accessible from similar aldoses via an enediol intermediate; for example, on standing in aqueous base, glucose , fructose, and mannose will slowly interconvert since they share an enediol form.
See mutarotation. Some unusual sugars are also accessible via aldol addition. See also.
22.8: Lengthening the Chain: The Kiliani-Fischer Synthesis
Successive iterations of the Kiliani—Fischer synthesis allow access to all diastereomers of any chain-length for a specific absolute stereochemistry of the initial reactant In practice, the Kiliani—Fischer synthesis is usually used for production of sugars that are difficult or impossible to obtain from natural sources. While it does provide access to every possible stereoisomer of any desired aldose, the process is limited in by its low yield and use of toxic reagents. In addition, the process requires having a supply of the previous sugar in the series, which may itself require substantial synthetic work if it is not readily available. For example, if successive iterations of the Kiliani—Fischer synthesis are used, the overall yield drops approximately exponentially for each additional iteration. The process only provides direct access to aldoses, whereas some sugars of interest may instead be ketoses. Some ketoses may be accessible from similar aldoses by isomerization via an enediol intermediate; for example, on standing in aqueous base, glucose , fructose , and mannose will slowly interconvert since they share an enediol form. See Lobry de Bruyn—van Ekenstein transformation.