In the late 1800s, in what still stands as a monument to chemical ingenuity and intellect, Emil Fischer elucidated the structure of D-glucose. The discussion that follows presents the salient features of Fischer's approach. In order to appreciate his logic, it is necessary to be aware of several chemical transformations that Fischer and his colleagues developed.
Treatment of aldoses with dilute nitric acid converts them into aldaric acids. The aldehyde function at one end of the molecule and the primary alcohol at the other are both oxidized to carboxylic acids. Equation 1 gives a generalized description of the process. The designation Cn(H,OH)n represents the chiral carbons in the structures without specifying stereochemistry. While all of the aldoses are chiral, not all of the aldaric acids are. Some of them contain internal an symmetry plane.
Exercise 2 There are four D-aldopentoses. Draw Fischer projections of each of them. Then draw Fischer projections of the aldaric acids they would yield. How many of those aldaric acids would be optically active?
Like ordinary aldehydes, aldoses undergo nucleophilic addition when treated with phenylhydrazine. When treated with an excess of phenylhydrazine, aldoses form compounds known as osazones. Equation 2 summarizes the overall transformation.
While the mechanism of the reaction is interesting, the important outcome is that the chiral center at C2 is destroyed. Consequently, aldoses that differ in configuration only at C-2 produce identical osazones. Aldoses that differ in configuration only at C-2 are called epimers.
Equation 3 summarizes the net transformation achieved by a series of reactions known as the Kiliani-Fischer synthesis.
This reaction sequence involves nucleophilic addition of cyanide ion to the carbonyl group of the aldose, base-promoted hydrolysis of the cyano group of the resulting cyanohydrin, and dissolving metal reduction of a cyclic ester (a lactone) that is formed as an intermediate. Again, the details of the process are secondary to the net result: the Kiliani-Fischer synthesis converts an aldose into two epimeric aldoses which each contain one more carbon.
The Ruff degradation converts an aldose containing n carbon atoms into a new aldose containing n-1 carbons. The process involves oxidation of the carbonyl group to a carboxylic acid followed by decarboxylation of the acid: C-1 is lost as CO2; C-2 becomes the carbonyl carbon in the new aldose. Equation 4 summarizes the overall process.
At the outset Fischer knew that D-glucose was an aldohexose. As such it contained 4 chiral centers. The question Fischer asked was "What is the relative disposition of the H and OH groups at C-2, C-3, C-4, and C-5?"
Another way of asking this question is "Which of the 16 (24) possible stereoisomers of an aldohexose is D-glucose?" The 16 stereoisomers constitute 8 pairs of enantiomers. Fischer knew that he could not assign absolute stereochemistry to any chiral center, so he arbitrarily designated those aldohexoses with the OH group at C-5 projecting to the right as D sugars. See Figure 2.
This reduced his task to determining the relative positions of the H and OH groups at C-2, C-3, and C-4. The 8 possibilites are displayed in Figure 3.
This set the stage for Fischer to interpret the results of a series of experiments involving the transformations outlined in Equations 1-4. A key feature of Fischer's interpretation was the relationship between optical activity and symmetry: molecules that contain a plane of symmetry are not optically active.
When Fischer treated D-glucose with dilute nitric acid, he obtained an aldaric acid that was optically active, i.e. did not contain a plane of symmetry. Figure 4 shows the aldaric acid, 1AA, that would be produced from aldohexose 1. The dashed line in the figure represents an internal symmetry plane that bisects the bond between C-3 and C-4. This aldaric acid would be optically inactive. Therefore aldose 1 cannot be D-glucose.
Ruff degradation of D-glucose produced D-arabinose, a sugar that Fischer had available to him. This result establishes that the configurations at C2, C3, and C4of D-arabinose are the same as those at C3, C4, and C5 of D-glucose. Notice that Ruff degradation of 1 would give the same aldopentose as obtained from 5. This fact, combined with the oxidation results, allowed Fischer to eliminate aldohexose 5.
Oxidation of D-arabinose with dilute nitric acid produced an aldaric acid that was optically active.
At this point Fischer had reduced the possible structures for D-glucose from 8 to 4.
When D-arabinose was subjected to Kiliani-Fischer conditions, D-glucose and D-mannose were formed. This means that D-glucose and D-mannose must have the same configurations at C3, C4, and C5. They differ only at C2. In other words, D-glucose and D-mannose are epimers. Comparing the structures in Figures 5 and 3, it is possible to state that D-glucose and D-mannose must be either 2 and 6 or 4 and 8.
Treatment of D-mannose with dilute nitric acid yielded an aldaric acid that was optically active.
Exercise 10 Given the results just described, D-glucose and D-mannose must be 2 and 6 4 and 8.
The apparent simplicity of the transformations shown in Figure 6 belies the synthetic challenge they presented to Fischer. Nonetheless, he was equal to the challenge. When he reduced C1 and oxidized C6 of D-glucose, he obtained a new sugar. When he reduced C1 and oxidized C6 of D-mannose, he obtained D-mannose. These results allowed Fischer to conclude that D-glucose was structure 2. Note that if you rotate structure 6' by 180o about an axis perpendicular to the page and bisecting the C3-C4 bond you get structure 6. In other words, 6 and 6' are the same compounds. If you rotate 2' about the corresponding axis, you do not get 2. These two compounds are isomers. Therefore, D-glucose must be aldohexose 2.
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