Fischers Proof of the Configuration of D-(+)-Glucose

Emil Fischer initiated his research on the stereochemistry of (+)-glucose in 1888, just 12 years after the proposal by vant Hoff and Le Bel concerning the tetrahedral nature of carbon which led to the concept of stereoisomerism. Structure determination at this time: 1) Melting Points 2) Polarimetry (optical rotation) 3) Chemical Derivatization/Degradation Known at this time: 1) (+)-glucose is an aldohexose 2) (+)-glucose has 4 stereocenters and thus has 24 = 16 possible stereoisomers 3) Absolute configuration of organic compounds could not be determined 4) Fischer had assigned D-(+)-gylceraldehyde the following configuration
H CHO OH CH2OH

D-(+)-glyceraldehyde

Fischer decided to limit his focus to the eight aldohexoses with the D configuration and arbitrarily assigned (+)-glucose to this family. It was not until 1951, when Bijvoet determined the absolute configuration of L-(+)-tartaric acid that Fischers assignment of (+)-glucose to the D family was shown to be correct. Fischers assignment of the structure shown below to (+)-glucose was based on the following reasoning:
H HO H H CHO OH H OH OH CH2OH

D-(+)-glucose

The Eight D-Aldohexoses

How can we deduce the structure of D-glucose??

Hermann Emil Fischer (9 October 1852 15 July 1919) was awarded the Nobel Prize in Chemistry in 1902 for his work on sugar and purine synthesis.

Step 1: Oxidation of (+)-glucose Nitric acid oxidation of (+)-glucose furnished an optically active aldaric acid.
? ? ? H CHO ? ? ? OH CH2OH ? ? ? H CO2H ? ? ? OH CO2H

HNO3

(By convention D-family has OH to the right)

Optically Active

This experiment eliminates 2 of the 8 possible D aldohexoses as the structures shown below would yield meso compounds upon oxidation.
H H H H CHO OH OH OH OH CH2OH H HO HO H CHO OH H H OH CH2OH

Step 2: Degradation of (+)-glucose Wohl degradation of (+)-glucose gives (-)-arabinose, and nitric acid oxidation of (-)arabinose gives an optically active aldaric acid.
? ? ? H CHO ? ? ? OH CH2OH 1) NH2OH 2) acetic anhydride 3)NaOCH3 Wohl degradation CHO ? ? ? ? H OH CH2OH (-)-arabinose CO2H ? ? ? ? H OH CO2H Optically Active

HNO3

(+)-glucose

This experiment eliminates 2 of the 4 possible structures for D-(-)-arabinose as the structures shown below would yield meso compounds upon oxidation. It also tells us that the orientation of the OH group at C2 of (-)-arabinose is left.
CHO H OH H OH H OH CH2OH CHO H OH HO H H OH CH2OH

By analogy to the observation above, this experiment also eliminates the following structures for (+)-glucose.
HO H H H CHO H OH OH OH CH2OH H H HO H CHO OH OH H OH CH2OH HO H HO H CHO H OH H OH CH2OH

These observations leave the following structures as possibilities for (+)-glucose.

H HO H H CHO OH H OH OH CH2OH HO HO H H CHO H H OH OH CH2OH HO HO HO H CHO H H H OH CH2OH

Step 3: Derivatization of (-)-arabinose Kiliani-Fischer synthesis beginning with (-)-arabinose furnishes (+)-glucose and (+)mannose.
1) NaCN, HCN 2) H2, Pd 3) H3O+ Kiliani-Fischer synthesis CHO OH H ? OH CH2OH CHO H H ? OH CH2OH

CHO HO H ? ? H OH CH2OH (-)-arabinose

H HO ? H

HO HO ? H

Shared structes of (+)-glucose and (+)-mannose

Nitric acid oxidation of (+)-mannose gives an optically active aldaric acid. This observation, together with the fact that (+)-glucose gives an optically active aldaric acid upon nitric acid oxidation, tells us the structure of (-)-arabinose.
CHO HO H H OH H OH CH2OH (-)-arabinose

Had (-)-arabinose been the C3 epimer (opposite orientation) of the structure shown above, the Kiliani-Fischer synthesis followed by nitric acid oxidation would have given one optically active aldaric acid and one meso compound. By analogy to the configuration assigned to (-)-arabinose, this experiment also eliminates the structure shown below for (+)-glucose.
HO HO HO H CHO H H H OH CH2OH

Step 4: Assignment of configuration to (+)-glucose The structures shown below now remain, one structure represents (+)-glucose and one represents (+)-mannose. Fischer observed that these two structures were epimeric at C2 but assigning the correct structure was most difficult.
H HO H H CHO OH H OH OH CH2OH HO HO H H CHO H H OH OH CH2OH

Fischer had previously developed a method for effectively interchanging the two end groups (-CHO and OH) of an aldose chain. With brilliant logic, Fischer realized that if the first structure was (+)-glucose, an interchange of end groups would yield a different aldohexose.
H HO H H CHO OH H OH OH CH2OH H HO H H CH2OH OH H OH OH CHO HO 180o HO H HO CHO H H OH H CH2OH

end-group interchange by chemical reactions

A new aldohexose

If the second structure was (+)-glucose, an interchange of end groups would yield the same aldohexose.

HO HO H H

CHO H H OH OH CH2OH

end-group interchange by chemical reactions

HO HO H H

CH2OH H H OH OH CHO

180

HO HO H H

CHO H H OH OH CH2OH

The same aldohexose

With this observation, Fischer conducted the end-group interchange starting with (+)glucose and found that the product was a new aldohexose. This outcome proved that (+)glucose had the structure shown below and Bijoet proved in 1951 with x-ray diffraction that Fischers arbitrary assignment of (+)-glucose to the D-family of aldohexoses was indeed a very good guess!
H HO H H CHO OH H OH OH CH2OH

D-(+)-glucose