Emil Fischer’s proof of the structure of glucose.

1891 (Nobel Prize 1902) (+)-glucose is an aldohexose * * * * CH 2 -CH-CH-CH-CH-CH=O OH OH OH OH OH Four chiral centers  2 4 = 16 stereoisomers

1 2 3 4 5 6 CH=O ?

?

?

OH CH 2 OH Fischer arbitrarily assigned the configuration about C-5 to be D.

The structure was verified by X-ray crystallography in 1951

H H H H CHO OH OH OH OH CH 2 OH H H HO H CHO OH OH H OH CH 2 OH HO H H H CHO CH H OH OH OH 2 OH HO H HO H CHO H OH H OH CH 2 OH H HO H H CHO OH H OH OH CH 2 OH HO HO H H CHO H H OH OH CH 2 OH H HO HO H CHO CH OH H H OH 2 OH HO HO HO H CHO H H H OH CH 2 OH

(-)-arabinose is an aldopentose from which (+)-glucose can be made.

* * * CH 2 -CH-CH-CH-CH=O OH OH OH OH three chiral centers  2 3 = 8 stereoisomers If we artitrarily assign C-4 to be D, then there are 4 stereoisomers H H H CHO OH OH OH CH 2 OH HO H H CHO H OH OH CH 2 OH H HO H CHO OH H OH CH 2 OH HO HO H CHO H H OH CH 2 OH

Fact:

oxidation of (-)-arabinose yields an optically active dicarboxylic acid.

H CHO ?

?

OH CH 2 OH HNO 3 H COOH ?

?

OH COOH optically active

H H H COOH OH OH OH COOH

meso-

compound optically inactive HO H H COOH H OH OH COOH optically active H HO H COOH OH H OH COOH

meso-

compound optically inactive HO HO H COOH H H OH COOH optically active

In (-)-arabinose, the configuration about C-2 must be: HO H CHO H ?

OH CH 2 OH HNO 3 HO H COOH H ?

OH COOH optically active

Fact:

Using the Kiliani-Fischer synthesis to add a new chiral center to (-)-arabinose yields a mixture of (+)-glucose and (+)-mannose.

HO H CHO H ?

OH CH 2 OH K.-F.

H HO H CHO OH H ?

OH CH 2 OH + HO HO H CHO H H ?

OH CH 2 OH

Fact:

Oxidation of both (+)-glucose and (+)-mannose yield optically active dicarboxylic acids.

H HO H H COOH OH H OH OH COOH optically active H HO HO H COOH OH H H OH COOH

meso-

compound optically inactive HO HO HO H COOH H H H OH COOH optically active HO HO H H COOH H H OH OH COOH opticaly active

The only way that both (+)-glucose and (+)-mannose can give optically active dicarboxylic acids upon oxidation is if the configuration about C-4 is with the –OH on the right in the Fischer projection.

But, which compound is (+)-glucose and which one is (+)-mannose?

Fact:

Oxidation of both (+)-glucose and (+)-gulose yield the same dicarboxylic acid.

Fact:

The dicarboxylic acid produced from (+)-mannose is not made by the oxidation of any other aldohexose.

HO HO H H CHO H H OH OH CH 2 OH (+)-mannose HNO 3 HO HO H H COOH H H OH OH COOH This oxidation prodct is not made by the oxidation of any other aldohexose

H HO H H CHO OH H OH OH CH 2 OH (+)-glucose HO HO H H CHO H H OH H CH 2 OH (+)-gulose H HO H H COOH OH H OH OH COOH HO HO H HO COOH H H OH H COOH same compound

Therefore, (+)-glucose has the following configuration: 1 2 3 4 5 6 H HO H H CHO OH H OH OH CH 2 OH C-5 was assigned arbitrarily by Fischer.

C-3 is known from the observation that the oxidation product of (-) arabinose is optically active; and (+)-glucose and (+)-mannose can be made from (-) arabinose by the Kiliani-Fischer synthesis.

C-4 is known from the fact that both (+)-glucose and (+)-mannose yield optically active dicarboxylic acids.

C-2 is known from the fact that both (+)-glucose and (+)-gulose yield the same dicarboxylic acid.