The Ruff Degradation and Kiliani-Fischer Synthesis

Kiliani-Fischer Synthesis and the Ruff Degradation

• The Kiliani-Fischer Synthesis is a method for extending a carbohydrate chain by a single carbon.
• The Ruff Degradation is a method for shortening a carbohydrate chain by a single carbon.
• The Kiliani-Fischer Synthesis involves addition of cyanide ion to an open-chain aldehyde (in the case of aldoses) which is then partially reduced and then hydrolyzed to give a new aldehyde. In the absence of chiral reagents, a mixture of diastereomers (epimers) will be produced.
• The Ruff Degradation is a method for peforming the reverse reaction. A sugar is oxidized to a carboxylic acid with bromine water, and then oxidation with iron sulfate and oxygen liberates CO₂.

Table of Contents

1. Cyanide Ions Are Useful For Extending Carbon Chains
2. The Kiliani-Fischer Synthesis
3. The Ruff Degradation
4. Notes
5. (Advanced) References and Further Reading

1. Cyanide Ions Are Useful For Extending Carbon Chains

The cyanide ion (CN^–) can be a very useful tool for extending carbon chains by a single carbon.

A familiar example is the reaction of cyanide ion with primary alkyl halides in a nucleophilic substitution reaction (S_N2). The resulting nitrile can then be hydrolyzed with aqueous acid to give a carboxylic acid (which in turn can undergo many further reactions).

In the example below, a four-carbon alkyl halide is extended to a five-carbon chain carboxylic acid:

This process can be extended to other electrophiles besides alkyl halides.  For example, the reaction of cyanide ion with aldehydes gives cyanohydrins:

In this case, and almost all others, creates a new chiral center. In the absence of any chiral reagents, the result will be a mixture of two configurations (R and S) at the cyanohydrin carbon.

2. The Kiliani-Fischer Synthesis

This very same reaction can be used to extend the carbon chain of a very prominent class of aldehydes: aldoses  (i.e. carbohydrates containing an aldehyde). [See: The Big Damn Post of Sugar Nomenclature]

Formation of Cyanohydrins From Aldoses

For example, take the simplest sugar, the three-carbon aldose glyceraldehyde (below, we show D-glyceraldehyde).

As with the example above, attack of cyanide ion on the aldehyde results in a cyanohydrin, extending the length of the longest carbon chain from three to four. It also creates a new stereocenter, giving rise to a mixture of products with (R) and (S) configurations.

Since the stereocenter at the C-3 carbon (R) remains unchanged by this process, in the absence of any chiral reagents this process results in a mixture of diastereomers: (2R, 3R) and (2S, 3R).

Reduction and Hydrolysis Converts The Nitrile Into An Aldehyde

While these cyanohydrins can be hydrolyzed to carboxylic acids (with aqueous acid), it’s often more useful to adopt the process for the creating of a new aldose.

Using a poisoned catalyst (Pd/BaSO₄) in the presence of hydrogen gas (H₂) will reduce the nitrile to an imine.  In the presence of water, the imine will then be rapidly hydrolyzed to an aldehyde.

The result is an extension of a sugar by one carbon (as a mixture). For example, application of this procedure to D-glyceraldehyde results in the two diastereomers D-erythrose (2R, 3R) and D-threose (2S, 3R). (Since these two diastereomers only differ in the configuration at a single carbon, they are often called “epimers”. )

3. The Ruff Degradation

It’s also possible to go in the reverse direction, where an aldose is reduced in length by one carbon.

The procedure for going in this direction is called the Ruff Degradation, a procedure which dates back to the late 1890’s.

In the first step, the aldehyde is selectively oxidized to a carboxylic acid by bromine (Br₂) and water. Note that the secondary and primary alcohols are not oxidized here! 

The next step involves adding an iron (III) salt [Fe₂(SO₄)₃] with hydrogen peroxide, which involves the loss of carbon dioxide and oxidation of the adjacent C₂-OH to an aldehyde:

Most courses don’t generally go into the weeds as far as the mechanistic details, but we’ll have a stab at the Br₂/H₂O reaction down in Note 1.

So why is it important?

I’d be hard pressed to tell you that the Kiliani-Fischer and Ruff degradation reactions are at the cutting edge of modern organic chemistry. They’re not.  [Although, to be fair, enantioselective formation of cyanohydrins from aldehydes using chiral catalysts is important and useful. Examples here. ]

However, they do have great historical significance, in that they are two important tools that Emil Fischer used to determine the structure of glucose and other aldohexoses, an effort that won him the 1902 Nobel Prize in Chemistry.

Just to give you a taste, Fischer was able to show that D-glucose and D-mannose each formed the same product upon Ruff degradation (D-arabinose) indicating them to have opposite configurations at C-2 (epimers). Further Ruff degradations gave D-glyceraldehyde, which established the stereochemistry of the chiral center on C-5.

At some point we’ll go into further discussion when we investigate the Fischer Proof of the structure of glucose.

Notes

Note 1. Oxidation of aldehydes with Br₂ / H₂O

The first step is formation of a hydrate from addition of water to the aldehyde. The zwitterionic form (where there is O- ) is more nucleophilic than the neutral form, so here it’s shown acting as the nucleophile to attack Br₂. At some point the OH₂+ is neutralized ; here it’s shown occurring after attack on Br₂, but it could occur earlier.

Note that there is now a good leaving group on oxygen (Br). A weak base (H₂O) then deprotonates C-H, which forms a new C-O pi bond, with loss of Br (-) leading to formation of the carboxylic acid.

Note 2. We won’t go into the mechanism of the Ruff degradation here, but I will point out that iron and H₂O₂ are the ingredients of the Fenton reaction, a process that creates a hydroxyl radical.

(Advanced) References and Further Reading

1. Ueber das Cyanhydrin der Lävulose
   Heinrich Kiliani
   Ber. 1885, 18 (2), 3066-3072
   DOI: 10.1002/cber.188501802249
2. Reduction von Säuren der Zuckergruppe
   Emil Fischer
   Ber. 1889, 22 (2), 2204-2205
   DOI: 10.1002/cber.18890220291
   First two papers on the 1-carbon homologation of sugars using cyanide by Heinrich Kiliani and Emil Fischer, German chemists of the 19^th century.
3. 2-Deoxy-D-ribose. VI.1 The Preparation of Derivatives of 3-Deoxy-D-ribo-hexonic Acid and 3-Deoxy-D-arabino-hexonic Acid Therefrom. Some Observations on the Kiliani Synthesis
   HARRY B. WOOD Jr. and HEWITT G. FLETCHER Jr.
   The Journal of Organic Chemistry 1961, 26 (6), 1969-1973
   DOI: 1021/jo01065a068
   This paper explores the synthesis of various carbohydrates through the Kiliani-Fischer synthesis.
4. Scalable Synthesis of l-Iduronic Acid Derivatives via Stereocontrolled Cyanohydrin Reaction for Synthesis of Heparin-Related Disaccharides Steen Uldall Hansen, Marek Baráth, Bader A. B. Salameh, Robin G. Pritchard, William T. Stimpson, John M. Gardiner, and Gordon C. Jayson
   Organic Letters 2009, 11 (20), 4528-4531
   DOI: 10.1021/ol901723m
   This paper shows the utility of the Kiliani-Fischer reaction in modern organic chemistry, enabling the synthesis of some disaccharides that cannot be synthesized other ways.