The Ruff Degradation and Kiliani-Fischer Synthesis

by James

in Carbohydrates, Organic Chemistry 2

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 (SN2). 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.

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 (2R, 3S). (Since these two diastereomers only differ in the configuration at a single carbon, they are often called “epimers”. )

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 the endnotes.

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

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.

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.

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