Gerog Wittig Synthesis

The Wittig Reaction

Georg Wittig’s pedigree is one of an artist, not necessarily a scientist. His father was a fine arts professor and was an excellent pianist. But Wittig’s love for chemistry won out and it was his choice to study chemistry at university. Despite his studying being interrupted by World War I, he accomplished a lot in the realm of scientific endeavors.

Wittig is most well known for his work in finding novel ways of creating carbon-phosphorous compounds to synthesize biologically active chemicals and medicines such as hydrocortisone. Along with Purdue professor Dr. Herbert Brown, he received the Nobel Prize for chemistry in 1979 for his work. The organic chemistry synthesis model Wittig developed is called the Wittig Synthesis or Wittig Reaction. It was considered the “ideal mechanism for the synthesis of alkenes” Essentially, this organic synthesis process reduces either an aldehyde or ketone to an alkene by reacting it with phosphonium ylide.

During his Nobel lecture, Wittig described how his work on this reaction began with his fascination with how ring strain acts on a ring if an accumulation of phenyl groups at two neighboring carbon atoms weakens the carbon to carbon bonding and makes it more likely for diradical or diyl formation. From there, Wittig experimented with many strategies until such time as he began his collaboration with Herbert C. Brown, whose work with boranes and organoboranes became a vital addition to Wittig’s work because it involved adding boranes to hydrocarbons using a redox reaction (Brown, 1979). This is similar to the reaction which Wittig was interested in.

The result of Wittig’s work was the following reaction:

[pic 1]

To complete this reaction one must create the phosphorous ylides, also known as the Wittig reagent. The Wittig reagent is what makes this reaction possible. By suspending phosphonium salt (made by reacting triphenylphosphine with an akyl halide) in diethyl ether or THF and treating it with a strong base, the very nucleophilic carbon compound known as the ylide is formed.

        The mechanism for the Wittig reaction is thought to proceed in the following way:

[pic 2]

In the above example illustration, we see the ylide complete a nucleophilic attack on the double bonded carbon in a generic aldehyde (R’ being whatever carbon chain group is attached to the aldehyde and R” being whatever carbon group is attached to the ylide). This creates a zwitterionic intermediate betaine

(though the existence of this has yet to proven). After which a four membered ring would form.

Obviously, a four membered ring has a lot of geometric stress created within it. Therefore, in the next step, creating a more stable compound becomes the impetus for the reaction to proceed. The next graphic illustrates how this stress pushes the oxygen to attack the phosphorous to create a double bond and forcing the phosphorous to give up its bond to the newly excluded carbon group (R”).

. [pic 3]

In this last step, the products are a trans or cis-alkene and triphenyl-phosphine oxide. Generally, the formation of the trans-alkene is a slower reaction than that of the cis-alkene. This is due to the different angle involved in the nucleophilic attack, caused by steric hindrance.

        This reaction is a preferred reaction for creation of alkenes because it forms the double bond in a single position without any ambiguity, unlike elimination reactions that form regioisomers, as determined by Saytzeff’s rule. It is also effective on many ketones and aldehydes.

 One of the biggest issues with the Wittig reaction is that it tends to only form Z- isomers of alkenes. However, this problem has been overcome with further work done by Schlosser and Christmann, who found that erytho betaine, which prefers to create the Z-isomer, can be converted to threo betaine and from there the E-isomer alkene can be formed. An example of this mechanism is below:

[pic 4]

        Because it is such a predictable reaction and has great utility, it has become a standard amongst synthetic chemists. This is an especially useful tool when dealing with addition of the methylene group to another organic compound.