The Wittig reaction was discovered in 1954 by Georg Wittig, for which he was awarded the Nobel Prize in Chemistry in 1979. It is widely used in organic synthesis for the preparation of alkenes. It should not be confused with the Wittig rearrangement.
Wittig reactions are most commonly used to couple aldehydes and ketones to singly substituted phosphine ylides. With simple ylides this results in almost exclusively the Z-alkene product. In order to obtain the E-alkene, the Schlosser modification of the Wittig reaction can be performed.
There are distinct differences in the mechanisms of aliphatic and aromatic aldehydes and of aromatic and aliphatic phosphonium ylides. Vedejs et al. have provided evidence that the Wittig reaction of unbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore under kinetic reaction control. Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions.
The simplest ylide used is methylenetriphenylphosphorane (Ph3P+−C−H2), and this is also the basis of an alternative synthesis of Wittig reagents. Substituted ylides can be made by alkylation of Ph3P=CH2 with a primary alkyl halide R−CH2−X, to produce a substituted phosphonium salt:
Ph3P=CH2 + R-CH2-X → Ph3P+−CH2− CH2−R X−
which can be deprotonated with C4H9Li to make Ph3P=CH−CH2−R.
However the phosphorane resonance requires expansion of the octet on phosphorus. This hypervalency cannot (yet) be explained well in terms of standard bonding theory, and this resonance is rather less favoured than the more familiar p–p overlap seen in π-bonded compounds as alkenes or imines. This means that the ylide form is a significant contributor, and the carbon is quite nucleophilic.
A large variety of ketones and aldehydes are effective in the reaction, though carboxylic acid derivatives such as esters fail to react usefully. Thus mono-, di- and trisubstituted alkenes can all be prepared in good yield in most cases. The carbonyl compound can tolerate several groups such as OH, OR, aromatic nitro and even ester groups. There can be a problem with sterically hindered ketones, where the reaction may be slow and give poor yields, particularly with stabilised ylides, and in such cases the Horner-Wadsworth-Emmons (HWE) reaction (using phosphonate esters) is preferred. Another reported limitation is the often labile nature of aldehydes which can oxidize, polymerize or decompose. In a so-called Tandem Oxidation-Wittig Process the aldehyde is formed in situ by oxidation of the corresponding alcohol.
As mentioned above, the Wittig reagent itself is usually derived from a primary alkyl halide, because with most secondary halides the phosphonium salt is formed in poor yield. This means that most tetrasubstituted alkenes are best made by other means. However the Wittig reagent can tolerate many other variants. It may contain alkenes and aromatic rings, and it is compatible with ethers and even ester groups. Even C=O and nitrile groups can be present if conjugated with the ylide- these are the stabilised ylides mentioned above. Bis-ylides (containing two P=C bonds) have also been made and used successfully.
One limitation relates to the stereochemistry of the product. With simple ylides, the product is usually mainly the Z-isomer, although a lesser amount of the E-isomer is often formed also- this is particularly true when ketones are used. If the reaction is performed in DMF in the presence of LiI or NaI, the product is almost exclusively the Z-isomer. If the E-isomer is the desired product, the Schlosser modification may be used. With stabilised ylides the product is mainly the E-isomer, and this same isomer is also usual with the HWE reaction.
The major limitation of the traditional Wittig reaction is that the reaction goes mainly via the erythro betaine intermediate, which leads to the Z-alkene. However Schlosser & Christmann found that the erythro betaine can be converted to the threo betaine using phenyllithium at low temperature (forming a betaine) followed by HCl. Upon workup this leads to the E-alkene product as shown.
Because of its reliability and wide applicability, the Wittig reaction has become a standard tool for synthetic organic chemists.
The most popular use of the Wittig reaction is for the introduction of a methylene group using methylenetriphenylphosphorane (Ph3P=CH2). In the example shown, even a sterically hindered ketone such as camphor can be successfully converted to its methylene derivative by heating with methyltriphenylphosphonium bromide and potassium tert-butoxide, which generate the Wittig reagent in situ. In another example, the phosphorane is produced using sodium amide as a base, and this successfully converts the aldehyde shown into alkene I in 62% yield. The reaction is performed in cold THF, and the sensitive nitro, azo and phenoxide groups all survive intact. The product can be used to incorporate a photostabiliser into a polymer, to protect the polymer from damage by UV radiation.
Another example of its use is in the synthesis of leukotriene A methyl ester. The first step uses a stabilised ylide, where the carbonyl group is conjugated with the ylid preventing self condensation, although unexpectedly this gives mainly the cis product. The second Wittig reaction uses a non-stabilised Wittig reagent, and as expected this gives mainly the cis product. Note that the epoxide and ester functional groups survive intact.
Methoxymethylenetriphenylphosphine is a Wittig reagent for the homologation of aldehydes.
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