Wittig Reaction - Scope and Limitations

Scope and Limitations

The Wittig reaction has become a popular method for alkene synthesis precisely because of its wide applicability. Unlike elimination reactions (such as dehydrohalogenation of alkyl halides), which produce mixtures of alkene regioisomers determined by Saytzeff's rule, the Wittig reaction forms the double bond in one position with no ambiguity.

A large variety of ketones and aldehydes are effective in the reaction. 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 stabilized 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. For this reason, tetrasubstituted alkenes are best made by means other than the Wittig reaction. 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.