Wittig reagents

In organic chemistry, Wittig reagents are organophosphorus compounds of the formula R₃P=CHR', where R is usually phenyl. They are used to convert ketones and aldehydes to alkenes:

Preparation

Because they typically hydrolyze and oxidize readily, Wittig reagents are prepared using air-free techniques. They are typically generated and used in situ. THF is a typical solvent. Some are sufficiently stable to be sold commercially.

Formation of phosphonium salt

Wittig reagents are usually prepared from a phosphonium salt, which is in turn prepared by the quaternization of triphenylphosphine with an alkyl halide. Wittig reagents are usually derived from a primary alkyl halide. Quaternization of triphenylphosphine with secondary halides is typically inefficient. For this reason, Wittig reagents are rarely used to prepare tetrasubstituted alkenes.

Bases for deprotonation of phosphonium salts

The alkylphosphonium salt is deprotonated with a strong base such as n-butyllithium:

[Ph₃P⁺CH₂R]X⁻ + C₄H₉Li → Ph₃P=CHR + LiX + C₄H₁₀

Besides n-butyllithium (ⁿBuLi), other strong bases like sodium and potassium t-butoxide (^tBuONa, ^tBuOK), lithium, sodium and potassium hexamethyldisilazide (LiHMDS, NaHMDS, KHDMS, where HDMS = N(SiMe₃)₂), or sodium hydride (NaH) are also commonly used. For stabilized Wittig reagents bearing conjugated electron-withdrawing groups, even relatively weak bases like aqueous sodium hydroxide or potassium carbonate can be employed.

[Ph₃PCH₃]⁺Br⁻, typical phosphonium salt.

The identification of a suitable base is often an important step when optimizing a Wittig reaction. Because phosphonium ylides are seldom isolated, the byproduct(s) generated upon deprotonation essentially plays the role of an additive in a Wittig reaction. As a result, the choice of base has a strong influence on the efficiency and, when applicable, the stereochemical outcome of the Wittig reaction.

Substituent effects

Electron-withdrawing groups (EWGs) enhance the ease of deprotonation of phosphonium salts. This behavior is illustrated by the finding that deprotonation of triphenylcarbethoxymethylphosphonium requires only sodium hydroxide. The resulting triphenylcarbethoxymethylenephosphorane is somewhat air-stable. It is however less reactive than ylides lacking EWGs. For example they usually fail to react with ketones, necessitating the use of the Horner–Wadsworth–Emmons reaction as an alternative. Such stabilized ylides usually give rise to an E-alkene product when they react, rather than the more usual Z-alkene.

A "stabilized" Wittig reagent.

Reactions

Olefination

Wittig reagents are used for olefination reactions, i.e. the Wittig reaction.

Protonation

Wittig reagents are prepared by deprotonation of alkyl phosphonium salts, and this reaction can be reversed. The methodology can be useful in the preparation of unusual Wittig reagents.

Alkylation

Alkylation of Ph₃P=CH₂ with a primary alkyl halide R−CH₂−X, produces substituted phosphonium salts:

Ph₃P=CH₂ + RCH₂X → Ph₃P⁺ CH₂CH₂R X⁻

These salts can be deprotonated in the usual way to give Ph₃P=CH−CH₂R.

Deprotonation

Although ylides are "electron-rich", they are susceptible to deprotonation of alkyl substituents. Treatment of Me₃PCH₂ with butyl lithium affords Me₂P(CH₂)₂Li. Having carbanion-like properties, lithiated ylides function as ligands. Thus Me₂P(CH₂)₂Li is a potential bidentate ligand.

Examples

• (Chloromethylene)triphenylphosphorane
• Methoxymethylenetriphenylphosphorane
• Methylenetriphenylphosphorane
• Triphenylcarbethoxymethylenephosphorane
• Hexaphenylcarbodiphosphorane

Structure

Wittig reagents are usually described as a combination of two resonance structures:

Ph₃P⁺CR₂⁻ ↔ Ph₃P=CR₂

The former is called the ylide form and the latter is called the phosphorane form, which is the more familiar representation.

Crystallographic characterization of methylenetriphenylphosphorane shows that the phosphorus atom is tetrahedral. The PCH₂ centre is planar and the P=CH₂ distance is 1.661 Å, which is much shorter than the other P-C distances (1.823 Å).

External links

• Wittig reaction in Organic Syntheses, Coll. Vol. 10, p. 703 (2004); Vol. 75, p. 153 (1998). (Article)
• Wittig reaction in Organic Syntheses, Coll. Vol. 5, p. 361 (1973); Vol. 45, p. 33 (1965). (Article)