Horner–Wadsworth–Emmons reaction
The Horner -Wadsworth- Emmons reaction (short: HWE reaction ), occasionally in textbooks - but incorrectly - referred to as the Wittig -Horner reaction or Horner -Wittig reaction is a chemical reaction that produced with the stereoselectively (E)- alkenes can be. To aldehydes or ketones, are reacted with the anions of organic phosphonates. The deprotonation takes place at the carbon.
1958 Leopold Horner published a modified Wittig reaction phosphonatstabilisierter ( after Georg Wittig ) using carbanions. William S. Wadsworth, later a professor at South Dakota State University, and William D. Emmons (1924-2001), both at the time chemist at Rohm and Haas (Philadelphia ), this reaction developed further.
In contrast to the phosphorus ylides of the Wittig reaction the phosphonatstabilisierten carbanions are nucleophilic and basic. Accordingly, these, unlike the phosphorus ylides can be alkylated. The Dialkylphosphatsalze, which are obtained as a by-product can be easily removed by aqueous extraction.
- 3.1 base- sensitive substrates
- 3.2 Still-Gennari variant
Reaction mechanism
The reaction mechanism of the Horner -Wadsworth- Emmon reaction is not yet known. Sure it starts with the deprotonation of the phosphonate, it forms the phosphonate carbanion 1 It is assumed further that the nucleophilic addition of the carbanion to the aldehyde 2 (or ketone ), which leads to the intermediate 3a or 3b, as the rate-determining step is considered. If R2 = H, the intermediate 3a and 4a and the intermediates can convert 3b and 4b together. Elimination of 4a and 4b give the (E)- alkene 5 and the (Z) -alkene 6
The ratio of the diastereomeric alkenes 5 and 6 is not dependent on the stereochemical outcome of the Carbanionadditon, but depends largely on the extent of chemical equilibrium between the intermediates.
The electron-withdrawing group (short: EEC - electron Withdrawing group) in α -position to the phosphonate is for the reaction absolutely necessary. In the absence of a " EEC " is the end product of the reaction, the α -H - hydroxy phosphonate 3a and 3b. These α -H hydroxyphosphonates can be converted to alkenes with diisopropyl carbodiimide.
Stereoselectivity
The HWE reaction preferred the formation of ( E)- alkenes. In general, the better can adjust the balance between the intermediates, the higher the selectivity or the (E)- Alkenanteil.
Disubstituted alkenes
SK Thompson and Clayton H. Heathcock published a systematic study of the reaction of trimethyl phosphonoacetate with various aldehydes. While the individual differences were small, there is a cumulative effect, which makes it possible to control the stereoselectivity using the structure of the phosphonate showed. The following conditions increase the E stereoselectivity:
- Increasing steric hindrance at the aldehyde
- Higher reaction temperatures
- Li > Na > K salts
- Solvent DME instead of THF
In another study it was shown that sterically demanding phosphonates and " EWGs " the (E)- alkene selectivity also increase.
Tri-substituted alkenes
The steric bulk of the phosphonates and the EWGs actually shows an effect on the reaction of α - branched phosphonates with aliphatic aldehydes.
Aromatic aldehydes usually give exclusively (E)- alkenes. If you want to (Z)- alkenes represent from aromatic aldehydes, the Still-Gennari variant (see below ) a possibility.
Olefination of ketones
The stereoselectivity of the HWE is here low to average.
Variations
Base- sensitive substrates
Since many substrates are sensitive to sodium hydride, some studies have been conducted to milder bases. For one, " Masamune and Roush " with lithium chloride and DBU and " Rathke " with lithium or magnesium halides with triethylamine and other bases.
Still-Gennari variant
Still and Gennari developed conditions that allow a reaction with very high stereoselectivity (Z)- alkenes. One uses phosphonates with electron-withdrawing groups (eg: trifluoroethyl ) together with strongly dissociating conditions ( KHMDS and -crown-6 in THF).
Ando this postulated that the use of electron-deficient phosphonates accelerates the elimination of the Oxophosphonante.