The Horner–Wadsworth–Emmons (HWE) reaction is a

chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...

used in

organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...

of stabilized phosphonate carbanions with

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

s (or

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

s) to produce predominantly E-

alkene In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...

Horner-Wadsworth-Emmons reaction example

In 1958, Leopold Horner published a modified Wittig reaction using phosphonate-stabilized carbanions. William S. Wadsworth and William D. Emmons further defined the reaction. In contrast to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic but less basic. Likewise, phosphonate-stabilized carbanions can be alkylated. Unlike phosphonium ylides, the dialkylphosphate salt byproduct is easily removed by

aqueous An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, also known as sodium chloride (NaCl), in wat ...

extraction. Several reviews have been published.

Reaction mechanism

The Horner–Wadsworth–Emmons reaction begins with the deprotonation of the phosphonate to give the phosphonate carbanion 1.

Nucleophilic addition In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...

of the carbanion onto the aldehyde 2 (or ketone) producing 3a or 3b is the rate-limiting step. If R² = H, then intermediates 3a and 4a and intermediates 3b and 4b can interconvert with each other. The final elimination of oxaphosphetanes 4a and 4b yield (''E'')-alkene 5 and (''Z'')-alkene 6, with the by-product being a dialkyl-

phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...

. The ratio of alkene

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...

s 5 and 6 is not dependent upon the stereochemical outcome of the initial carbanion addition and upon the ability of the intermediates to equilibrate. The electron-withdrawing group (EWG) alpha to the phosphonate is necessary for the final elimination to occur. In the absence of an electron-withdrawing group, the final product is the β-hydroxyphosphonate 3a and 3b. However, these β-hydroxyphosphonates can be transformed to

s by reaction with

diisopropylcarbodiimide ''N'','-Diisopropylcarbodiimide is a carbodiimide used in peptide synthesis. As a liquid, it is easier to handle than the commonly used Dicyclohexylcarbodiimide, ''N'','-dicyclohexylcarbodiimide, a waxy solid. In addition, ''N'','-diisopropylurea ...

Stereoselectivity

The Horner–Wadsworth–Emmons reaction favours the formation of (''E'')-alkenes. In general, the more equilibration amongst intermediates, the higher the selectivity for (''E'')-alkene formation.

Disubstituted alkenes

Thompson and Heathcock have performed a systematic study of the reaction of methyl 2-(dimethoxyphosphoryl)acetate with various aldehydes. While each effect was small, they had a cumulative effect making it possible to modify the stereochemical outcome without modifying the structure of the phosphonate. They found greater (''E'')-stereoselectivity with the following conditions: * Increasing steric bulk of the aldehyde * Higher reaction temperatures (23 °C over −78 °C) * Li > Na > K salts In a separate study, it was found that bulky phosphonate and bulky electron-withdrawing groups enhance E-alkene selectivity.

Trisubstituted alkenes

The steric bulk of the phosphonate and electron-withdrawing groups plays a critical role in the reaction of α-branched phosphonates with aliphatic aldehydes. Horner-Wadsworth-Emmons Branched Example

Horner-Wadsworth-Emmons Branched Example

Aromatic In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...

aldehydes produce almost exclusively (''E'')-alkenes. In case (''Z'')-alkenes from aromatic aldehydes are needed, the Still–Gennari modification (see below) can be used.

Olefination of ketones

The stereoselectivity of the Horner–Wadsworth–Emmons reaction of

s is poor to modest.

Variations

Base sensitive substrates

Since many substrates are not stable to sodium hydride, several procedures have been developed using milder bases. Masamune and Roush have developed mild conditions using

lithium chloride Lithium chloride is a chemical compound with the formula Li Cl. The salt is a typical ionic compound (with certain covalent characteristics), although the small size of the Li+ ion gives rise to properties not seen for other alkali metal chlorid ...

and DBU. Rathke extended this to

lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...

magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...

halides with

triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. Like triethanolamine and the tetraethylammonium ion, it is often abbreviated TEA. It is a colourless volatile liquid with a strong fishy odor remini ...

. Several other bases have been found effective.

Gennari-Still modification

W. Clark Still and C. Gennari have developed conditions that give ''Z''-alkenes with excellent stereoselectivity. Using phosphonates with electron-withdrawing groups (trifluoroethyl) together with strongly dissociating conditions ( KHMDS and 18-crown-6 in THF) nearly exclusive Z-alkene production can be achieved. Horner-Wadsworth-Emmons Still Example

Ando has suggested that the use of electron-deficient phosphonates accelerates the elimination of the oxaphosphetane intermediates.Ando, K. ''J. Org. Chem.'' 1997, ''62'', 1934–1939. ()

References

{{DEFAULTSORT:Horner-Wadsworth-Emmons reaction Olefination reactions Carbon-carbon bond forming reactions Name reactions