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

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

used in

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

of stabilized

phosphonate In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...

carbanions with

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

s (or ketones) to produce predominantly E-

alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...

Horner-Wadsworth-Emmons reaction example

In 1958, Leopold Horner published a modified

Wittig reaction The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide called a Wittig reagent. Wittig reactions are most commonly used to convert aldehydes and ketones to alkenes. Mos ...

using phosphonate-stabilized carbanions. William S. Wadsworth and William D. Emmons further defined the reaction. In contrast to phosphonium ylides used in the

, phosphonate-stabilized carbanions are more

nucleophilic In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

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, or sodium chloride (NaCl), in water would be re ...

extraction. Several reviews have been published.

Reaction mechanism

The Horner–Wadsworth–Emmons reaction begins with the

deprotonation Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...

of the phosphonate to give the phosphonate carbanion 1. Nucleophilic addition of the carbanion onto the aldehyde 2 (or ketone) producing 3a or 3b is the

rate-limiting step In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of th ...

. 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 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 orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

The ratio of alkene isomers 5 and 6 is not dependent upon the

stereochemical Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

outcome of the initial carbanion addition and upon the ability of the intermediates to equilibrate. The

electron-withdrawing group In chemistry, an electron-withdrawing group (EWG) is a substituent that has some of the following kinetic and thermodynamic implications: *with regards to electron transfer, electron-withdrawing groups enhance the oxidizing power tendency of the ...

(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 α-hydroxyphosphonate 3a and 3b. However, these α-hydroxyphosphonates can be transformed to

s by reaction with

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

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-(dimethylphosphono)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 * Using the solvent DME over

THF Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...

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 chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

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 ketones is poor to modest.

Variations

Base sensitive substrates

Since many substrates are not stable to

sodium hydride Sodium hydride is the chemical compound with the empirical formula Na H. This alkali metal hydride is primarily used as a strong yet combustible base in organic synthesis. NaH is a saline (salt-like) hydride, composed of Na+ and H− ions, in co ...

, 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 The decibel (symbol: dB) is a relative unit of measurement equal to one tenth of a bel (B). It expresses the ratio of two values of a Power, root-power, and field quantities, power or root-power quantity on a logarithmic scale. Two signals whose ...

. Rathke extended this to

lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...

magnesium Magnesium is a chemical element with the 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 of the periodic ta ...

halides with

triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...

. Several other bases have been found effective.

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 18-Crown-6 is an organic compound with the formula 2H4Osub>6 and the IUPAC name of 1,4,7,10,13,16-hexaoxacyclooctadecane. It is a white, hygroscopic crystalline solid with a low melting point. Like other crown ethers, 18-crown-6 functions as a ...

) 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