| Wittig reaction | |||||||||||
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| Named after | Georg Wittig | ||||||||||
| Reaction type | Coupling reaction | ||||||||||
| Reaction | |||||||||||
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| Conditions | |||||||||||
| Typical solvents | typicallyTHF ordiethyl ether | ||||||||||
| Identifiers | |||||||||||
| March's Advanced Organic Chemistry | 16–44 (6th ed.) | ||||||||||
| Organic Chemistry Portal | wittig-reaction | ||||||||||
| RSC ontology ID | RXNO:0000015  Y | ||||||||||
 N(what is this?) (verify) | |||||||||||
TheWittig reaction or Wittig olefination is achemical reaction of analdehyde orketone with a triphenyl phosphoniumylide called aWittig reagent. Wittig reactions are most commonly used to convert aldehydes and ketones to alkenes.[1][2][3] Most often, the Wittig reaction is used to introduce amethylene group usingmethylenetriphenylphosphorane (Ph3P=CH2). Using this reagent, even a sterically hindered ketone such ascamphor can be converted to its methylene derivative.
Mechanistic studies have focused on unstabilized ylides, because the intermediates can be followed byNMR spectroscopy. The existence and interconversion of the betaine (3a and3b) is subject of ongoing research.[4] For lithium-free Wittig reactions, studies support a concerted formation of theoxaphosphetane without intervention of a betaine. In particular, phosphonium ylides1 react with carbonyl compounds2 via a [2+2]cycloaddition that is sometimes described as having [π2s+π2a] topology to directly form the oxaphosphetanes4a and4b. Under lithium-free conditions, thestereochemistry of the product5 is due to the kinetically controlled addition of the ylide1 to the carbonyl2. When lithium is present, there may beequilibration of the intermediates, possibly via betaine species3a and3b.[5][6][7]Bruce E. Maryanoff and A. B. Reitz identified the issue about equilibration of Wittig intermediates and termed the process "stereochemical drift". For many years, the stereochemistry of the Wittig reaction, in terms of carbon-carbon bond formation, had been assumed to correspond directly with the Z/E stereochemistry of the alkene products. However, certain reactants do not follow this simple pattern.Lithium salts can also exert a profound effect on the stereochemical outcome.[8]
Mechanisms differ foraliphatic andaromaticaldehydes and foraromatic andaliphatic phosphonium ylides. Evidence suggests that the Wittig reaction ofunbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore underkinetic reaction control.[9][10]E. Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions.[11]
Strong evidence indicated that under Li-free conditions, Wittig reactions involving unstabilized (R1= alkyl, H), semistabilized (R1 = aryl), and stabilized (R1 = EWG) Wittig reagents all proceed via a [2+2]/retro-[2+2] mechanism under kinetic control, with oxaphosphetane as the one and only intermediate.[12]
The Wittig reagents generally toleratecarbonyl compounds containing several kinds of functional groups such asOH,OR,nitroarenes,epoxides, and sometimesesters andamides.[13] Evenketone,aldehyde, andnitrile groups can be present ifconjugated with the ylide — these are thestabilised ylides mentioned above. Bis-ylides (containing two P=C bonds) have also been made and used successfully.[14] There can be a problem withsterically hindered ketones, where the reaction may be slow and give poor yields, particularly with stabilized ylides, and in such cases theHorner–Wadsworth–Emmons (HWE) reaction (using phosphonate esters) is preferred. Another reported limitation is the often labile nature ofaldehydes, which can oxidize, polymerize or decompose. In a so-called tandem oxidation-Wittig process the aldehyde is formedin situ by oxidation of the corresponding alcohol.[15]
For the reaction with aldehydes, the double bond geometry is readily predicted based on the nature of the ylide. With unstabilised ylides (R3 = alkyl) this results in(Z)-alkene product with moderate to high selectivity. If the reaction is performed indimethylformamide in the presence oflithium iodide orsodium iodide, the product is almost exclusively the Z-isomer.[16] With stabilized ylides (R3 = ester or ketone), the (E)-alkene is formed with high selectivity. The (E)/(Z) selectivity is often poor with semistabilized ylides (R3 = aryl).[17]
To obtain the (E)-alkene for unstabilized ylides, the Schlosser modification of the Wittig reaction can be used. Alternatively, theJulia–Kocienski olefination provides the (E)-alkene selectively. Ordinarily, theHorner–Wadsworth–Emmons reaction provides the (E)-enoate (α,β-unsaturated ester), just as the Wittig reaction does. To obtain the (Z)-enolate, the Still-Gennari modification of the Horner-Wadsworth-Emmons reaction can be used.
The main limitation of the traditional Wittig reaction is that the reaction proceeds mainly via theerythrobetaine intermediate, which leads to the Z-alkene. The erythro betaine can be converted to the threo betaine usingphenyllithium at low temperature.[18] This modification affords the E-alkene.
Allylic alcohols can be prepared by reaction of the betaine ylide with a second aldehyde.[19] For example:
An example of its use is in the synthesis ofleukotriene A methyl ester.[20][21] The first step uses a stabilised ylide, where the carbonyl group is conjugated with the ylide preventing self condensation, although unexpectedly this gives mainly thecis product. The second Wittig reaction uses a non-stabilised Wittig reagent, and as expected this gives mainly thecis product.
The Wittig reaction was reported in 1954 byGeorg Wittig and his coworkerUlrich Schöllkopf. In part for this contribution, Wittig was awarded theNobel Prize in Chemistry in 1979.[22][23]
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