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Wittig reaction

(Redirected from Phosphonium ylide)
Not to be confused with Wittig rearrangement.

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.[1][2][3] Most often, the Wittig reaction is used to introduce a methylene group using methylenetriphenylphosphorane (Ph3P=CH2). Using this reagent, even a sterically hindered ketone such as camphor can be converted to its methylene derivative.

Wittig reaction
Named after Georg Wittig
Reaction type Coupling reaction
Reaction
aldehyde or ketone
+
triphenyl phosphonium ylide
↓
alkene
+
(Ph)3P=O
Conditions
Typical solvents typically THF or diethyl ether
Identifiers
March's Advanced Organic Chemistry 16–44 (6th ed.)
Organic Chemistry Portal wittig-reaction
RSC ontology ID RXNO:0000015 checkY
 ☒N(what is this?)  (verify)
Wittig Reaction

Reaction mechanism

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Mechanistic studies have focused on unstabilized ylides, because the intermediates can be followed by NMR spectroscopy. The existence and interconversion of the betaine (3a and 3b) is subject of ongoing research.[4] For lithium-free Wittig reactions, studies support a concerted formation of the oxaphosphetane without intervention of a betaine. In particular, phosphonium ylides 1 react with carbonyl compounds 2 via a [2+2] cycloaddition that is sometimes described as having [π2s+π2a] topology to directly form the oxaphosphetanes 4a and 4b. Under lithium-free conditions, the stereochemistry of the product 5 is due to the kinetically controlled addition of the ylide 1 to the carbonyl 2. When lithium is present, there may be equilibration of the intermediates, possibly via betaine species 3a and 3b.[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]

 
The mechanism of the Wittig reaction

Mechanisms differ for aliphatic and aromatic aldehydes and for aromatic and aliphatic phosphonium ylides. Evidence suggests that the Wittig reaction of unbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore under kinetic 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]

Scope and limitations

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Functional group tolerance

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The Wittig reagents generally tolerate carbonyl compounds containing several kinds of functional groups such as OH, OR, nitroarenes, epoxides, and sometimes esters and amides.[13] Even ketone, aldehyde, and nitrile groups can be present if conjugated with the ylide — these are the stabilised ylides mentioned above. Bis-ylides (containing two P=C bonds) have also been made and used successfully.[14] There can be a problem with sterically hindered ketones, where the reaction may be slow and give poor yields, particularly with stabilized ylides, and in such cases the Horner–Wadsworth–Emmons (HWE) reaction (using phosphonate esters) is preferred. Another reported limitation is the often labile nature of aldehydes, which can oxidize, polymerize or decompose. In a so-called tandem oxidation-Wittig process the aldehyde is formed in situ by oxidation of the corresponding alcohol.[15]

Stereochemistry

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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 in dimethylformamide in the presence of lithium iodide or sodium 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, the Julia olefination and its variants also provide the (E)-alkene selectively. Ordinarily, the Horner–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.

Schlosser modification

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The main limitation of the traditional Wittig reaction is that the reaction proceeds mainly via the erythro betaine intermediate, which leads to the Z-alkene. The erythro betaine can be converted to the threo betaine using phenyllithium at low temperature.[18] This modification affords the E-alkene.

 
The Schlosser variant of the Wittig reaction

Allylic alcohols can be prepared by reaction of the betaine ylide with a second aldehyde.[19] For example:

 
An example of the Schlosser variant of the Wittig reaction

Example

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An example of its use is in the synthesis of leukotriene 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 the cis product. The second Wittig reaction uses a non-stabilised Wittig reagent, and as expected this gives mainly the cis product.

 
An example of the use of the Wittig reaction in synthesis, making leukotriene A methyl ester

History

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The Wittig reaction was reported in 1954 by Georg Wittig and his coworker Ulrich Schöllkopf. In part for this contribution, Wittig was awarded the Nobel Prize in Chemistry in 1979.[22][23]

See also

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Wikimedia Commons has media related to Wittig reaction.

References

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  1. ^ Maercker, A. Org. React. 1965, 14, 270–490.
  2. ^ W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, Cambridge, UK, 1971, 81–90. (ISBN 0-521-31117-9)
  3. ^ R. W. Hoffmann (2001). "Wittig and His Accomplishments: Still Relevant Beyond His 100th Birthday". Angewandte Chemie International Edition. 40 (8): 1411–1416. doi:10.1002/1521-3773(20010417)40:8<1411::AID-ANIE1411>3.0.CO;2-U. PMID 11317288.
  4. ^ E. Vedejs & C. F. Marth (1990). "Mechanism of Wittig reaction: evidence against betaine intermediates". J. Am. Chem. Soc. 112 (10): 3905–3909. doi:10.1021/ja00166a026.
  5. ^ Bruce E. Maryanoff, A. B. Reitz, M. S. Mutter, R. R. Inners, and H. R. Almond, Jr., "Detailed Rate Studies on the Wittig Reaction of Non-Stabilized Phosphorus Ylides via 31P, 1H, and 13C NMR Spectroscopy. Insight into Kinetic vs. Thermodynamic Control of Stereochemistry", J. Am. Chem. Soc., 107, 1068–1070 (1985)
  6. ^ Bruce E. Maryanoff, A. B. Reitz, D. W. Graden, and H. R. Almond, Jr., "NMR Rate Study on the Wittig Reaction of 2,2-Dimethylpropanal and Tributylbutylidene-phosphorane", Tetrahedron Lett., 30, 1361–1364 (1989)
  7. ^ Bruce E. Maryanoff, A. B. Reitz, M. S. Mutter, R. R. Inners, H. R. Almond, Jr., R. R. Whittle, and R. A. Olofson, "Stereochemistry and Mechanism of the Wittig Reaction. Diastereomeric Reaction Intermediates and Analysis of the Reaction Course", J. Am. Chem. Soc., 108, 7664–7678 (1986)
  8. ^ A. B. Reitz, S. O. Nortey, A. D. Jordan, Jr., M. S. Mutter, and Bruce E. Maryanoff, "Dramatic Concentration Dependence of Stereochemistry in the Wittig Reaction. Examination of the Lithium-Salt Effect", J. Org. Chem., 51, 3302–3308 (1986)
  9. ^ E. Vedejs, C. F. Marth and R. Ruggeri (1988). "Substituent effects and the Wittig mechanism: the case of stereospecific oxaphosphetane decomposition". J. Am. Chem. Soc. 110 (12): 3940–48. doi:10.1021/ja00220a036.
  10. ^ E. Vedejs & C. F. Marth (1988). "Mechanism of the Wittig reaction: the role of substituents at phosphorus". J. Am. Chem. Soc. 110 (12): 3948–3958. doi:10.1021/ja00220a037.
  11. ^ Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1.
  12. ^ Byrne, Peter A.; Gilheany, Declan G. (2013). "The modern interpretation of the Wittig reaction mechanism". Chemical Society Reviews. 42 (16): 6670–96. doi:10.1039/c3cs60105f. hdl:10197/4939. ISSN 0306-0012. PMID 23673458.
  13. ^ Smith (2020), March's Organic Chemistry, rxn. 16-44.
  14. ^ B. E. Maryanoff & A. B. Reitz (1989). "The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects". Chem. Rev. 89 (4): 863–927. doi:10.1021/cr00094a007.
  15. ^ Richard J. K. Taylor, Leonie Campbell, and Graeme D. McAllister (2008). "(±) trans-3,3'-(1,2-Cyclopropanediyl)bis-2-(E)-propenoic Acid, Diethyl Ester: Tandem Oxidation Procedure (TOP) using MnO2 Oxidation-Stabilized Phosphorane Trapping" (PDF). Organic Syntheses. 85: 15–26{{cite journal}}: CS1 maint: multiple names: authors list (link).
  16. ^ L. D. Bergelson & M. M. Shemyakin (1964). "Synthesis of Naturally Occurring Unsaturated Fatty Acids by Sterically Controlled Carbonyl Olefination". Angew. Chem. 3 (4): 250–260. doi:10.1002/anie.196402501.
  17. ^ Robiette, Raphaël; Richardson, Jeffery; Aggarwal, Varinder K.; Harvey, Jeremy N. (1 February 2006). "Reactivity and Selectivity in the Wittig Reaction: A Computational Study". Journal of the American Chemical Society. 128 (7): 2394–2409. doi:10.1021/ja056650q. ISSN 0002-7863. PMID 16478195.
  18. ^ M. Schlosser & K. F. Christmann (1966). "Trans-Selective Olefin Syntheses". Angewandte Chemie International Edition in English. 5 (1): 126. doi:10.1002/anie.196601261.
  19. ^ E. J. Corey and H. Yamamoto (1970). "Modification of the Wittig reaction to permit the stereospecific synthesis of certain trisubstituted olefins. Stereospecific synthesis of α-santalol". J. Am. Chem. Soc. 92 (1): 226–228. doi:10.1021/ja00704a052.
  20. ^ I. Ernest, A. J. Main and R. Menasse (1982). "Synthesis of the 7-cis isomer of the natural leukotriene d4". Tetrahedron Letters. 23 (2): 167–170. doi:10.1016/S0040-4039(00)86776-3.
  21. ^ E. J. Corey, D. A. Clark, G. Goto, A. Marfat, C. Mioskowski, B. Samuelsson and S. Hammarstroem (1980). "Stereospecific total synthesis of a "slow reacting substance" of anaphylaxis, leukotriene C-1". J. Am. Chem. Soc. 102 (4): 1436–1439. doi:10.1021/ja00524a045.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Georg Wittig, Ulrich Schöllkopf (1954). "Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien I". Chemische Berichte. 87 (9): 1318. doi:10.1002/cber.19540870919.
  23. ^ Georg Wittig; Werner Haag (1955). "Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien II". Chemische Berichte. 88 (11): 1654–1666. doi:10.1002/cber.19550881110.
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