Winstein reaction
The Wittig reaction is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkene and triphenylphosphine oxide.[1][2]
The Wittig reaction was discovered in 1954 by Georg Wittig, for which he was awarded the Nobel Prize in Chemistry in 1979. It is widely used in organic synthesis for the preparation of alkenes.[3][4][5] It should not be confused with the Wittig rearrangement.
Wittig reactions are most commonly used to couple aldehydes and ketones to singly substituted phosphine ylides. With simple ylides this results in almost exclusively the Z-alkene product. In order to obtain the E-alkene, the Schlosser modification of the Wittig reaction can be performed.
Reaction mechanism
Classical mechanism
The steric bulk of the ylide 1 influences the stereochemical outcome of nucleophilic addition to give a predominance of the betaine 3. Carbon-carbon bond rotation gives the betaine 4, which then forms the oxaphosphatane 5. Elimination gives the desired Z-alkene 7 and triphenylphosphine oxide 6. With simple Wittig reagents, the first step occurs easily with both aldehydes and ketones, and the decomposition of the betaine (to form 5) is the rate-determining step. However with stabilised ylides (where R1 stabilises the negative charge) the first step is the slowest step, so the overall rate of alkene formation decreases and a bigger proportion of the alkene product is the E-isomer. This also explains why stabilised reagents fail to react well with sterically hindered ketones.
Recent developments
Recent research has shown that the reaction mechanism presented above does not account for all experimental results. Mechanistic studies have been done mostly on unstablilized ylides, because the intermediates can be followed by NMR spectroscopy. The existence and interconversion of the betaine (3a and 3b) is still under debate and a subject of ongoing research.[6] There is evidence that phosphonium ylides 1 can react with carbonyl compounds 2 via a π²s/π²a [2+2] cycloaddition to directly form the oxaphosphatanes 4a and 4b. The stereochemistry of the product 5 is due to the addition of the ylide 1 to the carbonyl 2 and to the ability of the intermediates to equilibrate.[7][8][9] Maryanoff and 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.[10]
There are distinct differences in the mechanisms of aliphatic and aromatic aldehydes and of aromatic and aliphatic phosphonium ylides. Vedejs et al. have provided evidence that the Wittig reaction of unbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore under kinetic reaction control.[11][12] Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions.[13]
Wittig reagents
Preparation of simple ylides
The Wittig reagent is usually prepared from a phosphonium salt, which is in turn made by the reaction of triphenylphosphine with an alkyl halide. To form the Wittig reagent (ylide), the phosphonium salt is suspended in a solvent such as diethyl ether or THF and a strong base such as phenyllithium or n-butyllithium is added.
Ph3P+−CH2−R X− + C4H9Li → Ph3P=CH−R + LiX + C4H10
The simplest ylide used is methylenetriphenylphosphorane (Ph3P+−C−H2), and this is also the basis of an alternative synthesis of Wittig reagents. Substituted ylides can be made by alkylation of Ph3P=CH2 with a primary alkyl halide R−CH2−X, to produce a substituted phosphonium salt:
Ph3P=CH2 + R-CH2-X → Ph3P+−CH2− CH2−R X−
which can be deprotonated with C4H9Li to make Ph3P=CH−CH2−R.
Stabilised Wittig reagents
These contain groups that can stabilise the negative charge from the carbanion-like carbon, for example Ph3P=CH−COOR, Ph3P=CH−Ph. These are less reactive than simple ylides, and so they usually fail to react with ketones, necessitating the use of the Horner-Wadsworth-Emmons reaction as an alternative. They can be prepared from the phosphonium salts using weaker bases than butyllithium such as alkoxides and (in some cases) sodium hydroxide. They usually give rise to an E-alkene product when they react, rather than the more usual Z-alkene.
Structure of the ylide
The Wittig reagent may be written in the phosphorane form (the more familiar representation) or the ylide form:
File:Wittig reagent structure.gif
However the phosphorane resonance requires expansion of the octet on phosphorus. This hypervalency cannot (yet) be explained well in terms of standard bonding theory, and this resonance is rather less favoured than the more familiar p–p overlap seen in π-bonded compounds as alkenes or imines. This means that the ylide form is a significant contributor, and the carbon is quite nucleophilic.
Scope and limitations
The Wittig reaction has become a popular method for alkene synthesis precisely because of its wide applicability. Unlike elimination reactions (such as dehydrohalogenation of alkyl halides), which produce mixtures of alkene regioisomers determined by Zaitsev's rule, the Wittig reaction forms the double bond in one position with no ambiguity.
A large variety of ketones and aldehydes are effective in the reaction, though carboxylic acid derivatives such as esters fail to react usefully. Thus mono-, di- and trisubstituted alkenes can all be prepared in good yield in most cases. The carbonyl compound can tolerate several groups such as OH, OR, aromatic nitro and even ester groups. There can be a problem with sterically hindered ketones, where the reaction may be slow and give poor yields, particularly with stabilised 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.[14]
As mentioned above, the Wittig reagent itself is usually derived from a primary alkyl halide, because with most secondary halides the phosphonium salt is formed in poor yield. This means that most tetrasubstituted alkenes are best made by other means. However the Wittig reagent can tolerate many other variants. It may contain alkenes and aromatic rings, and it is compatible with ethers and even ester groups. Even C=O 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.
One limitation relates to the stereochemistry of the product. With simple ylides, the product is usually mainly the Z-isomer, although a lesser amount of the E-isomer is often formed also- this is particularly true when ketones are used. If the reaction is performed in DMF in the presence of LiI or NaI, the product is almost exclusively the Z-isomer.[15] If the E-isomer is the desired product, the Schlosser modification may be used. With stabilised ylides the product is mainly the E-isomer, and this same isomer is also usual with the HWE reaction.
The Schlosser modification
The major limitation of the traditional Wittig reaction is that the reaction goes mainly via the erythro betaine intermediate, which leads to the Z-alkene. However Schlosser & Christmann[16] found that the erythro betaine can be converted to the threo betaine using phenyllithium at low temperature (forming a betaine) followed by HCl. Upon workup this leads to the E-alkene product as shown.
E. J. Corey and H. Yamamoto found that the utility can be extended to a stereoselective synthesis of allylic alcohols, by reaction of the betaine ylid with a second aldehyde.[17] For example:
Examples of use
Because of its reliability and wide applicability, the Wittig reaction has become a standard tool for synthetic organic chemists.[18]
The most popular use of the Wittig reaction is for the introduction of a methylene group using methylenetriphenylphosphorane (Ph3P=CH2). In the example shown, even a sterically hindered ketone such as camphor can be successfully converted to its methylene derivative by heating with methyltriphenylphosphonium bromide and potassium tert-butoxide, which generate the Wittig reagent in situ.[19] In another example, the phosphorane is produced using sodium amide as a base, and this successfully converts the aldehyde shown into alkene I in 62% yield.[20] The reaction is performed in cold THF, and the sensitive nitro, azo and phenoxide groups all survive intact. The product can be used to incorporate a photostabiliser into a polymer, to protect the polymer from damage by UV radiation.
Another example of its use is in the synthesis of leukotriene A methyl ester.[21][22] The first step uses a stabilised ylide, where the carbonyl group is conjugated with the ylid 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. Note that the epoxide and ester functional groups survive intact.
Methoxymethylenetriphenylphosphine is a Wittig reagent for the homologation of aldehydes.
See also
- Corey-Chaykovsky reagent
- Horner-Wadsworth-Emmons reaction
- Julia-Lythgoe olefination
- Peterson olefination
- Tebbe reagent
- Organophosphorus chemistry
- Homologation reaction
References
- ↑ Georg Wittig, Ulrich Schöllkopf (1954). "Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien I". Chemische Berichte. 87: 1318. doi:10.1002/cber.19540870919.
- ↑ Georg Wittig, Werner Haag (1955). "Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien II". Chemische Berichte. 88: 1654–1666. doi:10.1002/cber.19550881110.
- ↑ Maercker, A. Org. React. 1965, 14, 270-490. (Review)
- ↑ W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, Cambridge, UK, 1971, pp81-90. (ISBN 0-521-31117-9)
- ↑ 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. Unknown parameter
|doilabel=ignored (help) - ↑ E. Vedejs and C. F. Marth (1990). "Mechanism of Wittig reaction: evidence against betaine intermediates". J. Am. Chem. Soc. 112 (10): 3905–3909. doi:10.1021/ja00166a026.
- ↑ B. 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)
- ↑ B. 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)
- ↑ B. 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)
- ↑ A. B. Reitz, S. O. Nortey, A. D. Jordan, Jr., M. S. Mutter, and B. E. Maryanoff, "Dramatic Concentration Dependence of Stereochemistry in the Wittig Reaction. Examination of the Lithium-Salt Effect", J. Org. Chem., 51, 3302-3308 (1986)
- ↑ 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): 3940–3948. doi:10.1021/ja00220a036.
- ↑ E. Vedejs and 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.
- ↑ Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1.
- ↑ Template:OrgSynth
- ↑ L. D. Bergelson and 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.
- ↑ M. Schlosser and K. F. Christmann (1966). "Trans-Selective Olefin Syntheses". Angewandte Chemie International Edition in English. 5 (1): 126. doi:10.1002/anie.196601261.
- ↑ 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.
- ↑ B. E. Maryanoff and 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.
- ↑ Fitjer, L.; Quabeck, U. Synthetic Communications 1985, 15(10), 855-864.
- ↑ F. A. Bottino, G. Di Pasquale, A. Pollicino, A. Recca and D. T. Clark (1990). "Synthesis of 2-(2-hydroxyphenyl)-2H-benzotriazole monomers and studies of the surface photostabilization of the related copolymers". Macromolecules. 23 (10): 2662–2666. doi:10.1021/ma00212a011.
- ↑ 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.
- ↑ 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.
External links
- Wittig reaction in Organic Syntheses, Coll. Vol. 10, p.703 (2004); Vol. 75, p.153 (1998). (Article)
- Wittig reaction in Organic Syntheses, Coll. Vol. 5, p.361 (1973); Vol. 45, p.33 (1965). (Article)
ca:Reacció de Wittig de:Wittig-Reaktion it:Reazione di Wittig lb:Wittig-Reaktiounen nl:Wittig-reactie