- Wittig reaction
The Wittig reaction is a
chemical reactionof an aldehydeor ketonewith a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkeneand triphenylphosphine oxide. [cite journal
Georg Wittig, Ulrich Schöllkopf
year = 1954
volume = 87
pages = 1318
title = Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien I
doi = 10.1002/cber.19540870919] [cite journal
author = Georg Wittig, Werner Haag
year = 1955
volume = 88
pages = 1654–1666
title = Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien II
doi = 10.1002/cber.19550881110]
The Wittig reaction was discovered in
1954by Georg Wittig, for which he was awarded the Nobel Prize in Chemistryin 1979. It is widely used in organic synthesisfor the preparation of alkenes. [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)] [cite journal | author = R. W. Hoffmann | title = Wittig and His Accomplishments: Still Relevant Beyond His 100th Birthday | year = 2001 | journal = Angewandte Chemie International Edition| volume = 40 | issue = 8 | pages = 1411–1416 | doi = 10.1002/1521-3773(20010417)40:8<1411::AID-ANIE1411>3.0.CO;2-U] 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-alkeneproduct. In order to obtain the E-alkene, the Schlosser modification of the Wittig reaction can be performed.
The steric bulk of the
ylide1 influences the stereochemical outcome of nucleophilic additionto 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 oxide6. 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 research has shown that the
reaction mechanismpresented 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. [cite journal | author = E. Vedejs and C. F. Marth | title = Mechanism of Wittig reaction: evidence against betaine intermediates | year = 1990 | journal = J. Am. Chem. Soc.| volume = 112 | issue = 10 | pages = 3905–3909 | doi=10.1021/ja00166a026] There is evidence that phosphonium ylides 1 can react with carbonyl compounds 2 via a π²s/π²a [2+2] cycloadditionto directly form the oxaphosphatanes 4a and 4b. The stereochemistryof 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. [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)] 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. Lithiumsalts can also exert a profound effect on the stereochemical outcome. [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)]
There are distinct differences in the mechanisms of
aliphaticand aromatic aldehydes and of aromaticand aliphaticphosphonium 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. [cite journal | author = E. Vedejs, C. F. Marth and R. Ruggeri | title = Substituent effects and the Wittig mechanism: the case of stereospecific oxaphosphetane decomposition | year = 1988 | journal = J. Am. Chem. Soc.| volume = 110 | issue = 12 | pages = 3940–3948 | doi = 10.1021/ja00220a036] [cite journal | author = E. Vedejs and C. F. Marth | title = Mechanism of the Wittig reaction: the role of substituents at phosphorus | year = 1988 | journal = J. Am. Chem. Soc.| volume = 110 | issue = 12 | pages = 3948–3958 | doi = 10.1021/ja00220a037] Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions. [Vedejs, E.; Peterson, M. J. "Top. Stereochem." 1994, "21", 1.]
Preparation of simple ylides
The Wittig reagent is usually prepared from a
phosphonium salt, which is in turn made by the reaction of triphenylphosphinewith an alkyl halide. To form the Wittig reagent (ylide), the phosphonium salt is suspended in a solvent such as diethyl etheror THF and a strong base such as phenyllithiumor "n"-butyllithium is added.
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 halideR−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.
tabilised 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-Emmonsreaction 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.
tructure of the ylide
The Wittig reagent may be written in the phosphorane form (the more familiar representation) or the ylide form:
However the phosphorane resonance requires expansion of the octet on phosphorus. This
hypervalencycannot (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.
cope and limitations
The Wittig reaction has become a popular method for
alkenesynthesis precisely because of its wide applicability. Unlike eliminationreactions (such as dehydrohalogenationof 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 acidderivatives such as esters fail to react usefully. Thus mono-, di- and trisubstituted alkenes can all be prepared in good yield in most cases. The carbonylcompound can tolerate several groups such as OH, OR, aromatic nitroand 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 situby oxidation of the corresponding alcohol. [OrgSynth | author = Richard J. K. Taylor, Leonie Campbell, and Graeme D. McAllister | title = (±) trans-3,3'-(1,2-Cyclopropanediyl)bis-2-(E)-propenoic Acid, Diethyl Ester: Tandem Oxidation Procedure (TOP) using MnO2 Oxidation-Stabilized Phosphorane Trapping | year = 2008 | volume = 85 | pages = 15-26 | url = http://www.orgsyn.org/orgsyn/pdfs/V85P0015.pdf]
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 estergroups. Even C=O and nitrilegroups 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
stereochemistryof 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. [cite journal | author = L. D. Bergelson and M. M. Shemyakin | title = Synthesis of Naturally Occurring Unsaturated Fatty Acids by Sterically Controlled Carbonyl Olefination | year = 1964 | journal = Angew. Chem.| volume = 3 | issue = 4 | pages = 250–260 | doi = 10.1002/anie.196402501] 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 betaineintermediate, which leads to the Z-alkene. However Schlosser & Christmann [cite journal | author = M. Schlosser and K. F. Christmann | title = Trans-Selective Olefin Syntheses | year = 1966 | journal = Angewandte Chemie International Edition in English| volume = 5 | issue = 1 | pages = 126 | doi = 10.1002/anie.196601261] found that the erythro betaine can be converted to the threobetaine using phenyllithiumat low temperature (forming a betaine) followed by HCl. Upon workup this leads to the E-alkeneproduct as shown.
E. J. Corey and
H. Yamamotofound that the utility can be extended to a stereoselectivesynthesis of allylic alcohols, by reaction of the betaine ylid with a second aldehyde. [cite journal | author = E. J. Coreyand H. Yamamoto | title = Modification of the Wittig reaction to permit the stereospecific synthesis of certain trisubstituted olefins. Stereospecific synthesis of α-santalol | year = 1970 | journal = J. Am. Chem. Soc.| volume = 92 | issue = 1 | pages = 226–228 | doi = 10.1021/ja00704a052] For example:
Examples of use
Because of its reliability and wide applicability, the Wittig reaction has become a standard tool for synthetic organic chemists. [cite journal | author = B. E. Maryanoff and A. B. Reitz | title = The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects | year = 1989 | journal =
Chem. Rev.| volume = 89 | issue = 4 | pages = 863–927 | doi = 10.1021/cr00094a007]
The most popular use of the Wittig reaction is for the introduction of a
methylenegroup using methylenetriphenylphosphorane (Ph3P=CH2). In the example shown, even a sterically hindered ketone such as camphorcan be successfully converted to its methylene derivative by heating with methyltriphenylphosphonium bromide and potassium tert-butoxide, which generate the Wittig reagent "in situ". [Fitjer, L.; Quabeck, U. "Synthetic Communications" 1985, "15(10)", 855-864.] In another example, the phosphorane is produced using sodium amideas a base, and this successfully converts the aldehydeshown into alkene I in 62% yield. [cite journal | author = F. A. Bottino, G. Di Pasquale, A. Pollicino, A. Recca and D. T. Clark | title = Synthesis of 2-(2-hydroxyphenyl)-2H-benzotriazole monomers and studies of the surface photostabilization of the related copolymers | year = 1990 | journal = Macromolecules | volume = 23 | issue = 10 | pages = 2662–2666 | doi = 10.1021/ma00212a011] The reaction is performed in cold THF, and the sensitive nitro, azoand phenoxidegroups 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. [cite journal | author = I. Ernest, A. J. Main and R. Menasse | title = Synthesis of the 7-cis isomer of the natural leukotriene d4 | year = 1982 | journal =
Tetrahedron Letters| volume = 23 | issue = 2 | pages = 167–170 | doi = 10.1016/S0040-4039(00)86776-3] [cite journal | author = E. J. Corey, D. A. Clark, G. Goto, A. Marfat, C. Mioskowski, B. Samuelsson and S. Hammarstroem | title = Stereospecific total synthesis of a "slow reacting substance" of anaphylaxis, leukotriene C-1 | year = 1980 | journal = J. Am. Chem. Soc.| volume = 102 | issue = 4 | pages = 1436–1439 | doi = 10.1021/ja00524a045] 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 epoxideand esterfunctional groups survive intact. Methoxymethylenetriphenylphosphineis a Wittig reagent for the homologation of aldehydes.
*Wittig reaction in
Organic Syntheses, Coll. Vol. 10, p.703 (2004); Vol. 75, p.153 (1998). ( [http://www.orgsynth.org/orgsyn/prep.asp?prep=v75p0153 Article] )
*Wittig reaction in
Organic Syntheses, Coll. Vol. 5, p.361 (1973); Vol. 45, p.33 (1965). ( [http://www.orgsynth.org/orgsyn/prep.asp?prep=cv5p0361 Article] )
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