- Wittig reaction
The Wittig reaction is a
chemical reaction of analdehyde orketone with a triphenyl phosphonium ylide (often called a Wittig reagent) to give analkene andtriphenylphosphine oxide . [cite journal
author =Georg Wittig ,Ulrich Schöllkopf
journal =Chemische Berichte
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
journal =Chemische Berichte
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
1954 byGeorg Wittig , for which he was awarded theNobel Prize in Chemistry in1979 . It is widely used inorganic synthesis for 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
ylide s. With simple ylides this results in almost exclusively theZ-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 ofnucleophilic 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 andtriphenylphosphine oxide 6. With simple Wittig reagents, the first step occurs easily with bothaldehyde s andketone s, and the decomposition of the betaine (to form 5) is therate-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 byNMR 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]cycloaddition to directly form the oxaphosphatanes 4a and 4b. Thestereochemistry 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. [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.Lithium salts 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
aliphatic andaromatic aldehyde s and ofaromatic andaliphatic 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 underkinetic 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.]Wittig reagents
Preparation of simple ylides
The Wittig reagent is usually prepared from a
phosphonium salt , which is in turn made by the reaction oftriphenylphosphine with analkyl halide . To form the Wittig reagent (ylide), the phosphonium salt is suspended in a solvent such asdiethyl ether or THF and a strong base such asphenyllithium 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.
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 theHorner-Wadsworth-Emmons reaction as an alternative. They can be prepared from the phosphonium salts using weaker bases than butyllithium such asalkoxide s 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
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 asalkene s orimine s. 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
alkene synthesis precisely because of its wide applicability. Unlikeelimination reactions (such asdehydrohalogenation ofalkyl halide s), which produce mixtures of alkeneregioisomer s determined byZaitsev's rule , the Wittig reaction forms the double bond in one position with no ambiguity.A large variety of
ketone s andaldehyde s are effective in the reaction, thoughcarboxylic acid derivatives such asester s fail to react usefully. Thus mono-, di- and trisubstituted alkenes can all be prepared in good yield in most cases. Thecarbonyl compound can tolerate several groups such as OH, OR, aromaticnitro 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 ofaldehyde s which can oxidize, polymerize or decompose. In a so-called Tandem Oxidation-Wittig Process the aldehyde is formedin situ by oxidation of the correspondingalcohol . [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 andaromatic ring s, and it is compatible withether s and evenester groups. Even C=O andnitrile 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. [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 betaine intermediate, which leads to theZ-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 thethreo betaine usingphenyllithium at low temperature (forming a betaine) followed by HCl. Upon workup this leads to theE-alkene product as shown.E. J. Corey and
H. Yamamoto found that the utility can be extended to astereoselective synthesis of allylic alcohols, by reaction of the betaine ylid with a second aldehyde. [cite journal | author =E. J. Corey and 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
methylene group using methylenetriphenylphosphorane (Ph3P=CH2). In the example shown, even a sterically hindered ketone such ascamphor can be successfully converted to its methylene derivative by heating with methyltriphenylphosphonium bromide andpotassium 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 usingsodium amide as a base, and this successfully converts thealdehyde shown 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 coldTHF , and the sensitivenitro ,azo andphenoxide groups all survive intact. The product can be used to incorporate a photostabiliser into apolymer , 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 theepoxide andester functional groups survive intact.Methoxymethylenetriphenylphosphine is a Wittig reagent for the homologation of aldehydes.ee also
*
Corey-Chaykovsky reagent
*Horner-Wadsworth-Emmons reaction
*Julia-Lythgoe olefination
*Peterson olefination
*Tebbe reagent
*Organophosphorus chemistry
*Homologation reaction References
External links
*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 inOrganic 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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