Wittig Reaction

(1)International Journal for Research in Applied Science & Engineering Technology (IJRASET) ISSN: 2321-9653; IC Value: 45.98; SJ Impact Factor: 7.177 Volume 7 Issue IX, Sep 2019- Available at www.ijraset.com. Wittig Reaction Surbhi Goyal Abstract: The Wittig Reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide. The reaction was given by George Wittig in 1950. He was awarded with Nobel Prize in 1979. The importance of Wittig reaction is that it provides a method for making carbon - carbon double bond formation in which the position of double bond formation is unambiguous. Otherwise, if we are using Grignard reagent positional isomers are formed. Hence the yield of the reaction decreases. Keywords: Wittig Reaction, Phosphonium ylide, Grignard Reagent, George Witig. I. INTRODUCTION The reaction between an aldehyde or ketone and phosphonium ylide to form an alkene and a phosphine oxide is known as Wittig reaction.. R1 R2. O. +. Aldehyde or Ketone. R3 Ph3P R4 Phosphonium Ylide. R1. R3. R2. R4. +. Ph3P O Phosphine Oxide. Alkene. The importance of Wittig reaction is that it provides a method for making carbon - carbon double bond formation in which the position of double bond formation is unambiguous. For example- cyclohexane react with phosphonium ylide to form methylene cyclohexane exclusively.. CH2. O + H2C PPh3 cyclohexanone. methylene cyclohexane. Otherwise, if we are using Grignard reagent positional isomers are formed. Hence the yield of the reaction decreases.. O CH3MgBr cyclohexanone. CH3. HO CH3. CH2. H 1-methylcyclohex-1-ene. methylene cyclohexane. A. Phosphonium Ylide Ylide is a species in which positive and negative charge are located on the adjacent atoms as in. H2C PPh3. the “yl” part of the. name ylide refers to the covalent bond in the substructure P CH2 . The “ide “part indicates that it also contain the ionic bond. OR We can also define ylide as the resonance structure between the covalent form ( -yl, where the carbanion exists as a methylidenyl group) and the ionic form ( -ide, as in methanide). ©IJRASET: All Rights are Reserved. 878.

(2) International Journal for Research in Applied Science & Engineering Technology (IJRASET) ISSN: 2321-9653; IC Value: 45.98; SJ Impact Factor: 7.177 Volume 7 Issue IX, Sep 2019- Available at www.ijraset.com B. Preparation Of Phosphonium Ylide Phosphonium ylides are prepared from phosphonium salt. Phosphonium salt is prepared by reaction of triphenylphosphine with alkyl halide. Then phosphonium salt is deprotonated with strong base giving phosphonium ylide. Ph H 3C. Ph P Ph. Ph I Ph P CH 3 Ph Phosphonium salt. I. Bu Li. Ph H Ph P C Ph H 2 I. Ph Ph P CH2 Ph Phosphonium ylide. Phosphonium ylide is also called Wittig reagent. For Wittig reaction, we always prefer a path in which Wittig reagent is derived from less hindered alkyl halide. For example we can prefer 3-Methyl hept-3-ene by two ways.. a. 3-methy l hept-3-ene. Ph3P. +. O butanal. b. O PPh3. + butan-2-one. Path b is more preferred than path a. because in path b, phosphonium ylide is derived from less hindered alkyl halide. C. Classification Of Phosphonium Ylides Phosphonium ylide are classified into three types on the basis of their reactivity. Table: Triphenyl phosphonium ylides: nomenclature, preparation and stereoselectivity of their Wittig reactions. S.No. P-Ylide Ylide type Ylide is prepared from 1,2-disubstituted prepared alkene PPh 3 CHR Hal. and 1. PPh3 CHAlkyl. Nonstablized ylide. in situ. n-BuLi. or. Na CH2S(. O)CH3. with ≥ 90% cisselectivity. or K O tert-Bu 2. PPh3 CHAryl. Semistablized ylide. PPh3 CHCOOR. Stablized ylide. 3.. in situ. in prior reaction. NaOEt or aq.NaOH. as cis,trans mixture. aq.NaOH. with > 90% trans-selectivity. “Stabilized ylide” have strongly conjugating substituent’s (e.g -COOMe, -CN, -SO2Ph) on the ylidic carbon and usually favour the formation of (E)-alkene. “Semistablized” ylides contain mildly conjugating substituents (Ph or allyl) and give mixture of cis and trans alkene. “Nonstablized” ylides contain alkyl substituents on the ylidic carbon and usually favour (Z)-alkenes. The three R groups present on phosphorous are nearly always phenyl group.. ©IJRASET: All Rights are Reserved. 879.

(3) International Journal for Research in Applied Science & Engineering Technology (IJRASET) ISSN: 2321-9653; IC Value: 45.98; SJ Impact Factor: 7.177 Volume 7 Issue IX, Sep 2019- Available at www.ijraset.com D. Mechanism of Wittig Reaction 1) Betaine Mechanism: It is two step mechanism in which firstly betaine is formed when carbonyl compound and phosphonium ylides are approach towards each other after this oxaphosphetane is formed from betaine which is then fragment into phosphine oxide and alkene.. R' A. R' A R'. R. B. A. +. R. PPh3. O. R. B O PPh3 Betaine. B O PPh3. +. Oxaphosphitane. Alkene. Ph3P O phosphine oxide. 2) Concerted Mechanism: It is one step mechanism in which directly oxaphosphetane is formed when carbonyl compound and phosphonium ylide approach towards each other.. R. R'. A. R' A. B. R. B O PPh3 Oxaphosphitane. +. PPh3. O. +. Ph3P O Phosphine oxide. Alkene. After this, oxaphosphetane fragment into alkene and phosphine oxide. The driving force for the fragmentation of oxaphosphetane into alkene and phosphine oxide is being provided by the formation of very strong phosphorous – oxygen bond. Some reactions proceed through via betaine mechanism and some reactions proceed through via concerted mechanism depending upon the nature of the substrate. E. Evidence For The Existence Of Intermediate Evidence for the existence of betaine intermediate from some experimental observations are 1) The formation of stable adducts between betaine and lithium halide in situ. 2) The trapping of betaine as β-hydroxy phosphonium salts by addition of acid at low temperature. 3) The prominent effect of lithium salt on the alkene stereochemistry. But in first time in 1973, Veejs reported that oxaphosphetanes are the only observable intermediates by P31 NMR spectroscopy in conventional reactions of non-stabilized ylides at low temperature -30o to 0oC. In the case of Semistablized ylides, oxaphosphetanes have generally have not been detected even at low temperature -100 to -80oC. Hence there is little hope for oxaphosphetanes formed from stabilized ylides. F. Stereoselectivity In Wittig Reaction The general rule is that stabilized ylide (R1=Ar, COR, C=C etc) react with aldehyde or ketone to give mostly (E)-isomer. While unstabilized ylide give (Z)-isomer.. Ph3P. R1. R2 +. ©IJRASET: All Rights are Reserved. H. O. R2. + R1 (E)-Alkene R1=COOMe, SO2Ph CN etc.. R1. R2. (Z)-Alkene R1=Alkyl. 880.

(4) International Journal for Research in Applied Science & Engineering Technology (IJRASET) ISSN: 2321-9653; IC Value: 45.98; SJ Impact Factor: 7.177 Volume 7 Issue IX, Sep 2019- Available at www.ijraset.com When reaction takes place between carbonyl compound and phosphonium ylide. Then they just approach to each other perpendicularly so that bulky groups are away from each other and (2π-2π) cycloaddition takes place in (supra + antara) mode in thermal condition to form four member puckered oxaphosphetane which is equivalent to syn oxaphosphetane. Since oxygen is more electronegative than carbon so the HOMO of the carbonyl group have larger orbital coefficient at oxygen while the LUMO will have a larger orbital coefficient at carbon the situation is similar with ylide. Since carbon is more electronegative than phosphorous .The HOMO of the ylide group have larger orbital coefficient at carbon. The ylidic carbon is act as nucleophile so the primary interaction will be between its HOMO and LUMO of the electrophillic carbonyl group. Since the orbital interact best where coefficients are large. This primary interaction will be in favour of forming C-C bond. For secondary interactions, the phosphorous have vacant d- orbital which act as LUMO and interact with HOMO of the carbonyl group which has its biggest coefficient on oxygen. So this bonding interaction will be in favour of forming P-O bond. HOMO. LUMO. The biases in the primary and secondary orbital interactions will lead to some distortions from the pure perpendicular approach which will become more pronounced the nearer two species get to each other. So, the ylide might rotate a bit so that its carbon atom will be closer to the carbonyl ‘s carbon atom and its phosphorous atom will be closer to the carbonyl’s oxygen atom in order to maximize the bonding overlap and of course the perpendicular approach of ylide and carbonyl group will proceed in such a way that their respective biggest substituent’s are as far away from each other as possible. If R = alkyl group, then phosphonium ylide is non-stabilized and more reactive. It reacts with carbonyl compound rapidly and form syn oxaphosphetane which is fragment into (Z)-alkene and phosphine oxide. The reaction is irreversible in this case. R3 P R2 R1 H PR O PR 3 3 H O H H O + R1 H H H R2 1 R1 2 R R2 H R four member syn (Z)-alkene (R2= alkyl group) puckered ring oxaphosphitane structure R3 P H H PR3 O PR3 O O 1 H 1 H R R H R2 2 R1 R2 2 H R (R =COCH 3) syn f our member puckered ring oxaphosphitane structure O PR3 H R2 1 R H anti oxaphosphetane. R1. H. H R2 (E)-alkene. If R = -COCH3, then phosphonium ylide is stabilized and less reactive. It reacts with carbonyl compound slowly and leads to reversible formation of syn oxaphosphetane in which two alkyl groups are on the same side of four member ring. So, it is less stable and breaks down into the starting materials faster than to the product alkene. The recombination takes place which prefer the formation of thermodynamically more stable trans - oxaphosphetane and which then fragment into (E)-alkene and phosphine oxide.. ©IJRASET: All Rights are Reserved. 881.

(5) International Journal for Research in Applied Science & Engineering Technology (IJRASET) ISSN: 2321-9653; IC Value: 45.98; SJ Impact Factor: 7.177 Volume 7 Issue IX, Sep 2019- Available at www.ijraset.com G. Stereoselectivity In Case Of Salt Free Conditions The stereoselectivity of the Wittig reaction depends not only on the substituents but also on the presence of salt. In absence of lithium salts ( “salt free” ), there is stereoselective synthesis of (Z)-alkene from non-stabilized ylide so the reaction in which (Z)alkene is desired are often carried out using sodium or potassium bases. For example, by using NaNH2, KO-tert-Bu, and KHMDS etc. Under salt free conditions, the cis oxaphosphetane formed from non stabilized ylides can be kept from participating in the stereochemical drift (i.e. the initially obtained cis-oxaphosphetane can subsequently isomerize irreversibly to a transoxaphosphetane with the rate constant kdrift × [ktrans / (ktrans +kcis )]. This isomerization is referred to as stereochemical drift.) and left intact until they decompose to give the alkene in the terminating step. This alkene is then a pure cis isomer. In other words, salt free Wittig reactions of non-stabilized ylides represent stereoselective synthesis of cis-alkenes. R3 P H R1. O. PR 3. + H. R2. (R2= alkyl group). H R1. O. H R2 four member puckered ring structure. O PR 3 H R1 R2 syn oxaphosphitane H. R1. R2. H. H. (Z)-alkene. Example. Br. PPh3 Br. PPh3. 1-bromo-2-methylpropane. O. Ph. H H. Ph. 1-((Z)-5-methylhex-3-enyl)benzene H. Stereoselectivity In Case Of Non-Salt Free Conditions If non-stabilized P-ylides react with salt carbonyl compounds in the presence of Li salts (i.e. non-salt free conditions ) then there is stereoselective synthesis of E-isomer occur because of the Li effect. Li salts are able to induce a heterolysis of the O-P bond of oxaphosphetanes. They thereby convert oxaphosphetanes into the so called lithiobetaines. This takes place because of high coordination power of lithium than that of the sodium or potassium with oxygen because lithium act as hard acid and oxygen act as hard base so according to the HSAB principle, hard acid prefer to interact with hard base strongly instead of soft base. After this a single oxido ylide B is produced from each of the diastereomeric lithiobetaines A and C. At this point, exactly 1.0 equivalent of HCl is added to protonate the oxido ylide. This produces a lithiobetaine again, but this time it is obtain diastereomerically pure as compound A. This species react very cleanly to give the alkene when it is treated with KOtert-Bu. This treatment establishes an equilibrium reaction in which the Li+ ion migrates from the lithiobetaine A to the tert-BuO- ion. This creates a betaine D, which lacks the stabilizing Li+ ion. As lithium free betaine are relatively unstable. Consequently, D collapses exergonically to the oxaphosphetane E. the stereocenters in E have the same configuration as the stereocenters in its precursor molecule D and the same configuration as in lithiobetaine A. the oxaphosphetane E is therefore uniformly trans which fragment into E-alkenes.. ©IJRASET: All Rights are Reserved. 882.

(6) International Journal for Research in Applied Science & Engineering Technology (IJRASET) ISSN: 2321-9653; IC Value: 45.98; SJ Impact Factor: 7.177 Volume 7 Issue IX, Sep 2019- Available at www.ijraset.com. start of the reaction O PPh3 R2. R1. O ktrans. R1. H. PPh3. +. R2. H. O PPh3. kcis ktrans. Li Hal. Li Hal. Li O H 1 R. A. PPh3 R2 H. R2. R1. PhLi. Li O H1 R. PPh3. PhLi. Li O H1 R. R2. B an oxide ylide. trans lithiobetaine. C. PPh3 H R2. cis lithiobetaine. HCl KOtert-Bu (-LiOtert-Bu). O. PPh3. R1. R2 D. O PPh3 R2. R1 E. R2 R1. +. O PPh3. end of the reaction. II. ACKNOWLEDGEMENT It is our proud privilege and duty to acknowledge the kind of help and guidance received from several people in preparation of this paper. It would not have been possible to prepare this paper in this form without their valuable help, cooperation and guidance. A special gratitude I give to Dr. Anju, Dr. Meenakshi, Miss Sapna whose contribution in stimulating suggestions and encouragement helped me to writing his paper. Last, but not the least, I wish to thank my parents for financing my studies as well as foronstantly encouraging me. REFERENCES [1] [2] [3] [4] [5] [6] [7]. B. E. Maryanoff, Allen B. Reitz. Chem. Rev. 1989, 863-927. J. Boutagy, Richard Thomas. Chem. Rev. 1974, 74, 87-99. [Synth] snypa.co.uk 19-2-2016. Chemistry.stackexchange.com 19-2-2016. Warren, S., Organic Synthesis: The Disconnection Approach Wiley Publication, Nisha Enterprises, Sahibabad, UP. 2014, 3, 120-124. Carruthers, W., Coldham, I.,Modern Methods of Organic Synthesis, Cambridge university Press, U.K., 2004, 4, 132-139. Bruckner, R., Harmata, M. (Eds), Organic Mechanisms, Reactions, Stereochemistry and synthesis, Springer-Verlag Berlin Heidelberg, 2010, 3, 457-465.. ©IJRASET: All Rights are Reserved. 883.

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