wittig reaction n suzuki reaction mechanism

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WITTIG REACTION AND SUZUKI COUPLING REACTION AISSMS College of Pharmacy Dt.8.11.2011 1 Presented by: Guided by: Ms.Bhakti Joshi Mrs. T. S. Chitre 1 st sem M. Pharm Asst. Professor Phamachemistry Pharmachemistry


CONTENTS 1. What is Wittig reaction 2. Wittig reaction mechanism 3. Stereochemistry 4. Advantage 5. Examples 6. Application 7. What is suzuki coupling reaction 8. About palladium 9. Sources of palladium 10. Suzuki reaction Mechanism 11. Stereochemistry 12. Advantage 13. Limitation 14. Examples 15. Application 16. References 2

What is Wittig reaction ? [1,2,3]:

What is Wittig reaction ? [1,2,3] It is a reaction between a carbonyl compound (aldehyde or ketone only) and a species known as a phosphonium ylid which gives alkene , which is the product of the reaction along with a phosphine oxide.[1] Also called as the Wittig olefination reaction . Discovered by George Wittig in 1954 and received Nobel prize in 1979. 3

General reaction [4] :

General reaction [4] 4

Preparation of phosphonium ylide [4,6]:

Preparation of phosphonium ylide [4,6] An ylid (or ylide) is a species with positive and negative charges on adjacent atoms. A phosphonium ylid carries its positive charge on phosphorus. The reaction of a phosphine (triphenylphosphine) with an alkyl halide gives a phosphonium salt . Phosphonium ylids are made from phosphonium salts by deprotonating them with a strong base . 5

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6 A phosphonium salt Methyltriphenylphosphonium Bromide

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7 Mechanism for Phosphorous ylide [7] Step 1: Nucleophilic displacement of halide by triphenyl phosphine. Step 2: Treatment of the phosphonium salt with a very strong base such as BuLi , NaH , or NaNH 2

About phosphorous ylides [4]:

About phosphorous ylides [4] The reactivity of the phosphorus ylide strongly depends on substituent . When substituent is an electron withdrawing group, the reactivity at the ylide carbon is reduced. R can be both alkyl, or alkyl and aryl. For preparative use R often is a phenyl group. 8

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Simple ylides are sensitive towards water as well as oxygen. By reaction with water, the ylide is hydrolyzed to give the trisubstituted phosphine oxide and the hydrocarbon . By reaction with oxygen, the ylide is cleaved to the trisubstituted phosphine oxide and a carbonyl compound . e.g. the oxidative cleavage of benzylidene triphenyl phosphorane to give triphenylphosphine oxide and benzaldehyde 9

Reaction Mechanism [4,6]:

Reaction Mechanism [4,6] 10 The nucleophile is the carbanion part of the phosphonium ylid. The negatively polarized ylide carbon center attacks to the carbonyl carbon center which is the rate determinig step of the reaction


Contd … A betain is formed, in which a negatively charged oxygen attacks the positively charged phosphorus which cyclizes to give four membered ring i.e. oxaphosphetane as an intermediate. 11


Contd … The latter decomposes to yield a trisubstituted phosphine oxide and an alkene. The driving force for this reaction is the formation of the strong double bond between phosphorus and oxygen. 12

Reaction Condition:

Reaction Condition Mild reaction condition Non-stabilized ylides require a strong base (such as BuLi ) under inert conditions. while stabilized ylides require a weaker base (for example, alkali metal hydroxides in aqueous solution). 13

Stereochemistry [8]:

Stereochemistry [8] It is a regio and stereo selective formation of an alkenes. Stereospecificity : -It is non- stereospecific because both E- and Z -alkenes are formed. - oxaphosphetanes undergo stereospecific syn elimination to give the corresponding E- and Z-alkenes. 14

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Stereo selectivity: -it is possible to increases proportion of either E or Z isomer through appropriate choice of ylide: with stabilized ylids, the reaction is E selective e.g. carbonyl group in Ph 3 P=CH–COOR,CN in Ph 3 P=CH-CN with unstabilised ylids, the reaction is Z selective e.g. simple alkyl groups 15


Advantages Generation of new carbon–carbon double bond in the product at a fixed position. Used to prepare symmetrical alkenes. E- and Z- stereoselectivity are controlled through careful selection of the phosphorus reagent and reaction conditions. For the synthesis of sensitive alkenes e.g. highly unsaturated compounds like the carotinoid 16


Examples 17


Applications 18 Synthesis of β -carotene [9] Preparation of stilbene [4]

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19 β- bisabolene Synthesis of Bisabolene :

Suzuki Coupling Reaction [6]:

Suzuki Coupling Reaction [6] 20 The Suzuki reaction is a palladium-catalyzed coupling of a vinyl or aryl halide (R'X) with an organoborane (RBY 2 ) to form a product (R—R‘) with a new C—C bond. Discovered by A. Suzuki and N. Miyaura in 1979.

General Reaction [4]:

General Reaction [4] 21 R 1 = alkyl, allyl , alkenyl , aryl R 2 = alkyl, OH X = Cl , Br, I, OTf R 2 = aryl, alkyl Solvent = H 2 O, EtOH Base = Na 2 CO 3 , Ba (OH) 2 , KF, CsF , NaOH

About palladium [6]:

About palladium [6] It is a transition metal from d block with atomic number 46 e - configuration is 1s 2 2s 2 2p 6 3s 2 3p 6 3d 10 4s 2 4p 6 4d 10 So, 10 electrons are present in the valence shell. Hence palladium will lead to form a stable complex by satisfying the 18e - rule for a stable metal complex. 22


Contd … Stable metal complex formation is achieved by combining the e-, that the metal already possess with those donated by co- ordinating ligand . 23


Contd … Palladium reacts with just four triphenylphosphines (PPh 3 ) to give stable complex. 24 Triphenyl phosphine

Preactivation of catalyst:

Preactivation of catalyst 25 (4) Pd(II) is reduced to the catalytically active Pd(0) in situ, typically through the Oxidation of Phosphine ligand .

Sources of palladium:

26 Sources of palladium

Reaction Mechanism 1) Oxidative addition[13]:

Reaction Mechanism 1) Oxidative addition [13] The rate determining step of the catalytic cycle. Couples the palladium catalyst to the alkyl halide which gives rise to the organopalladium complex. The complex is initially in the cis conformation but isomerizes to the trans conformation 27

2) Transmetallation[14]:

Transfer of substituent( R) from boron to the palladium center, thus generating a palladium-(II) species that contains both the substituent R and R1 that are to be coupled. Organoboron compounds are highly covalent in character, and do not undergo transmetallation readily so the boronic acid is first converted to an activated species i.e. boronate ion by quaternisation containing a tetravalent boron center by reaction with a base. 28 2) Transmetallation [14]

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3) Reductive elimination[15]:

3) Reductive elimination [15] Isomerization to the cis complex is required before reductive elimination can occur. Relative rates of reductive elimination from palladium(II) complexes: Aryl - aryl > alkyl - aryl > n- propyl - n- propyl > ethyl - ethyl > methyl - methyl To yield the coupling product and the regenerated catalytically active palladium-(0) complex . 30

The Catalytic Cycle:

The Catalytic Cycle 31


Stereochemistry [6] 32 Stereochemistry with vinyl halides are retained but inversion of stereochemistry occurs with allylic or benzylic halides.


Advantages Mild reaction conditions. Commercial availability of many boronic acids. The organic byproducts are easily removed. Boronic acids are environmentally safer and much less toxic. Starting material tolerate wide variety of functional groups 33

Limitations of Suzuki reaction:

Limitations of Suzuki reaction Generally aryl halides react sluggishly. Only aryl bromides and iodides can be used as chlorides react slowly. Reaction can not proceed in the absence of base. Not particularly amenable to aqueous-phase catalysis. By products often formed Suzuki reactions generally employ organic solvents such as tetrahydrofuran and ethers as well as complex palladium catalysts which are soluble in these solvents. 34


Examples 35

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Applications 37 Vancomycin is a polycyclic glycopeptide antibiotic . [16]

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38 Curacin A , was first isolated from L. majuscula in 1994 and found to have various interesting biological activities. It is an antimitotic metabolite from a cyanobacterium [17]


References 1) G. Wittig, G. Geissler , Justus Liebigs Ann. Chem. 1953, 580, 44–57 . 2) A. W. Johnson, Ylid Chemistry, Academic Press, New York, 1979. 3) A. Maercker, Org. React. 1965,14, 270–490. 4) Thomas Laue, Andreas Plagens , Named Organic Reactions John Wiley and Sons Publication,2nd edition, 2005, pp154, 271-274, 293-297. 5) W. A. Smit , A. F. Bochkov , R. Caple : Organic Synthesis, The Science behind the Art, Published by The Royal Society of Chemistry, UK,1998 pg 61,82-85. 39

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40 6) J. Clayden , Organic Chemistry, Greeves , Warren and Wothers Oxford University Press, 2001 and Reprint 2008, pp 357, 650, 701 814–18 , 1279-1389. 7) M. Jones: Wittig Reaction, 16.17, pp 876-877. 8) Michael Edmonds and Andrew Abell , Modern Carbonyl Olefination, WILEY-VCH Verlag GmbH & Co. KGaA , Weinheim 2004 ,1-17 9) G. Wittig, H. Pommer , DBP 954 247, 1956; Chem. Abstr . 1959, 53, 2279 . 10) Suzuki A. In Metal-Catalyzed Cross-Coupling Reactions, Diederich F., and Stang , P. J., Eds.; Wiley-VCH: New, York 1998, pp. 49-97 . 11) Suzuki, A. J. Organometallic Chem. 1999, 147–168.576 ,

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12) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457– 2483. 13) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434–442. 14) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–470. 15) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 245- 248 16) K.C. Nicolaou , J.M. Ramanjulu , S. Natarajan , S. Bra¨se , H. Li, C.N.C. Boddy , F. Ru¨bsam , Chem. Commun . (1997) 1899. 17) J. D. White, T.-S. Kim, M. Nambu , J. Am. Chem. Soc. 119(1997) 103. 41

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