Wittig reaction

C=C bond generation in organic chemistry

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2. wittig reaction Dr. Shahid Rasool   Wittig reaction   CHEM5128 Advanced Named Reactions   2

3. Key Concepts Introduction to Wittig reaction Discussion of reacting species, bases Mechanism of reaction Explanation of mechanism step by step Synthetic applications 3

4. Wittig Reaction: In 1954, G. Wittig introduced the reaction Triphenylphosphane ( triphenylphosphine ) reacts alkyl halides to produce phosphonium salt Phosphonium salt is converted to phosphorane by a base Phosphorane (phosphorus ylide ) reacts aldehydes or ketones to produce alkene A way to prepare olefins from aldehydes or ketones Overall reaction,

5. Phosphane , Phosphonium salt & Phosphoranes : Organo -phosphorus compounds Phosphane or Phosphine is normally bonded phosphorus (3 bonds) Phosphonium salt is phosphorus with 4 bonds Phosphorane is phosphorus with 5 bonds PCl 3  + 3 PhMgCl → PPh 3  + 3 MgCl 2 PCl 3  + 3 PhCl + 6 Na → PPh 3  + 6 NaCl PCl 3  + 3 PhLi → PPh 3  + 3 LiCl

6. Phosphoranes or Phosphorus ylide : Phosphoranes are also called phosphorus ylide or phosphonium ylide Ylide is a compound having an uncharged molecule containing a negatively charged carbon atom directly bonded to a positively charged atom of sulphur , phosphorus, nitrogen, or another element Ylide is a species with opposite formal charges on adjacent atoms Carbon bears a nucleophillic character which attacks on carbonyl. Ylides have been known for sulphur , phosphorus, nitrogen and oxygen Ylene form or

7. Types of Phosphorus ylide : Unstabilized phosphorus ylide These have either H or alkyl groups connected to the C atom. Alkyl groups are EDG and destabilize charge separation. Ylene form predominates and reactions occur through it. Stabilized phosphorus ylide The subtituents on the C atom must be ones that can stabilize the negative charge by delocalization. Since charge stabilization is achieved through resonance delocalization, the ylide form predominates. Ylene form Ylide form

8. Alkylating agents and bases: Alkyl halides or Alkyl sulfonates can be used. Nature of alkyl group results into stabilized or unstabilized phosphorus ylide . Unstabilized phosphorus ylide reacts through its ylene form and produces Z- alkene predominantly. Stabilized phosphorus ylide reacts through its ylide form and produces E- alkene predominantly. Different bases used for deprotonation include alkyl lithium ( RLi ), NaH , LiH , NaNH 2 etc

9. Complete Mechanism:

10. Step-1, Formation of phosphonium salt: Triphenylphosphine reacts with alkyl halide through S N 2 mechanism. Triphenylphosphine acts as a nucleophile due to lone pair of phosphorus. Nucleophilicity of phosphorus is greater than that of nitrogen due to large size. The α -carbon of alkyl halide act as an electrophilic center. Why there is substitution and not elimination? (PPh 3 is a strong nucleophile and not a strong base)

11. Step-2, Ylide formation: Deprotonation of phosphonium salt results into ylide formation. Strong base can be used to remove proton. The α -hydrogen of phosphonium salt is removed by base. Resulting product has two forms i.e. Ylene form or Ylide form Why is it easy to remove proton from a C-H bond? Which form is dominating? Ylene form or Ylide form?

12. Step-2, Ylide formation: Preparation of Unstabilized Phosphorus Ylides Alkyl groups are EDG and destabilize charge separation. Ylene form predominates and reactions occur through it. Phosphonium group is EWG so C-H bond is acidic. (Lithium diisopropylamide )

13. Step-2, Ylide formation: Preparation of Stabilized Phosphorus Ylides EWG stabilizes the charge through resonance delocalization Ylide form predominates and reactions occur through it. Two EWG, so C-H bond is acidic.

14. Step-3, Olefin formation: The ylide reacts with aldehyde or ketone through a cyclic mechanism to form olefin. The – vely charged carbon of ylide acts as nucleophile . The step 1 and step 2 may occur simultaneously. The byproduct along with alkene is Ph 3 P=O, also called triphenyl ( oxo ) phosphorane or triphenylphosphine oxide.

15. Stereochemistry: Unstabilized phosphorus ylide reacts through its ylene form and produces Z- alkene predominantly. Stabilized phosphorus ylide reacts through its ylide form and produces E- alkene predominantly. Schlosser Modification: Reaction proceeds mainly via erythro betaine  intermediate- produces Z- alkene . ( erythro means identical group on same side) erythro betaine into threo by phenyllithium  at low temperature- produces E- alkene . ( threo means identical group on opposite side)

16. Stereochemistry (Schlosser Modification):

17. Stereochemistry: Unstabilized phosphorus ylide reacts through its ylene form and produces Z- alkene predominantly.

18. Stereochemistry: Stabilized phosphorus ylide reacts through its ylide form and produces E- alkene predominantly.

19. Advantages of Wittig Reactions: Alkenes can be synthesized from aldehydes or ketones Tolerance of carbonyl compounds with many different kinds of functional groups like OH group, OR group, etc. by the Wittig reagent. The geometry of the double bond can easily be predicted if the Ylide’s nature is known. Limitations of Wittig Reactions: Both the E and the Z double bond isomers can be formed. The reaction speed is very slow when sterically hindered ketones are used. The yield is also low for these reactions. Aldehydes can easily undergo oxidation, decomposition, or even polymerization.

20. Comparison of HWE and Wittig Reactions: HWE uses more nucleophillic and reactive phosphonate -stabilized carbanions than phosphonium ylide Phosphonium ylide bears a neutral form and neutral species are less reactive than charged species HWE byproduct dialkylphosphate salt is easily removed by water during workup than triphenylphosphine oxide (Wittig reaction) HWE produces E-alkenes and Wittig reaction produces  Z- alkenes. phosphonate -stabilized carbanions

21. Examples of Wittig Reaction: Sodium dodecyl sulfate (SDS)

22. Examples of Wittig Reaction: