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CONJUGATE ADDITION

CONJUGATE ADDITION. MICHAEL ADDITION. Addition of Nucleophiles to Enones Conjugate Addition or Michael Addition. -. -. :. :. :. :. :. +. +. :Nu. :Nu. 1,2-addition. 1,4-addition. Nu. conjugate addition. Nu. CONJUGATE ADDITION. -. :. :. :. -. H-OH. :.

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CONJUGATE ADDITION

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  1. CONJUGATE ADDITION MICHAEL ADDITION

  2. Addition of Nucleophiles to Enones Conjugate Addition or Michael Addition .. .. .. - - : : : : : + + :Nu :Nu 1,2-addition 1,4-addition Nu conjugate addition Nu

  3. CONJUGATE ADDITION .. .. - : : : - H-OH .. : In conjugate addition the nucleophile adds and then picks up a hydrogen from the solvent medium.

  4. CONJUGATE ADDITION GENERALIZATION stereochemistry also matters conjugated ketone b a strong bases direct to C=O 1,2-addition weak nucleophiles/bases conjugate addition 1,4-addition

  5. Strong Bases : 1,2-Addition • Strong bases give direct addition to C=O (1,2-addition) unless • the C=O group is sterically hindered by large groups Organolithium compounds RLi Grignard reagents RMgX Lithium Aluminum Hydride LiAlH4

  6. Weak Bases : 1,4-Addition • Good nucleophiles and weak bases give conjugate addition • (1,4-addition), also known as Michael Addition, especially if • the C=O group is hindered. .. Amines R-NH2 Alcohols R-O-H Water H-O-H Enolates Organocopper and cadmium compounds ( RMgX + CuCl or CdCl2 ) Lithium dialkylcuprates ( RLi + CuCl ) Cyanide ion :C N: .. .. .. ..

  7. ADDITION TO CARBONYL CH3MgI CuCl CH3Li (CH3)2CuLi or or CH3MgI (CH3)2Cd strong bases add by 1,2 addition weaker bases add by 1,4 addition C-Li and C-Mg bonds are more ionic (stronger bases) R-Cu and R-Cd bonds are more covalent (weaker bases)

  8. STEREOCHEMISTRY ALSO MATTERS LARGE GROUPS ON EITHER SIDE OF THE CARBONYL FAVOR CONJUGATE ADDITION large groups here promote 1,4 addition STERIC HINDRANCE major product large groups here can also promote 1,4 addition major product large groups here promote 1,2 addition small groups here make 1,2 addition more probable

  9. FRONTIER MO THEORY CONJUGATED KETONES

  10. FRONTIER MO THEORY NUCLEOPHILE HOMO LUMO FILLED MOs HOMO :Nu- E+ FILLED MOs ELECTROPHILE

  11. LUMO MAPPED ONTO ELECTRON DENSITY BLUE REPRESENTS MAXIMUM DENSITY OF LUMO A A B B

  12. ROBINSON ANNELATION FORMING RINGS BY COMBINING CONJUGATE ADDITION WITH AN ALDOL CONDENSATION METHYL VINYL KETONE (MVK)

  13. - : O-CH3 .. Conjugate Addition of Cyclopentanone to MVK MVK enolate weak base methyl vinyl ketone .. - .. .. .. : : : : : - : H-OCH3 NaOCH3 .. CH3OH .. : : .. .. - : O-CH3 + .. can continue

  14. ROBINSON ANNELATION USES MVK TO BUILD A RING FROM PREVIOUS SLIDE NaOCH3 CH3OH Michael addition - : - H3O+ Annelation (workup) (ring formation) internal aldol condensation

  15. ANOTHER EXAMPLE MICHAEL ADDITION + ALDOL CONDENSATION 2 ALDOL NaOEt 1 EtOH Most acidic set of hydrogens reacts first. MICHAEL

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