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chapter 22 alpha substitution and condensations of enols and enolate ions

Chapter 22. 2. Alpha Substitution. Replacement of a hydrogen on the carbon adjacent to the carbonyl, C=O.. =>. Chapter 22. 3. Condensation with Aldehyde or Ketone. Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition.. =>. Chapter 22. 4. Condensation with Esters. Loss of alkoxide ion results in nucleophilic acyl substitution..

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chapter 22 alpha substitution and condensations of enols and enolate ions

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    1. Chapter 22Alpha Substitution andCondensations of Enolsand Enolate Ions

    2. Chapter 22 2

    3. Chapter 22 3 Condensation withAldehyde or Ketone Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition.

    4. Chapter 22 4 Condensation with Esters Loss of alkoxide ion results in nucleophilic acyl substitution.

    5. Chapter 22 5 Keto-Enol Tautomers Tautomers are isomers which differ in the placement of a hydrogen. One may be converted to the other. In base:

    6. Chapter 22 6 Keto-Enol Tautomers (2) Tautomerism is also catalyzed by acid. In acid:

    7. Chapter 22 7 Equilibrium Amounts For aldehydes and ketones, the keto form is greatly favored at equilibrium. An enantiomer with an enolizable hydrogen can form a racemic mixture.

    8. Chapter 22 8 Acidity of ?-Hydrogens pKa for ?-H of aldehyde or ketone ~20. Much more acidic than alkane or alkene (pKa > 40) or alkyne (pKa = 25). Less acidic than water (pKa = 15.7) or alcohol (pKa = 16-19). In the presence of hydroxide or alkoxide ions, only a small amount of enolate ion is present at equilibrium. =>

    9. Chapter 22 9 Enolate Reaction

    10. Chapter 22 10 Acid-Base Reactionto Form Enolate Very strong base is required for complete reaction. Example:

    11. Chapter 22 11 ? Halogenation Base-promoted halogenation of ketone. Base is consumed. Other products are water and chloride ion.

    12. Chapter 22 12 Multiple Halogenations The ?-halo ketone produced is more reactive than ketone. Enolate ion stabilized by e--withdrawing halogen.

    13. Chapter 22 13 Haloform Reaction Methyl ketones replace all three Hs with halogen. The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.

    14. Chapter 22 14 Positive Iodoformfor Alcohols If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test.

    15. Chapter 22 15 Acid CatalyzedHalogenation of Ketones Can halogenate only one or two ?-Hs. Use acetic acid as solvent and catalyst.

    16. Chapter 22 16 Aldehydes and Halogens Halogens are good oxidizing agents and aldehydes are easily oxidized.

    17. Chapter 22 17 The HVZ Reaction The Hell-Volhard-Zelinsky reaction replaces the ?-H of a carboxylic acid with Br.

    18. Chapter 22 18 Alkylation Enolate ion can be a nucleophile. Reacts with unhindered halide or tosylate via SN2 mechanism.

    19. Chapter 22 19 Stork Reaction Milder alkylation method than using LDA. Ketone + 2? amine ? enamine. Enamine is ?-alkylated, then hydrolyzed.

    20. Chapter 22 20 Acylation via Enamines Product is a ?-diketone.

    21. Chapter 22 21 Aldol Condensation Enolate ion adds to C=O of aldehyde or ketone. Product is a ?-hydroxy aldehyde or ketone. Aldol may lose water to form C=C.

    22. Chapter 22 22 Mechanism for Aldol Condensation

    23. Chapter 22 23 Dehydration of Aldol Creates a new C=C bond.

    24. Chapter 22 24 Crossed AldolCondensations Two different carbonyl compounds. Only one should have an alpha H.

    25. Chapter 22 25 Aldol Cyclizations 1,4-diketone forms cyclopentenone. 1,5-diketone forms cyclohexenone.

    26. Chapter 22 26 Planning Aldol Syntheses

    27. Chapter 22 27 Claisen Condensation Two esters combine to form a ?-keto ester.

    28. Chapter 22 28 Dieckmann Condensation A 1,6 diester ? cyclic (5) ?-keto ester. A 1,7 diester ? cyclic (6) ?-keto ester.

    29. Chapter 22 29 Crossed Claisen Two different esters can be used, but one ester should have no ? hydrogens. Useful esters are benzoates, formates, carbonates, and oxalates. Ketones (pKa = 20) may also react with an ester to form a ?-diketone.

    30. Chapter 22 30 ?-Dicarbonyl Compounds More acidic than alcohols. Easily deprotonated by alkoxide ions and alkylated or acylated. At the end of the synthesis, hydrolysis removes one of the carboxyl groups.

    31. Chapter 22 31 Malonic Ester Synthesis Deprotonate, then alkylate with good SN2 substrate. (May do twice.) Decarboxylation then produces a mono- or di-substituted acetic acid.

    32. Chapter 22 32 Acetoacetic Acid Synthesis Product is mono- or di-substituted ketone.

    33. Chapter 22 33 Conjugate Additions When C=C is conjugated with C=O, 1,2-addition or 1,4-addition may occur. A 1,4-addition of an enolate ion is called the Michael reaction.

    34. Chapter 22 34 Michael Reagents Michael donors: enolate ions stabilized by two electron-withdrawing groups. ?-diketone, ?-keto ester, enamine, ?-keto nitrile, ?-nitro ketone. Michael acceptors: C=C conjugated with carbonyl, cyano, or nitro group. conjugated aldehyde, ketone, ester, amide, nitrile, or a nitroethylene. =>

    35. Chapter 22 35 A Michael Reaction Enolates can react with ?,?-unsaturated compounds to give a 1,5-diketo product.

    36. Chapter 22 36 Robinson Annulation A Michael reaction to form a ?-diketone followed by an intramolecular aldol condensation to form a cyclohexenone.

    37. Chapter 22 37 Mechanism for Robinson Annulation (1)

    38. Chapter 22 38 Mechanism for Robinson Annulation (2)

    39. Chapter 22 39 End of Chapter 22

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