1. Organic Chemistry, 6th Edition L. G. Wade, Jr.
Chapter 22 Alpha Substitution and Condensations of Enols and Enolate Ions
Jo Blackburn
Richland College, Dallas, TX
Dallas County Community College District
ã 2006, Prentice Hall

2. Alpha Substitution
Replacement of a hydrogen on the carbon adjacent to the carbonyl, C=O.
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Chapter 22

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

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

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

9. Enolate Reaction
As enolate ion reacts with the electrophile, the equilibrium shifts to produce more.
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Chapter 22

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

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

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

13. Haloform Reaction Methyl ketones replace all three H’s with halogen.
The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.
Iodoform,
yellow ppt. =>
Chapter 22

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

15. Acid Catalyzed Halogenation of Ketones
Can halogenate only one or two -H’s.
Use acetic acid as solvent and catalyst.
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Chapter 22

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

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

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

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

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

22. Mechanism for Aldol Condensation
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Also catalyzed by acid.
Chapter 22

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

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

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

26. Planning Aldol Syntheses
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Chapter 22

27. Claisen Condensation Two esters combine to form a -keto ester. =>
Chapter 22

28. Dieckmann Condensation
A 1,6 diester  cyclic (5) -keto ester.
A 1,7 diester  cyclic (6) -keto ester.
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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 =>
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.
acetoacetic ester, pKa =11
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malonic ester, pKa = 13
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.
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Chapter 22

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

35. A Michael Reaction
Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product.
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-keto acid
Chapter 22

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

37. Mechanism for Robinson Annulation (1)
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Chapter 22

38. Mechanism for Robinson Annulation (2)
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Chapter 22

39. End of Chapter 22
Chapter 22