Chapter 22 Alpha Substitution and Condensations of Enols and Enolate Ions

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Chapter 22Alpha Substitution andCondensations
of Enolsand Enolate Ions
Organic Chemistry, 6th EditionL. G. Wade, Jr.
Jo Blackburn Richland College, Dallas, TX Dallas
County Community College District ã 2006,
Prentice Hall
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Alpha Substitution

• Replacement of a hydrogen on the carbon adjacent
  to the carbonyl, CO.

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Condensation withAldehyde or Ketone

• Enolate ion attacks a CO and the alkoxide is
  protonated. The net result is addition.

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Condensation with Esters

• Loss of alkoxide ion results in nucleophilic acyl
  substitution.

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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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Keto-Enol Tautomers (2)

• Tautomerism is also catalyzed by acid.
• In acid

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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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Acidity of ?-Hydrogens

• pKa for ?-H of aldehyde or ketone 20.
• Much more acidic than alkane or alkene (pKa gt 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.
  gt

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Enolate Reaction
As enolate ion reacts withthe electrophile, the
equilibriumshifts to produce more.
gt
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Acid-Base Reactionto Form Enolate

• Very strong base is required for complete
  reaction. Example

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? Halogenation

• Base-promoted halogenation of ketone.
• Base is consumed.
• Other products are water and chloride ion.

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Multiple Halogenations

• The ?-halo ketone produced is more reactive than
  ketone.
• Enolate ion stabilized by e--withdrawing halogen.

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Haloform Reaction

• Methyl ketones replace all three Hs with
  halogen.
• The trihalo ketone then reacts with hydroxide ion
  to give carboxylic acid.

Iodoform, yellow ppt. gt
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Positive Iodoformfor Alcohols

• If the iodine oxidizes the alcohol to a methyl
  ketone, the alcohol will give a positive iodoform
  test.

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Acid CatalyzedHalogenation of Ketones

• Can halogenate only one or two ?-Hs.
• Use acetic acid as solvent and catalyst.

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Aldehydes and Halogens

• Halogens are good oxidizing agents and aldehydes
  are easily oxidized.

gt
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The HVZ Reaction

• The Hell-Volhard-Zelinsky reaction replaces the
  ?-H of a carboxylic acid with Br.

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Alkylation

• Enolate ion can be a nucleophile.
• Reacts with unhindered halide or tosylate via SN2
  mechanism.

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Stork Reaction

• Milder alkylation method than using LDA.
• Ketone 2? amine ? enamine.
• Enamine is ?-alkylated, then hydrolyzed.

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Acylation via Enamines

• Product is a ?-diketone.

gt
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Aldol Condensation

• Enolate ion adds to CO of aldehyde or ketone.
• Product is a ?-hydroxy aldehyde or ketone.
• Aldol may lose water to form CC.

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Mechanism for Aldol Condensation
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Dehydration of Aldol

• Creates a new CC bond.

gt
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Crossed AldolCondensations

• Two different carbonyl compounds.
• Only one should have an alpha H.

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Aldol Cyclizations

• 1,4-diketone forms cyclopentenone.
• 1,5-diketone forms cyclohexenone.

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Planning Aldol Syntheses
gt
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Claisen Condensation

• Two esters combine to form a ?-keto ester.

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Dieckmann Condensation

• A 1,6 diester ? cyclic (5) ?-keto ester.
• A 1,7 diester ? cyclic (6) ?-keto ester.

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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.
  gt

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?-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.

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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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Acetoacetic Acid Synthesis

• Product is mono- or di-substituted ketone.

gt
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Conjugate Additions

• When CC is conjugated with CO, 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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Michael Reagents

• Michael donors enolate ions stabilized by two
  electron-withdrawing groups.
• ?-diketone, ?-keto ester, enamine, ?-keto
  nitrile, ?-nitro ketone.
• Michael acceptors CC conjugated with carbonyl,
  cyano, or nitro group.
• conjugated aldehyde, ketone, ester, amide,
  nitrile, or a nitroethylene.
  gt

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A Michael Reaction

• Enolates can react with ?,?-unsaturated compounds
  to give a 1,5-diketo product.

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Robinson Annulation

• A Michael reaction to form a ?-diketone followed
  by an intramolecular aldol condensation to form a
  cyclohexenone.

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Mechanism for Robinson Annulation (1)
gt
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Mechanism for Robinson Annulation (2)
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End of Chapter 22