Chapter 24: Carbonyl Condensation Reactions

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Chapter 24 Carbonyl Condensation Reactions

• The Aldol Reaction (24.1)
• Crossed Aldol Reactions (24.2)
• Directed Aldol Reactions (24.3)
• Intramolecular Aldol Reactions (24.4)
• The Claisen Reaction (24.5)
• Crossed Claisen and Related Reactions (24.6)
• The Dieckmann Reaction (24.7)
• The Michael Reaction (24.8)
• The Robinson Annulation (24.9)

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I. The Aldol Reaction A. General Features
Mechanism
Aldol Addition
b-hydroxybutyraldehyde3-hydroxybutanal
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Aldol Reaction of Propanal
Aldol Addition
a-methyl-b-hydroxyvaleraldehyde2-methyl-3-hydroxy
pentanal

• Aldol reactions are reversible.
• Products are favored with aldehydes.
• Reactants are favored with ketones.

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B. Dehydration of the Aldol Product Aldol
addition product readily loses H2O
2-butenal
Dehydration is unavoidable when the product
is highly conjugated.
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Mechanism
E1cB mechanism deprotonation of a C
precedes loss of leaving group from b C.

• Retrosynthetic Analysis1. Locate the a and b
  carbons.2. Disconnect to identify the aldehyde
  or ketone reactants.

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II. Crossed Aldol Reactions A. With Two
Different Aldehydes That Have a H
Atoms

• Four products are formed.
• Reaction is not synthetically useful.

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B. Synthetically Useful Crossed Aldol
Reactions 1. Only one Carbonyl Reactant
has a H

• Yield of crossed aldol product maximized when
  benzaldehyde is used in excess.

2. Reactions of Active Methylene Compounds

• Active methylene compounds are always the enolate
  component of crossed aldol reactions.

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Reaction of benzaldehyde with an active
methylene compound
III. Directed Aldol Reactions

• Variation of crossed aldol reaction
• Prepare enolate of first carbonyl compound
  with LDA.
• Add second carbonyl compound (electrophile).

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Retrosynthetic Analysis1. Locate the a and b
carbons.2. Disconnect to identify reactants.
IV. Intramolecular Aldol Reactions

• Enolate anion (nucleophile) and carbonyl
  (electrophile) are in the same molecule.
• Five and six-membered rings are favored.

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Mechanism
Intramolecular aldol reaction that forms a
six-membered ring
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V. The Claisen Reaction
Mechanism
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Retrosynthetic Analysis1. Locate a carbon
(between the carbonyls).2. Disconnect to
identify reactants.
ethyl hexanoateethyl caproate
VI. Crossed Claisen Related Reactions A.
Between Two Esters Only One Has a Hs
no a Hs
Also works with HCO2Et.
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B. Between an Ester and a Ketone
ethyl
b-dicarbonylformate
compound

• Works best with esters that lack aHs.

C. Between an Ester and Diethyl Carbonate
or Ethyl Chloroformate
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Mechanism

• Enolate formation
• Nucleophilic attack on CO
• Elimination of leaving group

b-keto ester
VII. Dieckmann Reaction

• Intramolecular Claisen reaction
• Forms five- and six-membered rings.

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Mechanism

• Formation of ester enolate anion
• Nucleophilic attack
• Leaving group departure
• Formation of b-keto ester enolate
• Add acid to get b-keto ester.

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VIII. Michael Reaction
resonance-stabilized a,b-unsaturated carbonyl
compound
Resonance hybrid both carbonyl carbon and b
carbon are electrophilic.
Michael Reaction
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• a,b-unsaturated carbonyl compound is
  electrophile (Michael acceptor).
• Nucleophile (Michael donor) is an enolate.
• Active methylene compounds are common.
• Hydrolysis and decarboxylation of Michael
  products give 1,5-dicarbonyl compound.

Mechanism
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IX. Robinson Annulation

• Tandem Michael addition and intramolecular aldol
  condensation
• Forms C-C bonds and six-membered ring.

Examples
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Mechanism, Part 1 Michael Addition
new C-C bond
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Mechanism, Part 2 Intramolecular Aldol
Reaction
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Retrosynthetic Analysis1. Locate ring that
contains a,b-unsaturated carbonyl.2.
Disconnect CC and Cb-C to identify
reactants.
Synthetic direction