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Introduction to Organic Chemistry 2 ed William H. Brown

Introduction to Organic Chemistry 2 ed William H. Brown. Enolate Anions. Chapter 15. Chapter 14. Acidity of a -Hydrogens. Hydrogens alpha to a carbonyl group are more acidic than hydrogens of alkanes, but less acidic than the hydroxyl hydrogen of an alcohol. Acidity of a -Hydrogens.

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Introduction to Organic Chemistry 2 ed William H. Brown

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  1. Introduction to Organic Chemistry2 edWilliam H. Brown

  2. Enolate Anions Chapter 15 Chapter 14

  3. Acidity of a-Hydrogens • Hydrogens alpha to a carbonyl group are more acidic than hydrogens of alkanes, but less acidic than the hydroxyl hydrogen of an alcohol

  4. Acidity of a-Hydrogens • a-Hydrogens are more acidic because • the electron-withdrawing inductive effect of the adjacent carbonyl group weakens the C-H bond and • resonance delocalization of the negative charge stabilizes the resulting anion

  5. Enolate Anions • enolate anions function as nucleophiles in carbonyl addition reactions • the special value of this reaction is that it results in formation of a new C-C bond

  6. The Aldol Reaction • The product of an aldol reaction is • a b-hydroxyaldehyde

  7. The Aldol Reaction • or a b-hydroxyketone

  8. The Aldol Reaction: base • The mechanism of a base-catalyzed aldol reaction can be divided into three steps • Step 1: formation of a resonance-stabilized enolate anion

  9. The Aldol Reaction: base • Step 2: nucleophilic addition of the enolate anion to the carbonyl group of another carbonyl-containing molecule to form a TCAI

  10. The Aldol Reaction: base • Step 3: reaction of the TCAI with a proton donor to give the aldol product

  11. The Aldol Products: -H2O • Aldol products are very easily dehydrated

  12. The Aldol Reaction: -H2O • in base-catalyzed dehydration, a second a-hydrogen is removed to form a new enolate anion, which then expels hydroxide ion

  13. The Aldol Reaction: -H2O

  14. Crossed Aldol Reactions • In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group

  15. Crossed Aldol Reactions • Crossed aldol reactions are most successful if • one of the reactants has no a-hydrogen and, therefore, cannot form an enolate anion and • the other reactant has a more reactive carbonyl group, namely an aldehyde

  16. Intramolecular Aldols • Intramolecular aldol reactions are most successful for formation of five- and six-membered rings

  17. Intramolecular Aldols • intramolecular aldol reaction of 2,7-octanedione might form a seven-membered ring • formation of five- and six-membered rings is favored over four- and seven-membered rings

  18. Intramolecular Aldols • in this example, only the 6-membered ring forms

  19. Claisen Condensation • Esters also form enolate anions which participate in nucleophilic acyl substitution • the product of a Claisen condensation is a b-ketoester

  20. Claisen Condensation • Claisen condensation of ethyl propanoate gives the this b-ketoester

  21. Claisen Condensation • Step 1: formation of an enolate anion

  22. Claisen Condensation • Step 2: attack of the enolate anion on a carbonyl carbon to give a TCAI

  23. Claisen Condensation • Step 3: collapse of the TCAI to form a b-ketoester and an alkoxide ion

  24. Claisen Condensation • Step 4: formation of the enolate anion of the b-ketoester, which drives the Claisen condensation to the right

  25. Dieckmann Condensation • An intramolecular Claisen condensation

  26. Crossed Claisen Condsns • Crossed Claisen condensations between two different esters, each with a -hydrogens, give mixtures of products and are not synthetically useful • Crossed Claisen condensations are possible, however, if there is an appreciable difference in reactivity between the two esters, for example, when one of the esters has no a-hydrogens

  27. Crossed Claisen Condsns • these esters have no a-hydrogens

  28. Crossed Claisen Condsns • the ester with no a-hydrogens is generally used in excess

  29. Hydrolysis and -CO2 • Saponification of a b-ketoester followed by acidification with HCl gives a b-ketoacid • Heating the b-ketoacid leads to decarboxylation

  30. Claisen Condensation • the result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone

  31. From Acetyl Coenzyme A • Carbonyl condensations are among the most widely used reactions in the biological world for formation of new carbon-carbon bonds in such biomolecules as • fatty acids • cholesterol, bile acids, and steroid hormones • terpenes • One source of carbon atoms for the synthesis of these biomolecules is acetyl coenzyme A (acetyl-CoA)

  32. Acetyl-CoA • Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase

  33. Acetyl-CoA • this is followed by an aldol reaction with a second molecule of acetyl-CoA

  34. Acetyl-CoA • enzyme-catalyzed reduction of the thioester group gives a 1° alcohol

  35. Acetyl-CoA • phosphorylation by ATP followed by b-elimination gives isopentenyl pyrophosphate

  36. Acetyl-CoA • isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules

  37. Enolate Anions End Chapter 14

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