1. 14 14-1 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Introduction to Organic Chemistry 2 ed William H. Brown

2. 14 14-2 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Enolate Anions Chapter 15 Chapter 14

3. 14 14-3 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acidity of  -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. 14 14-4 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acidity of  -Hydrogens  -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. 14 14-5 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 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. 14 14-6 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. The Aldol Reaction The product of an aldol reaction is a  -hydroxyaldehyde

7. 14 14-7 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. The Aldol Reaction or a  -hydroxyketone

8. 14 14-8 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 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. 14 14-9 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 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. 14 14- 10 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. The Aldol Reaction: base Step 3: reaction of the TCAI with a proton donor to give the aldol product

11. 14 14-11 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. The Aldol Products: -H 2 O Aldol products are very easily dehydrated

12. 14 14- 12 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. The Aldol Reaction: -H 2 O in base-catalyzed dehydration, a second  -hydrogen is removed to form a new enolate anion, which then expels hydroxide ion

13. 14 14- 13 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. The Aldol Reaction: -H 2 O

14. 14 14- 14 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Crossed Aldol Reactions In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group

15. 14 14- 15 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Crossed Aldol Reactions Crossed aldol reactions are most successful if one of the reactants has no  -hydrogen and, therefore, cannot form an enolate anion and the other reactant has a more reactive carbonyl group, namely an aldehyde

16. 14 14- 16 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Intramolecular Aldols Intramolecular aldol reactions are most successful for formation of five- and six- membered rings

17. 14 14- 17 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 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. 14 14- 18 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Intramolecular Aldols in this example, only the 6-membered ring forms

19. 14 14- 19 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation Esters also form enolate anions which participate in nucleophilic acyl substitution the product of a Claisen condensation is a  -ketoester

20. 14 14- 20 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation Claisen condensation of ethyl propanoate gives the this  -ketoester

21. 14 14- 21 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation Step 1: formation of an enolate anion

22. 14 14- 22 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation Step 2: attack of the enolate anion on a carbonyl carbon to give a TCAI

23. 14 14- 23 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation Step 3: collapse of the TCAI to form a  -ketoester and an alkoxide ion

24. 14 14- 24 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation Step 4: formation of the enolate anion of the  - ketoester, which drives the Claisen condensation to the right

25. 14 14- 25 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Dieckmann Condensation An intramolecular Claisen condensation

26. 14 14- 26 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Crossed Claisen Condsns Crossed Claisen condensations between two different esters, each with  -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  -hydrogens

27. 14 14- 27 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Crossed Claisen Condsns these esters have no  -hydrogens

28. 14 14- 28 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Crossed Claisen Condsns the ester with no  -hydrogens is generally used in excess

29. 14 14- 29 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Hydrolysis and -CO 2 Saponification of a  -ketoester followed by acidification with HCl gives a  -ketoacid Heating the  -ketoacid leads to decarboxylation

30. 14 14- 30 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Claisen Condensation the result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone

31. 14 14- 31 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 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. 14 14- 32 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acetyl-CoA Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase

33. 14 14- 33 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acetyl-CoA this is followed by an aldol reaction with a second molecule of acetyl-CoA

34. 14 14- 34 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acetyl-CoA enzyme-catalyzed reduction of the thioester group gives a 1° alcohol

35. 14 14- 35 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acetyl-CoA phosphorylation by ATP followed by  -elimination gives isopentenyl pyrophosphate

36. 14 14- 36 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Acetyl-CoA isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules

37. 14 14- 37 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. Enolate Anions End Chapter 14