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19-1 Enolate Anions Chapter 19. 19-2 Reactions of Chapter 19  Aldol reaction (aldehyde or ketone) Crossed Aldol Intramolecular Aldol (cyclic)  Claisen.

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Presentation on theme: "19-1 Enolate Anions Chapter 19. 19-2 Reactions of Chapter 19  Aldol reaction (aldehyde or ketone) Crossed Aldol Intramolecular Aldol (cyclic)  Claisen."— Presentation transcript:

1 19-1 Enolate Anions Chapter 19

2 19-2 Reactions of Chapter 19  Aldol reaction (aldehyde or ketone) Crossed Aldol Intramolecular Aldol (cyclic)  Claisen reaction (esters) Crossed Claisen Dieckmann (cyclic)  Enamines (2 o amine + aldehyde or ketone)  Acetoacetic ester reaction  Malonic ester reaction  Michael addition ( ,  -unsaturated carbonyl) Robinson Annulation (cyclic from Michael + aldol) Gilman alkylation (Michael)

3 Formation of an Enolate Anion  Enolate anions are formed by treating an aldehyde or ketone with base. most of the negative charge in an enolate anion is on oxygen.

4 19-4 Reaction Types with Enolate Anions  Enolate anions are nucleophiles in S N 2 reactions and carbonyl addition reactions

5 19-5 The Hell-Volhard-Zelinsky reaction  This reaction is a synthesis of  -haloacids. The starting acid must have an  -hydrogen. It is treated with Br 2 and PBr 3 then hydrolyzed. Remember we had  -halogenation of ketones in chapter 16. O CH 3 -C-OH CH 2 =C-Br Br 2 Br-CH 2 -C-OH O PBr 3 CH 3 -C-Br O OH CH 2 =C-Br Br-CH 2 -C-Br OHO HOH

6 The Aldol Reaction  The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound.  This reaction with aldehydes or with ketones is an Aldol reaction. although these reactions may be catalyzed by either acid or base, base catalysis is more common.

7 19-7 The Aldol Reaction  The product of an aldol reaction is: a  -hydroxyaldehyde. or a  -hydroxyketone.

8 19-8 The Aldol Reaction  Base-catalyzed aldol reaction: Step 1: formation of a resonance-stabilized enolate anion. Step 2: carbonyl addition gives a TCAI. Step 3: proton transfer to O - completes the aldol reaction.

9 19-9 The Aldol Reaction: acid  Acid-catalyzed aldol reaction: Step 1: acid-catalyzed equilibration of keto and enol forms. Step 2: proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone.

10 19-10 The Aldol Reaction: acid Step 3: attack of the enol of one molecule on the protonated carbonyl group of another molecule. Step 4: proton transfer to A - completes the reaction.

11 19-11 The Aldol Products: -H 2 O aldol products are very easily dehydrated to ,  - unsaturated aldehydes or ketones. aldol reactions are reversible and often little aldol present at equilibrium.  K eq for dehydration is generally large. if reaction conditions bring about dehydration, good yields of product can be obtained.

12 19-12 Crossed Aldol Reactions  In a Crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group.  Note: Formaldehyde has no  -carbon.  To be useful the electrophile must not have a hydrogen on the  -carbon.

13 19-13 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. Aldehydes without an  -H

14 19-14 Crossed Aldol Reactions  Nitro groups can be introduced by way of an aldol reaction using a nitroalkane. nitro groups can be reduced to 1° amines.

15 19-15 Intramolecular Aldol Reactions intramolecular aldol reactions are most successful for formation of five- and six-membered rings. consider 2,7-octadione, which has two  -carbons.

16 19-16 Cannizzaro Reaction  An aldehyde which has no  - hydrogens undergoes oxidation-reduction when treated with base: R 3 C-C-H O - NaOH + Acetaldehyde O OH R 3 C-C-H O OH + R 3 C-C-H O R 3 C-C-O O + - R 3 C-CH 2 -OH - oxidized reduced

17 A. Claisen Condensation  Esters also form enolate anions which condense in a Claisen condensation. the product of a Claisen condensation is a  -ketoester.

18 19-18 Claisen Condensation Claisen condensation of ethyl propanoate gives this  -ketoester. The base generally used is the alkoxide corresponding to the alcohol moiety of the ester.

19 19-19 Claisen Condensation Step 1: formation of an enolate anion. Step 2: attack of the enolate anion on a carbonyl carbon gives a TCAI.

20 19-20 Claisen Condensation Step 3: collapse of the TCAI gives a  -ketoester and an alkoxide ion. Step 4: an acid-base reaction drives the reaction to completion.

21 19-21 B. Dieckman Condensation  A Dieckman condensation is an intramolecular Claisen condensation (forms a cyclic product).

22 19-22 C. Crossed Claisen Condsns  Crossed Claisen condensations between two different esters, each with  -hydrogens, give mixtures of products and are not useful. useful crossed Claisen condensations are possible, however, if there is an appreciable difference in reactivity between the two esters; that is, when one of them has no  -hydrogens. Esters without an  -H

23 19-23 Crossed Claisen Condensations the ester with no  -hydrogens is generally used in excess.

24 19-24 D. Use of the Claisen Condensation  Claisen condensations are a route to ketones.

25 19-25 Claisen Condensation The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.

26 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).

27 19-27 Acetyl-CoA Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase.

28 19-28 Acetyl-CoA this is followed by an aldol reaction with a second molecule of acetyl-CoA.

29 19-29 Acetyl-CoA enzyme-catalyzed reduction of thioester group. phosphorylation by ATP followed by  -elimination.

30 19-30 Acetyl-CoA isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules.

31 Enamines  Enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone. the 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine. PyrrolidineMorpholine N O N H H

32 19-32 Enamines Examples:

33 19-33 A. Enamines – The Stork Reaction  The value of enamines is that the  -carbon is nucleophilic and gives an S N 2 alkylation. enamines undergo S N 2 reactions with methyl and 1° haloalkanes,  -haloketones, and  -haloesters. treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.

34 19-34 Enamines - Alkylation hydrolysis of the iminium halide (Schiff base) gives an alkylated aldehyde or ketone. Morpholinium chloride 2-Allylcyclo- hexanone + HCl/H 2 O + Br - N O O + Cl - N O HH Remember, a C=N is a Schiff base. These will hydrolyze in acid to give the amine and carbonyl.

35 19-35 B. Enamines - Acylation enamines undergo acylation when treated with acid chlorides and acid anhydrides.

36 Acetoacetic Ester Synthesis  The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types.

37 19-37 Acetoacetic Ester Synthesis this occurs by alkyation of the carbon between the carbonyl groups followed by hydrolysis of the ester then decarboxylation of the  -ketoacid consider the AAE synthesis of this target molecule, which is a monosubstituted acetone.

38 19-38 Acetoacetic Ester Synthesis Step 1: formation of the enolate anion of AAE. Step 2: alkylation with allyl bromide.

39 19-39 Acetoacetic Ester Synthesis Steps 3 & 4 saponification followed by acidification. Step 5: thermal decarboxylation.

40 19-40 Acetoacetic Ester Synthesis to prepare a disubstituted acetone, treat the monoalkylated AAE with a second mole of base, etc.

41 Malonic Ester Synthesis  The strategy of a Malonic ester (ME) synthesis is similar to that of an acetoacetic ester synthesis. The starting material is a  -diester rather than a  -ketoester.

42 19-42 Malonic Ester Synthesis  is useful for the preparation of mono- and disubstituted acetic acids.  Consider the synthesis of this target molecule. This is the R group from alkylation of malonic ester

43 19-43 Malonic Ester Synthesis treat malonic ester with an alkali metal alkoxide. alkylate with 1-bromo-3-methoxypropane.

44 19-44 Malonic Ester Synthesis saponify and acidify. decarboxylation. Disubstitution can be obtained in the same manner as used with acetoacetic ester

45 A. Michael Reaction  Michael reaction:  Michael reaction: the nucleophilic addition of an enolate anion to an ,  -unsaturated carbonyl compound. Example: Electron donorElectron recipient

46 19-46 Michael Reaction, Table 19.1

47 19-47 Michael Reaction Example: the double bond of an ,  -unsaturated carbonyl compound is activated for nucleophilic attack.

48 19-48 Michael Reaction  Mechanism: Step 1: proton transfer to the base. Step 2: addition of Nu: - to the  carbon of the ,  - unsaturated carbonyl compound.

49 19-49 Michael Reaction Step 3: proton transfer to HB gives an enol. Step 4: tautomerism of the less stable enol form to the more stable keto form.

50 19-50 Michael Reaction  **A final word about nucleophilic addition to ,  - unsaturated carbonyl compounds. resonance-stabilized enolate anions and enamines are weak bases, react slowly with ,  -unsaturated carbonyl groups, and instead give 1,4-addition products. organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and give primarily 1,2-addition.

51 19-51 Michael Reaction  Thermodynamic versus kinetic control.

52 19-52 Michael Reactions enamines also participate in Michael reactions.

53 19-53 B. Robinson Annulation + Ethyl 2-oxocyclohexane carboxylate 3-Buten-2-one (Methyl vinyl ketone) 1. NaOEt, EtOH (Michael reaction) 2. NaOEt, EtOH (Aldol reaction) COOEt O O COOEt OOO COOEt A Michael reaction followed by a cyclic aldol.

54 19-54 Another example: Michael addition followed by an aldol condensation. CH 2 =CH-C-CH 3 O + O - OH O CH 2 -CH 2 -C-CH 3 O Michael O CH 2 -CH 2 -C-CH 3 O Aldol O - OH

55 19-55 C. Gilman Reagents  Gilman reagents undergo conjugate addition to ,  -unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction. Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4-addition. other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition.

56 19-56 Retrosynthesis of 2,6-Heptadione

57 19-57 Enolate Anions End Chapter 19

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