Addition and Condensation reactions of Enol and Enolate Ions

1. Addition and Condensation reactions of Enol and Enolate Ions • Properties of enol and enolate ions • Tautomerization (acid/base) • alpha substitution reactions • halogenation, alkylation, condensation • Conjugate addition reactions • Dieckman cyclization • Robinson annulation

2. Properties of enols and enolates The presence of a carbonyl dramatically increases the acidity of the protons on the  carbon. The pKa of the  protons in aldehydes and ketones is about 20. In the presence of hydroxide or alkoxide only very small amount of the enolate is formed. (what are the pka’s of water and alcohols)

3. Properties of enols and enolates Reportonation of the enolate ion can occur on the oxygen atom to give the enol or on the -carbon to give the starting carbonyl compound (keto). There is an equilibium between the keto form and the enol form.

4. Keto-Enol Tautomerism Carbonyl compounds with alpha hydrogen can exist in two different forms. Conversion from one form to the other involves the shift of a proton and a double bond. This type of isomerization is called tautomerism. DO NOT confuse tautomerism with resonance structures (resonance structures are different representations of the same compound. The individual isomers are called tautomers. Tautomers are different compounds. ?

5. Keto- enol Tautomerism • The interconversion between the keto-enol tautomers can be either base or acid catalyzed. Base-catalyzed tautomerism Acid-catalyzed tautomerism

6. Properties of enols and enolates Though the concentration of the enolate is very small, it can be used as a nucleophile. As the enolate reacts with an electrophile the equilibrium for the formation of the enolate shifts to the right. Ultimately, this results in the starting carbonyl compound being consumed by the reaction.

7. Examples of alpha substitution on an enolate ion

8. Properties of enols and enolates The equilibrium mixture of the enolate and base (hydroide and alkoxide) are sometimes not useful because of side reactions between the base and the electrophile. In these cases a stronger base is used to completely convert the carbonyl compound to the enolate. OH- + E+ E-OH

9. Properties of enols and enolates One of the most effective bases for converting a carbonyl compound to the enolate is lithium diisopropylamide (LDA). LDA is prepared by treating diisopropylamine with n-butyllithium. Note the LDA is a hindered molecule that would be a poor nucleophile.

10. Properties of enols and enolates Treatment of cyclohexanone with LDA results in 100% conversion to the enolate.

11. Alpha halogenation reaction The alpha halogenation of a carbonyl compound can be done under either basic or acidic conditions. Under basic conditions the reaction is called base promoted because an equivalent of base is consumed during the reaction.

12. Alpha halogenation reaction Multiple halogenation is common with base promoted halogenation. As a result it is not used to prepare monohalo ketones. The second halogen addition is much faster than the first because of the increased stability of the enolate formed from the alpha-haloketone.

13. Alpha halogenation reaction When there is an excess of halogen and base, the base promoted halogenation generally continues until the alpha carbon is completely halogenated. In the case of a methyl ketone, a trihalomethyl ketone is obtained. Trihalomethyl ketone

14. Alpha halogenation reaction (haloform reaction) In the case of a methyl ketone, a trihalomethyl ketone is obtained. Under basic conditions the trihalomethyl group serves a leaving group, when the carbonyl carbon under goes nucleophlic attack . If the nucleophile is hydroxide the product is a carboxlate ion. When iodine is use in the reaction it is referred to as the iodoform test. Which gives a yellow precipitate with methyl ketones.

15. Alpha halogenation reaction In contrast to the base promoted reaction the acid-catalyzed alpha halogenation allows for replacement of a single alpha hydrogen. The enol serve as the nucleophile. The carbonium ion intermediate is not stabilized by the halogen. Note that aldehydes can not be halogenated because they are easily oxidized to carboxylic acids by the halogen.

16. Alpha halogenation reaction What would be the product from acid-catalyzed bromination of: 2-methylcyclohexanone methylisopropyl ketone

17. Alpha bromination of carboxylic acids • Alpha bromination of a carboxylic acid is accomplished by the Hell-Volhard-Zelinsky (HVZ) reaction. The reaction involves treatment of the acid with a combination of bromine and phosphorous tribromide, followed hydrolysis of the intermediate acyl bromide. • The initial step of the reaction is the formation of the acyl bromide. • The acyl bromide is then brominated in the alpha position via a mechanism similar to the acid-catalyzed alpha halogenation of a ketone. • The intermediate alpha bromo acyl bromide can be isolated and used to prepare other acid derivatives (ie esters) or hydrolyzed to the alpha bromoacid.

18. Alpha bromination of carboxylic acids

19. Alpha alkylation of enolate ions As we have seen the enolate ion is a nucleophile. The enolate ion can be used as a nucleophile in many of the nucleophilic substitution reactions that we have studied. The substrate should be an unhindered halide or tosylate. • enolate ions have two nucleophilic sites: oxygen and the alpha carbon

20. Alpha alkylation of enolate ions Alkylation reactions of enolate ions usually use very strong non-nucleophilic bases like LDA. Bases such as hydroxide and alkoxide are not used because of issues with competing side reactions. If more than one type of alpha hydrogen is present multiply products are possible.

21. Alpha alkylation of enolate ions Predict the products / reactants from the following reactions.

22. Alpha alkylation via the Stork Reaction The Stork reaction allows for the alpha alkylation reaction to be done under mild reaction conditions. The initial step of the reaction is the conversion of the carbonyl compound to the enamine. The enamine will then serve as the nucleophile in the alkylation or acylation reaction.

23. Alpha alkylation via the Stork Reaction Enamines are formed by the acid catalyzed condensation reaction between a secondary amine and either an aldehyde or a ketone. (Do not confuse enamines with imines, which are form from primary amines.) .

24. Alpha alkylation via the Stork Reaction Draw the enamines formed the following reactions

25. Alpha alkylation via the Stork Reaction Mechanistically the alkylation and acylation reaction of an enamine are the same, with the enamine serving as the nucleophile. The stock reaction works best with very reactive halides and acid chlorides. Note that the stork reaction gives mono substitution products.

26. Alpha alkylation via the Stork Reaction Predict the products from the following reactions.

27. Aldol condensation reactions of aldehydes and ketones The aldol condensation involves the nucleophilic attack of an enolate ion on a second carbonyl group. The initial product of this reaction is a β-hydroxy ketone or aldehyde. The initially formed β-hydroxy carbonyl compound can then undergoes dehydration to give the α, β -unsaturated carbonyl compound. Draw the mechanism for the base catalyzed formation of the aldol product of acetaldehyde. Page 1058

28. Aldol condensation reactions of aldehydes and ketones The first step of the aldol condensation is an equilibrium process. Aldehydes generally produce more of the aldol product at equilibrium than ketones. ie. Acetaldehyde produces ~50% aldol product at equilibrium, while acetone produces only about 1% of the aldol product. Good conversion of ketones to the aldol product can be accomplished using unique experimental techniques. Page 1058

29. Aldol condensation reactions of aldehydes and ketones The aldol condensation will also occur under acidic conditions. Under acidic conditions the nucleophile is the enol and the electrophile is a protonated carbonyl. Draw the acid catalyzed mechanism for the condensation of acetaldehyde. Page 1059

30. Aldol condensation reactions of aldehydes and ketones The dehydration of the aldol product can be carried out under either acid or basic conditions. Mechanistically the acid dehydration is the same as the acid dehydration of any other alcohol. The base catalyzed dehydration involves removal of the second alpha hydrogen followed by loss of hydroxide as a leaving group. α, β-unsaturated carbonyl

31. Crossed Aldol Condensation The crossed aldol reaction generally involves reacting an aldehyde or ketone that can form an enolate ion with a second carbonyl compound that can not form an enolate. For example consider what would result from the reaction of acetaldehyde with propanal. Draw the aldol condensation product for acetaldehyde and benzaldehyde.

32. Internal aldol condensations (cyclization) When there are two carbonyl groups present in a molecule the aldol condensation can be used to form 5 and 6 member ring structures. The starting materials for these reactions are generally 1,4-dicarbonyl compounds or 1,5-dicarbonyl compounds.

33. Internal aldol condensations (cyclization) Examples:

34. Internal aldol condensations (cyclization) How were these materials formed via aldol condensation?

35. Claisen condensation: synthesis of beta keto esters The first step of the Claisen condensation is similar to the aldol condensation. A strong base, usually an alkoxide abstracts an alpha hydrogen generating an enolate ion. The resulting enolate ion will then serve as a nucleophile, attacking a second ester molecule. The alpha hydrogens pka of an ester are not as acidic as those of aldehydes and ketones, but the ion is resonance stabilized in a similar way.

36. Claisen condensation: synthesis of beta keto esters The second step of the reaction is the nucleophilic attack of the enolate on a second ester molecule. Followed by loss of an alkoxide ion. This reaction is considered to be a base promoted reaction because the base is consumed in the reaction. The base is actually consumed in a reaction to form the keto ester enolate.

37. Claisen condensation: synthesis of beta keto esters Predict the products from the following reactions.

38. Dieckman condensation The Dieckman condensation is simply an internal Claisen condensation that occurs in molecules that contain two ester functional groups. Heating the beta keto ester in acidic condition results in hydrolysis of the ester followed by decarboxylation.

39. Dieckman condensation Predict the products:

40. Crossed Claisen condensation The crossed Claisen involves reacting the enolate (nucleophile) formed from an ester that has alpha hydrogens with an ester that does not have alpha hydrogens (the electrophile). Crossed Claisen condensations can also be carried out with ketones and esters. Some useful ester that do not have alpha hydrogens are benzoates, formates, carbonates and oxalates. Page 1071

41. Crossed Claisen condensation Examples:

42. Crossed Claisen condensation Predict the products: Ester + ketone/aldehyde

43. Beta-dicarbonyl compounds The alpha hydrogens in beta-dicarbonyl compounds are much more acidic then the alpha hydrogens in aldehydes, ketones and esters.

44. Malonic ester and acetoacetic ester synthesis Reactions involving beta-dicarbonyl compounds fall into one of two categories. The first is the Malonic ester synthesis and the second is the acetoacetic ester synthesis.

45. The malonic ester synthesis is used to prepare substituted acetic acid derivatives as shown below. Malonic ester and acetoacetic ester synthesis

46. The reaction of acetoacetic esters is very similar to the malonic ester synthesis, however the product that is obtained after decarboxylation is a methyl ketone. Malonic ester and acetoacetic ester synthesis See page 1081 for example problems.

47. The beta carbon of an alpha beta-unsaturation carbonyl compound has a partial positive charge and is subject to attack by a nucleophile. Michael addition reaction (conjugate addition). The addition reaction can occur either to two way. The first is called 1,2-addition and the second is called 1,4 addition.

48. Michael addition reaction (conjugate addition).

49. Michael addition reaction (conjugate addition).

50. Michael addition reaction (conjugate addition). Propose a synthesis for the following materials.