1. Organic Chemistry IIAlpha Substitution Reactions Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

2. The  Position • The carbon next to the carbonyl group is designated as being in the  position

3. Objectives • Keto-enol tautomerism • Enols –  substitution • Enol acidity – the enolate • Alkylation of the enolate • Carbonyl Condensation Reactions • Aldol • Claisen • Michael Reaction • Stork Enamine • Robinson Annulation

4. Enolization • conditions permit the enolization of ketones • Substitution can occur at the alpha position through either an enol or enolate ion

5. Equilibrium of Tautomerism • Enol formation is equilibrium process • Keto form is predominant species • Enol is present in sufficient concentration to be involved in any reaction

6. Tautomers • Tautomers are structural isomers • Tautomers are not resonance forms • Resonance forms are representations of contributors to a single structure • Tautomers interconvert rapidly while ordinary isomers do not

7. Enols • The enol tautomer is usually present to a very small extent and cannot be isolated • However, since it is formed rapidly, it can serve as a reaction intermediate

8. Acid Catalysis of Enolization • Brønsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the  protons

9. Base Catalysis of Enolization • Brønsted bases catalyze keto-enoltautomerization • The hydrogens on the  carbon are weakly acidic and transfer to water is slow • In the reverse direction there is also a barrier to the addition of the proton from water to enolate carbon

10. Reactivity of Enols • Enols have very e- rich double bonds • Very Nucleophilic • React with variety of electrophiles

11. Generalized Reaction • When an enol reacts with an electrophile the intermediate cation immediately loses the OH proton to give a substituted carbonyl compound

12. Halogenation • Aldehydes and ketones can be halogenated at their  positions by reaction with Cl2, Br2, or I2 in acidic solution

13. Kinetics • Rate is independent of identity of X2 • Cl2, Br2, I2 react at same rate • Rate is independent of [X2] • Rate determining step occurs before X2 • Rate determining step is enolization step • Rate = k[ketone][H+]

14. Ramification of Enolization • Optically active ketones can lose optical activity

15. Elimination Reactions of-Bromoketones • -Bromo ketones can be dehydrobrominated by base treatment to yield ,b-unsaturated ketones

16. Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii Reaction • Carboxylic acids do not react with Br2 (Unlike aldehydes and ketones) • They are brominated by a mixture of Br2 and PBr3 (Hell–Volhard–Zelinskii reaction)

17. Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation • Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60) • The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen

18. Enolate Formation - Bases • Ketones are weaker acids than the OH of alcohols so a a more powerful base than an alkoxide is needed to form the enolate • NaOH and NaOCH3) are too weak • Sodium hydride (NaH), sodamide (NaNH2), or lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form the enolate

19. Lithium Diisopropylamide (LDA) • LDA is made from butyllithium (BuLi) and diisopropylamine (pKa 40) • Soluble in organic solvents and effective at low temperature with many compounds (see Table 22.1) • Not nucleophilic

20. Similar Bases • Lithium tetramethylpiperdide • Lithium dicyclohexylamide

21. Acidity of the alpha Hydrogen

22. Acidity of -Dicarbonyls • When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced • Negative charge of enolate delocalizes over both carbonyl groups

23. Acidities of Organic Compounds

24. Reactivity of Enolate Ions • The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive)

25. Enolate Reactions • Enolate has two resonance forms • Reacts at both sites with E+ depending upon conditions

26. Two Reactions Sites on Enolates • Reaction on oxygen yields an enol derivative • Reaction on carbon yields an a-substituted carbonyl compound

27. Enol Ether Formation • Enolates react with trimethylsilyl chloride to form the enol ether

28. Alkylation • Alkylation occurs at C

29. Revisit Halogenation of the Enolate The Haloform Reaction • Base-promoted reaction occurs through an enolate ion intermediate

30. Further Reaction: Cleavage • Monohalogenated products are themselves rapidly turned into enolate ions and further halogenated until the trihalo compound is formed from a methyl ketone • The product is cleaved by hydroxide with -CX3 as the leaving group, stabilized anion

31. Halogenation: Summary • Base catalyzed process • Can’t be stopped at one halogen • Cleaves methyl ketones to give HCX3 • Acid catalyzed process • Second halogenation is very slow • Useful reaction for monohalo ketones

32. Alpha Selenylation • Used to make unsaturated ketones

33. Alkylation of Enolate Ions • Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide or tosylate and displaces the leaving group

34. Constraints on Enolate Alkylation • SN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate • R should be primary, methyl, allylic or benzylic • Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination

35. Alkylation of Ketones • Base must be weaker acid than ketone • Complete proton abstraction • Base cannot be nucleophilic • Adds to carbonyl • LDA meets both criteria • Consider:

36. Deprotonation by LDA

37. Analysis • Least hindered product predominates • Steric size of base • Approach to more substituted side restricted • Increase in the size of the base increases the predominance of the less substituted side product

38. The Malonic Ester Synthesis • For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms

39. Formation of Enolate and Alkylation • Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol • The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an a-substituted malonic ester

40. Dialkylation • The product has an acidic -hydrogen, allowing the alkylation process to be repeated

41. Hydrolysis and Decarboxylation • The malonic ester derivative hydrolyzes in acid and loses CO2 (“decarboxylation”) to yield a substituted monoacid

42. Malonic Acid Syntheses • Very useful reaction, • For example • All can be decarboxylated to the mono acids

43. Decarboxylation of b-Ketoacids • Decarboxylation requires a carbonyl group two atoms away from the CO2H • The second carbonyl permit delocalization of the resulting enol • The reaction can be rationalized by an internal acid-base reaction

44. Decarboxylation • Beta-dicarboxylic acids readily lose CO2 • Other beta carboxy carbonyls should also • Look at Ethyl acetoacetate (pKa = 11)

45. Acetoacetate Synthesis

46. Reminder of Overall Conversion • The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms

47. Decarboxylation of Acetoacetic Acid • b-Ketoacid from hydrolysis of ester undergoes decarboxylation to yield a ketone via the enol

48. Generalization: b-Keto Esters • The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to b-keto esters in general • Cyclic b-keto esters give 2-substituted cyclohexanones

49. Carbonyl Condensation Reactions • Carbonyls behave • Electrophile or Nucleophile • Electrophilic Behavior • Nu: add to C=O • Nucleophilic Behavior • Enols or enolates react with E+ • Condensation Reactions • Combine both reactions • Uses two carbonyl compounds • One is the Nu: through an enolate • Second is the E+

50. The Aldol Reaction • Equilibrium reaction • Products favored for aldehydes • Reactants favored for ketones