Chapter 22: Carbonyl Alpha-Substitution Reactions

1. Chapter 22: Carbonyl Alpha-Substitution Reactions Why this Chapter? Many schemes make use of carbonyl a-substitution reactions. These reaction are one the few general methods for making C-C bonds.

2. The  Position • The carbon next to the carbonyl group is designated as being in the  position • Electrophilic substitution occurs at this position through either an enol or enolate ion

3. 22.1 Keto–Enol Tautomerism • A carbonyl compound with a hydrogen atom on its alpha carbon rapidly equilibrates with its corresponding enol • Compounds that differ only by the position of a moveable proton are called tautomers • Tautomers are structural isomers: They are not resonance forms! (Resonance forms are representations of contributors to a single structure) • Tautomers interconvert rapidly while ordinary isomers do not

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

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

6. Base Catalysis of Enolization • The hydrogens on the  carbon are weakly acidic and transfer to water is slow • Transfer of the a hydrogen to a base though is rapid

7. Base Catalysis of Enolization • Brønsted bases catalyze keto-enol tautomerization

8. Learning Check: • Name the following and draw structures for their enol tautomers : A. B. C. D. E.

9. Solution: • Name the following and draw structures for their enol tautomers : A. Cyclopentanone Ethyl acetate B. C. Methyl thioacetate Acetic Acid D. Phenylacetone E.

10. Which of the following explains why protons α to a carbonyl group show enhanced acidity? Learning Check: • An inductive effect from the adjacent carbonyl weakens the C-H bond. • The conjugate base is stabilized by resonance. • The charge that results after deprotonation is delocalized. • An inductive effect from the adjacent carbonyl weakens the C-H bond; and the conjugate base is stabilized by resonance. • all of these

11. Which of the following explains why protons α to a carbonyl group show enhanced acidity? Solution: • An inductive effect from the adjacent carbonyl weakens the C-H bond. • The conjugate base is stabilized by resonance. • The charge that results after deprotonation is delocalized. • An inductive effect from the adjacent carbonyl weakens the C-H bond; and the conjugate base is stabilized by resonance. • all of these

12. 22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions • Enols behave as nucleophiles and react with electrophiles because the enol double bonds are electron-rich

13. General Mechanism of Addition to Enols • When an enol reacts with an electrophile the intermediate cation immediately loses the OH proton to give a substituted carbonyl compound

14. 22.3 Alpha Halogenation of Aldehydes and Ketones • Aldehydes and ketones can be halogenated at their  positions by reaction with Cl2, Br2, or I2 in acidic solution

15. Mechanism of Acid-Catalyzed Bromination • The enol tautomer reacts with an electrophile • The keto tautomer loses a proton

16. Evidence for Rate-Limiting Enol Formation • The rate of halogenation is independent of the halogen's identity and concentration • In D3O+ the  H’s are replaced by D’s at the same rate as halogenation (if addition of D were involved in the rate determining step then the rate would have slowed with D20) • This because the barrier to formation of the enol goes through the highest energy transition state in the mechanism • (Formation of the enol is the rate determining step)

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

18. Learning Check: Know how to…. • Write the complete mechanism of the deuteration of acetone on treatment with D3O+

19. Learning Check: • Show how you might prepare 1-penten-3-one from 3-pentanone.

20. Solution: • Show how you might prepare 1-penten-3-one from 3-pentanone.

21. 22.4 Alpha Bromination of Carboxylic Acids: The Hell–Volhard–ZelinskiiReaction • Carboxylic acids do not react with Br2(unlike aldehydes and ketones) • So Carboxylic acids must be converted to acid halides first and then the acid halide hydrolyzed back to the acid. • Bromination of carboxyilic acids by a mixture of Br2 and PBr3is the Hell–Volhard–Zelinskii reaction

22. Mechanism of Bromination by Hell–Volhard–Zelinskii • PBr3 converts -COOH to –COBr, which can enolize and add Br2

23. Learning Check: Know how to…. • If methanol rather than water is added at the end of a Hell-Volhard-Zelinskii reaction a methyl ester is produced. Show the reagents needed and propose a mechanism for each step.

24. 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation • Carbonyl compounds can act as weak acids • The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen

25. Reagents for Enolate Formation • Ketones are weaker acids than the OH of alcohols so a more powerful base than an alkoxide is needed to form the enolate Sodium hydride (NaH) or Lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form the enolate

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

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

30. Learning Check: • Identify the most acidic hydrogens in each of the following: • Rank in order of decreasing acidity.

31. Solution: • Identify the most acidic hydrogens in each of the following: • Rank in order of decreasing acidity. (#1 most acidic) 3 2 1

32. 22.6 Reactivity of Enolate Ions • The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive) • Reaction on oxygen yields an enol derivative (less common) • Reaction on carbon yields an a-substituted carbonyl compound (more common) More common

33. Base promoted a-halogenation • Iodoform Reaction: Test for a methyl ketone Iodoform = CHI3 = yellow solid

34. 22.7 Alkylation of Enolate Ions • Base-promoted reaction occurs through an enolate ion intermediate • SN2 reaction:,the leaving group X can be -Cl, -Br, -I, or tosylate • R should be 1o or methyl and preferably should be allylic (CH=CH-CH2-X ) or benzylic (Ph-CH2-X ) • 2o halides react poorly, and 3o halides don't react at all because of competing elimination

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

36. 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

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

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

39. Decarboxylation of -Ketoacids • Decarboxylation requires a carbonyl group two atoms away from the CO2H

40. Overall Conversion • The malonic ester synthesis converts an • alkyl halide  carboxylic acid while • lengthening the carbon chain by 2 atoms

41. Preparing Cycloalkane Carboxylic Acids • 1,4-dibromobutane reacts twice, giving a cyclic product • 3-, 4-, 5-, and 6-membered rings can be prepared in this way

42. Learning Check: Use a malonic ester synthesis to prepare the following:

43. Solution: Use a malonic ester synthesis to prepare the following:

44. Learning Check: Use a malonic ester synthesis to prepare the following:

45. Solution: Use a malonic ester synthesis to prepare the following:

46. Acetoacetic Ester Synthesis • Overall: converts an alkyl halide into a methyl ketone

47. Acetoacetic Ester (Ethyl Acetoacetate) •  carbon flanked by two carbonyl groups readily becomes an enolate ion that can be alkylated by an alkyl halide • Process can be repeated to add a second alkyl halide

48. Generalization: -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. Learning Check: Prepare 2-pentanone using an acetoacetic ester synthesis: Hint:

50. Solution: Prepare 2-pentanone using an acetoacetic ester synthesis: Hint: