α -Substitution and Carbonyl Condensation Reactions

2. α-Substitution and Carbonyl Condensation Reactions Alpha-substitution reactions occur at the carbon next to the carbonyl carbon – the a position • Involve substitution of a-hydrogen by electrophile • Proceed through enol or enolate ion intermediate Carbonyl condensation reactions occur between two carbonyl partners • Combination of a-substitution and nucleophilic addition steps • Gives b-hydroxy carbonyl compound

3. 17.1 Keto-Enol Tautomerism Carbonyl compounds with a-hydrogens rapidly equilibrate with corresponding enol (ene + alcohol) • Interconversion known as keto-enol tautomerism • Greek tauto, meaning “the same,” and meros, meaning “part” • Individual isomers called tautomers

4. Keto-Enol Tautomerism Tautomers are constitutional isomers • Isomers are different compounds with different structures • Atoms arranged differently • Different from resonance structures that differ only in the position of their electrons • Most carbonyl compounds exist almost exclusively in the keto form at equilibrium

5. Keto-Enol Tautomerism Mechanism of acid-catalyzed enol formation • Protonated intermediate can lose H+, either from the oxygen atom to regenerate the keto tautomer or from the a carbon atom to yield an enol tautomer

6. Keto-Enol Tautomerism Mechanism of base-catalyzed enol formation • The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to generate the starting keto tautomer or on oxygen to give an enol tautomer

7. Keto-Enol Tautomerism Only a-hydrogens are acidic • a-Hydrogens are acidic because the enolate ion that results from deprotonation is resonance stabilized with the electronegative oxygen of the carbonyl • b-, g-, d-Hydrogens (and so on) are not acidic because the ion that results from deprotonation is not resonance stabilized

8. 17.2 Reactivity of Enols: α-Substitution Reactions Enols are nucleophiles that react with electrophiles • There is a substantial build-up of electron density on the a carbon of the enol

9. Reactivity of Enols: α-Substitution Reactions Mechanism of carbonyl a-substitution reaction on an enol • Enol is formed with acid catalysis • Electron pair from C=C bond of enol attacks an electrophile (E+), forming new C-E bond and a resonance stabilized intermediate • Loss of H+ from oxygen yields the neutral alpha- substitution product and restores the C=O bond

10. Reactivity of Enols: α-Substitution Reactions Common a-substitution reaction in the laboratory is halogenation of aldehydes and ketones at their a positions by reaction with Cl2, Br2, or I2 in acidic solution

11. Reactivity of Enols: α-Substitution Reactions Acid-catalyzed a-halogenation (Cl2, Br2, and I2) of aldehydes and ketones is a common laboratory reaction a-Halogenation occurs in biological systems • a-Halogenation of ketones in marine alga

12. Reactivity of Enols: α-Substitution Reactions Mechanism of acid-catalyzed bromination of acetone

13. Reactivity of Enols: α-Substitution Reactions Isotopic labeling experiments support reaction mechanism of acid-catalyzed halogenation • For a given ketone, the rate of deuterium exchange is identical to the rate of halogenation • Enol intermediate involved in both processes

14. Reactivity of Enols: α-Substitution Reactions a-Bromoketones are dehydrobrominated by base to yield a,b-unsaturated ketones • E2 reaction mechanism • 2-Methylcyclohexanone gives 2-methylcyclohex-2-enone on heating in pyridine

15. 17.3 Alpha Bromination of Carboxylic Acids Carboxylic acids can be a brominated by a mixture of Br2 and PBr3 in the Hell-Volhard-Zelinskii (HVZ) reaction

16. Alpha Bromination of Carboxylic Acids • Mechanism involves a substitution of an acid bromide enol

17. 17.4 Acidity of α Hydrogen Atoms: Enolate Ion Formation Presence of neighboring carbonyl group increases the acidity of the ketone over the alkane by a factor of 1040 Proton abstraction from carbonyl occurs when the a C-H bond is oriented parallel to the p orbitals of the carbonyl group A carbon of the enolate ion has a p orbital that overlaps neighboring p orbitals of the carbonyl group Negative charge shared with oxygen atom by resonance

18. Acidity of α Hydrogen Atoms: Enolate Ion Formation Strong base required for enolate formation • If NaOCH2CH3 is used the extent of enolate formation is only about 0.1% • If sodium hydride, NaH, or lithium diisopropylamide (LDA), [LiN(i-C3H7)2], is used the carbonyl is completely converted to its enolate conjugate base • LDA is prepared by reaction of butyllithium with diisopropylamine

19. Acidity of α Hydrogen Atoms: Enolate Ion Formation A C-H bond flanked by two carbonyl groups is even more acidic • Enolate ion is stabilized by delocalization of negative charge over both carbonyl groups • Pentane-2,4-dione has three resonance forms

20. Acidity of α Hydrogen Atoms: Enolate Ion Formation

21. Acidity of αHydrogen Atoms: Enolate Ion Formation

22. Worked Example 17.1Identifying Acidic Hydrogens in a Compound Identify the most acidic hydrogens in each of the following compounds, and rank the compounds in order of increasing acidity:

23. Worked Example 17.1Identifying Acidic Hydrogens in a Compound Strategy • Hydrogens on carbon next to a carbonyl group are acidic. • In general, a b-dicarbonyl compound is most acidic, a ketone or aldehyde is next most acidic, and a carboxylic acid derivative is least acidic. • Remember that alcohols, phenols, and carboxylic acids are also acidic because of their –OH hydrogens

24. Worked Example 17.1Identifying Acidic Hydrogens in a Compound Solution • The acidity order is (a) > (c) > (b). Acidic hydrogens are shown in red:

25. 17.5 Alkylation of Enolate Ions Enolate ions are resonance hybrids of two nonequivalent contributors • Enolate ions are vinylic alkoxides (C=C–O-) • Reaction on the oxygen yields an enol derivative • Enolate ions are a-keto carbanions (-C–C=O) • Reaction on the carbon yields an a-substituted carbonyl compound

26. Alkylation of Enolate Ions Enolate ions undergo alkylation by treatment with an alkyl halide or tosylate • Nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction • Leaving group displaced by backside attack

27. Alkylation of Enolate Ions • Alkylations are subject to all constraints that affect all SN2 reactions • Alkyl group R should be primary or methyl and preferably allylic or benzylic • Secondary alkyl halides react poorly and tertiary are unreactive due to competing E2 reaction

28. Alkylation of Enolate Ions The Malonic Ester Synthesis • Preparation of carboxylic acids from alkyl halides while lengthening the carbon chain by two atoms

29. Alkylation of Enolate Ions Diethyl propanedioate, commonly known as diethyl malonate, or malonic ester is more acidic than monocarbonyl compounds (pKa = 13) because its a hydrogens are flanked by two carbonyl groups • Easily converted to enolate ion by sodium ethoxide in ethanol • “Et” is used as an abbreviation for –CH2CH3

30. Alkylation of Enolate Ions Malonic ester contains two a hydrogens • Product of a-alkylation can itself undergo alkylation

31. Alkylation of Enolate Ions Alkylated of dialkylated malonic ester undergoes hydrolysis to yield the diacid followed by decarboxylation (loss of CO2) to yield the monoacid

32. Alkylation of Enolate Ions Decarboxylation is unique to carboxylic acids with a second carbonyl group located at the b position • Substituted malonic acids and b-keto acids contain a second carbonyl group at b position Decarboxylation occurs via a cyclic mechanism • Involves initial formation of an enol

33. Alkylation of Enolate Ions Overall result of malonic ester synthesis is the conversion of an alkyl halide into a carboxylic acid while lengthening the carbon chain by two carbons

34. Alkylation of Enolate Ions Malonic ester synthesis can be used to prepare cycloalkane-carboxylic acids via intramolecular alkylation • Three-, four-, five-, and six-membered rings can all be prepared in this way

35. Worked Example 17.2Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid How would you prepare heptanoic acid using a malonic ester synthesis?

36. Worked Example 17.2Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid Strategy • The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. • Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane

37. Worked Example 17.2Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid Solution

38. Alkylation of Enolate Ions The Acetoacetic Ester Synthesis • The acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons

39. Alkylation of Enolate Ions Ethyl-3-oxobutanoate, commonly called ethyl acetoacetate or acetoacetic ester, contains a hydrogens flanked by two carbonyl groups • Enolate ion is readily formed and alkylated under SN2 reaction conditions • A second alkylation product can be derived from monoalkylated product

40. Alkylation of Enolate Ions Alkylated or dialkylated acetoacetic ester is hydrolyzed in aqueous acid to a b-keto acid b-Keto acid undergoes decarboxylation to yield ketone product

41. Alkylation of Enolate Ions Ketone product formed in three-step sequence: • Enolate formation • Alkylation • Hydrolysis/decarboxylation Sequence applicable to all b-keto esters with acidic a hydrogens

42. Alkylation of Enolate Ions • Cyclicb-keto esters such as ethyl 2-oxocyclohexanecarboxylate can be alkylated and decarboxylated to give 2-substituted cyclohexanones

43. Worked Example 17.3Using the Acetoacetic Ester Synthesis to Prepare a Ketone How would you prepare pentan-2-one by an acetoacetic ester synthesis?

44. Worked Example 17.3Using the Acetoacetic Ester Synthesis to Prepare a Ketone Strategy • The acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide: • Thus, the acetoacetic ester synthesis of pentan-2-one must involve reaction of bromoethane

45. Worked Example 17.3Using the Acetoacetic Ester Synthesis to Prepare a Ketone Solution

46. Alkylation of Enolate Ions Direct Alkylation of Ketones, Esters, and Nitriles • A strong, sterically hindered base such as LDA converts a ketone, ester, or nitrile to its enolate ion • Use of a sterically hindered base avoids nucleophilic addition • A nonprotic solvent such as THF is required • Aldehydes rarely give high yields of alkylation products because their enolate ions undergo carbonyl condensation reactions

47. Alkylation of Enolate Ions • Example alkylations

48. Alkylation of Enolate Ions • Example alkylations

49. Alkylation of Enolate Ions • Example alkylations

50. Worked Example 17.4Using an Alkylation Reaction to Prepare a Substituted Ester How might you use an alkylation reaction to prepare ethyl 1-methylcyclohexanecarboxylate?