1. Chapter 18 Lecture 1 Enols I.Enolate Ions A.Carbonyl Reactivity 1)Nucleophilic carbonyl oxygen 2)Electrophilic carbonyl carbon 3)  -carbon containing acidic  -protons (the subject of this chapter) B.Acidity of Aldehydes and Ketones 1)pKa of protons alpha to an aldehyde or ketone carbonyl = 19-21 a)Ethene pKa = 44 b)Ethyne pKa = 25 c)Alcohol pKa = 15-18 2)Strong bases can remove  -hydrogens to produce an Enolate Ion Enolate Ion

2. 3)Why are carbonyl  -protons acidic? a)The conjugate base is stabilized by the enolate ion resonance structures b)The  + carbon of the carbonyl destabilizes the  C—H bond C.Formation of Enolate Ions 1)LDA (lithium diisopropyl amide) or other strong bases are used 2)Aprotic solvents are used to prevent solvent deprotonation 3)Enolate Resonance Hybrid a)The  -carbon and the oxygen of an enolate ion are both nucleophilic b)Ambident = “two-fanged” = a species that can react at 2 different sites to give 2 different products

3. a)The carbon atom is the normal site of reaction by S N 2. This type of reaction is called alkylation or C1-alkylation of the enolate ion. b)The oxygen atom is the normal site of protonation, forming an enol, which will tautomerize to the original ketone. II.Keto-Enol Equilibria A.Ketone—Enol Tautomerization 1)This reaction is reversible, and the extent of reaction depends on conditions 2)Base-catalyzed Enol-Keto Equilibration a)Base removes proton from the enol b)The mechanism is the reverse of the original enolate formation

4. 2)Acid Catalyzed Enol-Keto Equilibration a)Protonation occurs at the double bond b)Resonance stabilized C is next to O c)Protonated carbonyl deprotonates to give the keto form 3)Both reaction are fast if the catalyst (B - or H + ) are present 4)Keto form is usually dominant 5)Keto to enol tautomerization mechanisms are the reverse of those above B.Effects of Substituents on Keto-Enol Equilibria 1)Ketone donating substituents stabilize keto form 2)Aldehyde lack of donating substituents pushes equilibria toward enol form

5. C.Deuteration of Carbonyl  -Carbons 1)Dissolving an aldehyde or ketone in D 2 O, DO - (or D + ) replaces all of the  - Hydrogens with Deuteriums 2)Even though the keto form dominates, a small % is always tautomerizing to the enol. Over time, reprotonation at C gives the fully deuterated product. 3)Reaction can be followed by 1 H NMR as  -H signal disappears D.Interconversion of  -C stereochemistry 1)Keto-Enol tautomerization proceeds through an achiral intermediate

6. 2)Loss of optical activity occurs under basic or acidic conditions III.Halogenation of Aldehydes and Ketones A.Acid-Catalyzed  -Halogenation of Ketones and Aldehydes 1)In acidic conditions, only one halogen is able to add 2)The reaction rate is independent of X 2 concentration, suggesting that the rate determining step depends only on the carbonyl compound

7. 3)Mechanism of acid catalyzed  monohalogenation 4)Why does the reaction stop after only one halogenation? a)Mechanism requires enolization b)Electron withdrawing Br prevents protonation needed in first step O is no longer basic enough To attack proton. Enolization Can’t happen.

8. B.Base Mediated Halogenation of  -Carbon Goes to Completion 1)Mechanism 2)Electron Withdrawing Br increases  -Hydrogen acidity, favoring complete bromination of all  -Carbons 3)The Iodoform test for Methyl Ketones is base catalyzed halogenation

9. IV.Alkylation of Aldehydes and Ketones A.Alkylation of Ketones Using NaH 1)Ketones with only one  -Hydrogen are alkylated in high yield a)Example: b)NaH is a strong base yielding enolate ion when reacted with carbonyls 2)Polyalkylation occurs if multiple  -H’s are present

10. 3)Unsymmetric Ketones give multiple products B.Enamine Route to Ketone/Aldehyde Alkylation 1)Enamine formation makes C=C bonds electron rich by resonance 2)The nucleophilic  -Carbon can then attack electrophiles

11. 3)The amine is removed from the alkylated product by acid to give the alkylated ketone or aldehyde 4)The Enamine Alkylation Route is Preferred a)No multiple alkylations b)Works on Aldehydes and Ketones