Chapter 18 Lecture 1 Enols

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

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

3. The carbon atom is the normal site of reaction by SN2. This type of reaction is called alkylation or C1-alkylation of the enolate ion. • The oxygen atom is the normal site of protonation, forming an enol, which will tautomerize to the original ketone. II. Keto-Enol Equilibria • Ketone—Enol Tautomerization • This reaction is reversible, and the extent of reaction depends on conditions • Base-catalyzed Enol-Keto Equilibration • Base removes proton from the enol • The mechanism is the reverse of the original enolate formation

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

5. Deuteration of Carbonyl a-Carbons • Dissolving an aldehyde or ketone in D2O, DO- (or D+) replaces all of the a-Hydrogens with Deuteriums • Even though the keto form dominates, a small % is always tautomerizing to the enol. Over time, reprotonation at C gives the fully deuterated product. • Reaction can be followed by 1H NMR as a-H signal disappears • Interconversion of a-C stereochemistry 1) Keto-Enol tautomerization proceeds through an achiral intermediate

6. Loss of optical activity occurs under basic or acidic conditions • Halogenation of Aldehydes and Ketones • Acid-Catalyzed a-Halogenation of Ketones and Aldehydes • In acidic conditions, only one halogen is able to add • The reaction rate is independent of X2 concentration, suggesting that the rate determining step depends only on the carbonyl compound

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

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

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

10. Unsymmetric Ketones give multiple products • Enamine Route to Ketone/Aldehyde Alkylation • Enamine formation makes C=C bonds electron rich by resonance • The nucleophilic a-Carbon can then attack electrophiles

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