Enolates: Deprotonation  to a Carbonyl

 + Base + Base  an enolate

Enolate chemistry is used to form new bonds (C-C or C-E) one carbon away from C=O group.

Enolates: Deprotonation  to a Carbonyl

 + Base + Base  an enolate

pKa 30 25 20 17 9

Acidity depends on stability of conjugate enolate. Enolates Best Formed With Strong, Non-Nucleophilic Bases

++OH H2O

pK = 20 pKa = 15 a -OH not strong enough to deprotonate quantitatively (but enough enolate is formed for some reactions).

+ +

pKa = 20 LDA deprotonates lithium pK = 36 diisopropylamide quantitatively. a (LDA) A strong, hindered base.

Enolizable Protons Racemize in Base

(S) (R)

+ OH + H2O + OH

addition of H+ to top yields (R)

addition of H+ to bottom yields (S) So, a pure sample of (S)-enantiomer will turn into a racemic mixture in even mild base. Halogenation at the  Carbon In Base:

-OH -OH

X2 X2

(X = Cl, Br, I) (unavoidable)

Problem: Electron-withdrawing halogen stabilizes negative charge at a carbon; Formation of second enolate easier than the first.

Even though enolate is not quantitatively generated by –OH, enough enolate is present to react.

Halogenation at the  Carbon In Base:

-OH -OH

X2 X2

(X = Cl, Br, I)

The Haloform Reaction: • Occurs only for methyl ketones. -OH – • Driven by stability of CX3.

+ HCX3

Even though enolate is not quantitatively generated by –OH, enough enolate is present to react. Halogenation at the  Carbon

In Base:

-OH -OH

X2 X2

(X = Cl, Br, I)

In Acid:

H O+ 3 Electron-withdrawing halogen X 2 inhibits further protonation; (X = Cl, Br, I) Monohalogenated product preferred.

Alkylation of Enolates

1. LDA

2. 2.

2. 2.

(X = halide, OTs) Enamine Alkylation

2° amine 1.

an enamine

catalytic H+ 2. an iminium ion

+ Combination of 2° amine and 3. H3O enolizable aldehyde or ketone forms a stable enamine. Enamine is readily hydrolyzed back to carbonyls in H2O. enolate alkylation product

Kinetic vs. Thermodynamic Enolates

Which carbon is deprotonated? 1. Which enolate is generated?

NaOH THF, -78 °C 25 °C

“kinetic” “thermodynamic” (less-substituted) (more-substituted) enolate enolate

2.

Bulky base removes Problem: - less-hindered OH is also nucleophilic; proton. will react with RX. Alkylation of Ester, Dialkylamide Enolates

1. LDA 1. LDA

NOT

(sterically 2. CH3I 2. CH3I hindered)

+

Alkylation of Ester, Dialkylamide Enolates

1. LDA

NOT

2. CH I (sterically 3 hindered)

CH3I approaches enolate from both top and bottom faces to generate racemic + mixture of products.