Enolates, Enols, and EnaminesPart 1

NaOHO

+

Ph H

ONaOH

H2O

OHO

PhH2O

O

Ph

Similar Structures cause Similar Reactions

Name Resonance contributors Resonance hybrid

Enolate

Enolalkene + alcohol

Enaminealkene + amine

Oδ−

δ−

HOδ+

δ−

R2Nδ+

δ−

α β

Reading: OCATSA Chapter 27

Nucleophilicat β-carbon

O O

HO HO

R2N R2N

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 1

Enolates: Formation

Recall the three C=O group fates:

•Nucleophilic attack at carbon

•Accept electrophile (usually H) at oxygenUsed extensively in C=O

addition and substitution reactions

•Form enolate:

H Base

O OO

Enolate

Important issues: •Which O=C-C-H is most acidic (removed first)?

•What base to use?

•How much enolate is formed?

Relative Acidity of H-C-C=O

Review: --OCATSA chapter 9

--Tutorials on course web site

--Chem 14C notes

Example:O

+

OO

+

OCH3

OBase

Which enolate is formed?

Most stableenolate

LowestpKa

comes from

indicated by

comes from

Example: H2SO4 pKa -9; H2O pKa 15.7

Most acidicH-C-C=O

Conjugate acidmost readilydeprotonated

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 2

Relative Acidity of H-C-C=O

•Keq ~ 10(pKa right acid – pKa left acid) = 10(15.7 – 19) = 10-3.3

•pKa values do not need to be memorized, but can be useful to know

•Enolate is often drawn as its most stable resonance contributor

Example: A ketone and its enolate

Ketones

Keq < 1 (more ketone than enolate) Keq > 1 (more enolate than ketone)

Equilibrium position?

•Acid/base equilibrium favors weakest (most stable) acid and weakest (most stable) base

pKa 19Weaker acid

pKa 15.7Stronger acid

O

+ HOO

+ H2O

Most acidic?

Ketone

β-diketone

Most stable enolate?

Ketone enolate

β-diketone enolate

More extensive delocalization?

Ketone enolate

β-diketone enolate

Relative Acidity of H-C-C=O

Keq ~

β-Diketones

Keq < 1 (more diketone than enolate) Keq > 1 (more enolate than diketone)

Ketone enolate:

β-diketone enolate:

O O

OO

+ CH3O

OO+ CH3OH

OO OO OO

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 3

Relative Acidity of H-C-C=O

Keq ~

Esters

Keq < 1 (more ester than enolate) Keq > 1 (more enolate than ester)

Ketone enolate:

Most acidic?

Ketone

Ester

Most stable enolate?

Ketone enolate

Ester enolate

Largest δ− charges?

Ketone enolate

Ester enolate

Ester enolate:CH3O

O

CH3O

O

CH3O

O

O O O δ−

δ−

CH3O

O

δ−δ+

δ−

CH3O

O

+ CH3O

CH3O

O

+ CH3OH

Relative Acidity of H-C-C=O

O

+

OO

+

OCH3

OBase

Which enolate is formed?

pKa 19 9 25

OO

•Most acidic proton removed first

CH3O

OO

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 4

Enolate Formation: A Potential ProblemProblem: Strong base is also usually strong nucleophile...

How to avoid addition, and get enolate formation only?

HO- is a base

HO- is a nucleophile

CH3O

O

+ HO

CH3O

O

CH3O

OHO

Competing pathways

Enolate Formation: A Potential ProblemHow to avoid addition, and get enolate formation only?

•Reduce nucleophilicity? Strong base usually also strong nucleophile

•Steric effects?

H

OBase/Nuc

Less hindered than C

More hindered than H

•Therefore use sterically hindered strong base to minimize attack at C=O

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 5

•LDA is a very strong base; equilibrium favors... enolate ester Keq ~ _________

Enolate Formation: A Potential ProblemSterically Hindered Base Minimizes Attack at C=O

•LDA favors deprotonation instead of addition

Lithium diisopropyl amideLDA

Li+ -N(iPr)2

N

Li

CH3O

O

H N(iPr)2

CH3O

O

+ H N(iPr)2

pKa 25 pKa 36

1011

Not formed

N

OCH3O

Example: Use of LDA to form ester enolate

What is an Enolate Good For?Now that I have an enolate, what do I do with it?

suggests

Less significant contributor:FC on carbon (EN = 2.5)

More significant contributor:FC on oxygen (EN = 3.0)

R

O

•Resonance suggests multiple spots to form new bonds

•Enolates accept most electrophiles at carbon

•Enolates useful to form new carbon-carbon bonds

R

O

Elec

R

O

Elec

Elec

R

OElec

Negative formal charge

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 6

Enolate Reactions: AlkylationEnolate (nucleophile) + alkyl halide (electrophile) SN2 reaction

Example:

New C-C bondnext to C=O

O

1. LDA

2. CH3I

O

CH3

Mechanism:

O O

CH3H N(iPr)2

O H3C I

SN2

O

CH3C

CH3H3C

Enolate Reactions: AlkylationEnolate (nucleophile) + alkyl halide (electrophile) SN2 reaction

•Enolate alkylation must meet usual SN2 requirements...

O

+ (CH3)3C-I

SN2 E2

O

+ CH2C CH3

CH3

Nuc + R3C–LGSolvent

Nuc–CR3 + LG

Enolates are usually

_________ nucleophiles

Enolate solventsOK for SN2

Not _______ Depends on electrophile

Example:

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 7

O

H OH

O

Ph H

O O

Ph

OH H OH O

Ph

OH

+ HO

Enolate Reactions: The Aldol ReactionEnolate + ___________________________

Another electrophileProduct?

Example: Predict product byworking out mechanism

Mechanism:•Strong base present so consider enolate pathways before addition/substitution

•PhCHO cannot form enolate

Keq = __________

Aldehyde more / less

electrophilic than ketone

O

Ph H

O

+NaOH

H2O

•HO- is ________________ and __________________.

Tetrahedral adduct...

Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 8