Chapter 18

Reactions at the α Carbon of Carbonyl CompoundsEnols and Enolates

Ch. 18 - 1

Ch. 18 - 2

O

RR'

Nu

Reactions at the α Carbon of Carbonyl Compounds:

Enols and Enolates

O

R R'δ+

δ−

O

RR'

Hα Hydrogens are weakly acidic (pKa = 19 – 20)

Nu

Ch. 18 - 3

1. The Acidity of the α Hydrogens of Carbonyl Compounds: Enolate Anions

H C C H H2C C H

H3C C

H

H

H

O

RR'

H

H

pKa 25 44

50 19-20pKa

Ch. 18 - 4

C C

O

R

H

Resonance structures forthe delocalized enolates

B:

C C

O

R

C C

R

O

Ch. 18 - 5

C C

R

O

Enolate

C CHO

R

Enol form

C

R

O H

Keto form

H+ H+

Ch. 18 - 6

2. Keto and Enol Tautomers

Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization

Ch. 18 - 7

O

H

OH

HAcetaldehyde

Keto form Enol form

(extremely small)(~100%)

O OHAcetone

(1.5 X 10-4%)(>99%)

O OH

Cyclohexanone

(1.2%)(98.8%)

Ch. 18 - 8

O OHO

Pentane-2,4-dione(24%)

O

Enol form(76%)

O OH

: ::

:

Resonance stabilization of the enol form

Hydrogen bond

O OH

: :

::

Ch. 18 - 9

3. Reactions via Enols & Enolates3A. Racemization

Racemization at an α carbon takes place in the presence of acids or bases

O

tBuEt

H Me

(chiral)(s)

OH

tBuEt

Me

OHor

H3O

Enol(achiral)

O

tBuEt

O

tBuEt

H MeMe H

+

H3O

( 1 : 1 ) racemate

Ch. 18 - 10

C C

H

O

HO

C C

O H+

Enol (achiral)HO

Base-Catalyzed Enolization

C C

OEnolate (achiral)

H OH

Ch. 18 - 11

C C

O

H

O HH

H

+ C C

O

H

H

O

H

H+

Acid-Catalyzed Enolization

C CO H

+O HH

HEnol

(achiral)

Ch. 18 - 12

3B. Halogenation at the α Carbon

C C

OH+ X2

acid

or baseC C

OX+ HX

(racemic)

Ch. 18 - 13

Base-Promoted Halogenation

C C

OHB: + + C C

Oδ−

δ−Step 1slow

C C

OH+

fast

Enolate

EnolB:

B:H: : : :

Step 2

C C

O

C C

O

+ X X

fast OX+ X

Enolate anion

: : : :

Ch. 18 - 14

Acid-Promoted Halogenation

C C

OH

C C

OH

fastC C

O H

Step 1

H+

Enol

+

:B

H:B H:B

: :

slow

Step 2fast

X X C C

O H+ C C

X O+ X

H

: :

C C

X O+ X

H fastC C

X O+ HX

Racemic

Step 3

Ch. 18 - 15

3C. The Haloform ReactionO

3 X2

3 OH

CX3

O

+ 3 X

OH

O

O

+CHX3A haloform

(X = Cl, Br, I)

Ch. 18 - 16

O

R

O

R O(Both in excess)

+ CHI3

A methylketone

Iodoform(a yellow

precepitate)

I2, HO

Ch. 18 - 17

O

RX + X

O

RH + B

Mechanism

O

R R

O

EnolateX X

Repeatsteps

twice

O

R CX3

Ch. 18 - 18

O

R CX3OH

O

R CX3

:OH

: :

● Acyl Substitution Step

O

R OH+ :CX3

O

R O:+CHX3

Ahaloform

Carboxylateanion

: :

HO

Ch. 18 - 19

3D. α-Halo Carboxylic Acids: The Hell–Volhard–Zelinski Reaction

O

OHR

O

OHR

X

1. X2, P

2. H2O

Ch. 18 - 20

OH

O

Br

O

OH

O

Br

Br

Br2

H2O

P

Example

Ch. 18 - 21

O

BrR

Br

O

OHR

P + Br2[PBr3]

O

BrR

O

BrR

H:Br Br

O

OHR

Br

H2O

Ch. 18 - 22

O

ClR

O

ClR

I

I2HI, SOCl2

O

ClR

Br

N

O

O

Br

HBr, SOCl2

(NBS)

Ch. 18 - 23

O

OHR

X O

OR

NH3α-Amino acid

NH3

O

OHR

OH

1. HO2. H3O

α-Hydroxy acid

Ch. 18 - 24

4. Lithium EnolatesO

H

O+ EtO Na

weakeracid

(pKa = 19)

weaker base

stronger base

strongeracid

(pKa = 16)

+ EtOH

O O+ iPr2N Li +

iPr2NH

H stronger base

weaker base

weakeracid

(pKa = 38)weaker

acid(pKa = 19)

Ch. 18 - 25

Preparation of lithium diisopropylamide (LDA)

Li N

H

+

N

THF

Li

Buyllithium(BuLi)

Diisopropylamine(pKa = 38)

Lithium diisopropylamine

[LDA or LiN(iPr)2]

Butane(pKa = 50)

+

Ch. 18 - 26

4A. Regioselective Formation of Enolates

O

H3CH3C

O

H

HLi N(iPr)2

DME

Li

Kineticenolate

Formation of a Kinetic Enolate

This enolate is formed faster because the hindered strong base removes the less hindered proton faster.

Ch. 18 - 27

Formation of a Thermodynamic Enolate

H3C

H

H

HO

2-Methylcyclo-hexanone

This enolate is more stable because the double bond is more highly substituted. It is the predominant enolate at equilibrium.

B

O

HH3CH

Kinetic(less stable)

enolate

O

H3C

Thermodynamic(more stable)

enolate

weak base in a protic solvent

Ch. 18 - 28

4B. Direct Alkylation of Ketones via Lithium Enolates

OO Li

LDA

DME

O

O

CH3

PhBr Ph

H3C I

(- LiI)

(- LiBr)

(56%)

(42-45%)

Ch. 18 - 29

4C. Direct Alkylation of Esters

O

OR'R

H

LDA

THF

O

OR'R

O

OR'R

E

E

Ch. 18 - 30

Examples

O

OMe

1. LDA, THF

2. MeI

O

OMe

Me

O

O

O

O

Ph1. LDA, THF

2. Ph Br

Ch. 18 - 31

5. Enolates of β-Dicarbonyl Compounds

O O

H

O

H

pKa = 9-11(more acidic)

pKa = 18-20

Ch. 18 - 32

Recall

O

H

O

+ + EtOHEtO

α-hydrogens of β-dicarbonyl compounds are more acidicO

H

+ + EtOHEtO

O O O

Ch. 18 - 33

O

CC

O

CC

C

O

C

O O

CC

C

O

Contributing resonance structures

Resonancehybrid

O

CC

C

O

δ−

δ−δ−

Ch. 18 - 34

6. Synthesis of Methyl Ketones: The Acetoacetic Ester Synthesis

O O

OEt

O O

OEt

EtO NaNa

O O

OEt

R X

R

O O

OEt

R

tBuO K

O O

OEt

R' X

R R'

(R, R' = 1o

alkyl groups)

Ch. 18 - 35

Synthesis of monosubstituted methyl ketones

O

OEt

O 1. EtO Na , EtOH O

OEt

O

2. Ph Br

Ph

O

OH

O1. NaOH

2. H3O+

Ph

heat

(- CO2)

O

Ph (Decarboxylationof β-keto acid)

Ch. 18 - 36

Synthesis of disubstituted methyl ketones

O

OEt

O1. EtO Na , EtOH O

OEt

O

Me

2. MeI

O

OEt

O1. tBuOK, tBuOH

2. Et-Br

Me Et

1. NaOH

2. H3O+

O

OH

O

Me EtO

Me

Etheat

(- CO2)

Ch. 18 - 37

O O O

Ethyl acetoacetate ion Acetate enolate

is the syntheticequivalent of

Ch. 18 - 38

Synthesis of γ-keto acids and γ-diketonesO

OEt

OEtO Na O

OEt

O

O

OEt

O

BrX

O

X

O

1. NaOH (aq)

2. H3O+

O

OH

O

O

X O

heat(- CO2)

X

O

α

βγ X=OH: γ-keto acid

X=R: γ-diketone

Ch. 18 - 39

6A. Acylation Synthesis β-diketones

O

OEt

O O

OEt

ONaHDMF

(cannot use EtOH because it will react with acid chloride)

O

OEt

O

R Cl

O

OR

1. NaOH (aq)

2. H3O+

O

OH

O

R O O

heat(- CO2)

R

O

Ch. 18 - 40

7. Synthesis of Substituted Acetic Acids: The Malonic Ester Synthesis

O

EtO

O

OEt

Diethyl malonate

O

EtO

O

OEt

is the synthetic equivalent of:

O

OEt

O

Oand

Ch. 18 - 41

O

EtO OEt

O

O

OHR

O

OHR

R'

Ch. 18 - 42

O

EtO OEt

O

R

Synthesis of monoalkylacetic acidO

EtO OEt

O

H

OEt O

EtO OEt

O

R X

1. NaOH (aq)

2. H3O+

O

HO OH

O

Rheat

O

HO O

O

R

H

HO

OH

RHO

O

R

Ch. 18 - 43

O

EtO OEt

O

R

1. tBuOK, tBuOH

2. R'X

R'

Synthesis of dialkylacetic acidO

EtO OEt

O

1. NaOH (aq)

2. H3O+

O

HO OH

O

R R'

heat

(- CO2)

O

HOR

R'

1. EtONa

2. RX

O

EtO OEt

O

R

Ch. 18 - 44

Example 1O

EtO OEt

O O

EtO OEt

O1. EtONa, EtOH

2.

Br

1. 50% KOH, reflux2. dil. H2SO4, reflux

O

HO OH

O(-CO2)

HO

O

(Heptanoic acid)

Ch. 18 - 45

Example 2

O

EtO OEt

O

Me

1. tBuOK, tBuOH

2. Ph Br

Ph

O

EtO OEt

O

1. NaOH (aq)

2. H3O+

O

HO OH

O

Me Ph

180oC

(- CO2)

O

HO

Me

Ph

1. EtONa, EtOH

2. MeI

O

EtO OEt

O

Me

Ch. 18 - 46

8. Further Reactions of Active Hydrogen Compounds

Z Z'

Active hydrogen compound

(Z and Z' are electron withdrawing groups)

Z, Z':O

R

O

H

O

OR

O

NR2

O

SR

S

O

O

R S OR

O

O

S NR2

O

O

N NO2

or

Ch. 18 - 47

Example

NCOEt

O

NCOEt

O1. EtONa, EtOH

2. Br

1. tBuOK, tBuOHNCOEt

O

Ph Br

Ph

2.

Ch. 18 - 48

O

CC

H

HN R

R

Aldehyde or ketone

2o Amine

+

9. Synthesis of Enamines: Stork Enamine Reactions

C C

H

N

OH R

R

C C

N

R

R

Enamine

+ H2O

Ch. 18 - 49

2° amines most commonly used to prepare enamines

NH

NH

NH

O

Pyrrolidine Piperidine Morpholine

N

H

O N

p-TsOH, −H2O

● e.g.

Ch. 18 - 50

NR X+

R = H2C CH

or Ph

N R

+ X

N-alkylated product

(a)

N

RC-alkylatedproduct

(b)

+ X

H2OO

R

H

N +

heat

(a)

(b)

Ch. 18 - 51

N O

ClR

Synthesis of β-diketones

O N

NH

p-TsOH(enamine)

O

R Cl

N O

R

O

R

O

H2O

Ch. 18 - 52

N

NH

p-TsOH(enamine)

BrOEt

O

Synthesis of γ-keto esters

O

N

OEt

O

O

H2OOEt

O

Ch. 18 - 53

Enamines can also be used in Michael additions

NCN+

N

CNEtOH

reflux

OH2OCN

Ch. 18 - 54

10. Summary of Enolate Chemistry1. Formation of an Enolate

O

R

H

+ :B

Resonance-stabilized enolate

O

R

O

RH:B +

Ch. 18 - 55

2. Racemization

Ph

OR'

HR

Enantiomers

Ph

OH

R

R'OH

or H3O

Enol(achiral)

Ph

OR'

RH

OH

or H3O

Ch. 18 - 56

3. Halogenation of Aldehydes & KetonesO

RR'

H

O

RR'

X

+ X2acid

or base

Specific example: haloform reactionO

PhH

H

O

Ph

X

+ 3 X2OH

H2O

X

X

O

Ph OCHX3 +

H

Ch. 18 - 57

4. Halogenation of Carboxylic Acids: The HVZ Reaction

O

OHR

O

OHR

X

1. X2, P

2. H2O

Ch. 18 - 58

5. Direct Alkylation via Lithium Enolates

Specific example:

O

H(R')

O

H(R')

LDA, THFR

(formation of thekinetic enolate)

RR'' X

O

H(R')R

-78oC

R''

O O Li O

CH3ILDA, THF

-78oC

Ch. 18 - 59

6. Direct Alkylation of Esters

O

OEtR

O

OEtR

LDA

THF

R' BrO

OEtR

R'

Ch. 18 - 60

7. Acetoacetic Ester SynthesisO

OEt

1. NaOEt

2. RBr

O O

OEt

O

RO

1. OH−, heat2. H3O

+

3. heat, (− CO2)R

O

OEt

1. tBuOK

2. R'Br

O O

OEt

O

O

R

RR R'

R'

1. OH−, heat

2. H3O+

3. heat, (− CO2)

Ch. 18 - 61

8. Malonic Ester SynthesisO

OEt

1. NaOEt

2. RBrEtO

O O

OEtEtO

O

R

HO

O1. OH−, heat2. H3O

+

3. heat, (− CO2)R

O

OEt

1. tBuOK

2. R'BrEtO

O O

OEtEtO

O

HO

O

R

RR R'

R'

1. OH−, heat

2. H3O+

3. heat, (− CO2)

Ch. 18 - 62

9. Stork Enamine Reaction

1.2. heat3. H2O

O

RR + R'2NH R

NR'2

R

R R

O

R''

R'' Br

Enamine

Ch. 18 - 63

END OF CHAPTER 18

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