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Enols and Enolates: Properties, Reactions, and Synthetic Applications, Study notes of Organic Chemistry

An in-depth exploration of enols and enolates, their structures, and their role in organic chemistry. Topics covered include enol content and enolization, enolates, tautomers, acidity of carbonyl compounds, and various reactions such as the aldol condensation, Claisen condensation, and acylation of enolates. The document also discusses the importance of lithium diisopropylamide (LDA) in enolate reactions and the regiochemistry of ketone deprotonation.

What you will learn

  • What are the typical pKa values of the α-protons in different types of carbonyl compounds?
  • What is the difference between an enol and an enolate?
  • Why is one enol favored over the other in a given reaction?
  • What is the role of lithium diisopropylamide (LDA) in enolate reactions?

Typology: Study notes

2021/2022

Uploaded on 09/27/2022

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187
C10H11N
7.3
(5H, m)
3.72
(1H, t, J=7.1)
1.06
(3H, t, J=7.4)
1.92
(2H, dq, J=7.4, 7.1)
CDCl3 TMS
120.7
129.0
128.0
127.3
135.8
38.9 29.2
11. 4
188
Chapter 20: Enols and Enolates
O
α
β
γ
α'
β'
γ'
H
O
carbonyl OH
O
Enol
Enolate
E
O
E
+
E
+
20.1: Enol Content and Enolization
94
pf3
pf4
pf5
pf8
pf9
pfa
pfd
pfe
pff
pf12

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C 10 H 11 N

(5H, m)

(1H, t, J=7.1) 1.

(3H, t, J=7.4)

(2H, dq, J=7.4, 7.1)

120.7^ CDCl^3 TMS

Chapter 20: Enols and Enolates

O

α

β α' γ

β' γ'

H

O

carbonyl (^) O H

O

Enol

Enolate E

O

E +

E+

20.1: Enol Content and Enolization

C C

O H

C CH

O

enol keto

C=C ΔH° = 611 KJ/mol!

C-O 380!

O-H 426!

C=O ΔH° = 735 KJ/mol!

C-C 370!

C-H 400!

Δ H° = -88 KJ/mol!

H 3 C CH 3

O

H 3 C CC

OH

H

H

Tautomers: isomers, usually related by a proton transfer, that are

in equilibrium.

Keto-enol tautomeric equilibrium lies heavily in favor of the keto

form (see Table 20.1, p. 821).

Enolization is acid- and base-catalyzed (p. 823):

Base-catalyzed mechanism:

Acid-catalyzed mechanism:

20.2: Enolates

Typical p K a’s of the α-protons carbonyl compounds

(Table 20.1, p. 825):

aldehydes 17

ketones 19

esters 25

amides 30

nitriles 25

H 3 C CCH 3

O

H 3 C CH

O

H 3 C COCH 3

O

H 3 C CN(CH 3 ) 2

O H

3 C^ C^ N

Acidity of 1,3-dicarbonyl compounds

H 3 C COCH 3

O

H 3 C CCH 3

O

C CCH 3

O

H 3 C^ C

O

H H

ketone

pKa = 19

1,3-diketone

pKa = 9

C COCH 3

O

H 3 CO^ C

O

H H

ester

pKa = 24

1,3-diester

pKa= 13

C COCH 3

O

H 3 C^ C

O

H H

1,3-keto ester

pKa= 11

ester!

p K a = 24!

ester

p K a = 25

The inductive effect of the carbonyl causes the α-protons to be

more acidic. The negative charge of the enolate ion (the

conjugate base of the carbonyl compound) is stabilized by

resonance delocalization. The p K a of the α-protons of aldehydes

and ketones is in the range of 16-

ethane acetone ethanol

p K a = 50-60 p K a = 19 p K a = 16

H 3 C CCH 3

O

H 3 C CH 3 H 3 CH 2 COH

C CO

H

C CO C CO

inductive

effect

resonance effect

C C H

O

B

C C

O

CC

O

Enolate anion

+ + H-B

carbonyl

δ+

δ - δ+ (^) δ+

H 3 C CC H 3

O

H 3 C CC

O

Cl H H^ H^3 C^ C

C

O

H H

H 3 C CC

O

C

H H^ CH^3

O

p K a 19 14 16 9

H 3 C CC H 3

O + H

2 O^ H 3 C CCH 2

O + H

3 O

acid base conjugate conjugate

base acid

p K a 19 -1.

(weaker acid) (weaker base) (stronger base) (stronger acid)

H 3 C CC H 3

O + HO

H 3 C CCH 2

O

+ H 2 O

acid base conjugate conjugate

base acid

p K a 19 15.

(weaker acid) (weaker base) (stronger base) (stronger acid)

acid base conjugate conjugate

base acid

p K a 9 15.

(stronger acid) (stronger base) (weaker base) (weaker acid)

H 3 C CC

O

C

H H

CH 3

O + HO

H 3 C CC

O

C

H

CH 3

O

+ H 2 O

_

Lithium diisopropylamide (LDA): a super strong base

N H +^ H 3 CH 2 CH 2 CH 2 C^ Li^ N^ Li^ +^ H^3 CH^2 CH^2 CH^3 C

diisopropylamine LDA

p K a = 36 p K a = 60

p K a = 19 p K a = 36

(stronger acid) (stronger base) (weaker base) (weaker acid)

H 3 C CCH 3

O

+ H

3 C^ CCH 2

O

NN LiLi (^) + N H

H 3 C COCH 2 CH 3

O

+ N H 2 C COCH 2 CH 3

O

+ N H

p K a = 25 p K a = 36

(stronger acid) (stronger base) (weaker base) (weaker acid)

The aldol product can undergo acid- or base-catalyzed

dehydration to an α,β-unsaturated carbonyl. The dehydration is

essentially irreversible. The dehydration is favored at higher

temperatures. (mechanism, p. 829)

aldol reactions involving α-monosubstituted

aldehydes are generally favorable

aldol reactions involving α,α-disubstituted

aldehydes are generally unfavorable

aldol reactions involving ketones are

generally unfavorable

C C H

O NaOEt R EtOH

H

H

C CH

O

H R

RC C

H H

HOH

C C H

O NaOEt R EtOH

H

R

C CH

O

R R

RC C

R H

HOH

C C R

O NaOEt R EtOH

H

H

C CR

O

R H

RC C

H H

HOR

20.4: Mixed and Directed Aldol Reactions –

Mixed aldol reaction between two different carbonyl compounds

– four possible products (not very useful)

Aldehydes with no α-protons can only act as the electrophile

C

O

H 3 CC H

H H

C

O

H 3 CH 2 CH 2 CC H

H H

NaOH,H 2 O

C

O

CC H

H 3 C H

H 3 CH 2 CH 2 CH 2 C

HOH

C

O

CC H

H 3 CH 2 CH 2 C H

H 3 CH 2 C

HO H

C

O

CC H

H 3 C H

H 3 CH 2 C

HO H

C

O

CC H

H 3 CH 2 CH 2 C H

H 3 CH 2 CH 2 CH 2 C

HO H

Preferred reactivity

C

O

H +

NaOH,H C 2 O

O

H 3 CC H

H H

C

O

C C H

H 3 C H

HOH

C

O

CC H

H 3 C H

H 3 CH 2 C

HO H

C

O

H +^ C

O

H 3 C CH 3

NaOH,H 2 O^ C

O

C CH 3

C

H H

HO H

Directed aldol reaction – Discrete generation of an enolate with

lithium diisopropyl amide (LDA) under aprotic conditions (THF as

solvent)

C

O

H 3 CH 2 CH 2 CC H

H H

LDA, THF, -78°C CO

H 3 CH 2 CH 2 CC H

H

Li+^ C

O

H 3 CC H

H H C

O

CC H

H 3 CH 2 CH 2 C H

H 3 CH 2 C

HOH

then H 2 O

C

O

H 3 CC H

H H

LDA, THF, -78°C OC

H 3 CC H

H

Li+^ C

O

H 3 CH 2 CH 2 CC H

H H

then H 2 O

C

O

CC H

H 3 C H

H 3 CH 2 CH 2 CH 2 C

HO H

20.5: Acylation of Enolates: The Claisen Condensation

Reaction. Base-promoted condensation of two esters to give a

β-keto-ester product

H 3 C COEt

O (^) Na + – OEt, EtOH then H 3 O +^ H 3 C CC

O

C OEt

O

H H

Ethyl acetate

Ethyl 3-oxobutanoate(ethyl acetoacetate)

The mechanism of the Claisen condensation (Mechanism 20.3, p.

834) is a base promoted nucleophilic acyl substitution of an ester

by an ester enolate and is related to the mechanism of the aldol

reaction.

Acylation of Ketones with Esters. An alternative to the Claisen

condensations and Dieckmann cyclization.

Equivalent to a mixed

Claisen condensation

Equivalent to a

Dieckmann cyclization

O a) LDA, THF, -78° C

b) C

O

O H 3 CO OCH 3

O

OCH 3

O

OR

O

C

O

+ H 3 C OCH 3

HH 3 CO-^ Na+^ , 3 COH

O a) LDA, THF, -78° C O b) C

O

H 3 CO OCH 3

O

OCH 3

O

HH 3 CO-^ Na+^ , 3 COH

H 3 CO

O

OCH 3

O

20.6: Alkylation of Enolates: The Acetoacetic Ester and

Malonic Ester Syntheses – enolate anions of aldehydes,

ketones, and esters can react with other electrophiles such as

alkyl halides and tosylates to form a new C-C bonds. The

alkylation reaction is an S N 2 reaction.

Reaction works best with the discrete generation of the enolate

by LDA in THF, then the addition of the alkyl halide

Acetoacetic Ester Synthesis: The anion of ethyl acetoacetate can

be alkylated using an alkyl halide (S N 2). The product, a β-keto

ester, is then hydrolyzed to the β-keto acid and decarboxylated to

the ketone. ( Ch. 18.16).

C

O

H 3 C CCO^2 Et

H H alkyl

halide

  • RH EtO^ Na+ 2 C-X

ethyl acetoacetate

C

O

H 3 C CCH^2 R

H H

ketone

C

O

H 3 C CCO^2 Et RH 2 C H

HCl, Δ (^) CO CO 2 H H 3 C C EtOH RH 2 C H

C COEt

O

H 3 CC

O

R'H 2 C CH 2 R

EtOEtOH Na +^ ,

C COH

O

H 3 CC

O

R'H 2 C CH 2 R

R'H 2 C-X

HCl, Δ H 3 C C C

O

CH 2 R

H CH 2 R'

_

- CO 2!

- CO 2!

An acetoacetic ester can undergo one or two alkylations to give

an α-substituted or α,α-disubstituted acetoacetic ester

The enolates of acetoacetic esters are synthetic equivalents to

ketone enolates

β-Keto esters other than ethyl acetoacetate may be used. The

products of a Claisen condensation or Dieckmann cyclization

are acetoacetic esters (β-keto esters)

OEt

O

OEt

O

EtONa, EtOH then H 3 O +

CO 2 Et

O

Dieckmann cyclization

H 3 CH 2 C C OEt

O

NaOEt then HEtOH 3 O^ +

HC C OEt

O

H 3 CH 2 CC

O

CH 3

acetoaceticester

Claisen condensation acetoaceticester

EtONa,EtOH

EtONa,EtOH

Br

Br C C^ OEt

O

H 3 CH 2 CC

O

CH 3

CO 2 Et

O H 3 O +

H 3 O +

O

H 3 CH 2 CCC CH 2 CH=CH 2

O

CH 3

H

C COCH 3

O

H 3 C^ C

O

H H

acetoacetic ester

pKa= 11

+ H 3 CO

C COCH 3

O

H 3 C^ C

O

H

+ H 3 COH

pKa= 16

C CCH 3

O

H

H H

acetoacetic ester

pKa= 19

+ H 3 CO

C C^ CH 3

O

H

+ H 3 COH

H pKa= 16

acetone

p K a = 19

The α,α,α -trihalomethyl ketone reacts with aquous hydroxide to

give the carboxylic acid and haloform (HCX 3 )

(Mechanism 20.4, p. 842)

Iodoform reaction : chemical tests for a methyl ketone

R CCH 3

O (^) NaOH, H 2 O I 2 R CO

O + HC I

3 Iodoform

Iodoform: bright yellow

precipitate

20.8: Conjugation Efects in α,β –Unsaturated Aldehydes and

Ketones – carbonyls that are conjugated C=C.

Conjugation of the C=C and C=O π-electrons is a stabilizing

interaction.

R

O

R= H, α,β-unsaturated aldehyde= enal

R≠ H, α,β-unsaturated ketone= enone

α,β -Unsaturated ketones and aldehydes are prepared by:

a. Aldol reactions with dehydration of the aldol

b. α-halogenation of a ketone or aldehyde followed by

E2 elimination

1,2 vs 1,4-addition to α,β -unsaturated ketone and aldehydes –

The resonance structures of an α,β-unsaturated ketone or

aldehyde suggest two sites for nucleophilic addition; the carbonyl

carbon and the β-carbon.

Organolithium reagents, Grignard reagents and LiAlH 4 react with

α,β-unsaturated ketone and aldehydes at the carbonyl carbon.

This is referred to as 1,2-addition.

Organocopper reagents, enolates, amines, thiolates, and cyanide

react at the β-carbon of α,β-unsaturated ketone and aldehydes.

This is referred to a 1,4-addition or conjugate addition.

R

O

R CC

O

C^ :Nu^

1) Nu:

2) H 3 O+

R C

O

C

Nu

H

C C^

Nu: No Reaction

When a reaction can take two possible path, it is said to be under

kinetic control when the products are reflective of the fastest

reaction. The reaction is said to be under thermodynamic control

when the most stable product is obtained from the reaction. In the

case of 1,2- versus 1,4 addition of an α,β-unsaturated carbonyl,

1,2-addition is kinetically favored and 1,4-addition is

thermodynamically favored.

NOTE: conjugation to the carbonyl activates the β-carbon toward

nucleophilic addition. An isolated C=C does not normally react

with nucleophiles

Robinson Annulation – The product of a Michael reaction is a 1,5-

dicarbonyl compound, which can undergo a subsequent

intramolecular aldol reaction to give a cyclic α,β-unsaturated

ketone or aldehyde.

annulation: to build a ring onto a reaction substrate

O

CO 2 Et O

EtONa,EtOH

O

CO 2 Et O Michael reaction

O

CO 2 Et

condensation and dehydration^ Intramolecular aldol

-H 2 O

HO (^) HO Lanosterol Cholesterol

H 3 C

HO

H

O

H

H

Estrone

H 3 C H 3 C O

H

OH

H

H

Testosterone

H 3 C

O O O

Robinsonannulation^ H^3 C^

O

O

H 3 C O

HO OH O O H+

H 3 C O

Li(0), NH 3 O O tBuOH H

H 3 C-I H^3 C O

O O

H

H 3 C

HO

O O

H

NaBH 4 H^3 C A-B ring precursor of steroids P-O

O

H

H 3 CO

O

O

H 3 C

O

Robinsonannulation

H 3 CO

O

H 3 C O

Synthetic Applications of Enamines ( Ch. 21, p.910). Recall

that the reaction of a ketone with a 2° amines gives an enamine

(Ch. 17.11, p. 712)

O

+ NH

or aldehyde^ ketone w/ α-protons 2° amine

N

-H 2 O

H+^ - H +^ N

Iminium ion (^) Enamine

Enamines are reactive equivalents of enols and enolates and

can undergo α-substituion reaction with electrophiles. The

enamine (iminium ion) is hydrolyzed to the ketone after alkylation.

N N

O H^ O^ H

Reaction of enamine with α,β-unsaturated ketones (Michael

reaction).

N

CH 3

+ O^ O^ O

then H 2 O

Enamines react on the less hindered side of unsymmetrical ketones

O

NH

H 3 C +

N

H 3 C

CH 3

O

then H 2 O

O O

H 3 C