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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
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
