Download 116 Chapter 22. Carbonyl Alpha-Substitution Reactions Tautomers

Chapter 22. Carbonyl Alpha-Substitution Reactions
O
"'
#'
"
!'
!
#
O
E+
O
H
O
Enolate
E
carbonyl
O
H
E+
Enol
228
Tautomers: isomers, usually related by a proton transfer,
that are in equilibrium
Keto-enol tautomeric equilibrium lies heavily in favor of the
keto form.
O
C
H
O
C
C
enol
C=C
C-O
O-H
C
H
keto
ΔH° = 611 KJ/mol
380
436
C=O
C-C
C-H
ΔH° = 735 KJ/mol
376
420
ΔH° = -104 KJ/mol
229
116
Keto-enol tautomerism is catalyzed by both acid and base
Acid-catalyzed mechanism (Figure 22.1):
Base-catalyzed mechanism (Figure 22.2):
The carbonyl significantly increases
the acidity of the α-protons
H H O H H
C
C
C
C
C
H H H H
230
22.2: Reactivity of Enols: The Mechanism of Alpha-Substitution
Reactions
O
C
H
C
OH
C
C
nucleophile
Enol
General mechanism for acid-catalzyed α-substitution of
carbonyls (Figure 22.3)
231
117
22.3: Alpha Halogenation of Aldehydes and Ketones
an α-proton of aldehydes and ketones can be replaced
with a -Cl, -Br, or -I (-X) through the acid-catalyzed
reaction with Cl2 , Br2 , or I2 , (X2) respectively.
O
C
C
O
X2, H+
H
C
X= Cl, Br, I
C
X
Mechanism of the acid-catalyzed α-halogenation (Fig. 22.4)
Rate= k [ketone/aldehyde] [H+]
rate dependent on enol formation
232
α,β-unsaturated ketones and aldehydes:
α -bromination followed by elimination
O
O
CH3 Br2, CH3CO2H
CH3
Br
O
(H3C)3CO- K+
CH3
E2
Why is one enol favored over the other?
OH
O
OH
CH3
CH3
CH3
22.4: Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinskii (HVZ) Reaction
α-bromination of a carboxylic acid
O
H
C
C
Br2, PBr3, AcOH
OH
then H2O
O
Br
C
C
OH
233
118
Mechanism (p. 828, please read)
α-bromo carboxylic acids, esters, and amides
O
O
Br2, PBr3, AcOH
OH
Br
then H2O
Br
H3CNH2
H2O
CH3CH2OH
O
O
OH
O
OCH2CH3
Br
Br
N
H
Br
CH3
234
α,β-unsaturated ketones and aldehydes:
α -bromination followed by elimination
O
O
CH3 Br2, CH3CO2H
CH3
Br
O
(H3C)3CO- K+
CH3
E2
Why is one enol favored over the other?
OH
O
OH
CH3
CH3
CH3
22.4: Alpha Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinskii (HVZ) Reaction
α-bromination of a carboxylic acid
O
H
C
C
Br2, PBr3, AcOH
OH
then H2O
O
Br
C
C
OH
235
119
22.5: Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
Base induced enolate formation
B
O
C
C
O
O
H
C
C
C
C
Enolate anion
The negative charge of the enolate ion (the conjugate base
of the aldehyde or ketone) is stabilized by delocalization
onto the oxygen
H
C C
C C
O
C C
O
O
O
H3C CH3
H3C
ethane
pKa= 60
C
H3CH2COH
CH3
acetone
pKa= 19
ethanol
pKa= 16
236
Base induced enolate formation
O
H3C
C
O
CH3
acetone
pKa= 19
(weaker acid)
+
H3CH2CO
H3C
ethoxide
(weaker base)
C
+
CH2
H3CH2COH
enolate
ethanol
pKa= 16
(stronger base) (stronger acid)
Lithium diisopropylamide (LDA): a very strong base
N
N H
Li
diisopropylamine
pKa = 40
LDA is used to generate enolate ions from carbonyl by
abstraction of α-protons
O
H3C
C
O
CH3
+ [(H3C)2CH]2N
pKa= 19
(stronger acid) (stronger base)
H3C
C
+
CH2
(weaker base)
[(H3C)2CH]2NH
pKa= 40
(weaker acid)
237
120
THF
N H
N
Li
H3CH2CH2CH2C
+
+
Li
pKa= 40
H3CH2CH2CH3C
pKa= 60
α-deprotonation of a carbonyl compound by LDA occurs
rapidly in THF at -78° C.
Typical pKa’s of carbonyl compounds (α-protons):
aldehydes 17
O
O
ketones
19
C
C
H C
CH
H C
H
H C
esters
25
O
amides
30
H C C N
C
H C
N(CH )
nitriles
25
3
3
3
O
C
3
OCH3
3
3
3 2
238
Acidity of 1,3-dicarbonyl compounds
O
O
H3C
C
H3C
C
O
C
C
OCH3
ester
pKa= 25
ketone
pKa= 19
O
C
H3C
CH3
O
O
CH3
H3CO
H H
C
O
C
C
OCH3
H H
1,3-diketone
pKa= 9
1,3-diester
pKa= 13
O
H3C
H H
C
O
C
C
O
C
O
H3C CH3
Meldrum's acid
pKa= 5
O
C
C
OCH3
H H
C
1,3-keto ester
pKa= 11
Why is Meldrum’s acid more acidic than other dicarbonyl
compounds?
239
121
Delocalization of the negative charge over two carbonyl groups
dramatically increases the acidity of the α-protons
H3C
O
O
O
O
O
C
C
C
C
C
C
CH3
H3C
H
C
C
O
C
OCH3
H3C
C
H
C
C
C
OCH3
H3CO
C
H3C
OCH3
C
H
CH3
pKa = 9
C
C
OCH3
pKa = 11
OCH3
pKa = 13
H
O
O
O
C
C
C
C
C
O
O
O
C
C
H
H
O
O
H3CO
H3C
CH3
H
O
O
H3C
C
O
H3CO
OCH3
O
C
C
H
H
Enolate formation for a 1,3-dicarbonyl is very favorable
O
O
H3C
C
C
C
O
O
+ H3CO
OCH3
H3C
H H
C
C
C
OCH3
+ H3COH
pKa= 16
H
acetoacetic ester
pKa= 11
240
22.6: Reactivity of enolate ions
By treating carbonyl compounds with a strong base such
as LDA, quantitative α-deprotonation occurs to
give an enolate ion.
Enolate ions are much more reactive toward electrophiles
than enols.
Enolates can react with electrophiles at two potential sites
B
O
C
C
H
O
O
C
C
E
E
E
O
C
C
C
C
E
O
C
C
241
122
22.7
Halogenation of Enolate Ions: The Haloform Reaction
Carbonyls undergo α-halogenation through base
promoted enolate formation
OH NaOH, H O
2
O
C
C
O
O
Br Br
C
H
C
C
C
Br
+ NaBr
Base promoted α-halogenation carbonyls is difficult to control
because the product is more acidic than the starting
material; mono-, di- and tri-halogenated products are
often produced
O
C
C
O
NaOH, H2O
Br
C
H H
O
Br Br
C
C
C
C
NaOH, H2O
O
Br2
Br
Br
H Br
Br
O
C
C
Br
Br
C
242
Br Br
Haloform reaction:
O
C
CH3
OH
O
NaOH, H2O
C
X2
C
O OH
C
X
C
X X
X
X X
O
C
+
O
CX3
OH
C
+
O
HCX3
Haloform
Iodoform reaction: chemical tests for a methyl ketone
O
R
C
O
NaOH, H2O
CH3
I2
R
C
+
O
HCI3
Iodoform
Iodoform: bright yellow
precipitate
243
123
22.8
Alkylation of Enolate Ions
Enolates react with alkyl halides (and tosylates) to form
a new C-C bond (alkylation reaction)
B
O
C
C
O
H
C
O
C
C
C X
SN2
O
C
C
C
C
Reactivity of alkyl halides toward SN2 alkylation:
H H
C
H H
C
_
~
X
benzylic
X
>
allylic
_
tosylate ~
H H
C
H
X
H H
C
R
X
>
methyl
>>
primary
R H
C
R
X
secondary
-I > -Br > -Cl
Tertiary, vinyl and aryl halides and tosylates do not
participate in SN2 reactions
244
Malonic Ester Synthesis
overall reaction
CO2Et
+
RH2C-X
CO2Et
diethyl
malonate
Et= ethyl
C
Na+, EtOH
C
C
OEt
RH2C-CH2-CO2H
then HCl, !
carboxylic
acid
alkyl
halide
O
O
EtO
EtO
EtO
H H
C
O
C
C
C
C
O
OEt
H H
+
OEt
EtOH
pKa= 16
H
diethyl malonate
pKa= 13
H
O
O
+ EtO
+ EtO
H
C
C
+
OEt
EtOH
pKa= 16
H
ethyl acetate
pKa= 25
245
124
A malonic ester can undergo one or two alkylations to give an
α-substituted or α-disubstituted malonic ester
Decarboxylation: Treatment of a malonic ester with acid and
heat results in hydrolysis to the malonic acid (β-di-acid).
An acid group that is β to a carbonyl will lose CO2 upon
heating.
EtO
O
O
C
C
C
OEt
H CH2R
O
O
HCl, !
HO
C
C
C
OH
H CH2R
- CO2
O
RH2C
C
C
OH
H H
246
Mechanism of decarboxylation:
β-dicarboxylic acid (malonic acid synthesis)
β-keto carboxylic acid (acetoacetic ester synthesis)
247
125
H
H
CO2Et
C
+
H3CH2CH2CH2C-Br
Na+, EtOH
EtO
H3CH2CH2CH2C
H
CO2Et
H
H
CO2Et
+
C
H3CH2CH2CH2C-Br
H3CH2C
H
H
CO2Et
C
Br-CH2-CH2-H2C-H2C-Br
+
CO2Et
H3CH2C
EtO
Na+, EtOH
EtO
CO2H
C
H
Br-CH2-CH2-H2C-H2C
H H
H
H C C CO2H
C
H C C H
H H H
HCl, !
Na+, EtOH
H3CH2C-Br
CO2Et
H
H H
H
H C C CO2Et
C
H C C CO2Et
H H H
Na+, EtOH
EtO
H3CH2CH2CH2C
CO2Et
CO2Et
C
CO2Et
C
H
HCl, !
H3CH2CH2CH2C-H2CCO2H
CO2Et
CO2Et
H3CH2CH2CH2C
HCl, !
H3CH2CH2CH2C
Na+, EtOH
EtO
CO2Et
C
CO2Et
C
CO2Et
cyclopentane
carboxylic acid
248
Acetoacetic ester synthesis
O
H3C
C
CO2Et
C
H H
ethyl acetoacetate
C
RH2C-X
EtO
C
C
OEt
ketone
O
O
+ EtO
H3C
C
C
O
CH3
H H
C
+
OEt
EtOH
pKa= 16
H
O
C
C
C
CH3
H H
alkyl
halide
H H
C
RH2C
then HCl, !
diethyl malonate
pKa= 11
H
O
Na+, EtOH
O
O
H3C
+
+ EtO
H
C
C
+
CH3
EtOH
pKa= 16
H
acetone
pKa= 19
249
126
An acetoacetic ester can undergo one or two alkylations to give
an α-substituted or α-disubstituted acetoacetic ester
Decarboxylation: Treatment of the acetoacetic ester with acid
and heat results in hydrolysis to the acetoacetic acid
(β-keto acid), which undegoes decarboxylation
250
H
H
CO2Et
C
+
H3CH2CH2CH2C-Br
EtO Na+,
EtOH
H3CH2CH2CH2C
H
C CH3
C
O
CO2Et HCl, !
H3CH2CH2CH2C-H2C
C CH3 - CO2
C
CH3
O
O
ethyl
acetoacetate
H
H
CO2Et
C
+
H3CH2CH2CH2C-Br
EtO Na+,
EtOH
H3CH2CH2CH2C
H
C CH3
CO2Et
EtO Na+,
EtOH
C CH3
H3CH2C-Br
C
O
O
ethyl
acetoacetate
H3CH2CH2CH2C
H3CH2C
CO2Et
C
C CH3
HCl, !
- CO2
O
H3CH2CH2CH2C
C C CH
3
H3CH2C
H
O
H
H
CO2Et
C
+
Br-CH2-CH2-H2C-H2C-Br
EtO Na+,
EtOH
H
C CH3
O
ethyl
acetoacetate
Br-CH2-CH2-H2C-H2C
CO2Et
C
EtO Na+,
EtOH
C CH3
O
H H
H
H C C CO2Et
C
CH3
H C C
H H
H O
HCl, !
- CO2
H H O
H
H C C C CH
3
C
H C C H
H H H
251
127
acetoacetic
ester
CO2Et
O
O
EtO Na+,
EtOH
O
O
Br
CO2Et
HCl, !
CO2Et
H
- CO2
Summary:
Malonic ester synthesis: equivalent to the alkylation of a
carboxylic (acetic) acid enolate
CO2Et
+
RH2C-X
EtO
Na+, EtOH
RH2C-CH2-CO2H
then HCl, !
CO2Et
base
O
H3C-CO2H
H2C
C
RH2C-X
RH2C-CH2-CO2H
OH
Acetoacetic ester synthesis: equivalent to the alkylation of an
acetone enolate
O
H3C
C
C
CO2Et
+
EtO
RH2C-X
C
C
CH3
H H
O
O
C
RH2C
then HCl, !
H H
H3C
O
Na+, EtOH
base
CH3
RH2C-X RH C
2
O
H2C
C
C
C
CH3
H H
CH3
252
Direct alkylation of ketones, esters and nitriles
α-Deprotonation of ketones, esters and nitriles can be
accomplished with a strong bases such as lithium
diisopropylamide (LDA) in an aprotic solvent such as THF.
The resulting enolate is then reacted with alkyl halides
to give the α-substitution product.
O
O
H3C
RH2C-X
H3C
RH2C-X
RH2C
CH2R
O
H3C
major
LDA, THF
-78° C
O
H3C
H3C
O
minor
253
128
Ester enolate
O
C
O
OEt LDA, THF
C
RH2C-X
CH2R
OEt
CO2Et
-78° C
O
O
O
LDA, THF
O
RH2C-X
O
CH2R
O
-78° C
Nitrile enolate
C
N
C
LDA, THF
N
CH2R
RH2C-X
C
-78° C
N
254
Biological decarboxylation reactions:
pyruvate decarboxylase
H
N
Enzyme
H B
O
OO O P
P
OO O
S
N
+
NH2
N
PPO
OH
S
N
OH
S
N
CH3
R
Enzyme
H B
:B
PPO
O
S
CH3
N
CH3
Pyridoxal Phosphate
(Vitamin B6)
N
N
H
NH3
H
O
R
R
ON
PO
L-DOPA
Enzyme
H B
R
L-DOPA
decarboxylase
Imine formation
N
PO
CO2
HO
O
H3C C H
O
HO
+
+
N
R
R
OH
3PO
- CO2
S
PPO
H
H
L-DOPA decarboxylase
H
O
CH3 O
Enzyme
R
O
OH
R
R
Thiamin Diphosphate (Vitamin B1)
2-O
S
N
N
PPO
PPO
O
H3C C CO2H
S
PPO
N
- CO2
H
O
PO
N
H
N
H
R
H
H
N
PO
N
H
H
O
H
O
O
H2O
2-O
H
HO
OH
3PO
NH3
+
HO
N
Dopamine
255
129