Transcript Document

Chapter 20: Enols and Enolates
O
E+
O
H
O
Enolate
E
carbonyl
O
H
E+
Enol
20.1: Aldehyde, Ketone, and Ester Enolates
189
Table 20.1, p. 868
Typical pKa’s of carbonyl compounds (-protons):
aldehydes
ketones
esters
amides
nitriles
17
19
25
30
25
Acidity of 1,3-dicarbonyl compounds
ester
pKaa== 24
25
190
The inductive effect of the carbonyl causes the -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 pKa of the -protons of aldehydes
and ketones is in the range of 16-20
resonance effect
inductive
effect
d+
H
C C
O
ethane
pKa= 50-60
C C
O
acetone
pKa= 19
C C
O
ethanol
pKa= 16
191
pKa
19
acid
pKa
14
16
9
base
conjugate
base
19
-1.7
(weaker acid) (weaker base)
acid
pKa
base
conjugate
base
conjugate
acid
15.7
(weaker acid) (weaker base)
pKa
(stronger base) (stronger acid)
19
acid
conjugate
acid
base
9
(stronger acid) (stronger base)
(stronger base) (stronger acid)
_
conjugate
base
conjugate
acid
15.7
(weaker base) (weaker acid)
192
Lithium diisopropylamide (LDA): a super strong base
N H
+
H3CH2CH2CH2C
Li
diisopropylamine
pKa= 36
Li
+
H3CH2CH2CH3C
LDA
pKa= 60
pKa= 19
(stronger acid) (stronger base)
pKa= 25
(stronger acid)
N
(stronger base)
(weaker base)
pKa= 36
(weaker acid)
(weaker base)
pKa= 36
(weaker acid)
193
20.2: Enolate Regiochemistry – deprotonation of unsymmetrical
ketones.
More substituted enolate:
thermodynamically more stable
Less substituted enolate:
less hindered, formed
faster kinetically
The more substituted (thermodynamic) enolate is formed under
reversible conditions (tBuO- K+, tBuOH).
The less substituted (kinetic) enolate is formed under irreversible
conditions (LDA, THF, -78°C).
194
20.3: The Aldol Condensation- An enolate of one carbonyl
(nucleophile) reacts with the carbonyl carbon (electrophile) of
a second carbonyl compound resulting in the formation of a
new C-C bond. Mechanism of the base-catalyzed aldol reaction
(p. 874):
The position of the equilibrium for the aldol reaction is highly
dependent on the reaction conditions, substrates, and steric
considerations of the aldol product. Low temperature tends
195
to favor the aldol product.
aldol reactions involving -monosubstituted
aldehydes are generally favorable
aldol reactions involving -disubstituted
aldehydes are generally unfavorable
aldol reactions involving ketones are
generally unfavorable
The aldol product can undergo base-catalyzed dehydration to
an ,-unsaturated carbonyl. The dehydration is essentially
irreversible. The dehydration is favored at higher temperatures.
(mechanism, p. 876)
196
20.4: Mixed Aldol Reactions - Aldol reaction between two
different carbonyl compounds
Four possible products (not very useful)
Aldehydes with no -protons can only act as the electrophile
Preferred reactivity
197
Discrete generation of an enolate with lithium diisopropyl amide (LDA) under aprotic
conditions (THF as solvent)
20.5: The Claisen Condensation Reaction. Base-promoted
condensation of two esters to give a -keto-ester product
198
The mechanism of the Claisen condensation (p. 883) is a base
promoted nucleophilic acyl substitution of an ester by an ester
enolate and is related to the mechanism of the aldol reaction.
199
20.6: Intramolecular Claisen Condensation: The Dieckmann
Cyclization. Dieckmann Cyclization works best with 1,6-diesters,
to give a 5-membered cyclic -keto ester product, and 1,7-diesters
to give 6-membered cyclic -keto ester product.
Mechanism: same as the Claisen Condensation
200
20.7: Mixed Claisen Condensations. Similar restrictions as the
mixed aldol condensation.
Four possible products
Esters with no -protons can only act as the electrophile
Discrete (in situ) generation of an ester enolate with LDA
201
20.8: 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
202
20.9: Alkylation of Enolate - 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 SN2 reaction.
Reaction works best with the discrete generation of the enolate
by LDA in THF, then the addition of the alkyl halide
203
20.10: Acetoacetic Ester Synthesis - The -keto ester
products of a Claisen condensation or Dieckmann cyclization
can be hydrolyzed to the -keto acid and decarboxylated to the
ketone (acetoacetic ester synthesis – Ch. 20.10).
Similarly, -diesters can be hydrolyzed to the -dicarboxylic
acids and decarboxylated to the carboxylic acid (malonic acid
synthesis – Ch. 20.11).
204
Acetoacetic Ester Synthesis - The anion of ethyl acetoacetate
can be alkylated using an alkyl halide (SN2). The product, a
-keto ester, is then hydrolyzed to the -keto acid and
decarboxylated to the ketone.
O
H3C
C
EtO
C
CO2Et + RH2C-X
H H
ethyl acetoacetate
EtOH
alkyl
halide
Na+
O
C
CO2Et
H3C
C
RH2C H
_
EtO Na+,
EtOH
HCl, D
O
O
C
CO2H
H3C
C
RH2C H
- CO2
H3C
C
C
CH2R
H H
ketone
R'H2C-X
O
O
O
C
C
H3C
C
OEt
R'H2C CH2R
HCl, D
O
C
C
H3C
C
OH
R'H2C CH2R
O
- CO2
H3C
C
C
CH2R
H CH2R'
An acetoacetic ester can undergo one or two alkylations to give
an -substituted or -disubstituted acetoacetic ester
The enolates of acetoacetic esters are synthetic equivalents to
ketone enolates
205
acetone
pKa = 19
-Keto esters other than ethyl acetoacetate may be used. The
products of a Claisen condensation or Dieckmann cyclization
are acetoacetic esters (-keto esters)
206
20.11: The Malonic Acid Synthesis.
CO2Et
CO2Et
diethyl
malonate
Et= ethyl
Na+
EtO
+
RH2C-X
EtO2C
EtOH
C
CO2Et
HCl, D
HO2C
EtO Na+,
EtOH
C
HO2C
CO2Et
O
C
C
carboxylic
acid
C
CO2H
-CO2
CH2R
CH CO2H
CH2R'
RH2C CH2R'
RH2C CH2R'
H
RH2C-CH2-CO2H
R'H2C-X
HCl, D
EtO2C
-CO2
RH2C H
RH2C H
alkyl
halide
C
CO2H
carboxylic
acid
O
+ EtO
OEt
H H
H
C
C
+
OEt
EtOH
pKa= 16
H
ethyl acetate
pKa= 25
O
O
EtO
C
C
C
+ EtO
OEt
H H
diethyl malonate
pKa= 13
EtO
O
O
C
C
C
+
OEt
EtOH
pKa= 16
H
207
Summary:
Acetoacetic ester synthesis: equivalent to the alkylation of an
ketone (acetone) enolate
Malonic ester synthesis: equivalent to the alkylation of a
carboxylic (acetic) acid enolate
20.12: Alkylation of chiral Enolates (please read)
Chiral Auxiliaries
208
20.13: Enolization and Enol Content
Tautomers: isomers, usually related by a proton transfer,
that are in equilibrium.
Keto-enol tautomeric equilibrium lies heavily in favor of the
keto form.
C=C
C-O
O-H
DH° = 611 KJ/mol
380
426
C=O
C-C
C-H
DH° = 735 KJ/mol
370
400
DH° = -88 KJ/mol
Enolization is acid- and base-catalyzed
209
Base-catalyzed mechanism (p. 899):
Acid-catalyzed mechanism (p. 899):
210
20.14:  Halogenation of Aldehydes and Ketones- -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. The reaction proceeds through an enol.
O
X2, H-X
H
H
X= Cl, Br, I
O
X
H
+ H-X
Mechanism of the acid-catalyzed -halogenation of aldehydes
and ketones (p. 901)
Rate= k [ketone/aldehyde] [H+]
rate dependent on enol formation and not [X2]
211
,-unsaturated ketones and aldehydes:
 -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
H+
CH3
CH3
The Haloform Reaction. In the base promoted reaction, the
product is more reactive toward enolization and resulting in
further -halogenation of the ketone or aldehyde. For methyl
ketone, an ,, -trihalomethyl ketone is produced.
212
The ,, -trihalomethyl ketone reacts with aquous hydroxide
to give the carboxylic acid and haloform (HCX3) (p. 903)
Iodoform reaction: chemical tests for a methyl ketone
Iodoform: bright yellow
precipitate
213
20.15: -Halogenation of Carboxylic Acids:
The Hell-Volhard-Zelinsky Reaction.
Mechanism of -halogenation goes through an acid bromide
intermediate. An acid bromide enolizes more readily than a
carboxylic acid. Mechanism is analogous to the -halogenation
of aldehydes and ketones
The -halo carboxylic acid can undergo substitution to give
-hydroxy and  -amino acids.
214
20.16: Some Chemical and Stereochemical Consequences
of Enolization (please read)
20.17: Effects of Conjugation in -Unsaturated Aldehydes
and Ketones. -Unsaturated carbonyl have a
conjugated C=C
R= H, -unsaturated aldehyde= enal
R H, -unsaturated ketone= enone
Conjugation of the -electrons of the C=C and C=O is a
stabilizing interaction
215
-Unsaturated ketones and aldehydes are prepared by:
a. Aldol reactions with dehydration of the aldol
b. -halogenation of a ketone or aldehyde followed by
E2 elimination
20.18: Conjugate Addition to -Unsaturated Carbonyl
Compounds. The resonance structures of an -unsaturated
ketone or aldehyde suggest two sites for nucleophilic addition;
the carbonyl carbon and the -carbon
216
1,2 vs 1,4-addition -unsaturated ketone and aldehydes
Organolithium reagents, Grignard reagents and
LiAlH4 react with -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 -carbon of -unsaturated ketone and aldehydes.
This is referred to a 1,4-addition or conjugate addition.
217
When a reaction can take two possible path, it is said to be under
kinetic control when the products are reflective of the path that
reacts fastest. 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 unsaturated carbonyl, 1,2-addition is kinetically favored and
1,4-addition is thermodynamically favored.
NOTE: conjugation to the carbonyl activates the -carbon toward
nucleophilic addition. An isolated C=C does not normally react
with nucleophiles
218
20.19: Addition of Carbanions to-Unsaturated Carbonyl
Compounds: The Michael Reaction. The conjugate addition
of a enolate ion to an -unsaturated carbonyl. The Michael
reaction works best with enolates of -dicarbonyls.
electrophile
nucleophile
This Michael addition product can be decarboxylated.
The product of a Michael reaction is a 1,5-dicarbonyl compound,
which can undergo a subsequent intramolecular aldol reaction
to give a cyclic -unsaturated ketone or aldehyde. This is
known as a Robinson annulation.
219
220
20.20: Conjugate Addition of Organocopper Reagents to
-Unsaturated Carbonyl Compounds
Recall from Ch. 14.10 the preparation of organocopper reagents
2 Li(0)
R-X
R-Li
+
Dialkylcopper lithium: (H3C)2CuLi
LiX
pentane
Divinylcopper lithium: (H2C=CH)2CuLi
ether
2 R2Li +
CuI
R2CuLi + LiI
diorganocopper reagent
(cuprate, Gilman's reagent)
O
H3C
(H3C)2CuLi
O
C6H13
C6H13
O
O
O
O
(H2C=CH)2CuLi
O
O
Diarylcopper lithium: Ar2CuLi
-unsaturated ketones and
aldehydes react with
diorganocopper reagents to
give 1,4-addition products (C-C
bond forming reaction)
O
O
Ph2CuLi
H3C
H3C
H 3C
CH3
H3C
Ph
CH3
221
Synthetic Applications of Enamines (p.984). Recall that the
reaction of a ketone with a 2° amines gives an enamine
(Ch. 17.11, p. 751)
Enamines are reactive equivalents of enols and enolates and
can undergo -substituion reaction with electrophiles. The
enamine (iminium ion) is hydrolyzed to the ketone after
alkylation.
Reaction of enamine with -unsaturated ketones (Michael
reaction).
Enamines react on the less hindered side of unsymmetrical ketones
Organic Synthesis
Robert B. Woodward (Harvard): 1965 Nobel Prize in Chemistry
"for his outstanding achievements in the art of organic synthesis"
224
225
O
R1
aldol
reaction
O
+
H
H
OH
O
R1
OH
-vs- R1
H
H
R1
R1
R1
syn stereochemistry
OH
O
anti stereochemistry
O
R1
OH
O
-vs- R1
H
H
R1
R1
(2S, 3R) stereochemistry
(2R, 3S) stereochemistry
OH
NH2
O
OH
O
HO
HO
O
O
Cl
O
O
HO
OH
Cl
O
O
O
H
N
O
H
N
N
H
N
H
HN
N
H
O
O
HN
O
HO
NH2
O
OH
HO
OH
Vancomycin
226