cm2006 carbonyl lec9
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carbonyTRANSCRIPT
Lecture 9
-Alkylation of Carbonyl Compounds
-Alkylation of ketones - via the enolate anion - can be a useful
technique for extending or modifying the alkyl chain in aldehydes and
ketones at the -carbon:
C6H5C
O
CH3
LDA
C6H5C
O
CH2
CH3
I
C6H5C
O
CH2
CH3
C6H5C
O
CH2
_
_
Acetophenone
Propiophenone
The reaction is most useful with 1 alkyl halides - with 2
halides -elimination competes significantly with alkylation.
As we saw earlier a problem here is that the intermediate enolate can be
a strong enough base to deprotonate the alkylated product at an -
carbon. This yields a new enolate which can then itself be alkylated -
hence mixtures which may be difficult to separate can be formed:
H3C CH3
O
CH2
CH2
O
CH3H3C
H3C CH2
O
H3C CH2
O
CH3
H2C CH2
O
CH3
Base _
_
CH3I
CH3I
CH3COCH2-
lkylation of -ketocarboxylic esters provides a clean alternative route
to direct -alkylation of ketones:
CH3C
COEt
O
CH2
O
CH3C CH3
O
CH3C CH2
O
C3H7
CH3C
COEt
O
CH
O
CH3C
COEt
O
CH
O
C3H7
CH3C
COH
O
CH
O
C3H7
_
N.B. Mono-alkylation only - the mono-alkylated product is lessacidic and more stericallyhindered than the -ketoesterstarting material - cannot bedeprotonated by enolate.
- CO2
1 Eq. NaOEt
CH3CH2CH2Br
CH3CH2CH2Br
H3O+
Na+
Claisen condensationof ethyl acetate
[Quantitative]
The activating effect of the ester group increases the acidity of the
'doubly -' CH, directing alkylation to that carbon but di-alkylation is
sterically inhibited. Following removal of the ester group by
hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.
yields the same product as - clean -monoalkylation of acetone.
The strategy of using a -ketoester as a synthetic 'stand-in' for a ketone
in alkylation reactions (in technical language, as a 'synthetic
equivalent' of a ketone) can also be applied to carry out effective
stepwise di-alkylation - to ketone carbonyl:
CH3C
COEt
O
CH2
O
CH3C CH3
O
CH3C
COEt
O
C
O
C3H7
CH3C
COEt
O
C
O
H3C C3H7
CH3C
HC
O
H3C C3H7
CH3C
COEt
O
CH
O
CH3C
COEt
O
CH
O
C3H7
, - CO2
1 Eq. NaOEt
_
1 Eq. NaOEt_
H3O+
CH3I
CH3CH2CH2Br
Na+
- H+
- H+
(i) C3H7I, EtO-
(ii) CH3I, EtO-
Ethyl acetoacetate fromClaisen condensation ofethyl acetate.
Mono-alkylation
[Quantitative]
Although the reactions discussed above involve several steps, the
ability to exercise precise choice of mono- vs. di-alkylation and the
ability to attach two different alkyl groups to the -carbon makes
them significantly more useful than direct alkylation of the ketone
enolate.
Revision: Indirect clean -monoalkylation of ketones via the Claisen
condensation:
CH3C
COEt
O
CH2
O
CH3C CH3
O
CH3C CH2
O
C3H7
CH3C
COEt
O
CH
O
CH3C
COEt
O
CH
O
C3H7
CH3C
COH
O
CH
O
C3H7
_
N.B. Mono-alkylation only - the mono-alkylated product is lessacidic and more stericallyhindered than the -ketoesterstarting material - cannot bedeprotonated by enolate.
- CO2
1 Eq. NaOEt
CH3CH2CH2Br
CH3CH2CH2Br
H3O+
Na+
Claisen condensationof ethyl acetate
[Quantitative]
The activating effect of the ester group, increases the acidity of the
'doubly -' CH, directing alkylation to that carbon but sterically
inhibiting di-alkylation. Following removal of the ester group by
hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.
yields the same product as - clean -monoalkylation of acetone.
Some further examples of indirect ketone monoalkylation:O
CO2Et
Br
O
CO2Et
O O
CO2H
O
CO2Et
O
CO2Et
_
- H+
_
, - CO2
NaOEt
H3O+3-Bromopropene
Allyl bromide
[Equivalent to -allylation of cyclohexanone]
H3O+
CH3C C
H2
O
COEt
O
CH3C
HC
O
COEt
O
(i) NaOEt
CH2CO2Et
CH3C CH2CH2CO2H
O
CH3C
HC
O
COH
O
CH2CO2H
, - CO2
Ethyl Bromoacetate
(ii) BrCH2CO2Et
[Equivalent to alkylation of acetone by BrCH2CO2H]
Malonic Ester Synthesis - A synthesis of -substituted carboxylic
acids - equivalent to clean indirect mono- or di- -alkylation of acetic
acid:
H2C
CO2Et
CO2Et
Diethylmalonateaka Malonic Ester
H2C
CO2H
CO2H
Malonic Acid
(i) Base, RX
(ii) Base, R1X
(iii) H3O+,
C
H
CO2H
R
R1
RR1CHCO2H
C
CO2Et
CO2Et
Me
CH CO2H
CH
CO2Et
CO2Et
Me
EtC
Me CO2Et
CO2Et
HC
CO2Et
CO2Et
EtCH
MeCO2H
H2C
CO2Et
CO2Et
_
_(i) H3O+
(ii) , - CO2
EtO-
EtO-
-2
MeBr
EtBr
(i) MeBr; (ii) EtBr
The CH2 hydrogens in diethylmalonate are 'doubly -' to the two ester
carbonyl groups and therefore have enhanced acidity. One or two
deprotonation/alkylation steps leads cleanly to monoalkylated or
dialkylated products (compare the -ketoester chemistry just studied)
Hydrolysis of both ester groups gives a -dicarboxylic acid which - like
a -keto carboxylic acid - undergoes rapid decarbonylation to a
monocarboxylic acid. The overall reaction is equivalent (i.e. gives the
same product as) the clean indirect di--alkylation of acetic acid.
The Knoevenagel Condensation - The 'doubly -' enolate anion of
diethyl malonate behaves as the nucleophile in an aldol-like reaction
with an aldehyde or ketone forming an ,-unsaturated diester.
Following hydrolysis and decarboxylation, the final product is an ,-
unsaturated carboxylic acid. Here diethyl malonate acts as a synthetic
equivalent of the enolate anion of acetic acid.
PhCH CHCO2H
H2C(CO2Et)2
HC
O
Ph
HC
CO2Et
CO2Et
C
CO2Et
CO2Et
C
OH
H
Ph
C
CO2Et
CO2Et
C
H
Ph
HC(CO2Et)2
H2O
CH
CO2Et
CO2Et
C
O
H
Ph
CH
CO2Et
CO2Et
C
OH
H
Ph
CHCO2HPhHC
PhCH C(CO2Et)2
NH
H2C(CO2Et)2 + PhCHO Mild base
(i) H3O+ (ii) , - CO2
PiperidinePiperidine =
Š
_
_
Base_
(i) H3O+
(ii) , - CO2
- OH-
Tutorial Question:
In the base-catalysed Aldol-Claisen Condensation of a ketone and an
ester the ketone behaves as the nucleophile and the ester behaves as the
electrophile:
CH2C
O
H3C H3CC
O
OEt
CO
H3CCH2 C
O
CH3
CO
H3CCH2 C
O
OEt
CH3
_
_
- OEt-
Etc.
In the base-catalysed Knoevenagel Condensation of malonic ester and a
ketone the ester behaves as the nucleophile and the ketone behaves as
the electrophile:
CH3C
O
Ph
HC
CO2Et
CO2Et
CH
CO2Et
CO2Et
C
O
H
Ph
CH
CO2Et
CO2Et
C
OH
H
Ph
_
_
H2O
Etc.
How do you explain the difference?
Enamines - nitrogen analogues of enols:
C C
OH
C C
O
H
C C
NH2
C C
NH
H
Enol Carbonyl
Enamine Imine
C C
NR2
Isolable because tautomerism is now impossible
Preparation of 3° enamines - acid-catalysed addition of a secondary
amine to an enolisable ketone:
HO NHMe2
H2O NMe2
H
OH
NMe Me
H
OHO
NMe Me
+ +
++
- H2O
Me2NHH3O+
TsOH
Methylene imminium cation
Reactivity of enamines:
C C
NR2
C C
NR2+
_
Nucleophiliccarbon
-Alkylation of enamines - another synthetic equivalent of clean -
monoalkylation of ketones:
Me2NMe2N Me2N
CH3CH3 I
O
CH3
O
+
Me2NH +
The neutral enamine - unlike the anionic
enolate - is a weak base and does not de-
protonate the mono-alkylated product.
Hence no di-alkylation occurs.
Base/CH3I
Poor control - mono & di-alkylation
I-
H2O
+
_
Although a multi-step process, ketone alkylation via enamines may be
more efficient than direct alkylation via the enolate.
Special properties of conjugated carbonyl compounds:
Carbonyl compounds in which other multiple bonds are conjugated
with the C-O double bond are significantly more stable than their non-
conjugated isomers. For this reason ,-unsaturated carbonyl
compounds readily isomerise to the more stable conjugated ,-
unsaturated isomers via enol (acidic conditions) or enolate (basic
conditions) intermediates:
H2C CH
CH2
CO
HH3C C
HCH
CO
H
Catalysis byH+ or OH-
Acid catalysis:
H2C CH
CH2
CO
HH2C C
HCH
COH
H
:
:
H2C CH
CH
COH
H
H+
+_H+
H3C CH
CH
COH
H
+
- H+
H3C CH
CH
CO
H
-Unsaturated carbonyl compounds have two electrophilic carbon
sites - the carbonyl carbon and the -carbon:
H3C CH
CH
CO
H+
-H3C C
HCH
CO
H
_
+
Electrophiliccarbon
Electrophiliccarbon
Addition reactions tto the C=C or C=O double bond alone are called
'normal' or 1,2 additions:
CC
CC
O
X Y CC
CC
O
X
Y
CC
CC
OY
X
or+1
2 1
2
Addition reactions that involve the conjugated system as a whole are
called 'conjugate additions' or 1,4 additions:
CC
CC
O
X Y CC
CC
O
X
Y
+
1
23
4
Note that here '1,2' and '1,4', do not refer to the numbering system for
identifying carbon atoms in the systematic naming of the molecules.
Examples of 1,4 (i.e. conjugate) addition:
H2C CH
C
O
CH3 ClH2C CHH
C
O
CH3+ HCl
This reaction looks like a 'normal' or 1,2 - although anti-Markownikov
- addition of HCl to the C-C double bond. However the mechanism
involves acid-catalysed 1,4-addition:
H2C CH
C
O
CH3
H2C CH
C
OH
CH3
H2C CH
C
OH
CH3
ClH2C CH
C
OH
CH3
Cl-
ClH2C CH
C
O
CH3
+ H3O+
+
+
H
This apparent contradiction arises because 1,4-addition of HZ to the
C=C-C=O structure yields an enol which then tautomerises to the
corresponding keto form which has the same structure as would be
produced by anti-Markovnikov 1,2-addition to the C=C bond.