Chem 3020 Chapter 22: Carbonyl Alpha-Substitution Reactions F'01
Problems: 1-8, 10-16, 21, 22, 24, 26, 30, 42,
Introduction: The chemistry in Ch. 22 and 23 is based on enolate anions
These anions are generated from the a-H of a carbonyl compound
Their reactions as nucleophiles provide a
good review of much of the course
22.1
Keto-Enol Tautomerism - Tautomers are rapidly interconverting isomers that
differ only in the location of the H and
the double bond (p 280)
Note
the difference between tautomers and resonance contributors
Simple
carbonyl compounds exist mostly in the keto form (acetone and cyclohexanone)
Even though one form is favored, the
equilibrium is still rapid
The
enol tautomer is usually favored in b-dicarbonyl
compounds, O=C-CH-C=O
O=C-C=C-OH is favored over O=C-CH-C=O
H-NMR and C-NMR evidence for
2,4-pentanedione
Acid
catalyzed enol-keto equilibrium, Fig 22.1. In either direction
protonation ® resonance stabilized cation intermediate ® deprotonation
Base
catalyzed enol-keto equilibrium, Fig 22.2. In either direction
deprotonation ® resonance stabilized enolate
anion ®
protonation
the resonance stabilized enolate anion is
the starting point for many reactions below and in Ch. 23
The
enolate anion is the conjugate base of H-C-C=O
a-H to carbonyl (H-C-C=O)
is dramatically more acidic than
1. b-H (H-C-C-C=O)or g-H
(H-C-C-C-C=O)of the same compound
(bottom, p. 902)
2. H-C=O, in aldehydes
3. a-H of alkyl halides (H-C-Cl), alcohols, etc
The enolate ion's stability is due to
resonance (Fig 22.2)
H-C-C=O
®
enolate anion is analogous to H-O-C=O
®
carboxylate anion, p. 819
both anions are
resonance stabilized
More on this in Sect 22.5 and following
22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions
In this and the next section the
reactions are neutral or acid catalyzed
Fig
22.3 Initially a carbonyl compound is converted to its enol tautomer (Fig 22.1)
The Lewis base character of the C=C in the
enol attacks E+ in the normal way - as in Fig 5.4
Avoid writing steps with more than one
curved arrow showing electron pair movement;
(exception: in the SN2
incoming nucleophile C
and leaving group loss C
is clear)
Instead, write all resonance forms. One of
them usually suggests the next step
After
addition of the E, the resulting cation intermediate is resonance stabilized
Loss
of H+ (typically the last step during acid catalyzed reactions)
leads to product
The
net reaction is a substitution of H+ by E+ at the a-position
of the carbonyl substrate
22.3
Alpha Halogenation of Ketones and Aldehydes - neutral or acid catalyzed
The
steps in Sect 22.2 are applied to a-halogenation
Fig
22.4 essentially repeats Fig 22.3 with the same unnecessary arrows
As
before, the starting point is really the enol
The
target of C=C acting as a Lewis base is Br-Br (like the first step in Fig 7.1)
Note
that HO-C=C + Br2 ®
HO-C+-C-Br + Br-
and not ®
HO-CBr-C+ + Br-
why?
Deprotonation
leads to the product. Net result is that Br+ (green) replaces H+
(blue)
it's easier to envision the deprotonation
as coming from the left resonance contributor, C=O+H
(General
note on resonance-stabilized intermediate ions:
1. Creation: Resonance stabilized ions are
favored over ions not so stabilized
example above
2.
Setting up the contributing Lewis/Kekule structures: see sect 2.5
find
ways to distribute charge and
don't
give much importance to contributing structures that create + and - charges
3.
Moving on to the next intermediate or product:
one
of the resonance forms already drawn will suggest the next step
frequently
it is just a deprotonation or reprotonation
Demonstrate
with problems 36 and 37)
22.4 Alpha Bromination of
Carboxylic Acids: The Hell-Volhard-Zelinskii Reaction
Another
example of enol bromination
Bottom,
p. 868 Acid bromide enol is formed via Fig 22.1
From
there, the bromination is as in Sect 22.3
Net
result, Br+ (green) replaces H+ (blue)
Previous
sections were based on acid catalysis, enols and cation intermediates
Remaining
sections are on base catalyzed reactions with enolate anions
22.5
Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
Compare
CH3C(=O)CH3, acetone, pKa = 19 vs. CH3-CH3,
pKa ~ 60, without the C=O
Fig 22.5 orbital picture of the enolate
anion
P. 912 enolate resonance contributors are not equivalent,
nevertheless, the anion is
stabilized
no resonance stabilization for the
CH3CH2- anion
P
871 comparison between CH3C(=O)OH, pKa = 5 vs.
CH3OH pKa = 16
The carboxylate resonance contributors
happen to be equivalent
No resonance stabilization is available
for CH3O-
Isolation of enolate anion of cyclohexanone requires strong base,
LDA,
p. 912, is used; more on p.923
Table 22.1 pKa values of acids.
Example: for CH3-C(=O)OC2H5 with a pKa
of 25,
In order to create the -CH2-C(=O)C2H5
enolate anion in substantial concentrations,
one must use a base whose conjugate acid has a pKa ~27 or higher
Table 22.1: pKa of LDA's conjugate
acid (diisopropylamine) is 40
22.6 Reactivity of Enolate Ions - more reactive
than enols
Once
generated by base, they can either act as bases themselves
Or
they can react as nucleophiles at two sites Fig 22.6 - either at C:- or at O:-
22.7
Halogenation of Enolate Ions: The Haloform Reaction
Enolate
acts as nucleophile at the a
carbon with Br-Br ®
Br-C-C=O
beginning
from the carbonyl compound (H-C-C=O), the sequence is
deprotonation ® enolate anion, then reaction with Br2 ®
Br-C-C=O + Br-
(contrast with the same reaction, acid
catalyzed: H-C-C=O ®
Br-C-C=O, Fig 22.4)
note
that Br-Br reacts with the enolate anion's a-C- and not at its O-
thus the nucleophile is -:C-C=O
and not C=C-O:-
Haloform (HCX3) formation
A continuation of the base catalyzed
reaction of methyl ketones with X2
If 3 a-H's present as CH3-C=O, then all three a-H's
will be replaced ® CX3-C=O
The buildup of halogen atoms at the a carbon makes this group a good leaving group,
-CX3 ® -:CX3
Since OH- is present it functions
as the nucleophile,
And a nucleophilic acyl substitution
reaction results, problem 73, Ch. 21. ® iodoform
22.8
Alkylation of Enolate Ions - -C-C=O as a nucleophile in SN2
reactions
The
usual steric restrictions apply to the compound undergoing substitution,
usually an alkyl halide
In
the three main reactions below the carbonyl compound that produces the enolate
nucleophile
is set up in advance to convert
alkyl halides to predetermined alkylated products
The first two reactions begin with b-dicarbonyl
compounds, malonic ester and acetoacetic ester
These are chosen because of their
relatively low pKa values
(and their sizes make them unreactive for carbonyl condensation reactions, Ch. 23)
The third reaction with ketones, esters
and nitriles is more general,
but the reactants are much less
acidic, and a much stronger base must be used:
|
Conversion of RX via |
Carbonyl compound / pKa |
Base used / pKa of conj.
acid |
Alkyl Products |
||
|
Malonic Ester Synthesis |
CH2(COOC2H5)2 = C2H5OOCCH2COOC2H5 |
13 |
Na+ -OC2H5 |
16 |
R-CH2COOH |
|
Acetoacetic Ester Synthesis |
CH3C(=O)CH2COOC2H5 |
11 |
Na+ -OC2H5 |
16 |
CH3C(=O)CH2-R |
|
Direct Alkylation of Ketones, Esters and Nitriles |
CH-C=O,
CH-COOR',
CH-CºN |
19-25 |
Li+ -N(C3H7)2 |
40 |
R-C-C=O, R-CHCOOR', R-C-CºN |
pKa
values are from Table 22.1
The
Malonic Ester Synthesis: General scheme, p. 918
Overall
conversion: R-X ® ® RCH2COOH or
R-X and R'-X ® ®
RR'CHCOOH
Sodio
malonic ester, -:CH(COOC2H5)2
is generated from malonic ester + base
"ester"
in these sections refers to the ethyl ester, -OC2H5
The base used is ethoxide, -OC2H5.
What if ethoxide reacted as a nucleophile
instead as a base with malonic ester?
Be
clear on the reason for sodio malonic ester's stability
Sodio malonic ester reacts as the nucleophile with R-X in an SN2 reaction:
-:CH(COOC2H5)2 + R-X ®
RCH(COOC2H5)2, "alkylated malonic ester"
The
next step depends on whether RCH2COOH or RR'CH-COOH is the final product
A. Option - if RCH2COOH is the
desired product
RCH(COOC2H5)2
is hydrolyzed (two ester hydrolysis reactions) ® RCH(COOH)2
Then RCH(COOH)2 is heated
to remove CO2 ®
RCH2COOH, the target product
B. Option - if RR'CHCOOH is the desired
product
RCH(COOC2H5)2
is treated again with Na+ -OC2H5
to form a second sodio
malonic ester, -:CR(COOC2H5)2
This reacts as a nucleophile again
in a second SN2 reaction with R'-X
The product is RR'C(COOC2H5)2
the "dialkylated malonic ester"
This diester is hydrolyzed as above
to form the corresponding diacid, RR'C(COOH)2
The diacid is then heated to remove
CO2 to form the target product RR'CHCOOH
For
either product, ester hydrolysis is acid catalyzed, Fig 21.10
For
either product, CO2 is lost (decarboxylation) - p. 919
mechanism need not be memorized
the net reaction is C-COO-H ® C-H
+ CO2
only one CO2 is lost, the other
COOH is retained
Examples,
p. 919, 920
The
Acetoacetic Ester Synthesis General scheme, p. 921
R-X ® ®
R-CH2C(=O)CH3 or
R-X and R'-X® ®
RR'CHC(=O)CH3.
This
synthesis is very similar to the malonic ester synthesis
1. An enolate anion from a b-dicarbonyl
compound serves as a nucleophile
2. SN2 reaction of this with an
alkyl halide, R-X
3. Option to either A. hydrolyze
immediately to form a monoalkylated acid
this leads to the a-monosubstituted
product after decarboxylation
or B. a second alkylation via SN2 to a dialkylated ester,
then hydrolysis to a
dialkylated acid
this leads to an a,a-disubstituted
product after decarboxylation
The parallel sequence of the two synthetic paths are shown below
with the a-carbon in bold
for each case
|
Species |
Formed After |
Malonic Ester |
Acetoacetic Ester |
||
|
Reactant |
|
H-CHCOOC2H5 COOC2H5 |
H-CHC(=O)CH3 COOC2H5 |
||
|
Initial Enolate Anion |
deprotonation with Na+ -OC2H5 |
-:CHCOOC2H5 COOC2H5 |
-:CHC(=O)CH3 COOC2H5 |
||
|
Monoalkylated Ester |
SN2 reaction
with R-X |
R-CHCOOC2H5 COOC2H5 |
R-CHC(=O)CH3 COOC2H5 |
||
|
l
or m |
l
or m |
l
or m |
l
or m |
||
|
Option A Product
¯ |
hydrolysis then decarboxylation ¯ |
R-CH2COOH monosubstituted ¯ acetic acid |
R-CH2C(=O)CH3 disubstituted ¯ acetic acid |
||
|
|
|
|
|
|
|
|
Option B, 2nd
enolate anion |
deprotonation with another Na+ -OC2H5 |
|
-:CRCOOC2H5 COOC2H5 |
|
-:CRC(=O)CH3 COOC2H5 |
|
dialkylated ester |
second SN2 reaction with R'-X |
|
R'-CRCOOC2H5 COOC2H5 |
|
R'-CRC(=O)CH3 COOC2H5 |
|
Option B Product |
hydrolysis then
decarboxylation |
|
RR'CHCOOH monosubstituted acetone |
|
RR'CHC(=O)CH3 disubstituted acetone |
How
the groups are modified in each case
|
|
Malonic
Ester |
Acetoacetic
Ester |
|
difference in reactant structure |
CH2COOC2H5 COOC2H5 |
CH2C(=O)CH3 COOC2H5 |
|
In
all cases at least one of the two a-H
is substituted with R |
>CCOOC2H5 COOC2H5 |
>CC(=O)CH3 COOC2H5 |
|
in
all cases the lower -COOC2H5 is eventually replaced
with -H |
>CCOOC2H5 H |
>CC(=O)CH3 H |
|
In the
acetoacetic ester case the remaining COOC2H5
is changed to COOH |
>CCOOH H |
|
Direct
Alkylation of Ketones, Esters, and Nitriles R-X ® ®
R-C-C=O or R-C-CºN
Enolate
anions generated from compounds with only one carbonyl group (or nitrile)
require much stronger base; in this
case LDA [(= Li+ -N(C3H7)2]
is used
H-C-C=O
+ LDA ®
:-C-C=O + H-N(C3H7)2
(LDA is not only stronger, it is
larger; this prevents it from acting as a nucleophile)
The enolate anion generated reacts
as a nucleophile with R-X as before
-:C-C=O
+ R-X ® R-C-C=O
(SN2)
Examples of H-C-C=O ® R-C-C=O on p. 923-4
using
a lactone (ester), an ester, a nitrile and a ketone
Anions
generated from nitriles are similarly stabilized
H-C-CºN + LDA ® [-:C-CºN «
C=C=N:-] + H-N(C3H7)2
this anion can react as an SN2
nucleophile with R-X
Thus
H-C-CºN ®
R-C-CºN by
the same process