CHEM 4113 ORGANIC CHEMISTRY II
CHAPTER 22
1.
LECTURE NOTES
Introduction
The carbonyl group greatly increases the reactivity of the hydrogens on the carbons α to the
carbonyl. Thus, carbonyl compounds, especially aldehydes, esters and ketones, are able to undergo
alpha substitution reactions. These substitution reactions occur via the formation of two key
intermediates: enols and enolate ions. Carbonyl compounds form enols under acidic conditions, and
enolates when treated with a base.
2.
Alpha Substitution of Enols
Carbonyl compounds that have hydrogen atoms on their α carbons are rapidly inter
convertible with they enol forms when treated with acid. Enols are tautomers (structural isomers
related by the shift of a hydrogen and one
bond). Most carbonyl compounds exist almost
exclusively as the keto form, however the enol form is always present, albeit in low concentrations.
The rate at which the keto-enol inter convert is relatively slow unless catalyzed by H+, which greatly
accelerates the process. However the addition of H+ does nothing to shift the equilibrium, it is only a
catalyst.
One class of carbonyl with a high percentage of enol present at equilibrium is the 1,3dicarbonyl compounds (or ß-dicarbonyl compounds). The enol form of a 1,3-dicarbonyl compound
has stabilizing resonance conjugation between one carbonyl and the enol form of the other.
R
H
O
C
O
C
-7
Keq = 10
CH3
-4
Keq = 10
CH3
OH
C
H
CH2
OH
O
OH
C
R
CH2
-5
Keq = 10
Enols are tautomers of carbonyl compounds
Simple aldehydes and ketones have low
concentrations of the enol form at equilibrium.
Cyclic ketones have higher enol concentrations
than acyclic ketones, aldehydes higher concentrations still.
Mechanism of acid catalyzed enol formation
O H
O
H+
O H
O H
Hα
-Hα
Enols of Aldehydes and Ketones
a.
Alpha Halogenation of Aldehydes and Ketones (Halogenation in Acidic Solution)
Aldehydes and ketones are rapidly halogenated at the alpha position by reaction with chlorine,
bromine or iodine in the presence of an acid (often glacial acetic acid is used as the solvent). The rate
is independent of the halogen concentration; this means that the slow step (rate determining step) is the
enolization process. The enol, once formed (in low concentrations) reacts rapidly with the
halogenating agent to afford product. The halogenation is essentially irreversible, the equilibrium
greatly favoring product. This removal of the enol cause the keto to tautomerize in order to maintain
equilibrium; this to reacts with the halogen to form product. Halogenation in acidic solution
1
proceeds cleanly to the mono-halogenation carbonyl product. The inductive effect of the
halogen retards further enolization of the α-haloketone or aldehyde.
O
O H
O H
O H
Hα
H+
Enol in low
concentrations
-Hα
Very
Fast
Further enolization and
bromination of this product
is prevented by the electronegative Br atom at the α
position.
O
Br
Br2
O H
-H+
O H
Br
Br
Fast
Mechanism of Alpha Halogenation of Aldehydes or Ketones
Alpha halo ketones and aldehydes are useful in organic synthesis because they can be
dehydrohalogenated by base to give α,β−unsaturated carbonyl compounds. The reaction occurs by
an E2 mechanism will give high yields even with a weak base such as pyridine.
O
O
O
HBr, Br2
Br pyridine
Mechanism of elimination
O
Br
N
H
Elimination of HX from
α−halocarbonyl compounds
results in the formation of
α,β−unsaturated carbonyls
O
E2
pryridine acts
as a weak base
+
N
H
Br
pyridinium bromide
Synthesis of α,β−Unsaturated Carbonyls
b.
Alpha Bromination of Carboxylic Acids (Hell-Volhard-Zelenski Reaction)
Direct halogenation of carbonyl compounds is limited to aldehydes and ketones since the
equilibrium enol content of esters, amides and carboxylic acids is very low (too low for halogenation
to take place). Carboxylic acid can be brominate by a mixture of PBr3 and Br2 in a process called the
Hell-Volhard-Zelinski reaction. The first step in the HVZ reaction is conversion of the acid into the
acid bromide derivative by the action of PBr3 . The HBr released in this step catalyzes the enolization
2
of the acid bromide and the enol reacts rapidly with Br2. Hydrolysis of the α−bromo acid bromide
with water forms the α−bromo acid.
Hell-Volhard-Zelinskii Reaction
HO
O
C
1) PBr3, Br2
HO
2) H2O
O
C
FAST addition
of Br to enol
Br
mechanism
HO
O
C
O
C
Br
H O
C
Br
conversion of
acid to acid
bromide
Br
Br
- HBr
enolization enol present
in low
concentrations
HO
O
C
O
C
H2O
hydrolysis
to acid
Br
Br
Br
Synthesis of Alpha-Bromo Acids
3.
Acidity of α−Hydrogen atoms - Enolate Formation
H CH3
pKa =
CH2
C
H C
H
H2
55
H C
H2
42
O
C
OR H C
H2
25
O
C
R
H C
H2
19
O
C
H
17
INCREASING ACIDITY
CASE 1 Ketone of aldehyde enolates:
O −δ
α C+δ
H C
R
H2
O
C
-H+
H2C
O
C
R
H2C
R
CASE 2 Ester enolates:
O −δ
α C+δ
H C
OR
H2
O
-H+
α C
H C
OR
H2
O
C
H2C
O
C
OR
H2C
OR
The partial charge on the carbonyl weakens the C-H bond on the carbon. Esters have
an important resonanceform that neutralizes the amount of positive charge at the carbonyl
carbon; this is why esters are less acidic than either ketones or aldehydes.
Resonance and Electronic Effects in Enolates
3
Alpha hydrogen atoms of carbonyl compounds are acidic and can be abstracted by strong
bases to yield enolate anions. Two factors are important in determining the acidity of α−protons of
carbonyl compounds. The first factor relates to the inductive effect of the carbonyl group which
withdraws electron density from the adjacent C-H bonds. Any substitution of the carbonyl group
which increases the partial positive charge on the carbon of the carbonyl will increase the acidity of the
α−protons(decreases the pKa). Also, any substitution of the carbonyl which slightly decreases the
positive charge will decrease the acidity of the C-H bond. This is why aldehydes are slightly more
acidic than ketones (the alkyl group of the ketone is electron donating by hyperconjugation). A more
dramatic example of this effect is seen in esters where resonance donation of the lone pair electrons of
the alkoxy group partly neutralizes the positive charge of the carbonyl carbon, making the C-H bond
less acidic than in a ketone. The factor which most determines the acidity of carbonyl
compounds is the resonance stabilization afforded to the product enolate anion .
Enolate anions are highly reactive as nucleophiles because of their negative
charge.
a.
Halogenation of Aldehydes and Ketones in Basic Solution
While halogenation of carbonyl compounds under acidic conditions is easily controlled to stop
at the mono-halo stage, this is not the case when the reaction is done in basic solution. The reason for
this difference is that the initially produced mono-halo ketone or aldehyde is more acidic (because of
the inductive effect of the halogen) than the original compound. Thus, the enolate anion of this new
product is more likely to form (are present in higher concentrations) than the parent carbonyl
compound. The more abundant enolates then undergo preferential reaction with the halogenating
agent. The reaction proceeds rapidly to the trihalo product. When all the acidic protons
have been replaced by halogens(especially iodine atoms), the trihalomethyl group has acquired
enough electron-withdrawing groups to facilitate breaking a carbon-carbon bond.
In the case of a triiodomethyl group, the addition of water or dilute aqueous acid is able to
hydrolyze the compound, leading to the formation of an acid and iodoform.
4
R
O
C
NaOH
CH3
5
O Na
C
R
CH2
pKa = 19
I2
FAST
R
O
C
NaOH
CH2I
R
O
C
pKa = 17
R
O
C
CHI
O
C
CHI2
pKa = 15
+ CHI3
R
Reaction occurs by three consecutive
halogenations of the enolate anion.
I2
FAST
R
O
Na
O
C
NaOH
OH
+ CI3
R
O
C
Na
CI2
I2
FAST CI - anion is relatively
3
stable: CI3 is a good
O
leaving group during
C
R
CI3 acyl substitution
Acidity of reaction product increases as further halogenation occurs
The Iodoform Reaction: Halogenation of Methyl Ketones in Base.
b.
Direct Alkylation of Enolates Derived from Aldehydes, Ketones and Esters
Simple aldehydes (pKa=17), Ketones (pKa=19) and esters (pKa=25) don not form high
concentrations of enolates when treated with relatively weak bases like hydroxide and alkoxides (pKa
of water, alcohols ~16-18). To effect carbon alkylation of these enolates, and to avoid Aldol and
Claisen condensation reactions (chapter 23), it is necessary to use very strong bases such as sodium
hydride (NaH) and Sodium amide (NaNH 2 ).
A useful addition to these reagents is Lithium
Diisopropyl Amide (LDA) which rapidly and quantitatively deprotonates aldehydes, ketones and
esters at temperatures as low as -78˚C. The relative bulk of LDA allows us to selectively remove the
least hindered acidic α−proton. After the highly nucleophilic enolate has been formed it can be treated
with electrophiles and various α−substituted carbonyl compounds can be formed.
pKa = 35
pKa = 50
+
N
H
n-BuLi
Y
CH3
n-Butane
Li
Lithium diisopropyl amide
LDA
Diisopropylamine
O
C
+
N
Keq = 10-3 to -5
+ OH
Y
O
C
CH2
+ H2O
Y = H, R or OR
Y
O
C
Keq = 1011 to13
+
CH3
N
Y
O
C
CH2
+
N
H
LDA rapidly and quantitatively deprotonates aldehydes,
ketones and esters to form enolates.
Quantitative Enolate Formation
Treatment of an enolate with an alkyl halide will result in alkylation at the α−
position with formation of a new C-C bond. This reaction proceeds smoothly when R is a
primary or unhindered secondary alkyl halide.
Y
O
C
LDA
CH2CH3
THF
-78˚C
Y = H aldehydes
R ketones
OR esters
Y
O
C
CHCH3
Y
O
C
R X
CHCH3
FAST reaction
rapidly converts
the enolate to
product
LDA quantitatively converts carbonyl
compounds to the enolate
Y
Alkylation of Enolates
O
C
R
CH
CH3
6
CH3
O
C
O
C
CH2
CH3
CH
CH3
NaNH2
O
C
THF
-78˚C
CH2
O
C
CH3
CH3
CH
CH3
O
C
LDA
CH2
THF
-78˚C
CH3
CH
CH3
CH3
C
CH3
CH3
CH
CH3
7
CH3
CH
CH3
O +
CH3
C
C
CH3
CH3
CH3
CH3 CH2
CH3I
O
C
CH3I
CH3 CH2
O
C
CH3
CH
CH3
LDA is a "bulky" base and will abstract the least hindered, most accessable proton
Regioselectivity of LDA
Enolates react with benzeneseleneyl bromide to yield α−phenylselenenylated
products, which in turn give α,β−unsaturated carbonyl compounds when treated with
H 2 O2 .
Br
O
C
Y
LDA
THF
-78˚C
Y=H
R
OR
Y
Se
O
C
Ph
Y
O
C
H2O2
Y
O
C
+
PhSe-OH
SePh
generation of
enolate anion
oxidation
and elimination
selenation of
enolate anion
mechanism of elimination
Y
O
C
Ph
H
H
Se
H2O2
Oxidation to
form selenoxide
Y
O
C
Ph
H
H
Se
O
Y
Intramolecular
Elimination to
α,β−unsaturated
carbonyl
O
C
Ph
H
+
Se
OH
Enone Synthesis via Selenylation of Enolate ions
c.
Malonic Ester Synthesis and Acetoacetic Ester Synthesis
The malonic ester synthesis involves alkylation of diethyl malonate with one or two alkyl
halides, provides a method for preparing mono or dialkylated acetic acid derivatives. The two ester
groups of malonic ester activate the central methylene toward deprotonation since the enolate derived
from deprotonation of malonic ester can be more extensively delocalized than in a simple ester. The
methylene hydrogens of malonic ester are highly acidic (pKa = 13). Thus alkoxide anions derived
form alcohols (pKa= 16-18) will rapidly and quantitatively carry out the deprotonation to form the
enolate. The enolate so produced may be sequentially alkylated with alkyl halides via the SN2
reaction. Acid catalyzed hydrolysis of the two ester moieties, followed by acid catalyzed
decarboxylation at elevated temperature affords the substituted acetic acid derivative.
Malonate Ester Enolate
EtO
O
C
O
C
Na
EtO
OEt
CH2
O
C
OEt
O
C
CH
OEt
pKa = 13
EtO
EtO
O
C
O
C
O
C
O
C
CH
OEt
OEt
CH
Sodium ethoxide rapidly and quantitatively deprotonates malonic ester
EtO
O
C
CH2
O
C
NaOEt
OEt EtOH
H3O
R1
CH
O
C
EtO
O
C
O Na
C
OEt
CH
O
C
+
EtO
C
R2 R1
O
C
R1
X
EtO
O
C
CH
R1
OH
R1
R2
OEt
H3O+
1) NaOEt, EtOH
2)R2 X
OEt
O
C
CH2
O
C
OH
The Malonic Ester Synthesis
O
EtO
C
O
O
C
H3O
O
C
OEt
R1 R2
HO
heat
-2 EtOH
FIRST STEP: Acid
catalyzed hydrolysis
of diester
1,3-diacids and 1,3-ketoacids
rapidly undergo decarboxylation
under conditions of acid and heat.
C
C
C
OH
R1 R2
H O
CH
C
C
C
OH
R1 R2
- H+
- CO2
O H
Tautomerization
OH
R2
Mechanism of Acid Catalyzed Decarboxylation
O H
C
SECOND STEP:
acid catalyzed
cecarboxylation
O
R1
O
H+
+
R1
C
R2
C
OH
8
9
Acetoacetic ester enolate
EtO
O
C
O
C
CH2
Na
OEt
EtO
CH3
O
C
CH
O
C
CH3
pKa = 19
pKa = 11
EtO
EtO
O
C
O
C
O
C
CH
O
C
CH3
CH3
CH
Sodium ethoxide rapidly and quantitatively deprotonates acetoacetic ester
EtO
O
C
CH2
O
C
NaOEt
CH3 EtOH
H3O
R1
CH
O
C
EtO
+
EtO
CH3
R2
The AcetoaceticEster Synthesis
O
C
O
C
O Na
C
CH3
CH
C
R2 R1
O
C
CH3
R1
X
EtO
O
C
1) NaOEt, EtOH
2)R2 X
R1
CH
R1
O
C
CH3
H3O+
CH2
O
C
CH3