Lecture 3
Practical consequences - enantiopure enolisable aldehydes or ketones in
which the stereogenic centre is - to the carbonyl group must be
carefully protected from even traces of acid or base - otherwise
racemisation is rapid.
Stereogenic centres which are not - to a carbonyl group are not
racemised by enolisation:
H
Ph
O
OH
Me
H
H+ or
Ph
OH
Me
No racemisation
Stereogenic centres which are - to a carbonyl group but which do not
bear an enolisable hydrogen are not racemised by enolisation:
OH
O
Me
Ph
H+ or
OH
-
No racemisation
Me
Ph
Keto-Enol Tautomerism - summary of some important points:
O
OH
- C
C
C
C
C
C
H
Keto tautomer
Enol tautomer
• Structural isomerism of carbonyl compounds - an equilibrium reaction
and not resonance.
• Requires at least one hydrogen - (i.e. next to) the carbonyl group
• Enol tautomer (isomer) only present in very low concentration
• Enol formation very slow under neutral conditions
• Enol formation catalysed by either acid or base
• Catalysis involves either (Acid) Protonation on O followed by deprotonation at the -carbon
or
(Base) Deprotonation at the -carbon followed by re-protonation on
O
OH
+ OH
C
C
C
Š
C
C
C
Nucleophilic
site
• Resonance
stabilisation
of
enol
tautomer
renders
-carbon
nucleophilic
• Two equivalent ways of showing an enol acting as a carbon
nucleophile:
+ OH
OH
E+
C
C
C
C
E
C
+ OH
+ OH
E+
C
Š
C
C
C
C
E
C
C
• Enol tautomer is very reactive despite its low equilibrium
concentration so that many important reactions of carbonyl compounds
involve enols as intermediates, among them:
 Deuteration at the -carbon
 Acid- or base-catalysed racemisation of an - stereocentre
 Halogenation at the -carbon
Enols as reaction intermediates - -halogenation of ketones - the most
extensively studied example of enol reactivity.
Acid-catalysed halogenation:
O
O
Br2
H3C
CH3
CH3CO2H
+ HBr
H3C
CH2Br
Solvent and
catalyst.
The reaction exhibits autocatalysis - once formed, the HBr co-product
acts as a more efficient catalyst (stronger acid) than acetic acid.
If the reaction is carried out in water in the absence of added catalyst an
induction period is observed - very slow uncatalysed bromination must
first build up a sufficient concentration of HBr before rapid catalysed
bromination can take place.
Mechanism of acid-catalysed -halogenation of aldehydes and ketones:
O
H3O+
C
H3C
CH3
H3C
OH
+
OH
C
C
+
OH
OH
C
H3C
H3C
CH2
_
CH2
CH2
+
Br
Br
+ Br-
C
H3C
CH2Br
O
+ HBr
C
H3C
CH2Br
Further halogenation only takes place to a very minor extent replacement of H by electron-withdrawing Br decreases the basicity of
the ketone oxygen and inhibits further enolisation.
The rate of reaction of the enol with halogen is much faster than the rate
of enolisation - the latter is the rate-determining step:
Rate of halogenation = Rate of enolisation
= k[ketone][H+] or k'[ketone][OH-]
For a given ketone the rate of halogenation is independent of the
nature of the halogen - e.g. Rate Cl2 = Rate Br2 = Rate I2
Mechanism of base-catalysed -halogenation of aldehydes and ketones:
O
O
H2C
CH3
H3C
CH2
H
+
H2O
Enolate anion
OH
O
_
CH2
H3C
The electron-rich anionic enolate is more reactive towards electrophiles
such as Br2 than the neutral enol:
O
H3C
O
+
CH2 Br
Br
+ Br
C
H3C
CH2Br
Deprotonation of the mono-halogenated product is easier than for the
parent ketone due to stabilisation of the enolate anion by the electronwithdrawing halogen:
O
OH
C
H3C
CH2Br
O
O
C _
H3C
CHBr
_
C
H3C
CHBr
The equilibrium for this step favours the enolate anion more than in the
deprotonation of the parent ketone. A second bromination is therefore
more rapid than the first:
O
H3C
O
+
CHBr Br
Br
+ Br
C
H3C
-
CHBr2
A third bromination step is even more rapid but the trihalogenated
products are generally unstable.
This chemistry is the basis for a qualitative test for the presence of the COCH3 (i.e. acetyl) group in organic molecules, the iodoform test.
O
O
xs. I2
C
R
R
OHŠ,
CH3
O
O
C
C
CI3
OH
R
-
H2 O
C
R
CI3
-
O
C
R
CI
OH 3
O
OH
OH
H2 O + [CI3 ]
RCOCH3
OH
O
C
R
+ [CI3]
-
C
R
-
OH
xs. I2
Š
OH , H2O
O
-
-
+ CHI3
RCO2 Na + CHI3
Iodoform
Yellow insoluble
crystalline
precipitate
-
Summarising -halogenation of ketones:
Acidic conditions
Basic conditions
Neutral enol intermediate
Anionic enolate intermediate
Mainly monohalogenation
Polyhalogenation
Summarising reactions at carbon - to a carbonyl group:
For any given ketone under identical conditions (e.g. acidic or basic)
identical reaction rates are observed for:
- deuterium exchange
- chlorination
- bromination
- iodination
racemisation if -carbon is a stereogenic centre
Only reasonable explanation - all these reactions involve a common
intermediate - the rate of formation of which is the slowest, i.e. rate
determining, step in the process.
The only intermediates which explain the experimental data are the enol
(acidic conditions) or enolate anion (basic conditions).
Different ketones may, however, differ in reactivity due to
differences in enolisation rates.
Synthesis and Reactivity of Enolate Anions
O
OH
C
C
CH3
CH3
CH2
Keto tautomer
CH3
Enol tautomer
< 1%
O
O
_ C
CH2
CH3
C
CH2
CH3
Dominant resonance form O is more electronegative
than C
O
O
OH
C
C
H3C
CH3
pKa = ca. 20
H2O pKa = ca. 16
H2O
H2C
CH3
Low equilibrium
concentration
Efficient generation of enolate anions requires a much stronger base
than OH- - lithium di(isopropyl)amide - Li+[N(i-Pr)2]- - abbreviated
'LDA' - is commonly used.
CH3
CH3
CH3
CH3
CH
NH + n-C4H9 Li
CH
n-Butyl
lithium
CH3
Di(isopropyl)amine
pKa = ca. 40
CH3
CH3
CH
N- Li+ + C4H10
CH
pKa = ca. 50
CH3
Lithium Di(isopropyl)amide
LDA
n-Butyl lithium = CH3 CH2CH2 CH2Li CH3CH2 CH2CH2 Š Li+
The formation of LDA is essentially quantitative as n-butane is a much
weaker acid than (i-Pr)2NH and because it is very volatile is, in any
case, irreversibly lost from the reaction mixture.
LDA is (i) An extremely strong base
(ii) An extremely poor nucleophile due to the steric effects of the
bulky i-propyl groups. This is important in reactions with carbonyl
compounds so as to ensure that nucleophilic attack of the base on the
C=O group does not compete with -deprotonation.
(iii) Very easily hydrolysed by even traces of moisture - difficult to
store - usually generated immediately before use.
O
OH
O
-
C
H3C
C
CH3
H2O
H2C
pKa = ca. 20
CH3
Low equilibrium
concentration
H2O pKa = ca. 16
O Li+
O
+ LDA
H3C
-
+
H 3C
CH3
NH
CH2
Lithium enolate essentially quantitative
yield.
Other bases which can be used are sodium and potassium hydrides,
NaH and KH:
O
+ K+ H
(CH3)2HC
CH(CH3)2
O K+
+ H2
(CH3)2HC
C(CH3)2
With unsymmetrical ketones two isomeric enolates are possible:
O
O
O
CH3
CH3
KH
CH3
+
Using a sterically demanding base like LDA removes the less
sterically hindered proton only:
O
O
H
H
H
CH3
H
LDA
CH3
H
Comparison of enols and enolate anions:
Enol
Enolate anion
Cannot be isolated in a pure form Pure enolates can be prepared
- present in low equilibrium quantitatively in solution from
concentrations only.
carbonyl
compound
and
a
strong sterically bulky base.
Important in synthesis but only as Important
in
reaction intermediates present in reagents
which
low concentration.
synthesis
can
as
be
generated in high yield.
Neutral - moderately reactive to Negatively charged - much
electrophiles - moderately strong more
nucleophile.
reactive
towards
electrophiles - much stronger
nucleophile.