Lecture 2
(5) FORMAL REACTION WITH NUCLEOPHILIC HYDRIDE
ANION - REDUCTION TO ALCOHOLS:
O
(i) NaBH4 or LiAlH4
C
CH3
H
"H " Hydride anion
(ii) H2O
OH
C
CH3
H
H
1 alcohol
Reduction by sodium borohydride, NaBH4 or lithium aluminium
hydride, LiAlH4, is conveniently regarded as nucleophilic attack by
hydride anion on the electrophilic carbonyl carbon atom:
O
C
CH3
H
O
-
C
CH3
CH3
CH3
-
OH
H 2O
H
C
CH3
CH3
H
2 alcohol
However the actual mechnism is more complicated and does not
actually involve free hydride anion.
In the alcohol reduction product the hydrogen attached to the
carbonyl carbon arises from BH4Š or AlH4Š and that attached to
oxygen from water employed in the work-up:
O
O
(i) NaBD4
(ii) H2 O
D
(i) NaBH4
(ii) D2O
H
OH
OD
(6) OTHER REDUCTION REACTIONS OF ALDEHYDES AND
KETONES
(i) CATALYTIC HYDROGENATION
O
H2
[Pt]
H
OH
Addition of hydrogen across C-O double bond
(ii) REDUCTION WITH DEOXYGENATION
(a) Basic conditions - Wolff-Kischner reduction
O
N2H4, NaOH
H
ROH, Heat
H
(b) Acidic conditions - Clemmensen reduction
O
Zn/Hg
H
HCl, Heat
H
Zinc amalgam (a liquid zinc-mercury alloy) increases the reactivity of
zinc as a reducing agent.
The Clemmensen and Wolff-Kischner
reactions are complementary - one is suitable for acid-sensitive
compounds, the other for base sensitive materials.
(7) OXIDATION OF ALDEHYDES AND KETONES
Aldehydes:
O
CH3
O
[O]
C
CH3
H
C
O
Aldehyde
H
Carboxylic acid
Many suitable oxidising agents available: Ag2O, CrO3, H2O2, RCOO2H
(percarboxylic acid), KMnO4.
Ketones:
O
R
C
R
Ketone
Oxidation must break very stable C-C bond - very forcing conditions
required - decomposition.
(8) Reactivity at the -carbon atom - chemistry of Enols and Enolate
anions.
- O
+ C
R
R
Our main focus so far - the carbonyl group of aldehydes and ketones as
an electrophilic site. Are there any other reactive sites in the molecule?
Aldehydes and ketones undergo structural isomerisation in solution
which involves the movement of a hydrogen atom from the -carbon to
oxygen and the simultaneous relocation of the double bond between the
O-bonded carbon and the -carbon. This is kind of isomerism is called
tautomerism:
O
OH
- C
CH3
CH3
C
CH2
Keto tautomer
CH3
Enol tautomer
< 1%
Keto-enol tautomerism - 'ene' from the C=C bond,
'ol' from the C-OH structure.
The enol form is usually a very minor component of the equilibrium
mixture - mainly because the C=O bond is much more stable than
C=C.
However
the
reactivity
of the small
equilibrium
concentration of enol strongly affects the overall chemical
behaviour of carbonyl compounds.
Keq
=
[enol form]
[keto form]
O
CH3
C
CH3
OH
CH2
H
H
O
OH
C
CH2
Keq = 1.5 x 10-7
C
CH3
O
Keq = 2 x 10-5
C
CH3
OH
Keq = 5 x 10-5
The equilibrium concentration of enol is lower for ketones than for
aldehydes because the extra alkyl group stabilises the C=O bond more
than the C=C bond. The enol tautomer of cyclohexanone is favoured
over that of acetone because it contains a more stable (i.e. more
substituted) carbon-carbon double bond.
General reactivity of enols - carbon nucleophiles:
OH
CH3
+
OH
+
OH
CH2
CH3
_
CH2
CH3
Š
CH2
Nucleophilic
carbon
Under neutral conditions the rate of conversion of the pure keto form
into the enol form (ENOLISATION) is slow - but is greatly accelerated
by either acid or base catalysis.
Base-catalysed enolisation:
O
H2 C
O
_
H2C
CH3
CH3
+ H2O
H
OH
-
O
Partial deprotonation only pKa ca. 20
H2C
-
CH3
Resonance-stabilised
enolate anion
O
-
O
H
OH
H
+ OH
H2C
CH3
H 2C
-
CH3
Catalyst regenerated
Acid-catalysed enolisation:
H
+ H
O
+
O
H
O
H
+ H2O
H 3C
H3C
CH3
CH3
H
H
O
O
H 2C
+
H2C
CH3
+
CH3
H
H3O+
O
H
Catalyst regenerated
Unsymmetrical ketones
H
two isomeric enols:
OH
O
OH
Ph
Ph
Ph
C
H
CH3
C
H2
CH3
Inequivalent enolisable
protons.
C
H2
CH2
Enols as reaction intermediates - deuteration of carbonyl compounds:
O
O
D
D
D
Large excess of D2O
D
D+ or OD- catalysis
All enolisable hydrogens are replaced by deuterium. Mechanism:
+
O
O
D
D
O
H
D3O+
H
+ D2OH+
OD2
D
+
O
O
_
Enols are resonance-stabilised,
hence the -carbon is
electron-rich, i.e. nucleophilic.
D
+
O
O
D
+ D
O
D
D
O
H
H
D
D
D
+ D3O+
C-D bonds stronger than C-H - easier to remove -H than -D in
next cycle: hence all hydrogens - to C=O replaced by deuterium.
More examples:
D
H 3C
CH3
D D
D3O+
H 3C
CH3
O
O
O
O
CH3
D 3O
O
H 3C
D
D3
C
D
CH3
D
D
+
O+
O
D 3C
C
H
H
Note that only the enolisable hydrogens - to the carbonyl group are
replaced by deuterium.
Rate of H/D exchange = Rate of enolisation
= k[ketone][H+] or k'[ketone][OH-]
Information provided by H/D exchange experiments:
(1) Indirect evidence for the keto-enol equilibrium - required by the
proposed mechanism for H/D exchange.
(2) The number of deuterium atoms incorporated in a H/D exchange
experiment can be determined by:
(i) Comparison of the NMR spectrum of the parent and deuterated
compound.
(ii) Mass spectrum of the deuterated compound.
This information assists in the assignment of structures to unknown
carbonyl compounds by indicating the number of enolisable protons
present, i.e. the number of H atoms that are - to the carbonyl group.
Enols as reaction intermediates - racemisation at stereogenic centres
- to a carbonyl group:
O
O
H
Ph
H2O
H+ or
Et
Me
OH-
O
H
Ph
Et
+
H
Ph
Me
50%
Single
enantiomer
Me
50%
Racemic mixture
 t
D
Time
The critical step in racemisation is enol formation -
Et
O
Me
Ph
Et
H
C- reprotonated
from above plane
Tetrahedral
chiral sp3
OH
O
Me
H+ or
Ph
Et
H
Single
enantiomer
OH
-
Me
Ph
Enol
Et
Planar achiral sp2
C- reprotonated
from below plane
O
Me
Ph
H
Et
Since reprotonation from either side of the planar enol is equally likely
the result is a 50-50% mixture of both enantiomers, i.e. complete
racemisation.
Rate of racemisation = Rate of enolisation
= k[ketone][H+] or k'[ketone][OH-]