Lecture 6
There are several other reactions of carbonyl compounds which are
mechanistically related to the Aldol condensation:
H 3C
C
_
H2C
LDA or
NaNH2
N
Acetonitrile
C
N
_
pKa ca. 25
H2C
C
N
The CN group is somewhat
less electron-withdrawing than
a carbonyl group - hence the
need for a strong base to
produce complete deprotonation.
O
Ph
C
O
_
H 2C
C
Ph
N
H
-
C CH2 C
N
H
H2O
Ph
HC CH CN
-unsaturated
nitrile
OH
OH
-
- H 2O
Ph
C CH2 C
N
H
Here the anion of acetonitrile replaces the enolate anion of a basecatalysed aldol condensation.
H3C
NO2
O
_
H2C
NaOH
N
O
Nitromethane: pKa ca. 10
_
O
The nitro group is extremely
electron-withdrawing - hence
H2C
N
O
the relatively low pK a of
nitromethane and efficient
deprotonation by OH
-
O
H2C
N
O
_
O
Ph
C
O
_
H2C
Ph
NO2
H
-
C CH2 NO2
H
H2O
Ph
HC CH NO2
-unsaturated nitrocompound
OH
OH
Ph
- H2O
C CH2 NO2
H
(nitroalkene)
Any functional group that can render a C-H bond acidic enough to
result in deprotonation can allow generation of a C-nucleophile which
can take part in aldol-like condensations.
We will see further
examples of such reactions later on in the course.
Summary: Aldol and aldol-like condensation reactions:
RH2C
_
H2C
Base
Z
Z
Z = COR; CN, NO2 or other electron-withdrawing group
O-
O
R
_
H2C
C
R
Z
H
C CH2 Z
H
H2O
OH
OH
_
C CH
R
Base
Z
H
-
H+
R
C CH2 Z
H
- OHR
C
H
C
H
Z
Z = COR; unsaturated carbonyl cpd.
Z = CN; unsaturated nitrile
Z = NO2; unsaturated nitro-compound
i.e. a nitro-alkene
*
Carboxylic Acids and their Derivatives
Streitweiser: Chapters 18 & 19; McMurry (5th Ed.) Chapters 20 & 21.
O
General formula:
R
C
Z
O
R
O
Carboxylic acid
C
R
C
OH
X
Acid halide
aka acyl halide
O
R
O
C
O
R
Acid anhydride
R
C
Ester
OR1
C
O
O
R
Amide
C
NR1
2
An important general reaction for carboxylic acid derivatives (acyl
halides, anhydrides, esters and amides) - Addition-Elimination:
O
R
+ NuŠ
C
OŠ
Addition
R
C
Z
Nu
Z
O
O
C
C
R
H
R
R
H-, R- are normally very
poor leaving groups.
Carbonyl group
regenerated.
Elimination
O
R
+ ZŠ
C
Nu
Carboxylic acids - Synthesis:
(1) Oxidation of 1° alcohols:
RCH2OH
1 Alcohol
KMnO4
- H2
KMnO4
RCHO
RCO2H
+ 'O'
Aldehyde
Carboxylic
acid
(B) Hydrolysis of nitriles:
O
+
R
C
N
H or
OH
R
H+
C
NH2
Nitrile
or
OH
Amide
O
R
C
OH
Carboxylic
acid
(C) Reaction of organomagnesium reagents (aka Grignard reagents)
with carbon dioxide (cf. CM2005 lectures):
R
X
Mg
R
MgX
CO2
O
R
C
OMgX
H3O+
O
R
C
OH
Reactions of carboxylic acids:
(1) Acidity
O
R
C
O
R
+ H2O
C
OH
O
+ H3O+
-
pKa ca. 4.5
O
Resonance-stabilised carboxylate anion: R
-
O
C
R
C
O
_
O
[Compare HCl (-7); ROH (ca. 16); RCH2COR (ca. 20)]
Carboxylate anions are nucleophilic:
O
R
C
O-
CH3CH2
Br
SN2
O
R
C
O
Esterification under
basic conditions:
New bond
CH2CH3
Ethyl ester
This is not, however, the standard method of making esters which is:
H 3O +
O
R
C
+ HOCH2CH3
OH
Esterification under
acidic conditions:
O
R
New bond
C
O
CH2CH3
Ethyl ester
The mechanism of this reaction will be studied in more detail later.
(2) Regiospecific bromination of the alkyl side-chain in alkyl
carboxylic acids:
O
O
Br2
C
CH3
CH3
C
CH3CO2 H
CH3
CH2Br
-Halogenation of aldehydes and ketones is catalysed by acids and
takes place via the small equilibrium concentration of the corresponding
enol.
CH3
O
Br2
O
C
X
C
OH
BrCH2
OH
OH
Carboxylic acids
do not enolise.
C
CH2
OH
Carboxylic acids do not enolise and hence cannot be -halogenated
under similar conditions.
CH3CH2 CO2H
Trace PBr3
X2
CH3CHXCO2 H
-Halogenated
carboxylic
acid.
Phosphorus tribromide catalyses the -halogenation of carboxylic
acids.
Mechanism:
O
CH3
CH2
C
PBr3
O
CH3
CH2
C
OH
Br
Acyl halide
O
CH3
CH2
C
OH
CH3
CH
C
Br
Br
+
OH
+
OH
Acyl halides
do enolise.
CH3
CH
C
CH3
Br
Br
+ Br
_
CH
C
Br
+ Br
- Br
- H+
O
CH3
CH
Br
C
CH3CH2 CO2H
O
CH3
Br
The cycle starts again.
CH3
CH
C
Br
OH
+
O
CH2
C
Br
Esterification of Carboxylic Acids - An Addition/Elimination
Reaction
H3O+
RCOOR1 + H2O
RCOOH + R1 OH
O
H3C
H3O
+
OH
+
C
H3 C
OH
C
+
C
H3 C
OH
OH
OH
Protonation increases the electrophilicity of the carbonyl carbon
atom in the carboxylic acid.
+
OH
H3 C
OH
C
HO
OH
C
C2 H5
H3 C
OH
+ O C2 H5
Tetrahedral
intermediate
H
+
OH2
H3C
C
OH
OH
H3C
C
OH
+O
O
C2H5
H
C2H5
- H2O
+
OH
H3 C
O
- H+
C
H3 C
OEt
H2 O
C
+ H3 O+
OEt
RCOOH + xs. R1OH
H3 O+
RCOOR1 + H2O
Ester formation is an equilibrium process - driven towards ester
formation by removal of the water co-product and/or use of a large
excess of the alcohol.
H3O+
RCOOR + xs. H 2O
RCOOH + R 1OH
The mechanism of ester hydrolysis under acidic conditions simply
follows the reverse pathway of the equilibrium steps in the forward
process and is driven by an excess of water.
Proof that one oxygen atom in the ester is provided by the alcohol is
available from labelling experiments:
H3O+
O
H3C
+ HO18 C2H5
OH
C
O
H3C
C
+ H2O
O18C2H5
The addition-elimination mechanism is central to the reactions of
carbonyl
compounds
derivatives.
including
carboxylic
acids
and
their
Esters can also be synthesised under neutral conditions:
O
R
O
C
R
+ CH2N2
OH
O CH3
Methyl ester
Diazomethane
H2C
+
N
_
N
_
H2C
O
R
C
C
+
N
N
O
_
OH + H2C
R
+
N
C
N
O
+ H3C
+
N
Proton transfer
O
R
C
O
O
H3C
+
N
R
N
C
+ N2
O
CH3
Excellent
leaving - group
N
Hydrolysis of esters and other carboxylic acid derivatives:
While esters can be hydrolysed under acidic conditions it is more
common to do so under basic conditions - called saponification, 'soap
making' (basic ester hydrolysis was a step in early soap manufacture).
O
O
H3C C OH
H3C C
+ OH
OC2H5
OC2H5
O
O
H3C
C
O
+ C 2H5OH
H3C
C
OH
pKa ca. 16
H3O+
+ C 2H5O
pKa ca. 4.5
O
H3C
C
OH
Other carboxylic acid derivatives are similarly hydrolysed:
O
O
H2O
R C
R C
+ NH3
Acid or base
OH
NH2
O
R
C
Cl
O
R
C
O
R
C
O
H2O
Instantaneous
H2O
Instantaneous
O
R
C
+ HCl
OH
O
2 R
C
OH