NITROGEN AS A NUCLEOPHILE: IMINES AND ENAMINES
245
Box 7.10
Nucleophilic addition of carbon to imines: the Strecker synthesis of amino acids
A nice example of the chemical similarity between imines and carbonyl compounds is the Strecker synthesis of
amino acids. This involves reaction of an aldehyde with ammonia and HCN (usually in the form of ammonium
chloride plus KCN) to give an intermediate α-aminonitrile. Hydrolysis of the α-aminonitrile then produces the
α-amino acid.
H
O
R
NH 2
C
N
R
α-aminonitrile
H
+
H 2 O
NH 2
CO 2 H
R
α-amino acid
NH 4 Cl
KCN
(≡ NH 3 + KCN)
The sequence can be rationalized mechanistically as involving nucleophilic attack of ammonia onto the aldehyde
to produce an imine, which then acts as the electrophile for further nucleophilic attack, this time by the cyanide
ion (see Section 7.7.1). The racemic amino acid is then formed by acid-catalysed hydrolysis of the nitrile function,
as above (Box 7.9).
H
O
NH 3
NH 3
O
H
NH 2
OH
H
NH
C N
NH
C
N
NH 2
C
N
NH 2
CO 2 H
(±)-phenylanine
nucleophilic attack
of ammonia on to
carbonyl
− H
+
, + H
+
− H 2 O
nucleophilic attack of
cyanide on to imine
+ H
+
acid-catalysed
hydrolysis of nitrile
to acid, see Box 7.9
H
+
H 2 O
This synthesis is fairly general, and can be used for many amino acids, provided the R side-chain contains no
other functional group that is sensitive to the reagents (see Section 13.1). R groups containing –NH 2 , for example,
would require appropriate protection measures. There is also considerable scope for making labelled amino acids
via the use of
14 C-labelled cyanide.
Imine formation is an important reaction. It generates a C–N bond, and it is probably the most
common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thus, cyclization of 5-aminopentanal to
1 -piperideine is merely
intramolecular imine formation. A further property
of imines that is shared with carbonyl groups is
their susceptibility to reduction via complex metal
hydrides (see Section 7.5). This allows imines to be
reduced to amines, such as piperidine.
N
N
H
NH 2
O
H
5-aminopentanal
∆
1 -piperideine
piperidine
intramolecular
imine formation
LiAlH 4
reduction
of imine
245
Box 7.10
Nucleophilic addition of carbon to imines: the Strecker synthesis of amino acids
A nice example of the chemical similarity between imines and carbonyl compounds is the Strecker synthesis of
amino acids. This involves reaction of an aldehyde with ammonia and HCN (usually in the form of ammonium
chloride plus KCN) to give an intermediate α-aminonitrile. Hydrolysis of the α-aminonitrile then produces the
α-amino acid.
H
O
R
NH 2
C
N
R
α-aminonitrile
H
+
H 2 O
NH 2
CO 2 H
R
α-amino acid
NH 4 Cl
KCN
(≡ NH 3 + KCN)
The sequence can be rationalized mechanistically as involving nucleophilic attack of ammonia onto the aldehyde
to produce an imine, which then acts as the electrophile for further nucleophilic attack, this time by the cyanide
ion (see Section 7.7.1). The racemic amino acid is then formed by acid-catalysed hydrolysis of the nitrile function,
as above (Box 7.9).
H
O
NH 3
NH 3
O
H
NH 2
OH
H
NH
C N
NH
C
N
NH 2
C
N
NH 2
CO 2 H
(±)-phenylanine
nucleophilic attack
of ammonia on to
carbonyl
− H
+
, + H
+
− H 2 O
nucleophilic attack of
cyanide on to imine
+ H
+
acid-catalysed
hydrolysis of nitrile
to acid, see Box 7.9
H
+
H 2 O
This synthesis is fairly general, and can be used for many amino acids, provided the R side-chain contains no
other functional group that is sensitive to the reagents (see Section 13.1). R groups containing –NH 2 , for example,
would require appropriate protection measures. There is also considerable scope for making labelled amino acids
via the use of
14 C-labelled cyanide.
Imine formation is an important reaction. It generates a C–N bond, and it is probably the most
common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thus, cyclization of 5-aminopentanal to
1 -piperideine is merely
intramolecular imine formation. A further property
of imines that is shared with carbonyl groups is
their susceptibility to reduction via complex metal
hydrides (see Section 7.5). This allows imines to be
reduced to amines, such as piperidine.
N
N
H
NH 2
O
H
5-aminopentanal
∆
1 -piperideine
piperidine
intramolecular
imine formation
LiAlH 4
reduction
of imine