246
NUCLEOPHILIC REACTIONS OF CARBONYL GROUPS
A combined reductive amination sequence has
been developed as a useful way of synthesizing amines, with sodium cyanoborohydride as
the reducing agent of choice. This complex metal
hydride is a less reactive version of sodium
borohydride (see Section 7.5), since the electronwithdrawing cyano group lowers the ability to transfer hydride. Consequently, sodium cyanoborohydride
is rather selective, in that it will reduce iminium systems but does not reduce carbonyl compounds.
O
MeNH 2
NaCNBH 3
pH 6
HN
NHMe
Me
H
B
H
CN
H
HCHO
NaCNBH 3
HN
Me
N
Me
NH 3
NaCNBH 3
pH 6
NH 2
O
HCHO
NaCNBH 3
HN
via intermediate
iminium ion
CH 2
Me
pH 6
pH 6
iminium formation
cyanoborohydride
methyl introduced via MeNH 2
methyls introduced via HCHO
The combined reaction thus involves initial formation
of the iminium ion from the carbonyl compound and
amine at pH 6, and this intermediate is then reduced
by the complex metal hydride to give the amine.
This can also be a way of making methyl-substituted
amines via intermediate imines with formaldehyde.
We shall see later (see Section 15.6) that reductive amination of a keto acid is the way nature synthesizes amino acids, using the biological analogue
of a complex metal hydride, namely NADPH (see
Box 7.6).
Box 7.11
Pyridoxal and pyridoxamine: vitamins that participate via imine formation
The terminology vitamin B 6 covers a number of structurally related compounds, including pyridoxal and
pyridoxamine and their 5
-phosphates. Pyridoxal 5
-phosphate (PLP), in particular, acts as a coenzyme for
a large number of important enzymic reactions, especially those involved in amino acid metabolism. We shall
meet some of these in more detail later, e.g. transamination (see Section 15.6) and amino acid decarboxylation
(see Section 15.7), but it is worth noting at this point that the biological role of PLP is absolutely dependent upon
imine formation and hydrolysis. Vitamin B 6 deficiency may lead to anaemia, weakness, eye, mouth, and nose
lesions, and neurological changes.
Pyridoxal 5
-phosphate is an aldehyde, and this grouping can react with the amino group of α-amino acids
to form an imine; since an aldehyde is involved, biochemists often refer to this product as an aldimine. This
imine undergoes changes in which the heterocyclic ring plays an important role (see Section 15.6), changes
that lead to the double bond of the imine ending up on the other side of the nitrogen atom. This is in many
ways similar to rearrangement in an allylic system (see Section 8.2), and at its simplest can be represented
as shown. Conjugation with the heterocyclic ring system facilitates loss of a proton to start off the electron
redistribution.
NUCLEOPHILIC REACTIONS OF CARBONYL GROUPS
A combined reductive amination sequence has
been developed as a useful way of synthesizing amines, with sodium cyanoborohydride as
the reducing agent of choice. This complex metal
hydride is a less reactive version of sodium
borohydride (see Section 7.5), since the electronwithdrawing cyano group lowers the ability to transfer hydride. Consequently, sodium cyanoborohydride
is rather selective, in that it will reduce iminium systems but does not reduce carbonyl compounds.
O
MeNH 2
NaCNBH 3
pH 6
HN
NHMe
Me
H
B
H
CN
H
HCHO
NaCNBH 3
HN
Me
N
Me
NH 3
NaCNBH 3
pH 6
NH 2
O
HCHO
NaCNBH 3
HN
via intermediate
iminium ion
CH 2
Me
pH 6
pH 6
iminium formation
cyanoborohydride
methyl introduced via MeNH 2
methyls introduced via HCHO
The combined reaction thus involves initial formation
of the iminium ion from the carbonyl compound and
amine at pH 6, and this intermediate is then reduced
by the complex metal hydride to give the amine.
This can also be a way of making methyl-substituted
amines via intermediate imines with formaldehyde.
We shall see later (see Section 15.6) that reductive amination of a keto acid is the way nature synthesizes amino acids, using the biological analogue
of a complex metal hydride, namely NADPH (see
Box 7.6).
Box 7.11
Pyridoxal and pyridoxamine: vitamins that participate via imine formation
The terminology vitamin B 6 covers a number of structurally related compounds, including pyridoxal and
pyridoxamine and their 5
-phosphates. Pyridoxal 5
-phosphate (PLP), in particular, acts as a coenzyme for
a large number of important enzymic reactions, especially those involved in amino acid metabolism. We shall
meet some of these in more detail later, e.g. transamination (see Section 15.6) and amino acid decarboxylation
(see Section 15.7), but it is worth noting at this point that the biological role of PLP is absolutely dependent upon
imine formation and hydrolysis. Vitamin B 6 deficiency may lead to anaemia, weakness, eye, mouth, and nose
lesions, and neurological changes.
Pyridoxal 5
-phosphate is an aldehyde, and this grouping can react with the amino group of α-amino acids
to form an imine; since an aldehyde is involved, biochemists often refer to this product as an aldimine. This
imine undergoes changes in which the heterocyclic ring plays an important role (see Section 15.6), changes
that lead to the double bond of the imine ending up on the other side of the nitrogen atom. This is in many
ways similar to rearrangement in an allylic system (see Section 8.2), and at its simplest can be represented
as shown. Conjugation with the heterocyclic ring system facilitates loss of a proton to start off the electron
redistribution.