Chemistry Reference
In-Depth Information
3.4.8 Separation of enantiomers: resolution
We saw in Section 3.4.1 that
enantiomers
have the
same physical and chemical properties, except for opti-
cal activity, and thus they behave in exactly the same
manner. We also saw, however, that this generalization
did not extend into biological properties, and that there
were compelling reasons for administering drugs as a
single enantiomer rather than a racemate (see Box 3.7).
At some stage, therefore, it might be necessary to have
the means of separating individual enantiomers from a
racemic mixture. This is termed
resolution
.Thetra-
ditional method has been to convert enantiomers into
diastereoisomers
, because diastereoisomers have differ-
ent physical and chemical properties and can, therefore,
be separated by various methods (see Section 3.4.4).
Provided one can convert the separated diastereoisomers
back to the original compound, this offers a means of
separating or resolving enantiomers.
The simplest method has been to exploit salt for-
mation by reaction of a racemic acid (or base) with a
chiral base (or acid). For example, treating a racemic
acid with a chiral base will give a mixture of two salts
that are diastereoisomeric. Although there is no covalent
bonding between the acid and base, the ionic bond-
ing is sufficient that the diastereoisomeric salts can be
separated by some means, typically fractional crystal-
lization. Although fractional crystallization may have to
be repeated several times, and, therefore, is tedious, it
has generally been an effective means of separating the
diastereoisomeric salts. Finally, the salts can separately
be converted back to the acid, completing the resolution.
The bases generally employed in such resolutions
have been natural alkaloids, such as strychnine, brucine,
and ephedrine. These alkaloids are more complex than
the general case shown in the figure, in that they
contain several chiral centres (ephedrine is shown in
Section 3.4.4). Tartaric acid (see Section 3.4.5) has been
used as an optically active acid to separate racemic
bases. Of course, not all materials contain acidic or
basic groups that would lend themselves to this type of
resolution. There are ways of introducing such groups,
however, and a rather neat one is shown here.
A
O
HO
B
C
+
O
ester
formation
A
HO
O
B
C
phthalic anhydride
racemic alcohol
CO
2
H
A
O
B
C
O
+
salt
formation
CO
2
H
A
O
B
diastereoisomeric
salts
C
O
A
X
A
racemic acid
separate
HO
2
C
NH
3
O
2
C
B
Y
C
B
C
Z
X
NH
2
+
+
regenerate free
acid
Y
salt
formation
Z
A
X
A
HO
2
C
NH
3
O
2
C
optically
active base
C
B
Y
C
B
Z
hydrolyse ester
racemic acid
pair of diastereoisomeric
salts
separated
enantiomeric
alcohols
regenerate
fr
ee acid
A
X
A
HO
2
C
NH
3
O
2
C
C
B
Y
C
B
A racemic alcohol may be converted into a racemic
acid by reaction with one molar equivalent of phthalic
anhydride; the product is a half ester of a dicarboxylic
acid (see Section 7.9.1). This can now be subjected to
the resolution process for acids and, in due course, the
alcohols can be regenerated by hydrolysis of the ester.
A significant improvement on the fractional crystal-
lization process came with the introduction of chiral
H
+
Z
separate
physically
A
X
A
H
+
HO
2
C
NH
3
O
2
C
C
B
Y
C
B
regenerate
free acid
Z
separated
enantiomers
