Page 228 - Chiral Separation Techniques

206 8 Nonchromatographic Solid-Phase Purification of Enantiomers

As shown in Fig. 8-1, primary amine-macrocycle formation occurs by a three-
point interaction involving hydrogen bonding of the N–H groups of the amine and
the oxygen and nitrogen atoms of the macrocycle. We used this concept to develop
a number of pyridine-substituted cyclic polyethers, and studied their interaction with
a number of primary organic amines. In the case illustrated in Fig. 8-1, log K
(CH OH) values for the interaction of chiral ligand (S,S)-1 with (S)-NapEt and (R)-
3
NapEt were 2.06 and 2.47, respectively [10]. Crystallographic data [11] show that
the higher stability of the (S,S)-1-(R)-NapEt complex is steric in nature, as is illus-
trated schematically in Fig. 8-1. This selectivity is reversed if the (R,R)-1 ligand is
used.
The structures of both complexes shown in Fig. 8-1 indicate that in each the pri-
+
mary molecular interaction is between the –NH and the alternate macrocyclic ring
3
atoms. Additional stabilization results in each case from π-π interaction of the naph-
thyl group from the guest and the pyridine group of the host [6, 10]. Increased dif-
ferentiation between the enantiomers is accomplished by providing bulky groups at
appropriate positions on the chiral host. The steric effect of these groups (CH in the
3
case of (S,S-1)) is sufficient to cause an appreciable difference in log K values (2.06
compared to 2.47). The effect of various hosts, host substituents, and guests on enan-
tiomeric selectivity has been found to be appreciable in many cases [6]. Values of
∆ log K ranging from 0.1 to 0.7 have been observed and reviewed previously. Since
a ∆ log K value of 0.6 corresponds to an α value of 4, it is apparent that these sys-
tems have potential use in separations of enantiomers containing appropriate func-
tional groups. More recent work by IBC has shown ligand and solvent cases with
even greater selectivities, as discussed later in this chapter.

8.3 Nonchromatographic Separation Process Description

Use of the concepts of molecular recognition principles as described above allows
one to develop ligands that differentiate in their binding between two enantiomers.
If the difference in the magnitude of binding becomes great enough (∆ log K of 0.6
or greater), one can achieve a nonchromatographic, or bind-release separation. This
mode of separation confers a number of significant advantages in a separations pro-
cess, which are discussed later in this chapter. The ligand chemistry allows a chiral
host molecule to recognize and bind preferentially with one guest from a pair of
enantiomers. The desired enantiomer (eutomer) is then released from the solid phase
separations matrix and recovered in pure form. The unwanted enantiomer (distomer)
can, in some cases, be isomerized in good yield to form a racemic mixture for recy-
cling, and converted to the eutomer. In order to be useful in this method the chiral
host must favor the binding of one enantiomer over the other by at least 0.6 log K
units, corresponding to an α-value of 4.0 or greater.
The procedure used to accomplish enantiomer separation is shown in Fig. 8-2. It
is assumed that the α value is large enough to permit essentially complete separation