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to racemic compounds were then investigated. The results are sum-
marized in Table 3.
On the basis of the aforementioned experimental facts, we pre-
sumed that the presence of POAA in an equivalent amount with
the racemic compound would make the conditions of the crystalli-
zation of a diastereoisomeric salt favourable.
also accelerates the stabilization of the equilibrium system. In the
reciprocal resolution [in the solution there are (S)-AcPhA, POAA
*
and the racemic PhEA] crystallization of the achiral POAA ( )-
PhEA salt is the fastest and at the same time these crystals can ini-
tiate the crystallization of both diastereoisomeric salts. However,
this process works against the stabilization of the equilibrium sys-
tem, therefore, a longer crystallization time is necessary to achieve
the thermodynamically controlled endpoint of the resolution.
2.4. The influence of the time of the crystallization
Recently, we described16 that in certain cases, the duration of
crystallization has a strict role in determination of the efficiency
of the resolution. It was observed that during the crystallization
3. Conclusions
On the basis of the experimental data we have concluded that
the investigated structurally similar chiral compounds are suitable
resolving agents for each other. In other words, pure enantiomers
of the racemic starting compounds of the normal resolutions could
be used as resolving agents of the racemic mixture of the first
resolving agent (reciprocal resolutions).
These structurally similar compounds behaved analogously in
both cases: as racemic compounds and as resolving agents in the
separation of diastereomers. A practical consequence of these
observations is the enlargement of the number of possible resolv-
ing agents for a given racemate by simple chemical modification of
its enantiomer into a structurally similar derivative with opposite
acidic or basic character related to the original racemate.
It was also demonstrated that the addition of achiral com-
pounds with similar chemical structures to the resolving agents
BA, or similar to the racemates POAA may strongly influence the
efficiency of the resolutions. These achiral additives with relative
structures work as special ‘organocatalysts’ influence the rate
and the efficiency of the chiral discrimination processes. Their
amplification effect could be observed both at the normal and at
the reciprocal resolutions. The additives may affect the kinetics
of the crystallization and the position of the thermodynamic equi-
librium during diastereoisomeric salt forming resolutions, there-
fore, the duration of crystallization should be studied during the
optimization of any normal or reciprocal resolutions, respectively.
*
of FoPhA PhEA diastereoisomeric salts, the initially high enantio-
meric excess (90.8%) diminished when the filtration of the precip-
itated salt was carried out after a longer standing. This kinetic
control was verified by the different rates of crystallization of the
two diastereomers,17 i.e., a large difference was observed in the
kind of crystal growth of the diastereomers. The crystals of the fas-
ter crystallizing diastereoisomer grew independently from the
direction (every side of the nucleus), while the other diastereoiso-
mer formed only linear crystals (Table 4a).
Thus, the racemic N-acyl amino acids could be successfully re-
solved by bases with a similar structure, although, the most efficient
resolutions could be achieved using their N-acetyl derivatives.
As a result, the possibility of reciprocal resolution was exam-
ined. A racemic mixture of the base, applied earlier as a resolving
agent PhEA, was resolved with the enantiomers of N-acyl amino
acids (FoPhA and AcPhA). We were particularly interested in the
crystallization time dependence of the efficiencies of the reciprocal
resolutions. Therefore, resolution of racemic PhEA with optically
active FoPhA (Table 5a) and with a mixture of optically active Ac-
PhA and POAA (Table 5b) was investigated.
The data in Table 5 verify that the kinetic control is also present
at the reciprocal resolution, as it was observed in the direct resolu-
tion (FoPhA-PhEA). The positive effect of thermodynamic control
was observed in the reciprocal resolution of AcPhA-PhEA-POAA
system. When the reciprocal resolution of the same diastereomer
salt crystallized, the influence of both kinetic and thermodynamic
controls could be supposed.
A comparison of the results of the original resolutions with their
reciprocal versions can be seen in Figures 1 and 2. In the normal
and the reciprocal resolutions of FoPhA and PhEA, the ee values
(measured in the crystallized diastereoisomeric salt) decreased in
a similar way when the duration of crystallization was increased
(Fig. 1) because the normal and the reciprocal systems were very
similar: the same diastereoisomeric salt crystallized and the fil-
trate contained the other diastereoisomer and/or enantiomer,
which were in a mirror image relationship with each other regard-
ing the normal and the reciprocal resolution systems.
4. Experimental
4.1. General
Chemicals were the products of Aldrich (Steinheim, Germany).
Optical rotation data were measured with a Perkin–Elmer 241
automatic polarimeter.
4.1.1. Resolution of N-acyl amino acids using bases with relative
structure general method
A mixture of 20.0 mmol of the racemic N-acyl amino acid and
20.0 mmol of the resolving agent was dissolved in water under
heating. After cooling the precipitate was filtered off after one
day of standing, and washed with water (2 cm3), after which it
was suspended in water (10 cm3) and reacted with concentrated
HCl (4 cm3). After standing for 4 h, the precipitate was filtered off
and washed with water (2 ꢀ 1 cm3).
The AcPhA-PhEA-POAA system behaved differently (Fig. 2),
probably because an achiral additive (POAA) and its salt remained
in the filtrate together with the residue of the crystallized diaste-
reoisomer, while the three component supramolecular structure
in the solution influenced the chiral discrimination procedure in
the normal resolution process much better (the position of the
equilibrium) than that had occured in the reciprocal case.
The mother liquor of the diastereomeric salt was acidified with
conc. HCl (5 cm3), the precipitate was filtered off and washed with
water (2 ꢀ 1 cm3).
*
The (S)-AcPhA (R)-PhEA diastereoisomeric salt slowly crystal-
*
lized from the aqueous solution. The POAA (R)-PhEA salt crystal-
The results are shown in Table 1. Reproducibilities were good;
the experimentally determined error limit of the enantiomeric pur-
ity was 3%.
lized faster but its solubility is higher and solvation was also
faster than that of the diastereoisomeric salt. Therefore, from the
aqueous solution of the mixture of these salts, the diastereoiso-
meric salt crystallized practically alone.
4.1.2. Resolution of racemic N-acetyl phenylalanine with a
mixture of PhEA and POAA
During the normal resolution process, when racemic AcPhA,
POAA and (R)-PhEA are in the reaction mixture, the POAA (R)-
*
To a mixture of 10.0 mmol of racemic AcPhA, 10.0 mmol of
PhEA salt crystallizes first. This salt is probably the catalyst of crys-
tallization of the (S)-AcPhA (R)-PhEA diastereoisomeric salt and it
POAA and 18.0 mmol of (R)-(ꢁ)-PhEA was added 20 cm3 of water
*