Deracemization of a Racemic Compound by Using Tailor-Made Additives

Article abstract of DOI:10.1002/chem.201706088

Viedma ripening is a process that combines abrasive grinding of a slurry of crystals with solution-phase racemization, resulting in solid-phase deracemization. One of the major disadvantages of Viedma ripening is that the desired compound needs to crystallize as a racemic conglomerate, accounting for only 5–10 % of all chiral molecules. Herein, we show that use of a chiral additive causes deracemization under conditions, in which the compound normally crystallizes as a racemic compound. Although this concerns a single example, it is envisioned that through this new approach the scope of Viedma ripening can be significantly expanded.

Full text of DOI:10.1002/chem.201706088

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Accepted Article
Title: Deracemization of a Racemic Compound Using Tailor-Made
Additives
Authors: Ton Engwerda, Pim van Schayik, Henjo Jagtenberg, Hugo
Meekes, Floris P. J. T. Rutjes, and Elias Vlieg
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To be cited as: Chem. Eur. J. 10.1002/chem.201706088
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Deracemization of a Racemic Compound Using Tailor-Made Additives
[
a]
[a]
[a]
,[a]
Anthonius H. J. Engwerda , Pim van Schayik , Henjo Jagtenberg , Hugo Meekes* , Floris P. J. T.
Rutjes* and Elias Vlieg
,[a]
[a]
Abstract: Viedma ripening is a process that combines abrasive
grinding of a slurry of crystals with solution phase racemization,
resulting in solid phase deracemization. One of the major
disadvantages of Viedma ripening is that the desired compound
needs to crystallize as a racemic conglomerate, accounting for only
additives (small amounts of a chiral compound that closely
resembles the target compound) can be used to direct the
outcome towards formation of a specific enantiomer .
[
6]
The requirement of formation of racemic conglomerates remains
an inherent drawback for Viedma ripening. Since only 5-10% of
all chiral molecules crystallize as conglomerate crystals, Viedma
ripening is not suitable for the 90-95% of chiral compounds that
crystallize as a racemic compound. One solution to overcome
this challenge is to modify the crystallization behavior of solids in
such a way that conglomerate formation occurs. Examples
include salt formation and screening multiple counterions for
5-10% of all chiral molecules. In this work, we show that use of a
chiral additive causes deracemization under conditions in which the
compound normally crystallizes as a racemic compound. Although
this concerns a single example, it is envisioned that through this new
approach the scope of Viedma ripening can be significantly
expanded.
[
7]
conglomerate formation . Alternatively, when deracemization of
a certain class of neutral molecules is required, the problem can
be solved by engaging in a library synthesis of derivatives to
Deracemization of chiral small molecules using Viedma ripening
[8]
identify compounds that display conglomerate behavior . Both
[
1]
has attracted much attention during the past decade . This
method, which combines abrasive grinding of a slurry of crystals
with solution phase racemization, results in complete solid
phase deracemization (Figure 1a). The Viedma ripening process
is operating when the compound crystallizes as a racemic
conglomerate meaning that the enantiomers crystallize in
separate crystals. Viedma was the first to demonstrate this
method for the achiral inorganic salt sodium chlorate, which
approaches are however certainly not generally applicable; e.g.
many compounds cannot form salts. It would therefore be
beneficial to find approaches to apply attrition enhanced
deracemization to racemic compounds without using any
chemical modification. In this manuscript, we show that this can
be achieved by using tailor-made chiral additives.
Chiral additives:
[
2]
crystallizes in
a chiral fashion . We and others have
The concept of using additives in crystallization was applied long
before Viedma ripening had been developed. Extensive studies
were conducted by the group of Lahav, who focused on the
demonstrated that Viedma ripening can also be applied to
intrinsically chiral organic molecules, such as amino acid
[
3]
[4]
[5]
derivatives , metal-organic complexes and isoindolinones .
Although the outcome of a Viedma ripening experiment is in
principle stochastic, it has been demonstrated that enantiopure
[9]
resolution of conglomerates using additives . They used
enantiopure tailor-made additives that selectively bind to
surfaces of crystals of the same
chirality. This resulted in crystallization
from solution of only the opposite
enantiomer. The outcome of these
additive induced resolution experiments
is therefore generally described by the
Lahav rule of reversal; using a chiral
additive
results
in
preferential
[
9,
crystallization of the opposite chirality
1
0]
.
This rule also holds when using
additives in directing Viedma ripening
[6, 11]
processes
. Note that in all these
cases additives were used to direct the
outcome of the deracemization of a
Figure 1: Conceptual approaches for deracemization of racemic conglomerates via a) total spontaneous
resolution; b) Viedma ripening c) This paper: deracemization of a suspension of a racemic compound using
chiral additives. In this scheme, the formation of enantiopure crystals is always represented by blue (S)- compound that crystallized as
a
crystals.
racemic conglomerate.
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readily at such temperatures (t1/2 = 14.5 min in DMF at 50 °C ),
[
19]
whereas racemization at room temperature is slow
.
Since binaphthyl (1) crystallizes as a racemic conglomerate
above 85 °C, deracemization (via total spontaneous resolution)
above this temperature can be achieved, as was shown by the
[18]
[20]
groups of Pincock and Kondepudi . Below this temperature,
we tested whether additives can be used to induce
deracemization. As an additive, we chose BINOL (2) since it
closely resembles binaphthyl (1), but does not racemize at
[
21]
temperatures below 100 °C
. The additive in these
Figure 2: A chiral molecule that normally crystallizes as a racemic compound
can, in the presence of a chiral additive (green blue, closely resembling one of
the enantiomers), favor the preferential crystallization of a single enantiomer
by blocking the growth of the other crystal structures.
When a compound crystallizes as a racemic compound, several
methods for enantioenrichment have been reported in literature.
Klussman et al. showed that, starting from nonracemic but also
not enantiopure conditions the eutectic composition of
a
compound can be used to create very high solution
a
[
12]
enantiomeric excess (ee) . When the eutectic composition is
Figure 3: Both binaphthyl (1) and BINOL (2) are examples of atropisomers
having an axis of chirality with hindered, temperature dependent rotation
around the chiral axis.
unfavorable, crystal engineering (via co-crystal formation) can
[
13]
be used to increase the ee . In addition, a few examples exist
in which a single enantiomer of a racemic compound could be
crystallized from a saturated solution using a chiral additive. The
HCl-salt of histidine crystallizes as a racemic dihydrate below
experiments was envisioned to operate via a kinetic pathway,
blocking the growth of the racemic compound and one of the two
conglomerate forms.
4
5
°C and as
temperature. Using chiral polymeric additives,
enantiomer could be crystallized under conditions, where
a
conglomerate monohydrate above this
a
single
To study whether this additive could exert such an effect, a
series of Ostwald ripening experiments were performed. For
these experiments, nonane was selected as a solvent since
binaphtyl was very soluble in more polar solvent, resulting in a
large loss of material during these experiments. In addition, it
was determined that the half-life of racemization in nonane was
appropriate for these experiments (t1/2 = 2.3 min at 70°C, see
ESI). In these experiments, suspensions of equal amounts of
racemic and conglomerate 1 (with or without additive) were
gently stirred for two days. The solid phase was then
characterized using X-Ray Powder Diffraction (XRPD), chiral
HPLC and Scanning Electron Microscopy (SEM, Figure 4).
Ostwald ripening without an additive at 90 °C gave only
octahedral crystals, corresponding to the racemic conglomerate.
This indicates that the conglomerate is indeed the most stable
phase at this temperature. In the presence of the enantiopure
(S)-additive, similar size octahedrons were obtained containing
[
14]
normally the racemic compound would be stable (Figure 1c)
.
A similar approach has been used for the resolution of calcium
[
15]
tartrate hydrate
In contrast to these examples, our experiments will start from a
racemic suspension of crystals, seeded with just few
.
a
conglomerate crystals. In addition, the aim is not to separate the
enantiomers, but completely deracemize the solid phase. It
should be noted that both examples from the literature are
unsuited for this additive driven deracemization, since either
racemization is very difficult (calcium tartrate), or the additive
racemizes at similar conditions as the target molecule (histidine).
We now show that additives can be used to block the growth of
the racemic compound of 1,1’-binaphthyl (compound 1), favoring
the growth of a single enantiomer (Figure 2).
Since racemization of 1 spontaneously happens at the elevated
temperatures that were used, deracemization could be achieved. only the (S)-enantiomer implying that deracemization had taken
In addition, the obtained handedness of the product could be
directed by the chirality of the additive.
place during Ostwald ripening. In addition, experiments were
performed in which both enantiomers of the additive were added.
In these cases, the growth of all crystal forms (racemic
conglomerate and racemic compound) was expected to be
hampered. Indeed, when a racemic additive was used, the
average size of these crystals was much smaller. Again,
octahedrons of the racemic conglomerate were obtained, but
Binaphthyl (1, Figure 3) is an example of an atropisomer, a non-
planar molecule that displays chirality through the hindered
[
16]
rotation around a single bond . Binaphthyl crystallizes as a
racemic compound at room temperature, but converts into a
[
17],[18]
conglomerate at temperatures above 85 °C
. It racemizes
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suspension of crystals to create
Viedma ripening experiment. Since
binaphthyl crystallizes as racemic
compound below 85 °C, experiments at
such low temperatures were
a
a
unsuccessful. Therefore, the additive
approach was used to change the
crystallization behavior from a racemic
compound to a conglomerate.
When using this additive, deracemization
of binaphthyl became possible under
conditions where it is stable as a racemic
compound (in the absence of additives).
When using enantiopure additive 2 and a
small amount of racemic conglomerate
seed crystals, complete deracemization
could be achieved within 12 h (Figure
[
22]
5
a) . The resulting chirality could be
directed by the handedness of the
additive. Use of (R)-2 always resulted in
(
R)-1, while adding (S)-2 resulted in (S)-1.
Figure 4: SEM images of crystals resulting from Ostwald ripening experiments of binaphthyl (1) in the
presence and absence of 10% additive. The flat plates correspond to the racemic compound, the This implies that the outcome of these
octahedrons to the conglomerate. In the presence of the racemic additive at 75 °C, a featureless material
was obtained which by XRPD was shown to be the racemic compound.
experiments does not follow Lahav’s rule
of reversal, which is a discrepancy that
we at this point cannot explain.
To further study the deracemization process, XRPD
now no deracemization had taken place. At temperatures of 80
and 75 °C, thin plates corresponding to the racemic compound
measurements were performed on samples taken during the
were obtained in the absence of any additive. This proves that at
deracemization experiments. These measurements revealed
these temperatures indeed the racemic compound is the most
that the deracemization of 1 took place at the same rate as the
stable phase. However, in the presence of the enantiopure (S)-
conversion of the racemic compound into the conglomerate
additive, again conglomerate octahedrons were obtained
(
Figure 5b). This gives some indication towards a possible
containing only the (S)-enantiomer. Growth of both the (R)-
enantiomer and the racemic compound were hampered by the
additive. When both enantiomers of the additive were added, the
growth of all crystal forms was blocked. This resulted in a
material with a featureless morphology, of which XRPD showed
that it corresponded to the racemic compound.
mechanism of deracemization. During the grinding experiments,
both the racemic compound and conglomerate dissolved
resulting in (R)- and (S)-enantiomers in solution. The additive
then hampered crystal growth as depicted in Figure 2. When
using (S)-2 as an additive the growth of both the racemic and
conglomerate (R) -crystals were blocked (reverse rule of
reversal). The (S)-enantiomers in solution could, however, still
be incorporated into the existing (S)-crystals. Grinding ensured a
continuous increase in the number of these crystals. Since
racemization took place in solution, the (R)-enantiomers could
be converted and consequently also be incorporated into the
Deracemization experiments:
These observations indicate that the additive does indeed
exhibit the intended kinetic effect on the binaphthyl crystals.
Therefore, some larger-scale deracemization experiments were
performed. In these experiments, glass beads were added to a
(
S)-crystals. The racemic compound thus served as a gradual
Figure 5: (a) Deracemization curve of a grinding experiment of compound 1 at 80 °C in the presence and absence of 10% enantiopure BINOL. (b) The XRPD
of the solid phase of 1 during these deracemization experiments shows the conversion from a racemic compound to a conglomerate. The peak at 15.7
degrees corresponds to the {1 0 2} reflection of the conglomerate and the peak at 16.6 to the {1 1 -1} reflection of the racemic compound.
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feed for the (S)-crystals in contrast to standard Viedma ripening,
further from the peritectic (86 °C), i.e. when the racemic
conglomerate becomes increasingly unstable. Increased
additive concentrations can, however, be used to increase the
range at which this approach is viable.
[
23]
where only the opposite enantiomers serve as feed
.
Conclusion:
The main advantage of this additive approach to effect
deracemization is that Viedma ripening is no longer restricted to
the 5-10% of chiral molecules that crystallize as a racemic
conglomerate. When a compound is stable as a racemic
compound, deracemization can still be achieved by using
appropriate chiral additives. In the present case, an appropriate
additive was found by selecting a structurally closely related
molecule that cannot be racemized under the conditions used.
These additives cannot only be applied to peritectic systems in
which conglomerate and racemic compound are the stable
phase at different temperatures, but potentially also for
compounds for which the racemic compound is always the
stable phase (as long as the energetic difference between both
phases is not too large). This kinetic approach therefore
expands the scope of attrition enhanced deracemization.
Figure 6: Effect of the additive concentration on the deracemization of
compound 1 at 80°C.
Keywords: Chirality • Additives • Deracemization • Crystals •
Viedma ripening
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[
9]
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Entry for the Table of Contents
COMMUNICATION
A. H. J. Engwerda, P. van Schayik, H.
Jagtenberg, H. Meekes*, F. P. J. T.
Rutjes* and E. Vlieg
Add and go: Typically solid state
deracemization is limited to the 5-10%
of chiral compounds that crystallize as
a racemic conglomerate. By adding a
tailor-made additive, the attrition
Page No. – Page No.
Deracemization of a Racemic
Compound Using Tailor-made
Additives
enhanced deracemization of a
racemic compound could be achieved.
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