Photoracemization-Based Viedma Ripening of a BINOL Derivative

Article abstract of DOI:10.1002/chem.201904382

Viedma ripening is a deracemization process that has been used to deracemize a range of chiral molecules. The method has two major requirements: the compound needs to crystallize as a conglomerate and it needs to be racemizable under the crystallization c

Full text of DOI:10.1002/chem.201904382

A Journal of
Accepted Article
Title: Photoracemization-based Viedma ripening of a BINOL derivative
Authors: Giuseppe Belletti, Carola Tortora, Indra Mellema, Paul
Tinnemans, Hugo Meekes, Floris Rutjes, Svetlana Tsogoeva,
and Elias Vlieg
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To be cited as: Chem. Eur. J. 10.1002/chem.201904382
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Chemistry - A European Journal
10.1002/chem.201904382
Photoracemization-based Viedma ripening of a
BINOL derivative
Giuseppe Belletti , Carola Tortora‡[b], Indradevi D. Mellema[a],
‡
[a]
[
a]
[a]
[a]
Paul Tinnemans , Hugo Meekes , Floris P. J. T. Rutjes ,
Svetlana B. Tsogoeva*[b] and Elias Vlieg*[a]
[
a] G. Belletti, I. D. Mellema, Dr. P. Tinnemans, Dr. H. Meekes, Prof. Dr. F. P. J. T.
Rutjes, Prof. Dr. E. Vlieg
Radboud University, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ
Nijmegen, The Netherlands
[
b] C. Tortora, Prof. Dr. S. B. Tsogoeva
Chair of Organic Chemistry I, Department of Chemistry and Pharmacy, Friedrich-Alexander-
Universit ¨a t Erlangen-N u¨ rnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
‡
G. Belletti and C. Tortora have contributed equally to this work
Abstract
Viedma ripening is a deracemization process that has been used to deracemize a range of
chiral molecules. The method has two major requirements: the compound needs to crystal-
lize as a conglomerate and it needs to be racemizable under the crystallization conditions.
While conglomerate formation can be induced in different ways, the number of racemiza-
tion methods is still rather limited. In order to extend the scope of Viedma ripening, in the
1
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Chemistry - A European Journal
10.1002/chem.201904382
present research we applied UV light-induced racemization in a Viedma ripening process,
and report the successful deracemization of a BINOL derivative crystallizing as a conglomer-
ate. Irradiation by UV light activates the target compound in combination with an organic
base, required to promote the excited-state proton transfer (ESPT), leading thereafter to
racemization. This offers a new tool towards the development of Viedma ripening pro-
cesses, by using a cheap and “green” catalytic source like UV light to racemize suitable
chiral compounds.
1
Introduction
The increasing demand of single enantiomers for industrial applications continues to stim-
ulate the development of feasible and economically viable methodologies to reach enantiop-
urity.[1, 2] Besides classical resolution techniques and dynamic resolution methods, Viedma
ripening has been recognized as a valid deracemization process.[3–7] Since its discovery
in 2005, several conditions and parameters were screened to improve the efficiency of this
technique.[5, 8–10] Organic compounds such as amino acids and their derivatives,[11, 12]
organometallic complexes[13] and pharmaceutical intermediates[4, 5] were successfully der-
acemized using Viedma ripening. During the process, a slurry of the conglomerate crystals
in a saturated solution is intensively ground to promote breakage and dissolution as well as
growth of the crystals. In this way one can achieve an enantiopure crystalline final state, in
up to 100% yield.[14, 15] The technique is based upon two essential prerequisites: the target
molecule has to crystallize as a conglomerate, that is, a mechanical mixture of enantiomer-
ically pure crystals, and suitable racemization conditions have to be applied in solution, to
continuously interconvert one enantiomer into the other. Up to now, the Viedma ripening
process has had limited applications, given the finite number of molecules which meet the
two prerequisites. For finding conglomerates, several strategies have been proposed, but
the scope for racemization is still rather limited. Racemization strategies which have been
applied to Viedma ripening typically involve base catalysis,[5, 15–17] but this limits the op-
erations to acidic chiral carbons bearing protons that can be removed. The development of
2
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10.1002/chem.201904382
new racemization methods is therefore important and is the key to extend the applicability
of Viedma ripening to several other substrates. Photocatalysis is a powerful tool to promote
racemization of photosensitive organic compounds. The application of UV light to molecules
having sufficient absorbance in the UV region can lead to racemization by bond breakage or
by exciting the molecular orbitals, allowing rearrangements that are forbidden in the ground
state.[18] Up to now, a few successful examples of resolution via dynamic crystallization of
prochiral molecules racemizing under UV light starting from completely achiral conditions
have been reported.[19, 20] Here we aim to extend the application of Viedma ripening to
molecules racemizing by photocatalysis, and focus the attention on chiral BINOL deriva-
tives. This class of compounds is widely used as catalysts in organic synthesis, as templates
for chiral recognition and as building blocks for polymers and other molecules.[21, 22] These
compounds exhibit axial chirality, namely a bond around which rotation is hindered due to
large substituents in the closest positions, which are held in a spatial arrangement that is
not superimposable to its mirror image.[23] The photoracemization mechanism of BINOL
and its methyl ether was reported by Solntsev et al. in 2009.[24] They proposed that BINOL
derivatives bearing at least a free hydroxyl group reach the excited state upon irradiation
with UV light (337 nm), and undergo deprotonation via so-called intermolecular excited-
state proton transfer (ESPT) in the presence of a suitable base. The resulting binaphtholate
is the key achiral planar intermediate, leading to racemization after reprotonation to the hy-
droxyl moiety occurs. Inspired by these results we tested the combination of photo-induced
racemization and Viedma ripening, and we here demonstrate its successful application to
promote deracemization of a BINOL derivative. This research may pave the way for new
Viedma ripening applications to organic conglomerate-forming compounds that can undergo
photochemical racemization.
3
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2
Results and Discussion
2
.1 Conglomerate screening
As previously mentioned, one prerequisite for Viedma ripening is that the target compound
must crystallize as a conglomerate. Following the choice to use BINOL derivatives, based on
previous findings by Solntsev et al,[24] we focused on finding a conglomerate-forming target
compound. Compound 1, 2’-(benzyloxy)-[1,1’-binaphthalen]-2-ol (Figure 1) was previously
reported to manifest conglomerate behavior after crystallization in diethyl ether/hexane.[25]
However, in an attempt to reproduce this experiment, no conglomerate formation was ob-
served using diethyl ether/hexane as solvent/antisolvent composition. In fact, the compound
crystallized as a new racemic compound form, Figure 2a.
OH
O
Figure 1: rac-2’-(Benzyloxy)-[1,1’-binaphthalen]-2-ol (1).
Therefore, we searched for a crystal form of 1 that does show conglomerate behavior.
Recently, our group reported a systematic approach for predicting suitable coformers to ob-
tain stable cocrystals, some of which potentially being conglomerates.[26] However, given the
complexity that such coformers might add to the system, a convenient and simpler route to
explore conglomerate formation was to evaluate a library of different solvents that may give
rise to possible conglomerate solvates. Thus far, only one successful Viedma ripening der-
acemization involving a solvate had previously been reported, although that was a rare case
of a conglomerate co-crystal salt solvate.[27] Therefore, this work would represent a novel
example in which Viedma ripening was applied to a conglomerate solvate. To achieve this,
a crystallization screening was performed using approximately thirty solvents. As a result,
more than 70% of the crystallization experiments led to the stable, ansolvate racemic com-
pound form, Figure 2a. For a phase diagram study of compound 1, see Hoquante et al.[28]
4
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However, we found that compound 1 forms a conglomerate solvate when crystallization oc-
curred in toluene or chlorobenzene, displaying in both cases a similar crystal structure. As
shown in Figure 2b, two molecules of 1 coordinate one molecule of toluene in the asymmetric
unit. For all further racemization and deracemization experiments performed in this work
toluene was selected as the solvent of choice.
(
a)
(b)
Figure 2: a) the major conformation of the racemic ansolvate compound form. b) Crystal
packing of the solvate of 1 after crystallization in toluene (blue). Hydrogen atoms are
omitted for clarity. The two crystal structures are viewed along the a-axis and b-axis
respectively.
However, if a slurry of 1 was left longer than 24 hours in toluene, complete conversion
to the most stable racemic compound form occurred, which indicates that the conglomerate
is in fact metastable. A similar situation was previously reported by Spix et al., who
deracemized a metastable conglomerate of glutamic acid using Viedma ripening.[29]
2
.2 Racemization study
Xenon, mercury, deuterium and LED lamps were tested as potential light sources for the
racemization. Among them, the xenon UV lamp proved to be the best solution, having a
broad emission band covering both UV and visible regions. The UV-vis absorption spectrum
for 1 shows mainly three bands: a strong band at 230 nm, and two weaker bands at 285 and
3
35 nm, as also previously reported by Solntsev et al.[24] The solvents in which 1 crystallizes
as a conglomerate, toluene or chlorobenzene, also absorb in the UV region up to 285 nm
see UV-vis absorption spectrum in Supporting Information, Figure 6). Therefore parallel
(
5
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experiments were performed in both quartz and glass vials, as the latter show a cut-off of
radiation around 300 nm, and the respective effects and differences in the outcome of the
reactions were analyzed. Regardless the type of vial used, racemization was observed in
all experiments. Recalling the mechanism reported for BINOL and BINOL ethers,[24] we
report here a similar pathway for the target compound 1 (Figure 3).
Figure 3: Racemization mechanism proposed for compound 1. B indicates an organic
base.
Irradiation by UV light promotes compound 1 to its excited state, on which the ESPT
can occur. Deprotonation by suitable bases leads to a phenolate charged species, which is
in equilibrium with its achiral planar quinoidal form. Subsequently, reprotonation to the
hydroxyl moiety occurs, resulting in racemization of the starting enantioenriched material.
Some common organic bases, with pKa values between 11 and 14, were selected to be
screened for their ability to efficiently perform the ESPT. Figure 4 presents an overview of
racemization rates observed with different bases. Experiments were performed in toluene in
stoichiometric ratio or excess with respect to the substrate, using a xenon lamp as UV-vis
light source. Pyrrolidine and racemic sec-butylamine were finally considered to be the best
candidates, most likely because other bases with pKa values above 11 are too strong and
not suitable for allowing reprotonation to occur.
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Figure 4: Racemization rates with the use of different bases to promote the ESPT.
Two independent experiments using only the base or UV light were performed. No
change in the enantiomeric excess was observed, which remained constant at 100%, demon-
strating that the combination of base and UV light is essential for the racemization to
occur.
2
.3 Deracemization using Viedma ripening
Full conversion of the metastable conglomerate to the more stable racemic compound oc-
curred in about 24 hours, and thus Viedma ripening has to take place well within this time
frame. Experiments starting from racemic mixtures were not successful, due to the too long
deracemization time. Viedma ripening experiments were therefore performed starting from
a scalemic mixture (around 20% ee) in order to complete the deracemization more quickly.
Figure 5 shows the evolution of the ee during one of the Viedma ripening experiments. The
deracemization curve displays an initial steep increase of the ee, probably because of a rise
of the temperature due to the irradiation with UV light. After the temperature stabilizes
7
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to a value of about 40 °C, the amplification of the ee to reach (nearly) full enantiopurity is
decelerated. An ee of 96% was achieved in 4 hours. Analyses of the crystalline phase by
SFC (Supercritical Fluid Chromatography), coupled with UV-vis and mass analyzer detec-
tors, showed that no side products were present. XRPD measurements of the crystalline
compound, before and after the experiments, confirmed that during the deracemization the
crystals were consistently in their conglomerate form (see Supporting Information). Some of
the experiments, however, did not reach a complete enantiopurity probably due to a prema-
ture transformation of the conglomerate to the stable racemic compound form. In all cases,
the experiments were reproducible and successful both for pyrrolidine and sec-butylamine
as base, and deracemization was achieved in 4-5 hours.
Figure 5: Evolution of the ee during a Viedma ripening deracemization experiment. Pyrro-
lidine was the base used for this experiment.
Continued grinding under racemization conditions after deracemization was achieved,
however, led to a full conversion to the stable racemic compound, with a consequent drop of
the ee and loss of enantiopurity. Whereas ideally stopping the racemization, i.e. interrupting
the irradiation of the compound by UV light by simply switching off the UV lamp, would
8
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10.1002/chem.201904382
be sufficient to preserve enantiopurity of the crystals and allow for their collection, in the
present case some small conversion to the racemic compound still occurred. This is due to
a crystallization event taking place when the irradiation is stopped and the temperature
decreases, allowing the formation of crystals of the opposite enantiomer and also of the
racemic compound. Therefore, an ideal experiment is stopped by 1) harvesting and washing
the solid as soon as 100% ee is reached and 2) recrystallizing the final product in a different
solvent to allow the formation of a more stable form for the enantiomerically pure crystals.
In two cases, Viedma ripening experiments were started directly on the crude mixture
from the synthesis of 1, so containing residues such as the starting material (BINOL) and
the disubstituted side product. In presence of these “impurities”, the experiments proceeded
to completion in a much shorter time, leading in both cases to the final compound with (R)-
configuration. Steendam et al. already showed that the presence of small, chiral impurities
can steer the outcome of the deracemization and can speed up the process.[30] As recently
reported, a very small amount of chiral impurities can already be sufficient to halve the
deracemization time.[31]
3
Conclusions
We have reported here the first example of a photo-assisted Viedma ripening deracemization
using UV light. The compound investigated in this paper proved to be a metastable con-
glomerate solvate. A xenon lamp was the optimum light source as it has a broad emission
spectrum covering all UV absorption regions of the compound. Several bases were evaluated
for their ability to promote the subsequent ESPT, necessary for the racemization to occur.
Unlike a typical Viedma ripening experiment, an initial enantiomeric excess was required
to speed up the process to completion before the change of the metastable conglomerate
crystal phase to the stable racemic compound form occurred. This shows the importance
of detecting the different crystal forms of a specific compound when dealing with possible
metastable phases. Chiral impurities might be very helpful in the presence of metastable
conglomerates, when deracemization has to be completed in a short time frame. The appli-
9
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cation of Viedma ripening may be extended to other conglomerate-forming chiral organic
compounds which show racemization under UV light irradiation.
Experimental Section
Synthesis of the starting material
Racemic BINOL, (R)-BINOL, K2CO3 and benzyl bromide were purchased from Sigma-
Aldrich and used as received. Racemic and enantiopure 2’-(benzyloxy)-[1,1’-binaphthalen]-
2
-ol were synthesized following a reported procedure.[32] Racemic BINOL (500 mg, 1.75
mmol) or (R)-BINOL (500 mg, 1.75 mmol) was dissolved in ca. 15 mL of acetone, before
K2CO3 (2.62 mmol, 1.5 eq.) and benzyl bromide (1.75 mmol, 1 eq.) were added. The
solution was heated up to 60°C for about 4h until all the starting material was consumed,
monitored with TLC. The crude mixture was then concentrated under reduced pressure and
extracted with ethyl acetate (3×20 mL) and water. The organic phases were collected, dried
with magnesium sulfate and concentrated under reduced pressure. Column chromatography
(
heptane:ethyl acetate 8:2) was lastly used to collect the final product, recrystallized in
toluene to give a white powder (yield 80%). 1H NMR (400 MHz, chloroform-d) δ 7.91 (d,
J = 9.0 Hz, 1H), 7.87 – 7.83 (m, 1H), 7.80 (dt, J = 8.2, 0.9 Hz, 2H), 7.39 (d, J = 9.1 Hz,
1H), 7.33 – 7.26 (m, 2H), 7.24 (dt, J = 6.8, 1.3 Hz, 1H), 7.20 (dd, J = 6.7, 1.4 Hz, 1H),
7.15 (dddd, J = 8.2, 3.8, 3.0, 1.4 Hz, 2H), 7.10 (dt, J = 4.3, 1.6 Hz, 3H), 7.05 – 6.92 (m,
3
H), 5.12 – 4.93 (m, 2H), 4.85 (s, 1H). 13C NMR (100 MHz, chloroform-d) δ 154.94, 151.29,
136.92, 134.06, 133.82, 130.86, 129.83, 129.68, 129.15, 128.33, 128.13, 128.10, 127.65, 127.29,
126.89, 126.41, 125.04, 124.95, 124.43, 123.24, 117.50, 116.78, 115.94, 115.08, 77.02, 76.70,
71.13. XRPD diffractograms of the racemic and the enantiopure form were recorded using
a Bruker D8 Advance Diffractometer (see Supporting Information).
Racemization experiments
Experiments were performed at room temperature in 20 mL glass vials with cut-off of
radiation at 300 nm, as well as quartz vials. 25 mg of (R)-1 were dissolved in 3 mL of
10
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toluene, after which 1 eq. of the base was added to promote the ‘proton transfer’ mechanism,
and therefore the racemization. The solution was irradiated with a UV-xenon lamp 150
W and samples were taken every 10 minutes the first hour, and subsequently every 30
minutes. The lamp was positioned at a distance of about 20 cm from the vial used, to
prevent a drastic increase in the temperature at which the experiments took place. The
temperature measured during the experiments ranged from an initial 22 °C to a steady
value of 40 °C. The enantiomeric excess was measured using a Waters SFC (Supercritical
Fluid Chromatography), equipped with both UV and mass spectrometer detectors, on a
LUX amylose-1 column with a flow rate of 0.5 mL/min. Retention times were 2.2 min and
3
.2 min for the (S)- and (R)-enantiomers respectively. Chromatograms were recorded at
a wavelength of 230 nm, corresponding to the maximum absorption peak of the BINOL
derivative.
Deracemization experiments
Experiments were performed at room temperature in 20 mL glass vials with cut-off of
radiation at 300 nm, as well as quartz vials. An initial enantiomeric excess (ca. 20%)
was necessary to ensure that the deracemization process would reach completion before the
conversion to the more stable racemic compound crystals took place. A slurry was made
from 1.2 g of rac-1, 0.3 g of (R)-1 and 1.5 mL of toluene. Following a homogenization time
of about 15 minutes, 50 µL of the chosen base and 1 g Ø 2 mm glass beads were added.
The suspension was stirred at 700 rpm and then subjected to UV light exposure using a
UV-xenon lamp 150 W. The lamp was positioned at a distance of about 20 cm from the vial
used and the temperature measured during the experiments ranged from 22 °C to a steady
value of 40 °C. Placing the lamp closer to the vial resulted in complete dissolution of all solid
material, due to the heat produced by the lamp (nearly 50 °C). Samples were collected every
1
0 minutes for the first hour and then every 30 minutes, filtered off directly from the reaction
slurry and analyzed after being carefully washed with one or two drops of toluene. At the end
of the experiments, roughly 0.45 g of enantiopure material was collected, which represents a
net gain of half of the amount of enantiopure compound initially added. The enantiomeric
11
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excess was measured using a Waters SFC (Supercritical Fluid Chromatography), equipped
with both UV and mass spectrometer detectors, on a LUX amylose-1 column with a flowrate
of 0.5 mL/min. Retention times were 2.2 min and 3.2 min for the (S)- and (R)-enantiomers
respectively. Chromatograms were recorded at a wavelength of 230 nm, corresponding to
the maximum absorption peak of the BINOL derivative. No peaks of possible side products
forming during the exposure time were detected after SFC analyses. Characterization of
the final enantiopure product with XRPD showed an identical diffractogram as for the
starting material, indicating that the experiments were stopped in time before the crystals
would undergo any conversion to the racemic compound form. XRPD diagrams of all solid
samples collected during the deracemization experiments were also analyzed, to prove that
the toluene solvate compound was not converted.
CCDC Deposition Numbers 1940976-1940981 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/structures/.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors would like to thank Erik de Ronde for technical support. This research received
funding as part of the CORE ITN Project by the European Union’s Horizon 2020 Research
and Innovation Program under the Marie Sklodowska-Curie Grant Agreement No. 722456
CORE ITN.
Keywords
Chirality, crystal growth, deracemization, photoracemization, Viedma ripening.
12
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10.1002/chem.201904382
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10.1002/chem.201904382
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Chemistry - A European Journal
10.1002/chem.201904382
Table of Contents
In this work we present the application of UV light, as a “green” and cheap catalytic source,
to induce racemization in a Viedma ripening process and successfully yield enantiomerically
pure crystals of a BINOL derivative crystallizing as a metastable conglomerate solvate.
16
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