Chiral Symmetry Breaking of Spiropyrans and Spirooxazines by Dynamic Enantioselective Crystallization

Article abstract of DOI:10.1002/chem.201901889

Dynamic enantioselective crystallization enabled the chiral symmetry breaking of two spiropyrans and one spirooxazine. The three spiro compounds afforded racemic conglomerate crystals, and easily racemized in alcoholic solution without irradiation. Optically pure enantiomorphic crystals were obtained by vapor-diffusion crystallization or attrition-enhanced deracemization (Viedma ripening). Their absolute configurations were determined by single-crystal X-ray analysis and each enantiomorphic crystal was correlated with its solid-state circular dichroism (CD) spectrum.

Full text of DOI:10.1002/chem.201901889

A Journal of
Accepted Article
Title: Chiral Symmetry Breaking of Spiropyrans and Spirooxazines via
Dynamic Enantioselective Crystallization
Authors: Hiroki Ishikawa, Naohiro Uemura, Rei Saito, Yasushi Yoshida,
Takashi Mino, Yoshio Kasashima, and Masami Sakamoto
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To be cited as: Chem. Eur. J. 10.1002/chem.201901889
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10.1002/chem.201901889
Chemistry - A European Journal
RESEARCH ARTICLE
Chiral Symmetry Breaking of Spiropyrans and Spirooxazines via
Dynamic Enantioselective Crystallization
Hiroki Ishikawa,[a] Naohiro Uemura,[a] Rei Saito,[a] Yasushi Yoshida,[a][b] Takashi Mino,[a][b] Yoshio
Kasashima,[c] Masami Sakamoto*[a][b]
R1
Abstract: Chiral symmetry breaking of two spiropyrans and one
or
ν
ν
X
∆
∆
h
spirooxazine was performed by dynamic enantioselective
crystallization. The three spiro-compounds afforded racemic
conglomerate crystals, and easily racemized in alcoholic solution
without irradiation. Vapor-diffusion crystallization or attrition-
enhanced deracemization (Viedma ripening) gave optically pure
enantiomorphic crystals. Their absolute configurations were
determined by X-ray single crystal analysis and each enantiomorphic
crystal was correlated with its solid-state CD spectrum.
1
R3
N
O
or
h
2
R2
X = CH: Spiropyran
X = N: Spirooxazine
−
O
O
R3
R3
R1
R1
X
X
N+
R2
Introduction
N
R2
Spiropyrans and spirooxazines belong to a series of valuable
photochromic materials that undergo ring-opening and -closing
reactions by photoirradiation or thermal processes (Scheme 1).[1]
The spiro-carbon compounds are chiral; however, their
asymmetric synthesis has not been achieved except by optical
resolution using a chiral HPLC stationary phase.[2] This illustrates
the difficulty of the asymmetric synthesis, due to either the stability
of the chiral spiro-carbon atoms or the control of the asymmetric
environment by chiral materials.
We focused on the development of optically active spiropyrans
and spirooxazines via dynamic enantioselective crystallization.[3]
Dynamic enantioselective crystallization is also called total optical
resolution, and optically pure enantiomorphic crystals can be
obtained by only one crystallization (Figure 1).[4] The optical
resolution method can be applied to racemic conglomerate
crystals with fast racemization under the crystallization
conditions.[5] Valuable successful examples have been reported
for amino acid derivatives,[6] pharmaceutical materials,[7] and
axially chiral materials.[8]
merocyanine form
Scheme 1. Photochromism of spiropyrans and spirooxazines by ring-opening
and -closing reactions.
Dynamic crystallization via racemization by ring-opening and -
closing processes has been reported as a successful method for
asymmetric amplification of isoindolinones[9] and pyrrolinones[10]
having an aminal chiral center, but there are no reports of
asymmetric amplification reactions by racemization of spirocyclic
ring systems such as spiropyrans.
fast racemization in liquid phase
S
R
crystallization
or
S
R
enantiomorphic
conglomerate crystals
[a]
Mr. H. Ishikawa, Miss R. Saito, Mr. N. Uemura, Prof. Y. Yoshida,
Prof. T. Mino, and Prof. M. Sakamoto.
Department of Applied Chemistry and Biotechnology, Graduate
School of Engineering, Chiba University,
Figure 1. Chiral symmetry breaking by dynamic enantioselective crystallization.
Yayoi-cho, Inage-ku, Chiba, 263-8522 Japan
E-mail: sakamotom@faculty.chiba-u.jp
[b]
[c]
Prof. Y. Yoshida, Prof. T. Mino, Prof. M. Sakamoto.
Molecular Chirality Research Center, Chiba University
Yayoi-cho, Inage-ku, Chiba, 263-8522 Japan
Prof. Y. Kasashima
Education Center, Faculty of Creative Engineering
Chiba Institute of Technology
Results and Discussion
There are two requirements for asymmetric amplification by
dynamic crystallization. One is that the compound forms a
racemic conglomerate.[4,5] The second is that under conditions for
crystallization, it is necessary for the fast racemization to proceed
in the mother liquor. If these conditions are not met, asymmetric
Shibazono, Narashino, Chiba 275-0023, Japan
Supporting information for this article is given via a link at the end of
the document.
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amplification by dynamic crystallization cannot be achieved. In
this study, spiropyrans 1 and 2 and spirooxazine 3, whose crystal
structures are registered in the CCDC, were targeted, and
determination of their absolute structures by reexamination of
their crystal structures and symmetry breaking by crystallization
were investigated (Figure 2).
exhibited small absorptions from 480 to 630. Spirooxazine 3
showed a small absorption band around 550 to 630 nm in
methanol and MeCN solutions. 1H NMR spectra indicated that all
of these materials existed in closed form; however, these
observations in the absorption spectra strongly supported that all
the spiropyran analogs 1-3 were in equilibrium between the ring-
opened and merocyanine forms, especially in polar solvents.
N
O
Cl
N
O
NO2
Br
1
2
N
N
O
O
3
Figure 2. Examined spiropyrans 1 and 2 and spirooxazine 3 for chiral symmetry
breaking.
Figure 4. UV-VIS spectra of 1 (blue line), 2 (red line), and 3 (green line) in
cyclohexane (dotted line), MeCN (broken line), and MeOH (solid line) at 1.0 x
10-4 M.
We expected that 1) spiropyran derivatives would be transformed
to their respective colored merocyanine forms by UV irradiation or
solvation in a polar solvent (Scheme 1), and 2) these ring-opening
merocyanines could return to the colorless spiropyran forms
under the same conditions. The ring-opening and –closing
processes involve the racemization of these materials.
The three spiropyran derivatives 1-3 were synthesized according
to reported procedures.[11-13] All of them were obtained as
yellowish solids. Figure 3 shows a photo of the compounds in both
hexane and methanol. Spropyran 1 afforded a blue solution in
methanol, whereas the hexane solution presented as slightly
yellow (almost colorless). Spiropyran 2 was colorless in hexane
and slightly pink in methanol. The hexane solution of 3 was yellow,
and the MeOH solution exhibited a green color. In all of the
compounds, it was suggested that the merocyanine forms existed
in MeOH solution by the progress of the ring-opening reaction
without light irradiation.
Next, each racemic mixture was analyzed by HPLC using a chiral
column. CHIRALCEL® OD-H (Daicel Ind.) was selected for the
analysis of spiropyran 1 using hexane as an eluent. Spiropyran 2
was measured using CHIRALPAK® IF-3 (Daicel Ind.) with
hexane:EtOH = 99:1 as an eluent, and spirooxazine 3 was
separated using CHIRALPAK® IE-3 (Daicel Ind.) with
hexane:EtOH = 99:1 (Fig. 5). The enantiomeric peaks of 1 were
completely fused at 20 °C, and even when cooled down to 10 °C,
complete separation was difficult. The peaks for racemic 2 could
be separated by cooling to 10 °C, but a plateau was observed
above 20 °C. The racemization of 3 was relatively slow, and the
enantiomeric peaks could be observed completely separated at
room temperature, whereas a plateau was observed when the
measurement temperature was raised above 35 °C.
(a)
(b)
(c)
(a)
(b)
(c)
(d)
(e)
(f)
Figure 3. Photo of solutions of spiro compounds. (a) 1 in hexane, (b) 1 in MeOH,
(c) 2 in hexane, (d) 2 in MeOH, (e) 3 in hexane, and (f) 3 in MeOH.
Figure 5. HPLC analysis at 254 nm of 1-3 at various temperatures. (a)
Spiropyran 1 at 20, 15 and 10 oC using CHIRALCEL® OD-H (eluent, hexane
100%); (b) Spiropyran 2 at 30, 20 and 10 oC using CHIRALPAK® IF-3 (eluent,
hexane:EtOH
CHIRALPAK® IE-3 (eluent, hexane:EtOH = 99:1).
Figure 4 shows the UV-VIS spectra of 1-3 in cyclohexane,
acetonitrile, and methanol solutions. Although there was no
remarkable difference between the three solvents in the wave-
length region under 450 nm, the methanol solution of 1 exhibited
absorption from 450 to 670 nm. The spectra of 2 showed a long
wavelength shift in MeCN and methanol compared with the
cyclohexane solution. Furthermore, solutions in MeCN and MeOH
= 99:1); (c) Spirooxazine 3
at 45, 35 and 15 oC using
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Racemization will also take place by UV irradiation via their
merocyanine forms. Actually, all these spiro compounds in
hexane solution were colored in blue by UV irradiation, and the
color gradually faded by closing to spiro forms even at room
temperature. For asymmetric amplification by dynamic
crystallization the fast racemization is necessary, then, the
thermal racemization was selected.
using Viedma ripening.[14,15] A small amount of methanol, glass
beads, and a stirrer bar were added to the racemate crystals of 2
and they were suspended with stirring in a sealed vessel at 45 °C.
After 7 days, asymmetric amplification was observed to form
crystals of 95% ee. However, it was impossible to determine the
exact ee, because racemization of 2 proceeded gradually even at
room temperature in solution, and a slight plateau was observed
even when the HPLC column was cooled to 0 °C (Figures S4 and
S5). The solid-state CD spectra of both enantiomers yielded
symmetrical spectra (Figure 7-(b)).
Based on the above results, we examined the chiral symmetry
breaking of 1-3 by dynamic crystallization (Figure 6). First,
dynamic crystallization was performed by the solvent evaporation
method.[8-10] Each solid of 1-3 was dissolved in methanol and
crystallized by evaporating the solvent with stirring at room
temperature. The solid-state CD spectrum of the obtained crystal
was measured to judge whether it converged preferentially to any
optically active substance. When the crystallization was repeated
several times, 2 and 3 consistently formed only a racemic mixture,
but 1 converged on one of the enantiomer crystals. The probability
of forming crystals of each enantiomer was almost the same.
When enantiomorphic crystals were added as seed crystals
during the formation of the crystal nuclei, crystals of the same
enantiomer as the added seed crystals were obtained selectively.
There are many examples of controlling the directionality of chiral
crystallization by this seeding method, under the principle that the
added seed crystals grow as crystal nuclei, and the crystals
differentiated by stirring further grow as nuclei. In the mother
liquor, the racemization always occurs by the ring-opening and -
closing process, which prevents excess crystals of the opposite
enantiomer of the grown crystals. In Figure 7-(a), KBr pellets of
crystals of 1 obtained from different batches were prepared and
the solid-state transmission CD spectra were measured.
Racemization in solution phase via ring-opening and -closing reactions
−
O
R3
R1
X
N+
R2
∆
∆
Figure 7. Solid-state CD spectra of enantiomorphic crystals in KBr pellets. (a)
Enantiomorphic crystals of 1. (b) Enantiomorphic crystals of 2. (c)
Enantiomorphic crystals of 3.
∆
∆
R1
R1
X
X
R3
R3
N
N
O
O
R2
R2
dynamic
enantioselective
crystallization
(R)-crystal
(S)-crystal
Figure 6. Chiral symmetry breaking of spiropyrans via dynamic enantioselective
crystallization.
Figure 8. Attrition-enhanced deracemization of 3. (a) Experiment was
performed at 35 ºC. (b) Experiment was performed at 55 ºC.
With respect to spiropyran 2 and spirooxazine 3, which did not
converge to one enantiomer by the solvent evaporation
crystallization method, asymmetric amplification was examined
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We also succeeded in chiral symmetry breaking of spirooxazine
3 in the same manner as 2 by attrition-enhanced deracemization
(Viedma ripening) of racemate crystals. When 3 was suspended
with a small amount of methanol and glass beads at 35 °C, the
optical purity of the crystals started to increase from the 5th day
and turned to 99% ee crystals on the 10th day as shown by a
sigmoid curve (Figure 8). When the temperature was raised and
the mixture was suspended at 55 °C, asymmetric amplification
rapidly began on the second day, and on the third day, 99% ee of
the crystals was obtained. The experiment was repeated several
times, and it was confirmed that the probability of tilting to either
enantiomer crystal was about 1:1 and that the directionality of the
asymmetric amplification could be controlled by starting with a low
ee of crystals (< 2% ee). The solid-state CD spectra of both
enantiomers exhibited symmetrical spectra (Figure 7-(c)).
254 nm (Figures S4 and S5). In the case of crystal 3, the
measured crystals were in the S form of the P212121 space group,
and in the solid CD spectrum, the crystals exhibited (+) in the long
wavelength region (380 nm or more). Furthermore, the sign was
detected as (-) with a 254 nm CD detector by HPLC analysis
(Figures S6 and S7).
The rates of racemization were measured for the optically active
substances 1-3 obtained by chiral symmetry breaking.
Racemization of 1 was too fast to determine. We also tried to
determine the rate by dynamic NMR studies; however, the fusion
of the diastereotopic peaks could not be obtained under 150 °C.
For 2, the decay of the optical purity in MeOH at 0 °C was
determined by HPLC analysis. The activation free energy of
racemization was 20.9 kcal moL-1, and the half-life was 53.0 min,
indicating that 2 readily racemized at room temperature. For 3,
the activation parameters of racemization in chloroform and
MeOH were measured (Table S1 and S2). The activation free
energy of racemization in chloroform at 25 °C was 23.02 kcal moL-
(S)
1
N
and the half-life was 69 min. On the other hand, the activation
O
Cl
free energy of racemization in MeOH at the same temperature
was 22.96 kcal moL-1, the half-life was 63 minutes, and the
difference due to the solvent was not as large. According to the
increase of temperature, the activation free energy and the half-
life decreased. The half-life at 35 °C was 14 minutes in chloroform
and 17 minutes in methanol.
Br
1
P4
)
3
S
( )-
(
(S)
N
O
NO2
Conclusion
2
P2 2 2
)
1
S
( )-
(
1
1
Chiral symmetry breaking of spiropyrans 1, 2 and spirooxazine 3
could be achieved by dynamic crystallization involving
a
N
(S)
racemization reaction via a ring-opening and -closing process.
The solid-state CD spectrum of each enantiomorphic crystal of
the two spiropyran and one spirooxazine forming conglomerates
was measured by dynamic enantioselective crystallization. We
also succeeded in establishing their absolute structures by single
crystal X-ray structural analysis, which were correlated with solid-
state CD spectra and HPLC analysis. The racemization of 1 in
solution was too fast to analyze, but 2 and 3 confirmed the stability
of the chiral spiro-carbons. These processes are of great interest
to many scientists in a variety of areas, e.g., chiral symmetry
breaking could support the hypothesis of the origin of
homochirality on the primitive Earth.[16] This study provides the
first successful example of chiral symmetry breaking of
spiropyrans.
N
O
O
3
P
212121
S
( )-
(
)
Figure 9. Single crystal X-ray structure analysis of 1-3. (a) Perspective view of
(S)-1. (b) Perspective view of (S)-2. (c) Perspective view of (S)-3.
Next, their absolute configurations were determined by X-ray
single crystal analysis and each enantiomorphic crystal was
correlated with the CD spectrum. The crystal space group of (S)-
1 is P43 (Figure 9), and it is (+) in the wavelength range of 250 to
300 nm and 350 nm or more in the solid state CD spectrum
(Figure 7-(a)). For compounds 2 and 3, single crystal structure
analysis was associated with the peak sign of HPLC analysis
equipped with a CD detector, and furthermore, the signatures of
the optical rotations at 254 nm were correlated with the solid state
CD spectra. A relatively large crystal was prepared by the vapor
diffusion method using chloroform and hexane, and X-ray
crystallographic analysis was performed on part of the single
crystal to determine the absolute structure. The remaining part
was subjected to HPLC analysis and was also correlated with the
solid-state CD spectra. The space group of the crystal of 2 was
P212121 and the S form crystal showed a (+) optical rotation in the
wavelength range of 320 nm or more in the solid-state CD
spectrum. HPLC analysis showed a (-)-sign when measured at
Experimental Section
Preparation and characterization of spiropyrans 1-3. Three spiro
compounds were synthesized according to the reported procedures.[11-13]
Crystallization of 1 by the solvent evaporation method. In a vial, spiropyran
1 (50 mg) and methanol (1.0 mL) were stirred at 25 ºC until all solvent was
removed. The remaining solid was analyzed by solid-state CD
spectroscopy.
Attrition-enhanced deracemization of 2. In a sealed tube (L = 200 mm, Φ
= 25 mm), solid spiropyran 2 (100 mg) and methanol (0.5 mL) were kept
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RESEARCH ARTICLE
in suspension by stirring at 600 rpm for several days with glass beads (250
mg) at 45 ºC. The change of ee value of the crystalline material was
monitored by HPLC using a chiral column, CHIRALPAK® IF-3 (eluent,
hexane:EtOH = 99:1). Finally, crystalline 2 (>95% ee) was obtained after
7 days.
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Acknowledgements
This work was supported by Grants-in-Aid for Scientific Research
(Nos. 17K19114 and 16H04144) from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT) of the
Japanese Government. Mr. Uemura acknowledges financial
support from Frontier Science Program of Graduate School of
Science and Engineering, Chiba University.
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Keywords: chiral symmetry breaking • spiropyran • spirooxazine
• deracemization • dynamic crystallization
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10.1002/chem.201901889
Chemistry - A European Journal
RESEARCH ARTICLE
N. Uemura, S. Toyoda, H. Ishikawa, Y. Yoshida, T. Mino, Y. Kasashima,
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10.1002/chem.201901889
Chemistry - A European Journal
RESEARCH ARTICLE
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RESEARCH ARTICLE
Racemization in solution phase via ring-opening and -closing reaction
Chiral symmetry breaking of two
Hiroki Ishikawa, Naohiro Uemura,
Rei Saito, Yasushi Yoshida,
Takashi Mino, Yoshio Kasashima]
Masami Sakamoto*
−
O
spiropyrans and one spirooxazine
was performed by dynamic
enantioselective crystallization.
R3
R1
X
N+
R2
The
three
spiro-compounds
∆
∆
Page No. – Page No.
afforded racemic conglomerate
crystals, and easily racemized in
∆
∆
R1
R1
Chiral Symmetry Breaking of
Spiropyrans and Spirooxazines
via Dynamic Enantioselective
Crystallization
X
X
alcoholic
solution
Vapor-diffusion
or attrition-
deracemization
without
R3
R3
N
N
O
O
irradiation.
crystallization
enhanced
R2
R2
dynanic
enantioselective
crystallization
(Viedma ripening) gave optically
pure enantiomorphic crystals.
(R)-crystal
(S)-crystal
or
This article is protected by copyright. All rights reserved.