Asymmetric autocatalysis triggered by triglycine sulfate with switchable chirality by altering the direction of the applied electric field

Article abstract of DOI:10.1039/d1cc02162a

Triglycine sulfate (TGS) acts as a chiral trigger for asymmetric autocatalysis with amplification of enantiomeric excess,i.e., the Soai reaction. Therefore, molecular chirality of highly enantioenriched organic compounds is controlled by a ferroelectric crystal TGS, whose polarization is altered by an electric field.

Full text of DOI:10.1039/d1cc02162a

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21 June 2021
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Kenso Soai et al.
Asymmetric autocatalysis triggered by triglycine sulfate with
switchable chirality by altering the direction of the applied
electric field

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Asymmetric autocatalysis triggered by triglycine
sulfate with switchable chirality by altering the
direction of the applied electric field†
a
Cite this: Chem. Commun., 2021,
57, 5999
Received 23rd April 2021,
Accepted 13th May 2021
Tsuneomi Kawasaki,
Yoshiyasu Kaimori,a Seiya Shimada,a Natsuki Hara,a
Susumu Sato,a Kenta Suzuki,a Toru Asahi,b Arimasa Matsumoto‡a and
ac
DOI: 10.1039/d1cc02162a
Kenso Soai
*
rsc.li/chemcomm
Triglycine sulfate (TGS) acts as a chiral trigger for asymmetric been no apparent example of the control of molecular chirality
autocatalysis with amplification of enantiomeric excess, i.e., the in enantioselective reaction by a ferroelectric crystal, whose
Soai reaction. Therefore, molecular chirality of highly enantioen- chirality is induced by the application of a static electric field,
riched organic compounds is controlled by a ferroelectric crystal an achiral physical force.
TGS, whose polarization is altered by an electric field.
Here, we describe the asymmetric autocatalysis of 5-pyri-
midyl alkanol (the Soai reaction)12,16,19–24 initiated with
Control of molecular chirality by the application of physical force ferroelectric triglycine sulfate (TGS: (NH2CH2COOH)3ꢀH2SO4)
is one of the most challenging topics in science,1–3 and this crystal, whose handedness is controlled by the application of a
approach can provide a new methodology for enantioselective static electric field (Fig. 1).
synthesis.4–7 The induction of chirality by physical force8 is an
We first reported asymmetric autocatalysis with amplifica-
important topic to consider with respect to the origin of biological tion of ee as a real chemical reaction.16 When diisopropylzinc
homochirality,9 which continues to attract tremendous attention (i-Pr2Zn) addition to pyrimidine-5-carbaldehyde 1 was per-
from scientists in many fields of research.10–12 An electromagnetic formed in the presence of a catalytic amount of pyrimidyl
force is often considered a possible inducer of molecular chirality alkanol 2 with a very low ee (ca. 0.00005% ee), asymmetric
because electromagnetic waves can directly interact with organic autocatalysis could enhance the ee significantly to produce a
molecules. Actually, chiral electromagnetic force, circularly pola- final product with very high ee (499.5% ee).25 Asymmetric
rized light (CPL), can induce enantioselective decomposition13 autocatalysis, named as the Soai reaction,19,20 has enormous
and reactions14 of organic compounds, and asymmetric amplifi- power to recognize and amplify small chiral imbalances such as
cation during the crystallization15 or asymmetric autocatalysis16,17 carbon isotope chirality7 and crystal chirality;26,27 therefore,
can provide chiral organic products with a high enantiomeric asymmetric autocatalysis can connect the proposed origins of
excess (ee) initiated by CPL irradiation. Furthermore, recent chirality with enantiomerically enriched organic compounds.12
observations have experimentally demonstrated that the combi- To induce molecular chirality using the controlled chirality of
nation of path direction of linearly polarized light and magnetic TGS, asymmetric autocatalysis of 5-pyrimidyl alkanol
2
field can provide chiral effects leading to the formation of (its isopropylzinc alkoxide 20) in the addition reaction of
enantioenriched compounds.3,18 To our knowledge, there has i-Pr2Zn to pyrimidine-5-carbaldehyde 1 was performed with
TGS operating as a chiral trigger (Fig. 1b). We assumed that
this reaction would allow the crystal chirality of TGS to be
discriminated and afford highly enantioenriched product with
a Department of Applied Chemistry, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo, 162-8601, Japan. E-mail: soai@rs.kagu.tus.ac.jp
b Department of Life Science and Medical Bioscience, Waseda University (TWIns),
the handedness corresponding to TGS.
TGS (Fig. 2a) is a well-known ferroelectric crystal.28 Crystals
Wakamatsu-cho, Shinjuku-ku, Tokyo, 162-8480, Japan
c Research Organization for Nano & Life Innovation, Waseda University,
of this compound exhibit spontaneous electric polarization and
polarities, which can be controlled by the application of an
external static electric field. Moreover, crystals of TGS have
chirality even though the components including glycine and
sulfate ions are achiral. However, chiral crystals of TGS have
rarely been used as a chiral source for enantioselective reac-
tions despite their wide application as a ferroelectric material.
Wasedatsurumaki-cho, Shinjuku-ku, Tokyo, 162-0041, Japan
† Electronic supplementary information (ESI) available: Experimental methods,
crystallographic data, ortep drawings of P/M-triglycine sulfate and photo of
powdered TGS. CCDC 1993618 and 1993609. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/d1cc02162a
‡ Present address: Department of Chemistry, Biology and Environmental Science,
Nara Women’s University, Kita-Uoya Nishi-machi, Nara, 630-8506, Japan.
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TGS crystal belongs to the monoclinic P21 space group
(a = 9.44 Å, b = 12.6 Å, c = 5.74 Å, b = 1101),29 which does not
have inversion or mirror symmetry (Fig. 2b and Fig. S1, S2,
ESI†). There are three symmetrically independent glycine mole-
cules in a unit cell. One glycine molecule (glycine II) exists in
the zwitterion form and has a large torsion angle of ca. +211
(P-conformation) or ꢁ211 (M-conformation) for the N–C–C–O
bond, whereas the other two glycine molecules (glycines I and
III) exist as almost planar structures in the protonated form.
The twisted glycine II induces crystal polarity because no
symmetry operator can invert or rotate the b-axis direction in
the P21 space group. Typically, TGS crystals that are grown from
an aqueous solution are twinned crystals of both domains, in
which spontaneous polarizations align parallelly or anti-
parallelly to the b-axis. The ferroelectricity is induced by
expanding and shrinking these twin domain areas in the crystal
in an electric field. The important point is that the symmetrical
relationship between these two domains is not a 1801 rotation
but a reflection.30 This means that the electric field application
also inverts the crystal chirality in addition to the polarity under
an electric field.
To examine the control of chirality of TGS, we prepared
single crystals of TGS and undertook an absolute structure
determination by single-crystal X-ray diffraction analysis after
the application of an electric field. The naturally grown TGS
obtained from the slow evaporation of an aqueous solution of
sulfuric acid and glycine was elongated in the [010] direction
Fig. 1 Concept and scheme of the present work: (a) control of the
absolute molecular chirality by selecting the direction of the static
electric field applied to triglycine sulfate (TGS) and asymmetric auto-
%
%
and had well-developed {101} faces with characteristic {01},
%
catalysis with amplification of ee. (b) Asymmetric autocatalysis of 5- {110} and {201} faces (Fig. 2a). When the crystal is placed with
pyrimidyl alkanol 2 induced by P- and M-TGS as a heterogeneous
chiral trigger, leading to highly enantioenriched (R)- and (S)-alkanol 2,
respectively.
%
% %
%
the (011) and (011) faces up and triangle (201) face down
%
against the large front (101) surface, the polar b-axis was
directed and left in this axis setting. The crystal was sliced
Fig. 2 The chirality of TGS and its control by application of a static electric field. (a) Morphology of a single crystal of TGS [(NH2CH2COOH)3ꢀH2SO4].
(b) Comparison of the enantiomorphs of TGS at the molecular level and the twisted chiral structure of one glycine (glycine II) among three glycines in the
crystal lattice. (c) The absolute correlation between the direction of the applied electric field and the crystal chirality of the resulting TGS. (d) The control
of the chirality of TGS by switching the direction of the applied static electric field to one specific piece of TGS.
6000 | Chem. Commun., 2021, 57, 5999–6002
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Table 1 Asymmetric autocatalysis initiated with a TGS crystal after appli-
cation of an electric field. Series A: M- and P-TGS submitted to the
asymmetric autocatalysis were prepared by applying parallel and anti-
parallel electric fields to the sliced two pieces of TGS originating from one
specific single crystal, respectively (see also Fig. 2c). Series B: P- and M-
TGS submitted to the asymmetric autocatalysis were prepared by applying
parallel and anti-parallel electric fields successively to one specific sliced
piece of TGS (see also Fig. 2d)
perpendicular to the b-axis to give {010} surfaces (Fig. 2c). And a
static electric field was applied to this by attaching conductive
Cu tape on the {010} faces for poling the crystal. The chirality of
the resulting crystal was confirmed by anomalous dispersion
measurements in single-crystal X-ray diffraction analysis for
several points of the crystal, which revealed that the absolute
crystal chirality of TGS was well-controlled by this method even
in the bulk size slice of the crystal (ca. 4 cm long and 5–7 mm
thick). When the electric field was applied antiparallel to the
b-axis, the handedness of the resulting crystal was the
M-conformation, and generation of the opposite P-
conformation was observed when the electric field was applied
parallel to the b-axis. The Flack parameter with inversion twin
refinement is typically estimated to be around 0.1–0.2 with the
standard uncertainty around 0.1. The results mean that the
glycine molecules predominantly twist in one direction and
have controlled chirality by the electric field (ca. 60–80%
crystal ee).
TGS
Pyrimidyl alkanol 2
Single-crystal
batch
Direction of
E
Yield
Chirality (%)
ee (%)
Config.
Run
Series A
1
2
3
4
5
6
7
#1
#1
#2
#2
#3
#3
#4
-
’
-
’
-
’
-
M
P
M
P
M
P
M
73
62
41
50
69
74
65
68
43
40
76
39
S
R
S
R
S
R
S
67 (87)a 44
(499.5)a
80 (95)a 54
(499.5)a
8
#4
’
P
R
A mixture of pyrimidine-5-carbaldehyde 131,32 and TGS was
ground into a powder using a pestle and mortar, and then
i-Pr2Zn was added dropwise. Furthermore, asymmetric auto-
Series B
#5
10b #5
9
’
P
M
P
91
91
85
89
92
R
S
R
S
’ then -
’
’ then -
91
88
93
catalysis by subsequent addition of aldehyde 1 and i-Pr2Zn to 11 #6
12c #6
M
the mixture gave highly enantioenriched 5-pyrimidyl alkanol 2
a
by the amplification of ee (Fig. 1b). When the reaction was
performed in the presence of M-TGS, obtained from the appli-
cation of an electric field parallel to the b-axis, (S)-pyrimidyl
alkanol 2 was obtained with 65% ee (Table 1, series A, run 1). In
contrast, P-TGS was produced as a result of the application of a
static electric field from the direction antiparallel to the b-axis,
giving oppositely configured (R)-alkanol 2 with 68% ee after the
amplification of the ee by asymmetric autocatalysis (run 2).
These results demonstrate that the direction of the static
electric field can be used to control the molecular chirality of
organic compounds through chiral ferroelectric TGS and asym-
metric autocatalysis. It should be noted that P- and M-TGS used
in the experiments detailed in runs 1 and 2 were generated
from the one specific mother single crystal (crystal #1) by the
application of oppositely directed static electric fields. The
sense of enantioselectivity between TGS and alkanol 2 was
reproducible, as shown in runs 3–6. Moreover, the ee of product
2 could be enhanced to near enantiopure levels (499.5% ee) by
conducting additional rounds of asymmetric autocatalysis, as
shown in runs 7 and 8.
It was also found that the chirality of the same piece of TGS
crystal is controlled repeatedly by applying the parallel and
anti-parallel electric field successively (Fig. 2d and Table 1,
series B). Thus, to confirm the stereochemical relationship
between the direction of the electric field and the molecular
handedness of the product of the asymmetric autocatalysis,
switching experiments with chiral TGS and its use as a chiral
trigger for asymmetric autocatalysis were conducted (Table 1,
runs 9–12). After the application of an electric field parallel to
the b-axis, half of the resulting P-crystal piece was used for the
asymmetric autocatalysis affording (R)-product 2 with 92% ee
(series B, run 9). The other piece was exposed to the electric
field directed in the opposite direction, leading to its
Additional rounds of asymmetric autocatalyses were performed to
b
amplify the ee value significantly. TGS crystal #5 was first applied with
the static electric field parallel to the b-axis of TGS. The resulting P-TGS
was used in run 9. The chirality of the same P-TGS crystal in run 9 was
switched to M by applying the static electric field of the opposite
c
direction of anti-parallel to the b-axis of TGS. TGS crystal #6 was
treated in the same manner with the footnote b.
reconstruction as the opposite M-enantiomorph, which was
also used as a chiral trigger for asymmetric autocatalysis. As a
result, the enantioselectivity of the reaction was reversed to
form the opposite (S)-alkanol 2 with a high 91% ee after
significant amplification of the ee by asymmetric autocatalysis
(run 10). The results were reproducible, as shown in runs 11
and 12. Therefore, the switch of the direction of the electric
field is responsible for the change in the absolute configuration
of the resulting product of asymmetric autocatalysis via
ferroelectric TGS.
In summary, we have demonstrated that ferroelectric TGS,
whose chirality is switchable by changing the direction of the
applied static electric field, can induce a highly enantioselective
synthesis through the significant amplification of ee by asym-
metric autocatalysis of 5-pyrimidyl alkanol. The direction of an
achiral static electric field and highly enantioenriched organic
products were successfully linked with each other via the
ferroelectric crystal of TGS; therefore, the present results pro-
vide new insight into the origin and amplification of biological
homochirality.
The authors thank Yuko Araki, Kunihiko Hatase and Koichi
Abe for the preliminary experiments. This work has been
financially supported by Grant-in-Aid for Scientific Research
from Japan Society for the Promotion of Science (JSPS
KAKENHI Grant Numbers 23685012, 26810026, 15H03781,
18H04518, 19K05482 and 19K22190, Grant-in-Aid for JSPS
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