Direct Detection of Hardly Detectable Hidden Chirality of Hydrocarbons and Deuterated Isotopomers by a Helical Polyacetylene through Chiral Amplification and Memory

Article abstract of DOI:10.1021/jacs.7b10981

We report the first direct chirality sensing of a series of chiral hydrocarbons and isotopically chiral compounds (deuterated isotopomers), which are almost impossible to detect by conventional optical spectroscopic methods, by a stereoregular polyacetyle

Full text of DOI:10.1021/jacs.7b10981

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Article
Direct Detection of Hardly Detectable Hidden Chirality of
Hydrocarbons and Deuterated Isotopomers by a Helical
Polyacetylene through Chiral Amplification and Memory
Katsuhiro Maeda, Daisuke Hirose, Natsuki Okoshi, Kouhei Shimomura,
Yuya Wada, Tomoyuki Ikai, Shigeyoshi Kanoh, and Eiji Yashima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10981 • Publication Date (Web): 11 Jan 2018
Downloaded from http://pubs.acs.org on January 12, 2018
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JACS Article
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Direct Detection of Hardly Detectable Hidden
Chirality of Hydrocarbons and Deuterated
Isotopomers by a Helical Polyacetylene through
Chiral Amplification and Memory
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Katsuhiro Maeda,†,§,* Daisuke Hirose,† Natsuki Okoshi,† Kouhei Shimomura,† Yuya Wada,†
,
Tomoyuki Ikai,† Shigeyoshi Kanoh,† and Eiji Yashimaꢀ *
†Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan, §WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan, and ꢀDepartment of Molecular and Macromolecular
Chemistry, Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603,
Japan
ABSTRACT: We report the first direct chirality sensing of a series of chiral hydrocarbons and
isotopically-chiral compounds (deuterated isotopomers), which are almost impossible to detect by
conventional optical spectroscopic methods, by a stereoregular polyacetylene bearing 2,2’-biphenol-
derived pendants. The polyacetylene showed a circular dichroism due to a preferred-handed helix
formation in response to the hardly detectable hidden chirality of saturated tertiary or chiroptical
quaternary hydrocarbons, and deuterated isotopomers. In sharp contrast to the previously reported
sensory systems, the chirality detection by the polyacetylene relies on an excess one-handed helix
formation induced by the chiral hydrocarbons and deuterated isotopomers via significant
amplification of the chirality followed by its static memory, through which chiral information of the
minute and hidden chirality can be stored as an excess of a single-handed helix memory for a long
time.
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INTRODUCTION
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Chirality is critical for vital functions in living systems at the molecular, macromolecular, and
supramolecular levels because of the homochirality of biological polymers and components.
Therefore, a pair of enantiomers often shows quite different biological activities in living systems.
Hence, the development of facile and sensitive methods for the detection and assignment of the
chirality of a variety of chiral molecules has become one of the emerging research areas in chemistry,
pharmacy, and biology as well as in physics.
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A variety of achiral or dynamically racemic, but chromophoric receptors and helical polymers
have been developed for this purpose using circular dichroism (CD) spectroscopy, one of the most
powerful tools for detecting the chirality and/or optical activity of nonracemic (optically-active)
molecules.1 Upon complexation with nonracemic guests, a characteristic, exciton-type coupled
Cotton effect is induced in the absorption regions of the chromophoric receptors and polymers
resulting from generation of one of the enantiomeric or diastereomeric chiral conformers, which
enables the prediction of the absolute configurations of the chiral guests and to determine their
enantiomeric excess (ee) based on the sign and intensity of the Cotton effects, respectively.2 Designer
receptors bearing specific binding sites have been successfully used for the chiroptical sensing of
various kinds of functional chiral guests, such as amino acids, sugars, amines, alcohols, carboxy acids,
etc., and the resulting bimolecular host-guest complexes exhibit a characteristic induced CD (ICD)
in the absorption regions of the receptors.
As anticipated, the chirality-sensing of chiral saturated tertiary (3b–7b) and quaternary (9)
hydrocarbons composed of three and four alkyl substituents on the stereogenic carbon atom,
respectively (Figure 1), and isotopically-chiral compounds derived from H/D substitution (chiral
deuterated isotopomers) (10), by chromophoric chiral/achiral receptors and helical polymers using
CD appear to be extremely difficult. Therefore, the chiroptical sensing of these chiral molecules has
not been achieved at all by CD due to a lack of functionality for bimolecular interactions with
receptors/polymers and chemical inertness for derivatization.3-5
Among the chiral saturated hydrocarbons, the chirality of saturated quaternary hydrocarbons
bearing four different, but similar alkyl substituents at the stereogenic center, such as 5-ethyl-5-
propylundecane (9) (Figure 1), is hidden because of no detectable optical rotation ([α]λ20 < 0.001 (200
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nm < λ < 580 nm))6 or CD7 and such chiral molecules have been called “cryptochiral”.8 Therefore,
its direct separation into enantiomers by chiral chromatography and chirality-sensing by chiral/achiral
receptors using CD still remain a challenge. To the best of our knowledge, however, there is only one
precedent discriminating the hardly detectable chirality of the cryptochiral 9 that was achieved by the
asymmetric autocatalytic reaction triggered by (S)- or (R)-9 as reported by Soai et al., which was
accompanied by a significant enhancement of the product ee up to 97% after repeating the reaction
several times, thereby enabling the determination of the absolute configuration of 9 as well as those
of chiral saturated tertiary alkanes.11
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We now report the first direct chiroptical sensing of such a hidden chirality of cryptochiral 9 as
well as a series of chiral saturated and unsaturated tertiary hydrocarbons (3–8) and chiral deuterated
isotopomers (10), which are also very difficult to sense their chirality, by CD spectroscopy using a
helical polyacetylene bearing 4-biphenyl pendants with methoxymethoxy (MOM) groups at the 2,2’-
positions (poly-1). Poly-1 is optically-inactive, but forms an excess one-handed helix in the presence
of chiral molecules (3–10) accompanied by significant amplification of the chirality followed by its
memory, thus showing a characteristic ICD. The Cotton effect signs can be used to sense the chirality
of chiral hydrocarbons (Figure 1). The present direct chirality-sensing method using CD differs from
prior work by requiring no further chemical reactions and can enable the rapid detection of hardly
detectable hidden chirality in chiral hydrocarbons and deuterated isotopomers and their absolute
configurations together with their optical purities (% ee) can be determined.
As recently reported, poly-1 is a quite unique helical polymer whose main-chain helicity and
axial chirality of the biphenyl pendants can be induced in the solid state as well as in solution upon
interaction with a nonracemic alcohol, e.g., (S)-1-phenylethanol ((S)-2), thereby exhibiting split-type
ICDs in the polymer chromophore regions.12 Unlike previously reported dynamic helical
poly(phenylacetylene)s with functional pendants, such as carboxy and amino groups,13 the induced
helical chirality and axial chirality of poly-1 are automatically memorized after isolation of the
polymer by complete removal of (S)-2.14 In addition, subsequent immersion of the optically-active
poly-1 in the enantiomeric (R)-2 causes a complete inversion of both the helical and axial chiralities
that are also retained after isolation.ꢀBased on this unique switchable memory effect of poly-1, we
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succeeded in developing an unprecedented switchable chiral stationary phase (CSP) for HPLC, whose
elution orders or enantioselectivity can be reversibly switched.12,15
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Figure 1. Schematic illustration of a sequential induction of axial chirality at the biphenyl pendants
of poly-1 and its macromolecular helicity accompanied by chiral amplification through noncovalent
interactions with chiral tertiary (3–8) and quaternary (9) hydrocarbons, and chiral deuterated
isotopomers (10) and subsequent memory of the induced axial chirality and helicity of poly-1 after
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complete removal of chiral hydrocarbons and isotopomers. The structures of chiral hydrocarbons and
deuterated isotopomers are also shown.
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RESULTS AND DISCUSSION
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Since poly-1 is soluble in various hydrocarbons, we measured the CD and absorption spectra of
poly-1 in various chiral unsaturated (3a–8a) and saturated (3b–7b) tertiary hydrocarbons as the
solvents at –10 °C (Figure 2) and the ICD results are summarized in Table 1.16 Interestingly, poly-1
exhibited apparent ICDs in all the tested chiral hydrocarbons in the absorption region of the polymer
backbone due to a preferred-handed helix formation of poly-112 in response to the chirality of the
hydrocarbons despite the absence of functional groups capable of interacting with poly-1. Weak CH-
π interactions between the biphenyl pendants and the chiral hydrocarbons17 probably play a role in
inducing an excess one-handed helix on poly-1. There is a clear tendency that the chiral unsaturated
hydrocarbons always showed more intense ICDs than the chiral saturated hydrocarbons, and among
the chiral hydrocarbons used, (R)- and (S)-5a induced the most intense ICDs of the mirror images
(Figure 2a). Although there are a few reports of the chiroptical sensing of chiral hydrocarbons using
dynamically racemic receptors or helical polymers by CD,17a,18 they are limited to cyclic
hydrocarbons, such as naturally-occurring monoterpenes,19 except for one example.18d The chiroptical
sensing of chiral acyclic hydrocarbons including 3–8 has not been reported, indicating that poly-1 is
indeed the most sensitive and useful synthetic receptor for the chiroptical sensing of chiral
hydrocarbons.20
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Figure 2. CD and absorption spectra of poly-1 (1.0 mM) in optically-active unsaturated (3a–8a) (a)
and saturated tertiary hydrocarbons (3b–7b) (b) measured at –10 °C after heating at 50 °C for 5 h. (c)
The relationships between the sign of the second Cotton effect (Δε2nd) and the absolute configurations
of unsaturated ((S)-3a–(S)-8a) (left) and saturated ((R)-3b–(R)-7b) (right) tertiary hydrocarbons. The
substituents with blue circles are more bulky than those with yellow circles. The priority sequences
are also shown.
As shown in Table 1, there is a good correlation between the Cotton effect signs and the absolute
configurations of chiral tertiary unsaturated and saturated hydrocarbons (3a–8a, 3b–7b). The
relationships between the Cotton effect signs and the absolute configurations of chiral tertiary
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hydrocarbons (3a–8a, 3b–7b) can be generalized as follows. As shown in Figure 2c, the helical sense
of poly-1 preferentially induced by the chiral unsaturated (3a–8a) and saturated (3b–7b) tertiary
hydrocarbons appears to be governed by the steric difference in the bulkiness between the two alkenyl
or alkyl substituents on the stereogenic centers, respectively. The more bulky branched 4-methyl-3-
pentenyl groups (3a–8a) and the 4-methylpentyl groups (3b–7b) (Figure 2c) most likely serve as a
stereodemanding substituent. Therefore, the (S)-3a–8a and (R)-3b–7b induced the same right-handed
helicity in poly-112 to show ICDs with the same Cotton effect signs, which clearly revealed that the
absolute configurations of a series of chiral tertiary hydrocarbons can be determined by poly-1.21
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Table 1. Signs and Difference in Exciton Coefficient
Δε
of the Second Cotton ( 2nd) for Poly-1 in Various
Optically-Active Tertiary Hydrocarbons (3–8)a
chiral
second Cotton
Δε [M–1cm–1] (λ [nm])
run
sign
hydrocarbon
1
2
(S)-3a
(S)-4a
(S)-5a
(R)-5a
(S)-6a
(S)-7a
(S)-8a
(R)-3b
(R)-4b
(S)-4b
(R)-5b
(R)-6b
(S)-6b
(R)-7b
–
–
–
+
–
–
–
–
–
+
–
–
+
–
3.84
4.58
6.92
5.75
3.75
5.41
4.73
1.01
0.93
0.74
0.46
0.25
0.20
0.70
(378)
(379)
(380)
(380)
(380)
(380)
(379)
(382)
(379)
(382)
(375)
(375)
(375)
(378)
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a
Measured at –10 °C after heating at 50 °C for 5 h.
[poly-1] = 1.0 mM.
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Chart 1. Structures of Homopolymers (poly-A–poly-D, poly-F, and poly-1’) and Copolymers
(poly-(1r-co-B1–r), poly-(1r-co-E1–r))
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C
C
C
C
C
C
C C
1–r
1–r
H
r
r
H
H
H
n
n
n
n
H
H
O
R
O
O
O
O
O
O
O
O
O
O
O
OC12H25
R
O
O
OC12H25
poly-(1r-co-B1–r
OC12H25
OC12H25
poly-(1r-co-E1–r
OC12H25
R
)
)
poly-A (R = OCH2OCH2CH3)
poly-B (R = OCH3)
poly-C (R = OCH2CH2CH3)
poly-D (R = OCH2CH2OCH3)
poly-1' (R = OC4H9)
poly-F (R = COOC12H25
)
Figure 3. CD and absorption spectra of poly-1, poly-A–poly-D, and poly-F in (S)-5a measured at –
10 °C after annealing at 50 °C for 5 h (poly-1, poly-A–poly-D) and 18 h (poly-F) (a) and those of
poly-1 (red line) and poly-1’ (blue line) in (S)-5a/toluene (2/1, v/v) at 25 °C after annealing at 50 °C
for 1 h (b). [polymer] = 1.0 mM.
The effect of the substituents at the 4’-position as well as the 2,2’-positions of the biphenyl
pendants of poly-1 on the observed high chiroptical sensing ability toward chiral hydrocarbons was
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then investigated. Among the analogous homopolymers (poly-A-poly-D) possessing alkoxy groups
different from the methoxymethoxy (MOM) groups at the 2,2’-positions of the biphenyl pendants,
such as the ethoxymethoxy, methoxy, propoxy, and methoxyethoxy groups, respectively (Chart 1),
only poly-A bearing ethoxymethoxy groups showed a clear ICD, but its intensity was about one-third
that observed in poly-1 in (S)-5a (Figure 3a). Poly-1 derivatives with a short butoxy chain (poly-1’)
and a dodecyloxycarbonyl group at the 4'-position (poly-F)22 instead of the dodecyloxy group in poly-
1 were also prepared and their CD spectra were measured in the presence of (S)-5a (Figure 3a,b),
which revealed that the effect of the chain-length of the alkoxy group and an ester group at the 4’-
position of the biphenyl pendants of poly-1 on the chirality-sensing toward (S)-5a is not significant.
Moreover, the ICD intensity of the copolymers poly-(1r-co-B1–r) and poly-(1r-co-E1–r) in (S)-5a
at –10 °C significantly decreased with an increase in the content of B and (4-
dodecyloxyphenyl)acetylene (E) units in the copolymers, and the copolymers composed of more than
20 mol% B and E units exhibited no ICD (Figure S7). These results revealed that cooperative close
interactions between the neighboring biphenyl pendants with the alkoxymethoxy groups along the
helical polymer backbone play a crucial role, which enables direct chiroptical detection of otherwise
undetectable chirality of chiral hydrocarbons through an induction of non-racemic helicity in poly-1
with a high sensitivity. We assume that the chiral information of the chiral hydrocarbons first transfers
to the axial chirality in the biphenyl pendants, and subsequently, the induced axially twisted
conformation with a slight excess of a one-handed twist-sense would be further amplified in the
polymer backbone as an excess helical sense.12,22 Obviously, we need further studies to propose a
plausible mechanism of the helicity induction in poly-1 followed by its helicity memory upon
interacting with chiral compounds.
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A notable feature of the noncovalent helicity induction and subsequent memory of the helicity
of poly-1 after isolation12 enables the chirality detection of an extremely small amount of chiral
hydrocarbons. For example, a solution of poly-1 (0.46 mg) dissolved in 30 μL of (R)-5a followed by
heating at 50 °C for 5 h, through which a preferred-handed helicity was induced and automatically
memorized, then diluted with n-hexane (870 μL) ([poly-1] = 1.0 mM, [(R)-5a]/[poly-1] = 200)
(Figure 4a) exhibited an ICD as intense as that of poly-1 dissolved in 300 μL of (R)-5a ([poly-1] =
1.0 mM) after annealing at 50 °C for 5 h (Figure 4b).23 In contrast, when poly-1 was first dissolved
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in n-hexane (870 μL) followed by the addition of 30 μL of (R)-5a ([poly-1] = 1.0 mM), the poly-1
showed a very weak ICD after heating the solution at 50 °C for 5 h due to a weak bimolecular
interaction in the dilute solution (Figure 4c).
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Figure 4. CD and absorption spectra of poly-1 dissolved in 30 μL of (R)-5a followed by heating at
50 °C for 5 h, and then diluted with n-hexane (870 μL) ([poly-1] = 1.0 mM, [(R)-5a]/[poly-1] = 200)
(a), those dissolved in 300 μL of (R)-5a ([poly-1] = 1.0 mM) after heating at 50 °C for 5 h (b), and
those dissolved in n-hexane (870 μL) with (R)-5a (30 μL) after heating at 50 °C for 5 h ([poly-1] =
1.0 mM, [(R)-5a]/[poly-1] = 200) (c). All CD and absorption spectra were measured at –10 °C.
We next investigated whether poly-1 could respond to the hardly detectable chirality of the
cryptochiral quaternary hydrocarbon 9. Based on the noncovalent helicity induction and subsequent
memory strategy, poly-1 was first dissolved in tiny amounts of (S)- and (R)-9 (30 μL) and each
solution was heated at 50 °C for 5 h followed by standing at 25 °C for 5 days, then diluted with n-
hexane at –10 °C to measure the CD spectra. As shown in Figure 5a, poly-1 showed weak, but perfect
mirror image ICDs after helicity induction with the (S)- and (R)-9 followed by the helicity memory.
Furthermore, poly-1 could also detect the minute chirality of the deuterated isotopomers, such as (S)-
and (R)-10, and exhibited mirror image ICDs (Figure 5b).24,25 As a consequence, the hardly detectable
hidden chirality of a saturated quaternary hydrocarbon and deuterated isotopomers, which have never
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been detected by conventional optical spectroscopic methods, has been, for the first time, directly
visualized by CD spectroscopy using the helical polyacetylene as a powerful chirality sensor.
Because of the extremely high sensitivity of the polyacetylene toward the minute chirality
resulting from a unique memory effect through significant amplification of the chirality, the
chiroptical sensing and further determination of the absolute configurations of a series of chiral
saturated and unsaturated tertiary hydrocarbons and chiral deuterated isotopomers will be also
possible. The present system described here may have further application in the study of other chiral
compounds with hidden chiralities derived from other isotope substitutions, such as carbon (13C/12C)
and oxygen (18O/16O).26
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Figure 5. CD and absorption spectra of poly-1 (1.0 mM) dissolved in cryptochiral 9 (30 μL) followed
by heating at 50 °C for 5 h and standing at 25 °C for 5 days, and then diluted with n-hexane (870 μL)
(a) and those dissolved in isotopically chiral 10 (30 μL) followed by standing at 25 °C for 24 h and
then diluted with n-hexane (870 μL) at –10 °C (b). All CD and absorption spectra were measured at
–10 °C.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:.
Experimental procedures, characterizations of polymers, copolymers, and chiral
compounds, and additional spectroscopic data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*maeda@se.kanazawa-u.ac.jp
*yashima@chembio.nagoya-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank R. Ishidate (Kanazawa University) for his help in the synthesis of poly-1' and poly-F. This
work was supported in part by JSPS KAKENHI (Grants-in-Aid for Scientific Research (B), no.
16H04154 (K.M.) and Grant-in-Aid for Scientific Research (S), no. 25220804 (E.Y.)) and by the
Nanotechnology Platform Program (Molecule and Material Synthesis) of the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan.
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conditions, such molecules have been called “cryptochiral”.9 Meijere et al. proposed “crypto-optically
active” instead of “cryptochiral”.10
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(16)
The CD spectra were measured at –10 °C after heating the solutions at 50 °C for 5 h because
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temperature and reached a maximum value at 50 °C after 5 h (Figure S4).
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(19)
(1R)-α-pinene ((1R)-13), thus exhibiting similar ICDs in their patterns (Figure S5).
(20) The chiral discrimination of chiral saturated tertiary alkanes (3b–7b) has also been achieved
by Soai’s asymmetric autocatalysis.11
Poly-1 also responded to the chirality of monoterpenes, such as (R)-limonene ((R)-12) and
(21)
It should be noted that almost linear relationships between the enantiomeric excess (ee) of
4b or 5a and the ICD values of poly-1 were observed (Figure S6), although the CD values of poly-1
showed a strong positive nonlinear relationship with respect to the ee of 2 as previously reported.12
This is probably because the interaction of poly-1 with chiral hydrocarbons 4b and 5a is very weak.
These linear relationships allow us to use poly-1 to determine the ee of chiral hydrocarbons.
(22)
(a) Ishidate, R.; Ikai, T.; Kanoh, S.; Yashima, E.; Maeda, K. Chirality 2017, 29, 120-129;
(b) Ishidate, R.; Shimomura, K.; Ikai, T.; Kanoh, S.; Maeda, K. Chem. Lett. 2015, 44, 946-948.
(23)
(24)
Poly-1 dissolved in 3 μL of (R)-5a exhibited an ICD as intense as that in 30 μL of (R)-5a.
Poly-1 also detected the chirality of the isotopically chiral alcohol 11 (Figure S9) and
showed mirror image ICDs in the presence of (R)- and (S)-11 in toluene (2/10, v/v) after standing at
25 °C for 5 h. Toluene was used as the solvent because poly-1 was insoluble in 11.
(25)
Poly-1 also showed ICDs with chiral secondary alcohols ((S)-14 and (S)-15) and a chiral
secondary amine ((S)-16) (Figure S10) and the Cotton effect signs are the same when their absolute
configurations are the same (Table S3).
(26)
(a) Kawasaki, T.; Matsumura, Y.; Tsutsumi, T.; Suzuki, K.; Ito, M.; Soai, K. Science 2009,
324, 492; (b) Kawasaki, T.; Okano, Y.; Suzuki, E.; Takano, S.; Oji, S.; Soai, K. Angew. Chem., Int.
Ed. 2011, 50, 8131-8133; (c) Soai, K.; Kawasaki, T.; Matsumoto, A. Acc. Chem. Res. 2014, 47, 3643-
3654.
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