Amplification of enantioselectivity and sensitivity based on non-linear response of molecular wire bearing pseudo-18-crown-6 to chiral amines

Article abstract of DOI:10.1039/c2cc30417a

Exploiting a non-linear response for chiral discrimination, an intelligent system capable of chirality amplification was designed and constructed as poly(phenyleneethynylene) having chiral pseudo-18-crown-6. Both sensitivity and selectivity were amplified

Full text of DOI:10.1039/c2cc30417a

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COMMUNICATION
Amplification of enantioselectivity and sensitivity based on non-linear
response of molecular wire bearing pseudo-18-crown-6 to chiral amineswz
Keiji Hirose,* Shintaro Miura, Yui Senda and Yoshito Tobe*
Received 18th January 2012, Accepted 25th April 2012
DOI: 10.1039/c2cc30417a
Exploiting a non-linear response for chiral discrimination, an
intelligent system capable of chirality amplification was designed
and constructed as poly(phenyleneethynylene) having chiral
pseudo-18-crown-6. Both sensitivity and selectivity were amplified
from those limited by the law of mass action.
ranging from 420 to 600 nm.13 Such conjugated polymers are
attractive as active transducers for chirality indicators,14
though the amplification mechanisms of molecular wire type
chirality indicators are diverse and not always obvious. The
chiral pseudo-18-crown-6 ethers were selected as recognition
sites due to their high affinity for chiral primary and secondary
amines as well as ammonium salts.15 We envisioned that a PPE
such as (S,S)-1 incorporating the chiral pseudo-18-crown-6 ether
would exhibit not only enough enantioselective complexation
ability but also show non-linear response of fluorescent intensities
toward complexations with diastereomeric chiral amine substrates.
Chemosensors (S,S)-2 and (S,S)-3 bearing single recognition sites
were also synthesized as reference compounds (Fig. 1).
Because of the importance of chirality in pharmaceutical and
biological chemistry, the development of methodologies for
measurement of enantiomeric purity is an important issue.
Despite the efficiencies of modern chiral chromatographic
techniques,1 optical spectroscopies including NMR spectroscopy,2
mass spectrometry,3 UV-vis (in solution,4 liquid crystals,5 gels,6
and suspensions7), or fluorescence8 and IR spectrometry9 are
among the frequently used alternatives due to easy performance
and accessibility. Although significant development of chirality
indicators has been achieved, the creation of highly enantio-
selective as well as highly sensitive chirality recognition systems
remains still difficult and is one of the most challenging and
important goals of molecular recognition.8c The signals of chiral
chromogenic indicators and fluorogenic indicators with a static or
dynamic quenching mechanism are proportional to the amount of
the diastereomeric host–guest complexes according to the law of
mass action, providing a limitation in apparent enantioselectivity.10
In order to surmount this limitation, intelligent systems capable of
chirality amplification based on non-linear response7 need to be
developed.11 Here we report highly enantioselective chirality recog-
nition, which exceeds the above limitation, based on fluorescence
quenching phenomena exhibiting non-linear intensity changes.
We designed a molecular wire type chirality indicator (S,S)-1
composed of a poly(phenyleneethynylene) (PPE) chain and a
chiral pseudo-18-crown-6 ether connected by a triple bond which
permits effective transfer of binding information to the conjugated
polymer chain.12 PPEs are chemically stable, and can be made
either water- or organo-soluble by simple chemical modification.
In general, they are strongly fluorescent with emission maxima
Syntheses of chirality indicators (S,S)-1, (S,S)-2 and (S,S)-3
were carried out as shown in Scheme 1. Crown ether (S,S)-5
was obtained through selective demethylation of the known
chiral pseudo-18-crown-6 (S,S)-416 in 71% yield. Sonogashira
coupling of (S,S)-5 with (trimethylsilyl)acetylene followed by
deprotection gave (S,S)-6 in 85% (2 steps), which was coupled with
bromide 7 to give (S,S)-8 in 81% yield. Selective deprotection of the
TMS group of (S,S)-8 with K2CO3 in MeOH followed by coupling
with 10 and subsequent deprotection of TIPS gave monomer 11 in
43% (3 steps). Polymerization reaction of monomer 11 catalyzed by
Pd(PPh3)4 in the presence of CuI and (i-Pr)2NH in toluene afforded
(S,S)-1 in 91% yield. The detail of the syntheses of (S,S)-2 and
(S,S)-3 are described in ESI.w
(S,S)-1 has a polydispersity (Mw/Mn = 1.9) with a molecular
weight of Mn = 22 700 as determined by SEC. The UV-vis
spectrum of (S,S)-1 was measured in CH2Cl2 together with those
of (S,S)-2, and (S,S)-3 (Fig. S3-1, ESIw). Extension of the
conjugated p-system of (S,S)-2 to (S,S)-1 induced a bathochromic
shift of the absorption assigned to the phenol moiety from 350 to
319 nm. The emission spectra of (S,S)-1, (S,S)-2 and (S,S)-3
Division of Frontier Materials Science,
Graduate School of Engineering Science, Osaka University, 1-3
Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
E-mail: hirose@chem.es.osaka-u.ac.jp, tobe@chem.es.osaka-u.ac.jp;
Fax: +81-6-6850-6229; Tel: +81-6-6850-6228
w Electronic supplementary information (ESI) available: Details of
polymer and model syntheses, determination of binding constants and
Stern–Volmer constants. See DOI: 10.1039/c2cc30417a
z This article is part of the ChemComm ’Chirality’ web themed issue.
Fig. 1 Structures of polymer and monomer-type chiral chemosensors
(S,S)-1–3.
c
6052 Chem. Commun., 2012, 48, 6052–6054
This journal is The Royal Society of Chemistry 2012

ethers.19 The enantioselectivities (K(R)/K(S)) of (S,S)-2 for the
guests were moderate (3.6, 1.3, 3.4, respectively).
The fluorescence quenching behaviors of (S,S)-2 and (S,S)-1
upon formation of host–guest complexes with the primary
amines were also examined. In Fig. 2, the vertical axis of the
graph (I0/I) represents a ratio of the fluorescence intensities, and
the horizontal axis corresponds to the concentration of an amine
at an equilibrium. The obtained plots of (S,S)-2 with (R)-2APO
and (S)-2APO were approximated by straight lines according to
the Stern–Volmer equation.20 The obtained quenching constants
from the slope for (S,S)-2 were KSV(R) = 1.4 ꢀ 102 Mꢁ1 and
KSV(S) = 3.7 ꢀ 10 Mꢁ1, respectively, which were in good
agreement with the corresponding binding constants obtained by
UV-vis titration (K(R) = 1.1 ꢀ 102 Mꢁ1 and K(S) = 3.0 ꢀ 10 Mꢁ1
,
respectively (Table 1)). Therefore, it is deduced that quenching
of the monomer model (S,S)-2 occurs with a static quenching
mechanism. Thus, the enantioselectivity did not change by
changing the detection method from UV-vis to fluorescence
spectroscopy.
Next, the fluorescence quenching behavior of the molecular
wire (S,S)-1 (2.0 ꢀ 10ꢁ6 M)21 upon complexation with the
same primary amines was examined. As shown in Table 1, the
quenching constants of (S,S)-1 are about 5 to 10 times greater
than those of (S,S)-2. Therefore, sensitivity of the molecular
wire (S,S)-1 was significantly improved from that of the
monomer model (S,S)-2. For example, at 6.7 ꢀ 10ꢁ4 M of
2APO, the quenching degree (I0/I) of monomer (S,S)-2 is 1.064
for (R)-2APO and 1.018 for (S)-2APO. The complexation
ratios under these conditions are 6.1% ((R)-2APO) and
Scheme 1 Synthesis of chiral sensors (S,S)-1–3.
measured in CH2Cl2 exhibit maxima at 463 nm, 432 nm and
342 nm, respectively (Fig. S3-2, ESIw). The shape of the
fluorescence emission band of molecular wire (S,S)-1 is sharp,
which is a characteristic feature of molecular wires.
1.8% ((S)-2APO). The enantioselectivity (KSV(R)app/KSV(S)app
)
was 3.6. On the other hand, (Io/I) of the polymer (S,S)-1 was
significantly amplified (2.5 for (R)-2APO and 1.2 for (S)-2APO).
The apparent KSV at the guest concentration of 6.9 ꢀ 10ꢁ4 M were
2.3 ꢀ 103 Mꢁ1 and 3.0 ꢀ 102 Mꢁ1, respectively. The enantio-
selectivity was improved to be 7.8. Photographs of an effective
fluorescent quenching in complexation of (S,S)-1 with (R)-2APO
is shown in Fig. S5 (ESIw). At a lower concentration (1.3 ꢀ
10ꢁ4 M) of the guest, the apparent KSV (KSV app) were 1.2 ꢀ
103 Mꢁ1 for (R)-2APO and 3.5 ꢀ 10 Mꢁ1 for (S)-2APO and
the enantioselectivity reached 35.
The binding constants of monomer-type chemosensors
(S,S)-3 and (S,S)-2 with ethanolamine derivatives, 2-amino-
1-propanol (2APO), 1-amino-2-propanol (1APO), and valinol
(VLO) were determined by titration experiments conducted
using 1H NMR and UV-vis spectroscopy.17 Stern–Volmer
constants were also determined by fluorescent titration of
(S,S)-2 and (S,S)-1 (Table 1). The binding constants of
(S,S)-3 with 2APO, 1APO, and VLO were found to range from
3.4 to 5.5 ꢀ 10 Mꢁ1 and the enantioselectivities (K(R)/K(S)) were
high (4.8, 2.2, 3.7, respectively). All of the binding constants of
(S,S)-2 for the guests were in the same order of magnitude but
appreciably larger than the corresponding binding constants of
(S,S)-3, because of small substituent effects of conjugate systems
of (S,S)-2 and (S,S)-3 on binding properties of phenolic crown
Similarly, KSV app of (S,S)-1 for (R)- and (S)-1APO (1.4 ꢀ
103 Mꢁ3 and 1.2 ꢀ 103 Mꢁ1, respectively) increased from those
of (S,S)-2 (7.9 ꢀ 10 Mꢁ1 and 6.2 ꢀ 10 Mꢁ1, respectively).
However, the enantioselectivity (KSV(R) app/KSV(S) app) was not
improved (1.2). This is due to the fact that the sensitivity for
Table 1 Binding constants (K), Stern–Volmer constants (KSV), and the enantioselectivities of (S,S)-1, (S,S)-2 and (S,S)-3 with 2-amino-1-
propanol, 1-amino-2-propanol, and valinol at 30 1C
2-Amino-1-propanol (2APO)
1-Amino-2-propanol (1APO)
Valinol (VLO)
K(R)/
K(S) K(R)
K(R)/
K(S) K(R)
K(R)/
K(S)
K(R) K(S)
K(S)
K(S)
Host
(S,S)-3
(S,S)-2
(S,S)-2
(5.5 ꢂ 0.3)a ꢀ 10 (1.1 ꢂ 0.1)a ꢀ 10 4.8
(1.1 ꢂ 0.1)b ꢀ 102 (3.0 ꢂ 0.1)b ꢀ 10 3.6
(1.4 ꢂ 0.1)c ꢀ 102 (3.7 ꢂ 0.1)c ꢀ 10 3.6
(3.0 ꢂ 0.2)a ꢀ 10 (1.4 ꢂ 0.1)a ꢀ 10 2.2
(6.8 ꢂ 0.4)b ꢀ 10 (5.5 ꢂ 0.8)b ꢀ 10 1.3
(7.9 ꢂ 0.1)c ꢀ 10 (6.2 ꢂ 0.1)c ꢀ 10 1.3
(1.2 ꢂ 0.1)a ꢀ 10 3.4 ꢂ 0.1a
3.7
3.4
(2.4 ꢂ 0.5)b ꢀ 10 7.0 ꢂ 2.7b
(2.7 ꢂ 0.1)c ꢀ 10 (1.0 ꢂ 0.1)c ꢀ 10 2.6
(S,S)-118 2.3 ꢀ 103d
3.0 ꢀ 102d
3.5 ꢀ 10e
7.8
35
1.4 ꢀ 103f
1.2 ꢀ 103f
1.2
5.1 ꢀ 102g
1.0 ꢀ 102g
5.1
1.2 ꢀ 103e
a
b
c
d
K by 1H NMR titration in CDCl3. K by UV-vis titration in CH2Cl2. KSV by fluorescent titration in CD2Cl2. Apparent KSV (KSV app) at
[guest] = 6.9 ꢀ 10ꢁ4 M. Apparent KSV (KSV app) at [guest] = 1.3 ꢀ 10ꢁ4 M. Apparent KSV (KSV app) at [guest] = 1.1 ꢀ 10ꢁ3 M. Apparent KSV
e
f
g
(KSV app) at [guest] = 4.1 ꢀ 10ꢁ3 M.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6052–6054 6053

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18 KSV and KSV app of polymer (S,S)-1 shown are per unit of
monomer.
Fig. 2 Stern–Volmer plot for the quenching of the fluorescence of
(S,S)-1 (K) and (S,S)-2 (’) with (R)- (black) and (S)-2-amino-1-
propanol (gray) in CH2Cl2 at 20 1C.
both enantiomers was amplified by similar magnitude as
shown in Fig. S4-25 in ESI.w For VLO, KSV app of (S,S)-1
(5.1 ꢀ 102 Mꢁ3 and 1.0 ꢀ 102 Mꢁ1) increased by one order of
magnitude (2.7 ꢀ 10 Mꢁ3 and 1.0 ꢀ 10 Mꢁ1). In addition, the
enantioselectivity (KSV(R) app/KSV(S) app) improved from 2.6 to
5.1. Although the fluorescent quenching mechanism of (S,S)-1
was not clearly determined,22 the quenching efficiency is enhanced
compared to that of the corresponding monomer (S,S)-2. More
interestingly, the apparent enantioselectivity of the polymer can be
significantly enhanced at relatively low guest concentration as
exemplified for 2APO and VLO.
In conclusion, based on the nonlinear response of molecular
wire (S,S)-1 as exemplified in Fig. 2, we have demonstrated a
highly selective chirality recognition of chiral amine guests in
homogeneous solution by binding constants and the ratios
shown in Table 1. The fluorescence of (S,S)-1 was quenched upon
complexation with amine guests. At relatively low guest concen-
tration, the molecular wire showed both amplified sensitivity and
enantioselectivity compared to the model monomer (S,S)-2.
This work was financially supported by the Japan Science and
Technology Agency through a CREST project and Grant-in-Aid
of the Ministry of Education, Culture, Sports, Science and
Technology of Japan. The authors thank Dr Takehiro Kitaura,
and Professor Tatsuki Kitayama of Osaka University for the use
of the instruments.
Notes and references
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from ((I0/I) ꢁ 1)/[G] for (S,S)-1 with guest concentration.
21 UV-vis spectra of (S,S)-1 in CH2Cl2 were not affected by concentration
in the range of 2.0 ꢀ 10ꢁ6–4.0 ꢀ 10ꢁ5 M.
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22 The Stern–Volmer plots of (S,S)-1 with (S)- and (R)-2APO show
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¨
Models of the Forster resonance energy transfer mechanism and
Dexter energy transfer mechanism for fluorescent quenching were
also applied assuming that the binding constant (K) of one receptor
site in (S,S)-1 is same as that of (S,S)-2. However, none of the
models fit the experimental data.
c
6054 Chem. Commun., 2012, 48, 6052–6054
This journal is The Royal Society of Chemistry 2012