Chiral donor photoinduced-electron-transfer (d-PET) boronic acid chemosensors for the selective recognition of tartaric acids, disaccharides, and ginsenosides

Article abstract of DOI:10.1002/chem.201100033

A modular approach was proposed for the preparation of chiral fluorescent molecular sensors, in which the fluorophore, scaffold, and chirogenic center can be connected by ethynyl groups, and these modules can easily be changed to other structures to optim

Full text of DOI:10.1002/chem.201100033

DOI: 10.1002/chem.201100033
Chiral Donor Photoinduced-Electron-Transfer (d-PET) Boronic Acid
Chemosensors for the Selective Recognition of Tartaric Acids, Disaccharides,
and Ginsenosides
Yubo Wu,[a] Huimin Guo,[a] Xin Zhang,[a] Tony D. James,[b] and Jianzhang Zhao*[a]
Abstract: A modular approach was
proposed for the preparation of chiral
fluorescent molecular sensors, in which
the fluorophore, scaffold, and chirogen-
ic center can be connected by ethynyl
groups, and these modules can easily
be changed to other structures to opti-
mize the molecular sensing perfor-
mance of the sensors. This modular
strategy to assembly chiral sensors alle-
viated the previous restrictions of
chiral boronic acid sensors, for which
the chirogenic center, fluorophore, and
scaffold were integrated, thus it was
difficult to optimize the molecular
structures by chemical modifications.
We demonstrated the potential of our
new strategy by the preparation of a
sensor with a larger scaffold. The pho-
toinduced electron-transfer (PET)
effect is efficient even with a large dis-
tance between the N atom and the flu-
orophore core. Furthermore, the rarely
reported donor-PET (d-PET) effect,
which was previously limited to carba-
zole, was extended to phenothiazine
fluorophore. The contrast ratio, that is,
PET efficiency of the new d-PET
sensor, is increased to 8.0, compared to
2.0 with the previous carbazole d-PET
sensors. Furthermore, the ethynylated
phenothiazine shows longer excitation
wavelength (centered at 380 nm) and
emission wavelength (492 nm), a large
Stokes shift (142 nm), and high fluores-
cence quantum yield in aqueous solu-
tion (F=0.48 in MeOH/water, 3:1 v/
v). Enantioselective recognition of tar-
taric acid was achieved with the new d-
PET boronic acid sensors. The enantio-
selectivity is up to 10 (ratio of the bind-
ing constants toward d- and l-tartaric
acid, kD/kL). A consecutive fluores-
cence enhancement/decrease was ob-
served, thus we propose a transition of
the binding stoichiometry from 1:1 to
1:2 as the analyte concentration in-
creases, which is supported by mass
spectra analysis. The boronic acid sen-
sors were used for selective and sensi-
tive recognition of disaccharides and
glycosylated steroids (ginsenosides).
Keywords: boronic acids · chirality ·
fluorescence · ginsenosides · sensors
Introduction
1).[26] For 1, the 1,1’-bi-2-naphthol (BINOL) moiety plays
the role of fluorophore, scaffold, and the chirogenic center
as well. In a later study we used the same BINOL-based
chiral boronic acid sensors for enantioselective recognition
of tartaric acids.[25a] However, the BINOL fluorophore emits
UV light, whereas emission in the visible region is desired.
Furthermore, the fluorophore and the chirogenic centers of
the BINOL-based chiral sensors are integrated (the same is
true for the chiral sensors 1–7 and sensor 9, Sche-
me 1),[2,25a,b,f,g,26–29] thus it is difficult to change the fluoro-
phores, scaffold, or the binding sites to other structures to
optimize the molecular sensing performance, such as the
emission and recognition properties of the sensors.[25a] To
tackle these limitations to some extent, we developed an-
thracene-based chiral boronic acid sensors, which demon-
strated visible emission and good chiral selectivity toward
tartaric acid, sugar acids, and sugar alcohols (sensor 2, Sche-
me 1).[25b–d] More recently, we devised carbazole-based
donor photoinduced-electron-transfer (d-PET) chiral boron-
ic acids 9 and 10, with the fluorophore as the electron donor
of the photoinduced electron transfer (d-PET), and a pro-
tonated amine/boronic acid moiety as the acceptor of the
PET (a-PET); the background emission for the sensor at
acidic pH is much lower than with normal a-PET sensor-
s.[25e,f] However, the carbazole fluorophores in these sensors
Chiral fluorescent chemosensors are important for the de-
tection of chiral analytes.[1–9] Fluorescent chiral boronic acid
sensors are of particular interest due to the covalent bond-
ing nature of the enantioselective interaction between the
sensor and the analytes (such as tartaric acids, sugar, sugar
alcohol, and sugar acids), which ensures their applicability
for the analysis of biological samples.[10–26]
We have long been interested in chiral fluorescent boronic
acid sensors.[25] Previously, a chiral boronic acid sensor for
the recognition of glucose was reported (Scheme 1, sensor
[a] Y. Wu, Dr. H. Guo, X. Zhang, Prof. J. Zhao
State Key Laboratory of Fine Chemicals
School of Chemical Engineering
Dalian University of Technology
Dalian 116024 (P.R. China)
Fax : (+86)411-8498-6236
E-mail: zhaojzh@dlut.edu.cn
[b] Dr. T. D. James
Department of Chemistry, University of Bath
Bath, BA2 7AY (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100033.
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FULL PAPER
Scheme 1. Typical chiral fluorescence molecular sensors (1–9) with integrated fluorophore, molecular scaffold, and chirogenic centers. (Sensors 10–12 are
not chiral. The structures are presented for comparison). The N atoms that serve as the fluorescence switch in some typical PET sensors are marked by
arrows in sensors 1 and 2.
also serve as the scaffold, therefore this is still an integrated
molecular sensor.
chemosensors with improved enantioselectivity and photo-
physical properties.
The drawbacks of the current chiral boronic acid sensors
are as follows. 1) The fluorophore, scaffold, and the chiro-
genic centers are integrated (sensor 1, 3–7, Scheme 1). Thus
the selection of the fluorophore for chiral sensors is limited
to those with the dialdehyde motif. Because the chiral bor-
onic acid sensors usually require two binding sites, a dialde-
hyde motif is necessary to access the chiral boronic acid sen-
sors. 2) The typical fluorophore used for boronic acid sen-
sors are anthracene, BINOL, or naphthalene. The emission
wavelength of these chiral boronic acid sensors are usually
at near-UV region. A tailored fluorophore cannot be used
due to the intrinsic drawbacks of the structural motif men-
tioned in the first point. 3) Currently, the fluorophores of
the d-PET boronic acid sensors are restricted to carbazole,
which gives off UV emissions.[25f–k] 4) The PET efficiency of
the d-PET boronic acid sensors that use carbazole as the flu-
orophore is low; the emission enhancement (or the contrast
ratio) is approximately twofold upon switching the pH from
acidic pH to neutral pH. The a-PET sensor 2 (Scheme 1)
displays a contrast ratio of 10.[25b]
To tackle the aforementioned limitations, herein we pro-
pose a modular approach to the preparation of chiral boron-
ic acid sensors. With this new strategy to assemble chiral flu-
orescent sensors, the above challenges were addressed. The
sensors were used for enantioselective recognition of disac-
charides such as sucrose, lactose, and maltose. We also used
the sensors for recognition of glycosylated steroids (ginseno-
sides). Our modular concept for the construction of a chiral
sensor will be useful in the design of new chiral fluorescent
Results and Discussion
Design and synthesis: We devised sensor 20 (Scheme 2), in
which the fluorophore (phenothiazine) and the chirogenic
centers ((R)- or (S)-a-benzylamine) were modules and read-
ily assembled onto a scaffold of 2-iodo-1,4-benzenedicarbox-
aldehyde. The two parts are connected by p conjugation
through an ethynylene group (CꢀC). A large distance be-
tween the PET switch, that is, the N atom, and the fluoro-
phore core could be potentially detrimental to the PET effi-
ciency (contrast ratio). The ethynylene linker was used in-
stead of ethylene (C=C), because it is known that the cis/
trans isomerization of the C=C double bonds serves as an ef-
ficient drainpipe for the excited-state energy, thus the fluo-
rescence could be quenched. For the rigid ethynylene linker,
however, efficient through-bond electron/energy transfer
can be established. Furthermore, with a rigid linker between
the fluorophore and the boronic acid binding sites, the inter-
action between the binding sites and the fluorophore can be
avoided.[25d] We selected phenothiazine as the fluorophore
for the d-PET effect because of its well-known strong elec-
tron-donating ability.[30,31] Thus we expected that the con-
trast ratio of the d-PET effect of the new sensors may be im-
proved relative to our previously reported carbazole-based
d-PET fluorescent boronic acid sensors.[25f–h]
The binding pocket of sensor 20 is similar to the anthra-
cene-based chiral boronic acid sensors reported by us previ-
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J. Zhao et al.
Scheme 2. Synthesis of the chiral fluorescent boronic acid sensor 20 by using a modular approach. Reagents and conditions: i) NaNO3, HCl, 08C, 45 min,
KI, 18 h, RT, 26%; ii) AlH
methylammonium bromide, NaOH, nC4H9Br, acetone, reflux, 6 h, 60%; iv) bromine, glacial acetic acid, 08C, 1 h, 70%; v) [Pd
PPh3, ethynyltrimethylsilane argon atmosphere, reflux, 6 h, then K2CO3, MeOH, 1 h, 84%; vi) [Pd(PPh3)2Cl2], CuI, NEt3, PPh3, nitrogen atmosphere,
ACHUTGTNRNE(NUG iBu)2, THF/hexaneACTHUNGTRENNNUG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
reflux, 8 h, 40%; vii) (R)- and (S)-a-methylbenzylamine, THF, reflux, 8 h, then NaBH3(CN), 08C, 30 min, 40% (S,S)-19, 36% (R,R)-19; viii) acetonitrile,
K2CO3, 2-(2-bromomethylphenyl)-1,3,2-dioxaborinane, reflux, 10 h, 28% (S,S)-20, 30% (R,R)-20. The N atoms that serve as the fluorescence switch cen-
ters are marked by arrows in sensor 20.
ously (sensor 2, Scheme 1).[25b–d] It should be pointed out
that with the modular structural motif of 20, any fluoro-
phores that can be ethynylated are suitable for attachment
to the chirogenic moiety to assemble a chiral sensor and
achieve different emission properties, such as wavelength or
Stokes shift, and so forth. We will also need to study the
PET efficiency or the contrast ratio of the sensors (the varia-
tion of the fluorescence emission enhancement with the
switching off of the PET quenching effect), because the dis-
tance between the N switch and the fluorophore core is
quite large.
The synthesis was carried out with phenothiazine as the
starting material. Alkylation at the N position and bromina-
tion with Br2 led to 16 and the ethynylated phenothiazine 17
(the fluorophore). Sonogashira coupling with 2-iodo-1,4-
benzenedicarboxaldehyde (the modular scaffold) leads to di-
aldehyde 18. Then modular chiral sensor 20 ((R,R)-20 and
(S,S)-20) was obtained by reductive amination with chiral
amine (a-benzylamine) and finally introduction of the bor-
onic acid subunits (binding sites) to the sensor. Compounds
were obtained in moderate to low yields.
the contrast ratio of the PET effect of 25. The analytes are
summarized in Scheme 4.
Enantioselective recognition of d- and l-tartaric acid with
modular chiral d-PET fluorescent boronic acid sensor 20:
The emission properties of (S,S)-20 and (S,S)-25 were inves-
tigated (Figure 1). With excitation at 375 nm, emission cen-
tered at 488 nm was observed (F=0.487 in methanol/water,
3:1 v/v). The Stokes shift is up to 138 nm. A slightly redshift-
ed emission at 500 nm was observed for (S,S)-25. A similar
quantum yield was observed for (S,S)-25 (F=0.310 in meth-
anol/water, 3:1 v/v). It should be pointed out that the emis-
sion maximum (lem =492 nm) is significantly redshifted
when compared to the anthracene-based boronic acid sen-
sors (lem =429 nm) or the carbazole-based boronic acid sen-
To investigate the effect of the size of the binding pocket
of the boronic acid sensor on the enantioselective recogni-
tion, sensor 25 ((S,S)-25 and (R,R)-25) was also devised
(Scheme 2). The binding pocket of sensor 25 has been ex-
tended by using a larger scaffold (Scheme 3). The distance
between the PET switch (the N atom) and the fluorophore
of 25 is increased further relative to 20. Thus it will be inter-
esting to investigate the effect of this increased distance on
Figure 1. Normalized excitation and emission spectra of (S,S)-20 and
(S,S)-25: a) (S,S)-20, lex =375 nm, lem =488 nm; b) (S,S)-25, lex =380 nm,
lem =492 nm. We used 5.0ꢁ10ꢁ7 moldmꢁ3 of sensors in methanol/water
mixed solvent (3:1 v/v), pH 7.0, 208C.
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Boronic Acid Chemosensors
FULL PAPER
Scheme 3. Synthesis of the chiral fluorescent boronic acid sensor 25 by using a modular approach. Reagents and conditions: i) [Pd
ethynyltrimethylsilane, argon atmosphere, reflux, 6 h, then K2CO3, MeOH, 1 h, 81%; ii) [Pd(PPh3)2Cl2], CuI, NEt3, 1,3,5-tribromobenzene, argon atmos-
phere, reflux, 10 h, 60%; iii) [Pd(PPh3)2Cl2], CuI, NEt3, PPh3, nitrogen atmosphere, reflux, 8 h, 60%; iv) (R)- and (S)-a-methylbenzylamine, THF, reflux,
ACHTNUGTNERN(UGN PPh3)2Cl2], CuI, NEt3,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
8 h, then NaBH3(CN), 08C, 30 min, 75% ((S,S)-24), 65% ((R,R)-24); v) acetonitrile, K2CO3, 2-(2-bromomethylphenyl)-1,3,2-dioxaborinane, reflux, 10 h,
yields: 32% ((S,S)-25), 30% ((R,R)-25). The N atoms that serve as the fluorescence switch centers are marked by arrows in sensor 25.
sors (lem =375 nm). Furthermore, the larger Stokes shift of
sensor 20 (138 nm) relative to the previously reported an-
thracene-based boronic acid sensor (ꢂ20 nm) and the car-
bazole-based sensor (ꢂ40 nm) is also beneficial for fluores-
cence analysis. All these features are ideal for the applica-
tion of phenothiazine as a novel fluorophore for fluorescent
molecular sensors.
BODIPY dyes show small Stokes shift (typical Stokes shift
is less than 20 nm).
The photophysical parameters are summarized in Table 1.
We propose that phenothiazine is a promising fluorophore
for the design of molecular chemosensors.
Table 1. Photophysical parameters of sensors 20 and 25.
The solvent-polarity dependence of the emission of the
sensor was investigated (see the Supporting Information).
Sensor 20 shows similar emission wavelength and intensity
in dichloromethane, methanol, and methanol/water (3:1 v/
v). However, sensor 25 shows solvent-polarity-dependent
emission (see the Supporting Information). Many fluoro-
phores display solvent-dependent emission, such as Rhoda-
mines, dansylamine, naphthalimide, and so on. Polarity-sen-
sitive emission will complicate fluorescence sensing because
the response of the molecular sensors will be dependent not
only on the analytes, but also the polarity of the environ-
ment. Therefore, fluorophores with polarity-independent
emission are desired. Recently, some fluorophores with po-
larity-independent emission have been tested, such as 4,4-di-
fluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY). However,
Sensors
e[a]
labs
lem
Stokes
shift
[nm]
F[b]
F[b]
[nm]
[nm]
pH 3.0
pH 7.0
A
1.48ꢁ104
1.43ꢁ104
2.17ꢁ104
2.15ꢁ104
350
350
350
350
488
488
492
492
138
138
142
142
0.152
0.155
0.033
0.036
0.476
0.487
0.302
0.310
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] In methanol/water mixed solvent (3:1 v/v), pH 7.0. [b] Fluorescence
quantum yields, with quinine sulfate as the standard (F=0.54 in 0.05m
H2SO4). Concentrations of the sensors are 1.0ꢁ10ꢁ5 moldmꢁ3
.
Next, the pH dependence of the emission of sensor 20
was investigated (Figure 2). The sensor displays a weak
emission in the acidic pH region but intensified emission in
the neutral and the basic pH regions. Thus a d-PET effect
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J. Zhao et al.
Scheme 4. The chiral analytes used in the study.
(fluorophore as the electron donor of the PET) was ob-
orophore as the electron acceptor of PET), however, the
emission is intensified at acidic pH but diminished at basic
pH, due to the protonation of the amine N atom at acidic
pH and the suppression of the PET process (quenching
effect). Furthermore, the contrast ratio, or the PET efficien-
cy, of 20 is approximately 6.0 (the emission is intensified by
around sixfold upon termination the PET effect), which is a
significant improvement compared to the d-PET boronic
acid sensors reported by us previously (the contrast ratio of
sensor 10 is around 2.0, Scheme 1).[25f–h] Apparent pKa
values of 4.37ꢃ0.89 and 4.32ꢃ0.09 were observed for
(R,R)-20 and (S,S)-20, respectively.
served for sensor 20.[25f,h] For the normal a-PET sensors (flu-
Previously we reported a d-PET fluorescent boronic acid
sensor (sensor 10, Scheme 1). However, we found that the
d-PET effect vanished upon attaching a phenylethynyl
moiety to the carbazole fluorophore (sensor 12 Scheme 1)
due to the electron-deficient ethynylene group.[25g] In con-
trast, for ethynylated phenothiazine sensor 20, when an eth-
ynyl group is incorporated, the d-PET effect is retained. Fur-
thermore, we found that the amine precursor of sensor 20
shows the d-PET effect (see the Supporting Information).
With carbazole fluorophore, however, the boronic acid sub-
unit as an extra electron-withdrawing subunit is required for
the d-PET effect, that is, the amine precursor of the carba-
zole-based sensor shows the normal a-PET effect.[25g] Thus
we propose the phenothiazine moiety is a stronger electron
donor than the carbazole moiety to assemble d-PET fluores-
Figure 2. Fluorescence intensity pH profile of a) (R,R)-20 and b) (S,S)-20
in the presence of d-/l-tartaric acid, 5.0ꢁ10ꢁ7 moldmꢁ3 of sensors in
methanol/water mixed solvent (3:1 v/v). lex =375 nm, lem =488 nm, [d-/l-
tartaric acid]=0.01 moldmꢁ3, 208C.
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Boronic Acid Chemosensors
FULL PAPER
cent sensors. This finding will be very helpful for the future
design of d-PET fluorescent chemosensors.
acid and the profile was reversed with (R,R)-20. With (R,R)-
20, the binding constants toward d- and l-tartaric acid were
kD =(2.21ꢃ0.19)ꢁ105 mꢁ1 and kL =(3.80ꢃ0.70)ꢁ104 mꢁ1, re-
spectively. Thus the enantioselectivity is kD/kL =5.8:1. Fur-
thermore, the fluorescence enhancement was more signifi-
cant with l-tartaric acid. With (S,S)-20, however, the re-
sponse profile was reversed, that is, kD =(5.61ꢃ0.46)ꢁ
104 mꢁ1 and kL =(2.71ꢃ0.26)ꢁ105 mꢁ1, respectively. Thus
with (S,S)-20 the enantioselectivity was switched to kD/kL =
1:4.8. The fluorescence enhancement was more significant
with d-tartaric acid.
Enantioselectivity was observed at pH 7.0. For example,
the binding constant of (R,R)-20 toward l- and d-tartaric
acid was kL =(8.64ꢃ1.61)ꢁ104 mꢁ1 and kD =(2.11ꢃ0.21)ꢁ
105 mꢁ1, respectively. Thus the enantioselectivity was kL/kD =
1:2.4. With (S,S)-20, the binding constant toward l- and d-
tartaric acid was kL =(3.77ꢃ0.23)ꢁ105 mꢁ1 and kD =(6.10ꢃ
0.82)ꢁ104 mꢁ1, respectively; kL/kD =6.2:1. Enantioselectivity
was observed for recognition at pH 8.0.
These enantioselectivity values are much higher than the
previous d-PET chiral boronic acid based on carbazole,[25f]
for which the enantioselectivity (kL/kD) is less than 2.0. Fur-
thermore, a chiral boronic acid a-PET sensor based on an-
thracene failed to recognize tartaric acid at acidic pH.[25b]
Based on the structural motif of the sensors, we propose
that 1:1 binding—that is, formation of the cyclic binding
complexes—is responsible for the enantioselectivity.[25b]
To validate the enantioselectivity of sensor 20 toward d-
and l-tartaric acids, we studied the recognition of d- and l-
mandelic acid with 20 (see the Supporting Information, Fig-
ure S62). Based on our previous study,[25a–d,f] no enantioselec-
tivity should be observed for the recognition of d- and l-
mandelic acids with bisboronic acid 20 because the mandelic
acids have one a-hydroxyl carboxylic acid unit and thus can
interact with only one of the two binding sites of the bisbor-
onic acid sensor 20. On the contrary, tartaric acid can inter-
act with the two binding sites of the bisboronic acid sensor
20 simultaneously).
pH titration of the sensors in presence of d- and l-tartaric
acids was carried out (Figure 2). The emission was enhanced
in the acidic region; however, a significant reduction in
emission was observed in the neutral pH region in the pres-
ence of tartaric acid. We found that both the fluorescence
enhancement at acidic pH and the diminishment at basic
pH is enantioselective, that is, the response of the sensor
was different towards the d- or the l- tartaric acids. A mir-
rored effect was observed for (S,S)-20 (Figure 2b). In the
presence of d- and l-tartaric acids, the apparent pKa of
(R,R)-20 changed to 7.86ꢃ0.14 and 7.34ꢃ0.06, respectively
(Figure 2a). With (S,S)-20, however, the profile reversed,
with apparent pKa of 7.29ꢃ0.07 and 7.78ꢃ0.06 being ob-
served for (S,S)-20 in the presence of d- and l-tartaric acid,
respectively.
The binding constants of the sensors with tartaric acid
were determined at pH 3.0, 7.0, and 8.0 (Figure 3). At
pH 3.0, the emission response of the sensors was enantiose-
lective toward d- and l-tartaric acid and the profile was mir-
rored. For example, the fluorescence enhancement of sensor
20 was higher toward l-tartaric acid than towards d-tartaric
With (R,R)-20, binding constants of (6.97ꢃ0.68)ꢁ102 mꢁ1
and (7.07ꢃ0.96)ꢁ102 mꢁ1 were obtained for the d- and l-
mandelic acid, respectively, thus the enantioselectivity was
close to 1:1. Furthermore, the apparent pKa of the (R,R)-20
changed from 4.29ꢃ0.08 to 6.87ꢃ0.03 or 6.94ꢃ0.02 in the
presence of d- or l-mandelic acid, respectively. All these re-
sults indicate that there is no enantioselectivity for the rec-
ognition of mandelic acid. Furthermore, the binding con-
stants of mandelic acids with 20 are around 100 or 1000
times lower than those obtained for tartaric acid. The lower
binding constant of mandelic acid is due to the formation of
the noncyclic 1:2 binding complexes, which are devoid of
the synergetic effect of the 1:1 cyclic complexation that en-
hances binding.[25a,b,f] This result indicates that the enantiose-
lectivity observed for recognition of tartaric acid with 20
(Figure 2 and Figure 3) is due to the formation of a cyclic
1:1 binding complex.[25a,b,f]
Figure 3. Relative fluorescence intensity of (R,R)-20 and (S,S)-20 versus
concentration of d-/l-tartaric acid: a) (R,R)-20, pH 3.0; b) (R,R)-20,
pH 7.0; c) (R,R)-20, pH 8.0; d) (S,S)-20, pH 3.0; e) (S,S)-20, pH 7.0;
f) (S,S)-20, pH 8.0. lex =375 nm, lem =520 nm, 5.0ꢁ10ꢁ7 moldmꢁ3 of sen-
sors in MeOH/H2O mixed solvent 3:1 v/v, 208C.
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J. Zhao et al.
Chiral bisboronic acid sensor with a larger binding pocket—
Application of the modular approach: The potential of our
modular strategy to assemble chiral molecular sensors was
demonstrated by the preparation of sensor 25 (Scheme 3)
with a larger scaffold than sensor 20 (Scheme 2). With the
Sonogashira coupling reaction, the binding pocket of 20 was
increased and (S,S)-25 and (R,R)-25 was obtained
(Scheme 3). To control the binding pocket and not generate
too large of a binding pocket (otherwise recognition of
small analytes such as tartaric acid would be difficult), we
used the meso-substituted 3-bromobenzenealdehyde to con-
struct the sensor (Scheme 3). It should be noted that the dis-
tance between the N atom (PET switch) and the fluoro-
phore core is larger than that in sensor 20 (Scheme 2).
Interestingly, even with extra ethynylene moiety, up to an
eightfold enhancement was observed for the d-PET effect
for 25 (Figure 4). This result indicates that phenothiazine is
Figure 5. Relative fluorescence intensity of sensors 25 versus concentra-
tion of d- and l-tartaric acid. a) (S,S)-25, pH 4.0; b) (R,R)-25, pH 4.0;
c) (S,S)-25, pH 5.5; d) (R,R)-25, pH 5.5. lex =380 nm, lem =500 nm, 5.0ꢁ
10ꢁ7 moldmꢁ3 of sensors 25 in MeOH/H2O mixed solvent (MeOH/H2O=
3:1 v/v), 208C.
Enantioselectivity was also found for the binding con-
stants. For example, the binding constants of (S,S)-25 toward
d- and l-tartaric acid are kD =(7.83ꢃ0.76)ꢁ105 mꢁ1 and kL =
(7.15ꢃ1.11)ꢁ104 mꢁ1, respectively. Thus the enantioselectivi-
ty is kD/kL =11.0:1. With (R,R)-25, the selectivity was re-
versed, binding constants toward d- and l-tartaric acid are
kD =(8.90ꢃ0.41)ꢁ104 mꢁ1 and kL =(9.34ꢃ1.08)ꢁ105 mꢁ1, re-
spectively. Thus the enantioselectivity is kD/kL =1:10.5. The
enantioselectivity is higher than that of sensor 20. We pro-
pose that the enhanced recognition of tartaric acid with
sensor 25 is due to the increased size of the binding pocket.
Herein we noticed that there is no simple correlation be-
tween the magnitude of the binding constants (an around
tenfold difference between the enantiomers of tartaric
acids) and the emission enhancement (an only around 1.5-
fold difference in the fluorescence enhancement for the d-
and l-tartaric acids). We propose that this discrepancy is
due to the complexity of the fluorescence relay (transduc-
tion), that is, both tight binding (suppression of the PET
Figure 4. Fluorescence intensity pH profile of a) (S,S)-25 and b) (R,R)-25
in the presence of d-/l-tartaric acids, 5.0ꢁ10ꢁ7 moldmꢁ3 of sensors in
MeOH/H2O mixed solvent 3:1 v/v. lex =380 nm, lem =490 nm, [d-/l-tarta-
ric acid]=0.01 moldmꢁ3, 208C.
a much stronger electron donor than carbazole. Our findings
will be helpful for the design of d-PET fluorescent chemo-
sensors.
Compared to sensor 20, the detection window of 25 (the
area between the blank pH titration curve and the titration
curve in the presence of analytes) is increased (Figure 4).
The apparent pKa of the (S,S)-25 and (R,R)-25 are 4.35ꢃ
0.11 and 4.43ꢃ0.11, respectively. In the presence of tartaric
acid, the apparent pKa increased substantially. For example,
the pKa of (S,S)-25 was increased to 7.86ꢃ0.14 and 7.78ꢃ
0.14 in the presence of l-tartaric acid and d-tartaric acid, re-
spectively.
ꢁ
The emission of 25 in solvents with different polarity was
also investigated (see the Supporting Information, Fig-
ure S46). We found that the emission is not diminished in
protic solvents, such as methanol or the aqueous buffer.
These photophysical parameters are ideal for application in
fluorescent molecular sensor design.
Enantioselective recognition of tartaric acid with sensor
25 was observed at pH 4.0 (Figure 5a and b). For example,
the emission enhancement of (S,S)-25 toward l- and d-tarta-
ric acid is 2.2-fold and 1.4-fold, respectively (Figure 5a).
With (R,R)-25, the response profile reversed (Figure 5b),
and the emission enhancement towards l- and d-tartaric
acid are 1.4-fold and 1.9-fold, respectively.
effect through direct or indirect B N interaction) and con-
formation restriction will enhance the fluorescence.
The binding of 25 with tartaric acids at pH 5.5 was also in-
vestigated (Figure 5c and d). No significant enantioselectivi-
ty was observed for the binding constants. For example,
kD =(2.22ꢃ0.11)ꢁ105 mꢁ1 and kL =(2.05ꢃ0.22)ꢁ105 mꢁ1
were obtained for (S,S)-25. We noticed this phenomenon
previously,[25b] but we do not have a clear explanation at the
present time. However, the fluorescence diminishment is
enantioselective. For example, with (S,S)-25, the emission di-
minishment is more significant for d-tartaric acid than l-tar-
taric acid (Figure 5c). For (R,R)-25, however, the emission
diminishment is more significant with l-tartaric acid than
7638
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Boronic Acid Chemosensors
FULL PAPER
that with d-tartaric acid. Interaction or geometry restriction
may lead to emission enhancement.
Consecutive fluorescence enhancement/diminishment upon
increasing the analyte concentration—Transition of the
binding stoichiometry from 1:1 to 1:2: Sequential emission
enhancement/diminishment was found for sensor 25 with an
increase in the d- and l-tartaric acid concentration
(Figure 6). The binding at low tartaric acid concentration
We studied the recognition of d- and l-mandelic acids
with sensor 25; no enantioselectivity was observed (Support-
ing Information, Figures S63 and S64). The binding con-
stants of (R,R)-25 with d- and l-mandelic acid are (6.86ꢃ
1.50)ꢁ103 mꢁ1 and (6.94ꢃ0.70)ꢁ103 mꢁ1, respectively. Also,
no enantioselectivity was observed for the fluorescence di-
minishment. This result indicates that the enantioselectivity
observed for recognition of tartaric acid with sensor 25 is
most probably due to the formation of a cyclic 1:1 binding
complex.[25a,b,f]
The effect of the binding pocket size of 20 and 25 on the
recognition of sugar acids was also studied (Supporting In-
formation, Figure S47).[32] For example, 20 gives a small re-
sponse to d-gluconic acid (the emission of the blank sensor
is quenched slightly), but with sensor 25, a more significant
response to d-gluconic acid was observed (the emission of
sensor 25 was quenched more significantly). The favored
binding of d-gluconic acid by sensor 25 (with a bigger bind-
ing pocket than sensor 20) was also demonstrated by the
higher binding constant. For example, a binding constant of
k=(2.04ꢃ0.22)ꢁ103 mꢁ1 was observed with (S,S)-20. With
sensor (S,S)-25, however, a binding constant of (5.21ꢃ
1.08)ꢁ104 mꢁ1 was observed, which is twentyfold higher than
that of (S,S)-20. Furthermore, no enantioselectivity on d-glu-
conic acid was observed with sensor 20. With sensor 25,
however, a 1.5:1 enantioselectivity was observed. This result
indicates that the bigger binding pocket of sensor 25 is capa-
ble of effective chiral recognition of gluconic acid. The rec-
ognition of sugar alcohols with the sensors was also studied.
Enantioselectivity was observed for the recognition of the
sugar alcohols. The binding constants of the sensors with an-
alytes are summarized in Table 2.
Figure 6. Relative fluorescence intensity of a) (S,S)-25 and b) (R,R)-25
versus the concentration of d- and l-tartaric acid. pH 4.0, lex =380 nm,
lem =500 nm, 5.0ꢁ10ꢁ7 moldmꢁ3 of sensor 25 in MeOH/H2O mixed sol-
vent 3:1 v/v, 208C.
produces emission enhancement. At higher tartaric acid
concentration, however, the emission intensity decreased.
We propose the consecutive emission enhancement/dimin-
ishment with increasing the tartaric acid concentration at
pH 4.0 is due to a change of the binding stoichiometry from
1:1 to 1:2. Previously we observed a similar effect with the
BINOL-based chiral sensor 1 (Scheme 1).[25a]
With 20, however, no emission enhancement/diminish-
ment was observed. Thus we propose that the small binding
pocket of sensor 20 is the correct molecular size for tartaric
acid, and thus 1:1 binding is the favored stoichiometry. This
was demonstrated by our previous experiments with the an-
Table 2. Binding constants of the chiral bis-boronic acid sensors 20 and 25 with analytes.
Analytes
pH
(S,S)-20
E
G
ACHTUNGTRENN(UNG R,R)-25
[b]
[b]
d-tartaric acid
3.0
4.0
5.5
7.0
8.0
3.0
4.0
5.5
7.0
8.0
3.0
5.5
3.0
5.5
5.5
7.0
5.5
7.0
7.0
7.0
7.0
(5.61ꢃ0.46)ꢁ104 (›)
(2.21ꢃ0.19)ꢁ105 (›)
–
–
[b]
[b]
–
–
(7.83ꢃ0.76)ꢁ105 (›)
(2.22ꢃ0.11)ꢁ105 (fl)
(8.90ꢃ0.41)ꢁ104 (›)
(1.98ꢃ0.18)ꢁ105 (fl)
[b]
[b]
–
–
[b]
[b]
(6.10ꢃ0.82)ꢁ104 (fl)
(5.00ꢃ1.04)ꢁ102 (fl)
(2.71ꢃ0.26)ꢁ105 (›)
(2.11ꢃ0.21)ꢁ105 (fl)
(7.31ꢃ1.04)ꢁ102 (fl)
(3.80ꢃ0.70)ꢁ104 (›)
–
–
–
–
–
–
[b]
[b]
[b]
[b]
l-tartaric acid
[b]
[b]
–
–
–
–
(7.15ꢃ1.11)ꢁ104 (›)
(2.05ꢃ0.22)ꢁ105 (fl)
(9.34ꢃ1.08)ꢁ105 (›)
(2.28ꢃ0.19)ꢁ105 (fl)
[b]
[b]
[b]
[b]
(3.77ꢃ0.23)ꢁ105 (fl)
(7.06ꢃ0.58)ꢁ102 (fl)
(8.64ꢃ1.61)ꢁ104 (fl)
(5.21ꢃ0.75)ꢁ102 (fl)
(6.97ꢃ0.68)ꢁ102 (›)
–
–
–
–
–
–
–
–
–
[b]
[b]
[b]
[b]
[b]
d-mandelic acid
l-mandelic acid
d-gluconic acid
d-sorbitol
–
–
–
–
[b]
[b]
[b]
–
(6.86ꢃ1.50)ꢁ103 (fl)
[b]
[b]
[b]
(7.07ꢃ0.96)ꢁ102 (›)
–
[b]
[b]
[b]
–
–
(6.94ꢃ0.70)ꢁ103 (fl)
(3.58ꢃ0.71)ꢁ104 (fl)
[b]
[b]
–
(5.21ꢃ1.08)ꢁ104 (fl)
[b]
[b]
(2.04ꢃ0.22)ꢁ103 (fl)
(2.65ꢃ0.42)ꢁ103 (fl)
–
–
[b]
[b]
–
–
(2.99ꢃ1.25)ꢁ104 (fl)
(2.13ꢃ1.08)ꢁ104 (fl)
[b]
[b]
(1.04ꢃ0.11)ꢁ103 (fl)
(1.42ꢃ0.25)ꢁ103 (fl)
(1.59ꢃ0.54)ꢁ103 (fl)
(3.23ꢃ0.60)ꢁ104 (fl)
(1.21ꢃ0.10)ꢁ103 (fl)
(1.75ꢃ0.31)ꢁ103 (fl)
(1.22ꢃ0.25)ꢁ103 (fl)
(2.70ꢃ0.56)ꢁ104 (fl)
–
–
d-mannitol
d-glucose
xylitol
(4.77ꢃ1.96)ꢁ104 (fl)
(1.16ꢃ0.34)ꢁ104 (fl)
[b]
[b]
–
–
–
–
[b]
[b]
[a] Fluorescence enhancement (›) or diminishment (fl) in the presence of analytes are indicated. [b] Not determined due to the weak fluorescence re-
sponse at the specific pH, indicated by the pH titrations.
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7639

J. Zhao et al.
thracene-based chiral boronic acid sensor 2 (Scheme 1). For
sensor 20, the binding with tartaric acid is tight, thus 1:1
binding is favored. For sensor 25, however, 1:2 binding be-
comes dominant at high tartaric acid concentrations.
To prove the transition of the binding stoichiometry from
1:1 to 1:2, we measured the mass spectra of sensor (S,S)-25/
tartaric acid solutions (Supporting Information, Figures S39–
S41). The 1:1 binding complex of (S,S)-25/d-tartaric acid (m/
z 1254.3344, adduct with Na+) (with a dual-MeOH-inserted,
zwitterionic, intramolecular hydrogen-bond structure, Fig-
ure S41) was found for the 1:1 (S,S)-25/d-tartaric acid ratio
(Supporting Information, Figures S39 and S41). By increas-
ing the ratio of d-tartaric acid to 10:1 (over (S,S)-25), a par-
tially opened structure (m/z 1200.3722) was observed. A fur-
ther increase of the ratio of the mixture (100:1) resulted in
the appearance of the opened form (1:2 binding complex)
with m/z 1318.3667. Although some irregularities exist in
the mass spectroscopic analysis, the trend of the binding sto-
ichiometry transition from 1:1 to 1:2 upon increasing the
ratio of tartaric acid is clear. Unfortunately, attempts to
grow single crystals to support these assumptions failed.
Figure 7. Frontier molecular orbits of neutral and protonated sensor 25.
Note the HOMO and LUMO of the neutral 25 is localized on the pheno-
thiazine unit, whereas the HOMO!LUMO transition of protonated 25
is an electron-transfer process from the ethynylated phenothiazine frame-
work. Calculated with DFT methods on the B3LYP/3-21G level.
Rationalization of the d-PET effect of the chiral fluorescent
boronic acid sensors—DFT/time-dependent (TD)-DFT cal-
culations: Recently, DFT/TD-DFT calculations have been
used for investigation of the photophysics of fluorophores
and fluorescent molecular sensors.[33–35] Previously we used
DFT/TD-DFT calculations to study d-PET fluorescent bor-
onic acid sensors[25g,h] as well as fluorescent OFF/ON thiol
probes.[36,37]
ble for cell recognition. Thus recognition of polysaccharides
with fluorescent molecular sensors is significant.[39–41] The
binding pockets of the sensors, especially sensor 25, are
large, therefore the binding of a monosaccharide, such as
glucose, is not tight. For (R,R)-25 and (S,S)-25, no significant
binding was observed. We suppose that binding with disac-
charides may be tight for the sensors. Thus the disaccharides
of sucrose, lactose, and maltose were tested against the sen-
sors. We observed stronger binding than that with glucose.
The binding constants are usually up to 104 mꢁ1 scale.
Enantioselectivity, demonstrated by both the fluorescence
response and binding constants, was observed for the sen-
sors. For example, the (S,S)-25 and (R,R)-25 gives similar re-
sponse to lactose. Binding constants of (8.31ꢃ2.92)ꢁ103 mꢁ1
and (5.05ꢃ0.84)ꢁ103 mꢁ1 were found for the (S,S)-25 and
(R,R)-25, respectively (Figure 8a). With maltose, however,
(R,R)-25 and (S,S)-25 give drastically different responses.
The strategy we employed is to examine the property of
the lowest-lying singlet excited state (S1), which is responsi-
ble for the fluorescence emission (Kashaꢂs rule).[38] The S1
state of the protonated form of the d-PET boronic acid
sensor 10 (Scheme 1) is a dark state (with S0!S1 oscillator
strength close to zero). Thus the S0!S1 is a forbidden transi-
tion, as well as the S1!S0 transition. Therefore the protonat-
ed form of the d-PET boronic acid sensors produce a weak
emission (at acidic pH). For the neutral form of the d-PET
sensors, however, the S0!S1 oscillator strength increases sig-
nificantly, thus S0!S1 is an allowed transition and the
sensor is probably fluorescent (S1!S0 is allowed). Therefore,
an intensified emission at neutral pH will be observed.[25f,g]
For the protonated 25 (Figure 7), we observed a charge-
transfer character for the HOMO!LUMO transition. The
S1 state of protonated 25 is a dark state (f=0.0042), but the
S1 state of neutral 25 is probably a radiative state (f=0.69,
indicates an allowed S0!S1 transition, thus S1 is probably a
radiative state and the sensor is probably fluorescent; see
the Supporting Information, Table S1). Therefore, we pro-
pose that the neutral sensor 25 will display a stronger emis-
sion than the protonated form. This prediction is fully sup-
ported by the experimental results.
Figure 8. Fluorescent recognition of the a-lactose and maltose. a) and
b) Relative fluorescence intensity of (R,R)-25 and (S,S)-25 versus the
concentration of a-lactose and maltose. lex =380 nm, lem =500 nm, 5.0ꢁ
10ꢁ7 moldmꢁ3 of sensor in MeOH/H2O mixed solvent (MeOH/H2O=3:1
v/v), 208C.
Recognition of disaccharides and glycosylated steroids:
Polysaccharides and glycosylated steroids are biologically
important. For example, some oligosaccharides are responsi-
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Boronic Acid Chemosensors
FULL PAPER
Table 3. Apparent association constants (Ka) [mꢁ1] of sensors 20 and 25 with different disaccharides and ginse-
nosides Re and Rb1.[a]
We found that the emission
intensity of the sensors de-
creased in the presence of gin-
senosides Re and Rb1 (ginse-
nosides are not stable in acidic
pH, therefore pH titrations
Analytes
(S,S)-20
E
G
ACHTUNGTRENN(UNG R,R)-25
sucrose
a-lactose
maltose
ginsenosides Re
(4.01ꢃ1.08)ꢁ104 (fl) (6.28ꢃ1.79)ꢁ104 (fl) (2.50ꢃ0.41)ꢁ104 (fl) (3.10ꢃ1.30)ꢁ104 (fl)
(1.19ꢃ0.39)ꢁ104 (fl) (3.45ꢃ1.11)ꢁ104 (fl) (8.31ꢃ2.92)ꢁ103 (fl) (5.05ꢃ0.84)ꢁ103 (fl)
(1.03ꢃ0.45)ꢁ104 (fl) (2.19ꢃ0.83)ꢁ105 (fl) (7.18ꢃ1.78)ꢁ103 (fl) (2.48ꢃ0.56)ꢁ103 (fl)
(5.94ꢃ0.57)ꢁ105 (fl) (5.11ꢃ0.82)ꢁ105 (fl) (6.79ꢃ0.50)ꢁ105 (fl) (1.95ꢃ0.31)ꢁ105 (fl)
were
not
carried
out;
ginsenosides Rb1 (6.91ꢃ0.62)ꢁ105 (fl) (5.34ꢃ1.18)ꢁ105 (fl) (2.88ꢃ0.51)ꢁ106 (fl) (1.81ꢃ0.32)ꢁ106 (fl)
Figure 9). We found that 20
and 25 bind tightly with the
ginsenosides. For example, the
binding constants are generally
[a] Binding studies were conducted in MeOH/H2O mixed solvent (MeOH/H2O=3:1 v/v), pH 7.4. Fluorescence
enhancement (›) or diminishment (fl) in the presence of analytes are indicated.
For example, the fluorescence decrease of (S,S)-25 in the
presence of maltose is around 16%. With (R,R)-25, howev-
er, the emission decrease is only 5%. Furthermore, the
binding constants of (R,R)-25 and (S,S)-25 with maltose is
(7.18ꢃ1.78)ꢁ103 mꢁ1 and (2.48ꢃ0.56)ꢁ103 mꢁ1, respectively
(Figure 8b). Enantioselectivities were also found for (S,S)-20
and (R,R)-20 (Supporting Information). The bindings of 20
and 25 with disaccharides are summarized in Table 3. The
binding constants are generally much higher than recently
reported bis-boronic acid sensors for the detection of sac-
charides, including maltose and lactose (typically less than
500mꢁ1).[40b]
The binding pockets of 20 and 25 are large, therefore we
studied their interaction with large analytes such as glycosy-
lated steroids. Herein we used ginsenosides, which are be-
lieved to be responsible for the physiological benefits of gin-
seng, one of the most widely taken medical herbs. Current
analysis of ginsenosides requires sophisticated instruments,
such as HPLC analysis. To the best of our knowledge, fluo-
rescent chemosensors are rarely used for recognition of gin-
senosides.[40a]
on the scale of 5.0ꢁ105 mꢁ1. These binding constants are
around two-hundred-fold higher than a porphyrin receptor
for ginsenosides.[40a] We tentatively attribute the tight bind-
ing to the good fitting of the ginsenosides to the bis-boronic
acid binding pocket of sensors 20 and 25. Furthermore, we
observed enantioselectivity (either by the binding constants
or the fluorescence response) for the recognition of the gin-
senosides Re and Rb1. For example, the emission of (S,S)-
20 decreases to 42% of the initial intensity in the presence
of Rb1. With (R,R)-20, however, the emission decreases to
60%. Similar binding constants were observed for (R,R)-20
and (S,S)-20 with Rb1. Enantioselectivity was also found for
the recognition of Re with sensor 25 (Table 3).
Conclusion
In conclusion, we have devised a new modular approach for
the assembly of chiral fluorescent boronic acid sensors, in
which the fluorophore, the binding sites, and the chirogenic
centers are easily assembled onto a scaffold. This modular
approach for the preparation of chiral molecular sensors is
in contrast to the previously reported chiral sensors that
consist of an integrated fluorophore and chirogenic centers,
which are difficult to change into other structures. The ethy-
nylated phenothiazine fluorophore shows visible-light exci-
tation, emission at 492 nm, and large Stokes shift (142 nm);
a high fluorescence quantum yield was also found (F=
0.487). This makes the ethynylated phenothiazine an ideal
fluorophore for fluorescent chemosensor development. In
our modular chiral sensors, the fluorophore and the chiro-
genic center are connected by an ethynylene group (CꢀC),
which ensures efficient electron communication between the
N atom (PET switch center) and the fluorophore. A high
contrast ratio (ꢂ8.0) is observed; even the distance between
the N atom (PET switch) and the fluorophore core is large.
We attribute the high contrast ratio to the strong electron-
donating ability of the phenothiazine fluorophore. Further-
more, the chiral boronic acid sensors show a d-PET effect,
that is, the fluorophore serves as electron donor in the PET
process and the sensors show intensified emission at neutral
pH but diminished emission in the acidic pH region, which
is in stark contrast to the normal a-PET fluorescent chemo-
sensors. Enantioselective recognition of d- and l-tartaric
acid was achieved with the sensors, and the recognition of
the analytes is dependent upon the size of the binding
Figure 9. Fluorescent recognition of the ginsenosides Re and Rb1. a) and
b) Relative fluorescence intensity of (R,R)-20 and (S,S)-20 versus concen-
tration of Re and Rb1: lex =375 nm, lem =488 nm. c and d) Relative fluo-
rescence intensity of (R,R)-25 and (S,S)-25 versus concentration of Re
and Rb1: lex =380 nm, lem =500 nm. 5.0ꢁ10ꢁ7 moldmꢁ3 of sensor in
MeOH/H2O mixed solvent 3:1 v/v, 208C.
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7641

J. Zhao et al.
Then K2CO3 (1.65 g, 12 mmol) and methanol (5 mL) were added, and the
solution was stirred for 1 h at room temperature. The solvents were re-
moved under reduced pressure. The residue was taken up with CH2Cl2
and washed with water. The organic layer was dried over MgSO4. After
the solvent was removed, the residue was purified by column chromatog-
raphy (silica gel, CH2Cl2/petroleum ether, 1:6 v/v). Yield: 1.04 g (84%) of
a yellow liquid. 1H NMR (CDCl3, 400 MHz, TMS): d=7.23 (m, 2H),
7.09–7.16 (m, 2H,), 6.90 (t, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75
(d, J=8.4 Hz, 1H), 3.81 (t, J=7.2 Hz, 2H), 3.03 (s, 1H), 1.73–1.80 (m,
2H), 1.40–1.49 (m, 2H), 0.92 ppm (t, J=8.4 Hz, 3H); APCI-MS: m/z:
calcd for C18H17NS: 280.1 [M+H]+; found: 280.0.
pocket of the boronic acid sensors. The transition of binding
stoichiometry from 1:1 (closed form) to 1:2 (noncyclic open
form) upon increasing the tartaric acid concentration was
proposed for sensor 25 based on the fluorescence titration
(consecutive emission enhancement/diminishment was ob-
served with increasing the tartaric acid concentration) and
was supported by the mass spectroscopic analysis. The sen-
sors were used for enantioselective recognition of disacchar-
ides (sucrose, lactose, and maltose) and glycosylated steroids
(ginsenosides). Tight binding and selective recognition were
found. We believe that the modular structural motif of the
fluorescent chiral boronic acid sensor devised by us can be
generalized for the preparation of chiral molecular sensors,
not limited to boronic acid sensors, with binding sites other
than boronic acid groups. This would make it possible to
design chiral fluorescent molecular probes in which the fluo-
rophore and the chirogenic center are easily interchangeable
so as to tune the emission properties and enantioselectivity
of the sensors.
Compound 18: [PdACTHUNTRGNE(UNG PPh3)4] (46.8 mg, 0.04 mmol), CuI (7.7 mg,
0.04 mmol), and 17 (0.35 g, 1.35 mmol) were successively added to a de-
gassed solution of 2-iodo-1,4-benzenedicarboxaldehyde (0.37 g,
1.35 mmol) in dry Et3N (5 mL) and THF (3.0 mL). The mixture was
heated to reflux under nitrogen for 8 h. The solvents were removed. The
residue was washed with water and CH2Cl2. The organic layer was dried
over MgSO4. After the solvent was removed, the residue was purified by
column chromatography (silica gel, CH2Cl2/petroleum ether, 3:1 v/v).
Yield: 0.22 g (40%) of a red oil. 1H NMR (CDCl3, 400 MHz, TMS): d=
10.65 (s, 1H), 10.07 (s, 1H), 8.03–8.07 (m, 2H), 7.85 (d, J=8.0 Hz, 1H),
7.26–7.35 (m, 2H), 7.10–7.18 (m, 2H), 6.92 (t, J=8.0 Hz, 1H), 6.86 (d,
J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.83 (t, J=8.0 Hz, 2H),1.75–1.82
(m, 2H), 1.44–1.49 (m, 2H), 0.93 ppm (t, J=8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=191.1, 190.9, 146.5, 144.3, 139.4, 138.8, 134.6,
131.2, 130.3, 128.2, 128.0, 127.9, 127.5, 127.4, 125.1, 123.9, 123.0, 115.7,
115.2, 115.1, 97.8, 83.9, 47.3, 28.9, 20.1, 13.8, 0 ppm; TOF-MS (EI)+: m/z:
calcd for C26H21NO2S: 411.1293 [M+H]+; found: 411.1302.
Experimental Section
Compound (S,S)-19: (S)-1-Phenylethanamine (0.17 g, 1.46 mmol) was
added to a solution of 18 (0.02 g, 0.49 mmol) in dry THF (3 mL). The re-
action mixture was heated to reflux under nitrogen for 8 h. After the so-
lution was cooled to RT, NaBH3(CN) (0.15 g, 2.45 mmol) was added in
several portions to the stirred solution, and the stirring was continued for
1 h. The resulting mixture was evaporated to dryness. The residual was
purified by column chromatography (silica gel, CH2Cl2/MeOH, 30:1 v/v).
Yield: 0.12 g (40%) of a yellow oil. 1H NMR (CDCl3, 400 MHz, TMS):
d=7.11–7.47 (m, 17H), 6.91 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H),
6.77 (d, J=8.0 Hz, 1H), 3.54–3.89 (m, 8H), 1.75–1.83 (m, 2H), 1.32–1.49
(m, 8H), 0.93 ppm (t, J=8.0 Hz, 3H); TOF-MS (EI)+: m/z: calcd for
C42H43N3S: 622.3256 [M+H]+; found: 622.3275.
The fluorescence emission spectra of the sensors were determined as the
pH was changed from pH 2 to 11 in approximate intervals of approxi-
mately 0.5 pH units. The pH was controlled by using minimum volumes
of sodium hydroxide and hydrochloric acid solutions. The boronic acid
sensors can form methanol adducts (as indicated by the mass spectral
analysis). The fluorescence spectra of the sensors in the presence of the
analytes were recorded as increasing amounts of the analyte were added
to the solution. All the DFT/TD-DFT calculations were performed using
Gaussian 09.[42]
10-Butyl-10H-phenothiazine (15): nC4H9Br (8.2 g, 60 mmol) was added
to a stirred solution of phenothiazine (9.95 g, 50 mmol), hexadecyltrime-
thylammonium bromide (0.5 g), and NaOH (3.0 g) in acetone (50 mL).
The mixture was heated to reflux for 6 h. Then the solvent was removed
under reduced pressure, the residue was extracted with dichloromethane
(CH2Cl2), and washed with water. The organic phase was dried over an-
hydrous Na2SO4. The solvent was removed and the residue was purified
by column chromatography (silica gel, CH2Cl2/petroleum ether, 1:3 v/v).
Yield: 6.64 g (52%) of a light green liquid. 1H NMR (CDCl3, 400 MHz,
TMS): d=7.10–7.14 (m, 4H), 6.86 (t, J=7.2 Hz, 2H), 6.83 (d, J=8.4 Hz,
2H), 3.80 (t, J=7.2 Hz, 2H), 1.73–1.80 (m, 2H), 1.38–1.48 (m, 2H),
0.90 ppm (t, J=7.8 Hz, 3H); atmospheric-pressure chemical ionization
(APCI) MS: m/z: calcd for C16H17NS: 256.1 [M+H]+; found: 256.0.
Compound (R,R)-19: This compound was synthesized by using a proce-
dure similar to that of (S,S)-19. Yellow oil was obtained with a yield of
1
36%. H NMR (CDCl3, 400 MHz, TMS): d=7.13–7.43 (m, 17H), 6.92 (t,
J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.55–
3.88 (m, 8H), 1.76–1.83 (m, 2H), 1.38–1.52 (m, 8H), 0.93 ppm (t, J=
8.0 Hz, 3H); TOF-MS (EI)+: m/z: calcd for C42H43N3S: 622.3256
[M+H]+; found: 622.3285.
Sensor (S,S)-20: (S,S)-19 (100.0 mg, 0.16 mmol), 2-(2-bromomethylphen-
yl)-1,3,2-dioxaborinane (138.0 mg, 0.54 mmol), and K2CO3 (132.0 mg,
0.96 mmol) were mixed in dry MeCN (5.0 mL). Then the mixture was
heated to reflux for 10 h under N2. The reaction mixture was cooled to
room temperature and diluted HCl was added. Then the mixture was
stirred for a further 1 h. The solvent was removed under vacuum, and
CH2Cl2 was added to take up the residue. The organic layer was washed
with water and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure and the residue was purified by column chroma-
tography (silica gel, CH2Cl2/MeOH, 30:1 v/v). Yield: 40.0 mg (28%) of a
light yellow powder. M.p. 205–2068C; [a]2D5 =(ꢁ16.9ꢃ1.0)8 (c=0.11 in
CH2Cl2); 1H NMR (CDCl3, 400 MHz): d=7.75 (s, 2H), 7.08–7.41 (m,
23H), 6.94 (t, J=7.6 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz,
1H), 4.02–4.10 (m, 2H), 3.86–3.93 (m, 5H), 3.55–3.64 (m, 5H), 1.78–1.85
(m, 2H), 1.57 (d, J=8.0 Hz, 6H), 1.45–1.54 (m, 2H), 0.95 ppm (t, J=
8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3/CD3OD): d=145.5, 144.7,
141.7, 141.6, 136.4, 135.9, 133.0, 131.2, 130.6, 130.0, 129.6, 129.4, 129.3,
129.0, 128.2, 128.1, 127.7, 127.5, 127.2, 127.0, 124.9, 124.2, 123.3, 122.8,
116.9, 115.6, 115.1, 93.3, 87.8, 58.4, 57.4, 53.1, 50.9, 47.3, 29.0, 20.1, 15.9,
15.6, 13.7 ppm; TOF-MS (EI)+: m/z: calcd for C58H61B2N3O4S: 459.7363
[M+2MeOHꢁ2H2O+2H]2+]; found: 459.7363.
3-Bromo-10-butyl-10H-phenothiazine (16): NaOH (0.66 g, 6.44 mmol, in
40 mL glacial acetic acid) was added to
a solution of 15 (1.40 g,
5.48 mmol) in chloroform (10 mL). Then bromine (0.28 mL, 5.48 mmol,
in 6 mL glacial acetic acid) was added dropwise at 08C. The mixture was
stirred at 0–58C for 1 h. The solvents were removed. Water (50 mL) and
CH2Cl2 (100 mL) were added, and the organic layer was dried with
MgSO4. The solvent was removed, and the residue was purified by
column chromatography (silica gel, CH2Cl2/petroleum ether, 1:3 v/v).
Yield: 1.28 g (70%) of a light yellow liquid. 1H NMR (CDCl3, 400 MHz,
TMS): d=7.17 (d, J=8.0 Hz, 2H), 7.06–7.13 (m, 2H), 6.86 (t, J=8.0 Hz,
1H), 6.80 (d, J=8.0 Hz, 1H), 6.60 (t, J=8.0 Hz, 1H), 3.73 (t, J=8.0 Hz,
2H), 1.66–1.75 (m, 2H), 1.35–1.45 (m, 2H), 0.88 ppm (t, J=8.0 Hz, 3H);
APCI-MS: m/z: calcd for C16H16BrNS: 335.3 [M+H]+; found: 335.1.
10-Butyl-3-ethynyl-10H-phenothiazine (17): [PdCl2ACHTNUGTRENUNG(PPh3)2] (124.0 mg,
0.17 mmol), PPh3 (46.5 mg, 0.17 mmol), CuI (33.7 mg, 0.17 mmol), and
ethynyltrimethylsilane (435.0 mg, 4.43 mmol) were successively added to
a degassed solution of 16 (1.48 g, 4.43 mmol) in dry Et3N (8 mL) and
THF (5 mL). The reaction mixture was heated to reflux under N2 for 6 h.
7642
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7632 – 7644

Boronic Acid Chemosensors
FULL PAPER
Sensor (R,R)-20: This compound was synthesized by using a procedure
similar to that of (S,S)-20. A light-yellow powder was obtained in a yield
of 30%. M.p. 205–2068C. [a]2D5 =(+17.9ꢃ0.7)8 (c=0.11 in CH2Cl2);
1H NMR (CDCl3, 400 MHz): d=7.60 (s, 2H), 6.91–7.25 (m, 23H), 6.78
(t, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 3.71–
(100 MHz, CDCl3/CD3OD): d=145.9, 144.7, 141.5, 138.1, 134.0, 133.9,
131.4, 131.1, 130.6, 130.3, 130.0, 129.2, 128.6, 128.4, 127.9, 127.6, 127.5,
127.4, 125.0, 124.4, 124.2, 124.1, 122.3, 122.9, 122.7, 116.5, 115.7, 115.2,
94.6, 90.6, 90.3, 88.0, 87.8, 58.4, 57.4, 53.5, 47.4, 29.0, 20.2, 15.8, 13.9 ppm;
TOF-MS (EI)+: m/z: calcd for C58H51N3S: 411.6980 [M+2H]2+; found:
411.6967.
3.78 (m, 5H), 3.37–3.52 (m, 5H), 3.09–3.25ACTHNUTRGNE(NUG m, 2H), 1.63–1.70 (m, 2H),
1.41–1.46 (m, 6H), 1.31–1.39 (m, 2H), 0.80 ppm (t, J=8.0 Hz, 3H);
13C NMR (100 MHz, CDCl3/CD3OD): d=145.6, 144.7, 133.0, 131.2,
130.6, 129.9, 129.6, 129.5, 129.3, 129.1, 128.3, 127.7, 127.5, 127.2, 124.9,
124.2, 122.8, 116.9, 115.6, 115.1, 93.3, 87.8, 58.5, 57.4, 53.1, 50.9, 47.3, 29.0,
20.1, 15.9, 15.6, 13.8 ppm; TOF-MS (EI)+: m/z: calcd for C58H61B2N3O4S:
459.7363 [M+2MeOHꢁ2H2O+2H]2+; found: 459.7359.
Sensor (S,S)-25: Compound (S,S)-24 (100.0 mg, 0.12 mmol), 2-(2-bromo-
methylphenyl)-1,3,2-dioxaborinane (68 mg, 0.26 mmol), and K2CO3 (99 g,
0.72 mmol) were mixed in dry MeCN (5 mL), then the mixture was
heated to reflux for 10 h under N2. The reaction mixture was cooled to
RT and diluted HCl was added. Then the mixture was stirred for a fur-
ther 1 h. The solvent was removed under reduced pressure, and CH2Cl2
was added to take up the residue. The organic layer was washed with
water and dried over anhydrous MgSO4. The solvent was removed under
vacuum, and the residue was purified by column chromatography (silica
gel, CH2Cl2/MeOH, 30:1 v/v). Yield: 42.0 mg (32%) of a light yellow
powder. M.p. 204–2058C; [a]2D5 =(ꢁ5.8ꢃ0.9)8 (c=0.15 in CH2Cl2);
1H NMR (CDCl3, 400 MHz): d=7.79 (s, 2H), 7.62 (s 3H), 7.25–7.43 (m,
22H), 7.11–7.19 (s, 6H), 6.91 (t, J=7.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H),
6.81 (d, J=8.4 Hz, 1H), 4.05–4.10 (m, 2H), 3.84–3.92 (m, 4H), 3.60–3.68
(m, 4H), 3.33–3.37 (m, 2H), 1.76–1.83 (m, 2H), 1.58 (d, J=7.2 Hz, 6H),
1.42–1.51 (m, 2H), 0.93 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3/CD3OD): d=145.8, 144.6, 141.4, 138.9, 137.9, 136.0, 133.9, 133.7,
132.8, 131.3, 131.0, 130.5, 130.2, 130.0, 129.9, 129.1, 128.5, 128.3, 127.8,
127.5, 127.4, 127.3, 124.9, 124.3, 124.1, 124.0, 122.8, 122.6, 116.4, 115.6,
115.1, 90.5, 90.2, 87.9, 87.6, 58.3, 57.3, 53.4, 47.3, 28.9, 20.1, 15.8,
13.8 ppm; TOF-MS (EI)+: m/z: calcd for C72H65B2N3O4S: 559.7676
[M+2MeOHꢁ2H2O+2H]2+; found: 559.7643.
Compound (R,R)-24: This compound was synthesized by using a proce-
dure similar to that of (S,S)-21. A yellow oil was obtained in a yield of
65%. 1H NMR (CDCl3, 400 MHz, TMS): d=7.59 (s, 3H), 7.50 (s, 2H),
7.35–7.42 (m, 9H), 7.26–7.33 (m, 9H),7.11–7.17 (m, 2H), 6.91 (t, J=
8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.84–3.87
(m, 4H), 3.59–3.71 (m, 4H), 1.76–1.83 (m, 2H), 1.40–1.51 (m, 8H),
0.93 ppm (t, J=8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3/CD3OD): d=
145.8, 144.6, 141.4, 138.8, 137.9, 136.1, 133.9, 133.8, 132.8, 131.0, 130.6,
130.3, 130.1, 129.9, 129.1, 128.6, 128.3, 127.8, 127.5, 127.4, 127.3, 124.9,
124.3, 124.1, 124.0, 122.9, 122.7, 116.4, 115.6, 115.2, 90.5, 90.2, 87.9, 87.7,
58.3, 57.3, 53.5, 53.4, 47.3, 31.0, 28.9, 20.2, 15.8, 13.9 ppm; TOF-MS (EI)+
: m/z: calcd for C58H51N3S: 411.6980 [M+2H]2+; found: 411.6987.
3-Ethynylbenzaldehyde (21): [PdCl2ACHTUNTGRNEUNG(PPh3)2] (382.0 mg, 0.54 mmol), CuI
(104.0 mg, 0.54 mmol), and ethynyltrimethylsilane (3.2 g, 33.0 mmol)
were successively added to a degassed solution of 3-bromobenzaldehyde
(5.0 g, 27.2 mmol) in dry Et3N (10 mL) and THF (5 mL). The reaction
mixture was heated to reflux under N2 for 6 h. Then K2CO3 (3.7 g,
27.2 mmol) and methanol (10 mL) were added, and the solution was
stirred for 1 h at room temperature. The solvents were removed under re-
duced pressure. The residue was taken up with CH2Cl2 and washed with
water. The organic layer was dried over MgSO4. After the solvent was re-
moved, the residue was purified by column chromatography (silica gel,
CH2Cl2/petroleum ether, 2:1 v/v). Yield: 2.9 g (81%) of a yellow solid.
1H NMR (CDCl3, 400 MHz, TMS): d=10.00 (s, 1H), 7.99 (s, 1H), 7.85
(d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.49 (t, 1H, J=7.6 Hz),
3.17 ppm (s, 1H).
Compound 22: [PdCl2ACHTUNGTRENNUNG(PPh3)2] (450.0 mg, 0.64 mmol), CuI (73.0 mg,
0.39 mmol), and 3-ethynylbenzaldehyde (1.0 g, 7.69 mmol) were succes-
sively added to a degassed solution of 1,3,5-tribromobenzene (1.20 g,
3.85 mmol) in dry Et3N (8 mL) and THF (3 mL). The reaction mixture
was heated to reflux under N2 for 10 h. The solvents were removed
under reduced pressure. The residue was taken up with CH2Cl2 and
washed with water. The organic layer was dried over MgSO4. After the
solvent was removed, the residue was purified by column chromatogra-
phy (silica gel, CH2Cl2/petroleum ether, 3:1 v/v). Yield: 0.95 g (60%) of a
yellow solid. 1H NMR (CDCl3, 400 MHz, TMS): d=10.03 (s, 2H), 8.03
(s, 2H), 7.88 (d, J=7.6 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.66 (d, J=
8.8 Hz, 3H), 7.54 ppm (t, 2H, J=7.6 Hz); TOF-MS (EI)+: m/z: calcd for
C24H13Br2O2: 412.0099 [M+H]+; found: 412.0111.
Compound 23: [PdACHTUNGTRENNUNG(PPh3)4] (60.0 mg, 0.05 mmol), CuI (10.0 mg,
Sensor (R,R)-25: This compound was synthesized by using a procedure
similar to that of (S,S)-25. A light-yellow power was obtained in a yield
of 30%. M.p. 204–2058C; [a]2D5 =(ꢁ6.3ꢃ0.8)8 (c=0.15 in CH2Cl2);
1H NMR (CDCl3, 400 MHz, TMS): d=7.81 (d, J=8.0 Hz, 2H), 7.62 (s
3H), 7.25–7.43 (m, 22H), 7.11–7.19 (m, 6H), 6.91 (t, J=7.6 Hz, 1H), 6.86
(d, J=8.0 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.05–4.10 (m, 2H), 3.84–3.93
(m, 4H), 3.60–3.67 (m, 4H), 3.33–3.36 (m, 2H), 1.76–1.83 (m, 2H), 1.58
(d, J=7.2 Hz, 6H), 1.42–1.51 (m, 2H), 0.93 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3/CD3OD): d=145.8, 144.6, 141.4, 138.8,
137.9, 136.1, 134.9, 133.9, 133.8, 132.8, 131.4, 131.0, 130.6, 130.3, 130.1,
129.9, 129.2, 128.6, 128.3, 127.8, 127.5, 127.4, 127.3 124.9 124.3 124.0,
122.9 122.7 116.4, 115.6, 115.2, 90.5, 90.2, 87.9, 87.7, 58.3, 57.3, 53.5, 47.3,
31.0, 28.9, 20.2, 15.8, 13.8 ppm; TOF-MS (EI)+: m/z: calcd for
C72H65B2N3O4S: 559.7676 [M+2MeOHꢁ2H2O+2H]2+; found: 559.7665.
0.05 mmol), and 17 (0.48 g, 1.71 mmol) were successively added to a de-
gassed solution of 22 (0.85 g, 2.1 mmol) in dry Et3N (5 mL) and THF
(3 mL). The reaction mixture was heated to reflux under N2 for 8 h. The
solvents were removed. The residue was washed with water and CH2Cl2.
The organic layer was dried over MgSO4. After the solvent was removed
under reduced pressure, the residue was purified by column chromatog-
raphy (silica gel, CH2Cl2/petroleum ether, 3:1 v/v). Yield: 0.60 g (60%) of
1
a yellow oil. H NMR (CDCl3, 400 MHz, TMS): d=10.01 (s, 2H), 8.02 (s,
2H), 7.84 (d, J=7.6 Hz, 2H), 7.75 (d, J=7.6 Hz, 2H), 7.63 (s, 3H), 7.50
(t, J=7.6 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.10–7.17 (m,
2H), 6.91 (t, J=7.2 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz,
1H), 3.82 (t, J=7.2 Hz, 2H), 1.74–1.81 (m, 2H), 1.43–1.48 (m, 2H),
0.93 ppm (t, J=7.6 Hz, 3H); APCI-MS: m/z: calcd for C42H29NO2S:
612.19 [M+H]+; found: 612.30.
Compound (S,S)-24: (S)-1-Phenylethanamine (0.17 g, 1.44 mmol) was
added to a solution of 23 (0.40 g, 0.65 mmol) in dry THF (1 mL) and eth-
anol (5 mL). The reaction mixture was heated to reflux under nitrogen
for 8 h. After the solution was cooled to RT, NaBH3(CN) (0.21 g,
3.25 mmol) was added in several portions to the stirred solution, and the
stirring was continued for 0.5 h. The resulting mixture was evaporated to
dryness. The residue was taken up with CH2Cl2 and washed with water.
The organic layer was dried over MgSO4. After removing the solvent, the
residual was purified by column chromatography (silica gel, CH2Cl2/
MeOH, 30:1 v/v). Yield: 0.40 g (75%) of a yellow oil. 1H NMR (CDCl3,
400 MHz, TMS): d=7.61 (s, 3H), 7.49 (s, 2H), 7.24–7.38 (m, 18H), 7.11–
7.17 (m, 2H), 6.90 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.79 (d,
J=8.0 Hz, 1H), 3.80–3.87 (m, 4H), 3.58–3.68 (m, 4H), 1.75–1.82 (m,
2H), 1.39–1.51 (m, 8H), 0.93 ppm (t, J=8.0 Hz, 3H); 13C NMR
Acknowledgements
We thank the NSFC (20972024 and 21073028), Fundamental Research
Funds for the Central Universities (DUT10ZD212), the Royal Society
(UK) and NSFC (China) (China/UK Cost-Share Program, 21011130154),
the Ministry of Education (SRFDP-200801410004 and NCET-08-0077),
the Education Department of Liaoning Province (2009T015), the State
Key Laboratory of Fine Chemicals (KF0802), and Dalian University of
Technology for financial support. We also thank the Catalysis and Sens-
ing for our Environment (CASE) consortium for networking opportuni-
Chem. Eur. J. 2011, 17, 7632 – 7644
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7643

J. Zhao et al.
ties. T.D.J. would also like to thank Dalian University of Technology for
the award of a HaiTian Scholarship.
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Received: January 5, 2011
Published online: May 19, 2011
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