Selective anion sensing by chiral macrocyclic receptors with multiple hydrogen-bonding sites

Article abstract of DOI:10.1021/ol403643d

Chiral macrocycles featuring sulfonamide and/or amide groups as anion-binding sites were synthesized. X-ray crystal structures and DFT calculations have shown that they adopt different conformations that may lead to unique binding behavior. Indeed, various anions could be sensed by their colorimetric and/or fluorescence signal output. The chiral macrocycles showed chiral recognition for chiral anions. Furthermore, a multisensor array with two or four chiral receptors discriminated seven phosphate anions (AMP, ADP, ATP, CMP, GMP, Pi, and PPi) with 100% classification accuracy.

Full text of DOI:10.1021/ol403643d

Letter
pubs.acs.org/OrgLett
Selective Anion Sensing by Chiral Macrocyclic Receptors with
Multiple Hydrogen-Bonding Sites
Tadashi Ema,*,† Keiichi Okuda,† Sagiri Watanabe,† Takayuki Yamasaki,† Tsuyoshi Minami,‡
Nina A. Esipenko,‡ and Pavel Anzenbacher, Jr.*,‡
†Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Tsushima,
Okayama 700-8530, Japan
‡Department of Chemistry and Center for Photochemical Sciences, Bowling Green State University, Bowling Green, Ohio 43403,
United States
S
* Supporting Information
ABSTRACT: Chiral macrocycles featuring sulfonamide and/or
amide groups as anion-binding sites were synthesized. X-ray crystal
structures and DFT calculations have shown that they adopt different
conformations that may lead to unique binding behavior. Indeed,
various anions could be sensed by their colorimetric and/or
fluorescence signal output. The chiral macrocycles showed chiral
recognition for chiral anions. Furthermore, a multisensor array with
two or four chiral receptors discriminated seven phosphate anions
(AMP, ADP, ATP, CMP, GMP, Pi, and PPi) with 100% classification accuracy.
hiral anions are species ubiquitous in nature where they
1
Cplay a number of key roles. Therefore, highly selective
and sensitive anion receptors and sensors are useful in a
number of chemistry disciplines including biochemistry,
physiology, and analytical chemistry.1,2 The importance of
anion receptors as organocatalysts has been widely recognized.3
Consequently, new chiral anion receptors are highly desired.
Anion−receptor recognition can be driven by hydrogen
bonding, electrostatic interaction, and metal coordination.4−10
Hydrogen bonding, due to its relative strength (10−30 kJ/mol)
and, most importantly, donor→acceptor directionality, occu-
pies an important place in the receptor design. Various
functional groups, such as amide,5a,d,e,6 sulfonamide,5c,7
pyrrole,8 urea,5c,9 and triazole,5b,d,10 have been used as
Figure 1. Chemical structures of Chirabite-AR (1) and sulfonamide
hydrogen-bond donors. Wide implementation of chiral
receptors for the detection and separation of anions is hindered
by the lack of methods suitable for high-throughput screening.
For example, ion chromatography is popular but has drawbacks,
such as cost, and requires trained personnel. In contrast, optical
methods such as UV−vis and fluorescence methods are
generally sensitive and amenable to cost-effective high-
throughput analysis. Toward this point, chiral anion receptors
displaying analyte-induced change in color and/or fluorescence
are required.
Chirabite-AR (1, Figure 1), a chiral macrocyclic host, has
multiple H-bonding sites in the cavity as well as a fluorescent
binaphthyl moiety enabling us to follow the recognition process
using fluorescence. Recently, we have reported that 1 can bind
various neutral guests.11 In view of the importance of anion
recognition we decided to explore the binding ability of 1 for
chiral anions. Because the two amide NH groups of the lower
segment of 1 are the principal H-bond donor sites,11 we also
congeners 2 and 3. Only (R)-enantiomers are shown.
designed two sulfonamide congeners 2 and 3 (Figure 1) to
strengthen the H-bond donor ability. The pyridine rings of 2
have been replaced by the benzene rings to yield receptor 3
because the Lewis basic pyridine rings of 2 might be
unfavorable for the binding of anions (Lewis bases) and
because fluorescence intensity might increase. The binaphthyl
moiety is expected to impart chiral recognition in 1−3.12,13
Here we report on the synthesis of 2 and 3, X-ray crystal
structures of 1 and 3, and the anion recognition behavior of 1−
3. A multisensor array with (R)/(S)-2 and (R)/(S)-3
discriminated seven phosphate anions (AMP, ADP, ATP,
CMP, GMP, Pi, and PPi) with 100% classification accuracy.
Received: December 17, 2013
Published: February 14, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Macrocycle 1 was prepared according to the literature,11a
while 2 and 3 were newly synthesized (Supporting Information
(SI)). Single crystals of 1 and 3 were obtained by
recrystallization from CHCl3/EtOAc and CHCl3/hexane,
respectively, and were subjected to X-ray crystallographic
analysis (Figure 2). Figure 2 shows that 1 has a conjugated π-
disappeared upon addition of anions such as F−, AcO−, CN−,
−
and H2PO4 , and in the case of F− a new signal appeared at
−
16.1 ppm, which is assigned to HF2 . This suggests that the
nitrobenzamide and sulfonamide NH groups in 1−3 may have
been deprotonated. At the same time we noticed that solutions
of receptor 1 were colored differently upon addition of anions,
−
−
namely strong bases such as F−, N3 , AcO−, CN−, and H2PO4 .
In particular, the addition of CN− gave a deep reddish purple
solution of 1. Although CN−-induced color changes have been
reported for several receptors,14 the present color change is one
of the most dramatic changes. On the other hand, 2 and 3
experienced little or no color change upon addition of anions.
Instead, we found that 2 and 3 exhibited blue fluorescence
upon UV irradiation (365 nm), although 1 did not. The
absolute fluorescence quantum yields of 1, 2, and 3 in DMSO
(excitation at 300 nm) were <1%, 6.9%, and 19.4%,
respectively. It is likely that fluorescence from the binaphthyl
group in 1 is quenched by the nitrophenyl group in 1.
Interestingly, the fluorescence of 2 and 3 was quenched by the
addition of F−, N3 , AcO−, CN−, or H2PO4 (Figure 3).
−
−
Figure 2. X-ray crystal structures of (a) (R)-1 and (b) (R)-3.
plane in the lower segment, to which the binaphthyl moiety is
orthogonal, and that the four amide NH groups are directed
inside the macrocycle cavity. This structure is quite similar to
that obtained by ab initio calculations.11b Interestingly, a
molecule of EtOAc used as solvent is included in the cavity of
1, forming a rotaxane-like structure, where the O-atom of
EtOAc is H-bonded with the amide NH groups of 1. In
contrast, 3 adopts a folded conformation with the binaphthyl
moiety partially covering one side of the cavity; the four NH
groups of 3 are not directed to the side of the cavity. This is due
to the presence of the two sulfonamide groups intervening
between the three π-systems in the lower segment. A CHCl3
molecule is partially included in the calix-like cavity of 3 by
CH/π and van der Waals interactions. DFT calculations
indicated that 3 adopts the folded conformation even in the
absence of the CHCl3 molecule (SI). The solid state and DFT-
optimized structures suggest that 1 and 3 would show quite
different binding behavior. DFT calculations suggest that 2
adopts a similar but more folded conformation as compared
with 3 (SI).
Figure 3. (a) Color changes of 1 (15 mM) upon addition of anions
(5.5 equiv) in DMSO. Fluorescence changes of (b) 2 (15 mM) and
(c) 3 (15 mM) upon addition of anions (5.5 equiv) in DMSO. λex
=
365 nm. All anions were used as tetrabutylammonium salts.
−
Among them, N3 quenched the fluorescence of 2 but
−
quenched that of 3 only slightly. Thus, N3 could be
discriminated by using both 2 and 3. Importantly, Figure 3
also indicates that 2 and 3 show slightly different responses
−
even to AcO−, CN−, and H2PO4 , which helps us to selectively
detect these anions by using both 2 and 3.
Because of the biological importance, we turned our
attention to the anions of AMP, ADP, ATP, CMP, GMP,
H3PO4 (Pi), and H4P2O7 (PPi) (Figure 4). To evaluate the
binding abilities of 1−3, we determined the binding constants
of 1−3 for the AMP and CMP anions by the NMR titration
experiments (Table 1).11a,b (R)-1 showed no appreciable
affinity for AMP and CMP anions, and the binding constants
could not be determined. In contrast, (R)-2 and (R)-3 showed
appreciable affinities for the AMP and CMP anions. Because
the nucleotide anions used in this study are chiral, they are
expected to show different affinities for (R)- and (S)-receptors.
Indeed, AMP, bearing a purine base, exhibited a slightly higher
affinity for (S)-2, while CMP, bearing a pyrimidine base,
Initially, the binding of anions to the receptors was
confirmed by electrospray ionization (ESI) mass spectrometry.
The ESI-MS spectra showed the peaks of both the parent
macrocycle and the anion−receptor complex (SI). Next, we
attempted to determine the binding affinity of 1−3 for simple
anions in DMSO-d6 using NMR titrations. However, the
nitrobenzamide and sulfonamide NH signals of 1−3
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Organic Letters
Letter
All of the above fundamental results encouraged us to
investigate whether the multisensor array16 with (R)/(S)-2 and
(R)/(S)-3 could discriminate the seven anions of AMP, ADP,
ATP, CMP, GMP, Pi, and PPi (Figure 4). The assay was
performed in the standard 1536-well microplate, the data were
recorded with an automatic plate reader, and the output data
were analyzed using linear discriminant analysis (LDA)17 with
leave-one-out cross-validation. To our delight, LDA exhibited
an excellent discrimination capability for these biologically
important phosphates with 100% correct classification of all 160
data-points (20 data points for each of the seven analytes and
control) (Figure 6). It should be noted that this four-sensor
array could discriminate not only the number of phosphates but
also types of base moieties.
Figure 4. Chemical structures of guests. The corresponding anions
were used as tetrabutylammonium or sodium salts.
Table 1. Binding Constants of Hosts 1−3 for Anionic
a
Nucleotides
b
c
Ka (M−1
AMP
)
enantioselectivity
receptor
CMP
d
d
(R)-1
(R)-2
(S)-2
(R)-3
(S)-3
−
−
−
−
238
259
258
228
1.1 (S)
286
190
270
326
1.5 (R)
1.1 (R)
1.2 (S)
a
In DMSO-d6 at 22 °C. All anions were added as tetrabutylammonium
b
salts. The Ka values were calculated by the nonlinear least-squares
method. Ratio of the Ka values. The Ka value was too small to
c
d
Figure 6. LDA canonical score plots for the response of (R)-2, (S)-2,
(R)-3, (S)-3 sensor array (the four-sensor array) to seven phosphates
in an aqueous DMSO solution (water/DMSO = 1:9, v/v). The cross-
validation routine shows 100% correct classification. [guest] = 4.0 ×
10−5 M.
determine.
showed a 1.5-fold higher affinity for (R)-2. On the other hand,
interestingly, AMP exhibited a higher affinity for (R)-3, while
CMP showed a higher affinity for (S)-3. MM calculations
suggest that the nucleotide anions take U-shaped conforma-
tions and that, in addition to double hydrogen bonds between
the phosphate anion and the sulfonamide/amide groups, the
nucleobase of AMP or CMP makes contact with the binaphthyl
moiety of 2 or 3, which may lead to enantioselective binding
(SI). Despite the small differences in affinity, we envisioned
that 2 and 3 might sense and amplify the differences of various
phosphate anions via fluorescence quenching as seen in Figure
3b and c. We performed fluorescence titrations. Figure 5
displays dramatic fluorescence spectral changes for (R)-2 upon
addition of the AMP anion in an aqueous DMSO solution.15
Part of the motivation of this work was to establish the
correlation between the structural feature of each sensor and
the discriminatory power of the multisensor array, an effort that
could provide important information for developing an effective
analytical method for nucleotides. Toward that end, we
analyzed the discriminatory power of the sensor arrays with
various combinations of hosts. First, we attempted to
discriminate the seven phosphates by using fluorescence
responses arising from only one host. However, we could not
achieve 100% correct classification. In contrast, the excellent
resolution with 100% correct classification was achieved by the
combination of two hosts ((R)-2 and (S)-2). Furthermore, the
combination of (R)-2 and (R)-3 was also able to discriminate
the seven phosphates with 100% classification. This implies that
discrimination of the seven phosphates requires one enantio-
meric host pair or a combination of two types of receptor (the
two-sensor array), probably due to differential responses based
on diastereomeric interactions as demonstrated in Table 1.
In summary, new macrocycles 2 and 3, with sulfonamide and
amide groups in the cavity, were synthesized. The parent
receptor 1 could detect anions by coloration, while 2 and 3
could detect anions by quenching of the fluorescence. As
expected, the binding constants indicated that 2 and 3 showed
higher affinities for anions than 1. Receptors 1−3 showed chiral
recognition for chiral anions. Furthermore, we developed a
sensor array using 2 and 3 capable of distinguishing seven
phosphates in an aqueous DMSO solution with 100%
classification accuracy. Further exploration of the microarray
Figure 5. Fluorescence titration of (R)-2 by AMP in an aqueous
DMSO solution (water/DMSO = 3:97, v/v). λex = 304 nm. [AMP] =
(0−1.0) × 10−4 M.
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Letter
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ASSOCIATED CONTENT
* Supporting Information
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compounds, X-ray data, DFT and MM calculations, determi-
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microarray, canonical scores plots, and jackknifed classification
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ema@cc.okayama-u.ac.jp.
*E-mail: pavel@bgsu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Division of Instrumental Analysis,
Department of Instrumental Analysis & Cryogenics, Advanced
Science Research Center, Okayama University for the X-ray
measurements. We thank Dr. Hiromi Ota at the Division of
Instrumental Analysis for the X-ray single crystal structural
analyses. We are also grateful to the SC-NMR Laboratory of
Okayama University for the measurement of NMR spectra. P.A.
acknowledges support from the NSF (CHE-0750303 and
DMR-1006761).
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