UV–vis and fluorescence detection by receptors based on an isophthalamide bearing a phenylethynyl group

Article abstract of DOI:10.1016/j.tetlet.2017.09.043

We have successfully prepared 5-(2-phenylethynyl)isophathalilc acid as a signaling unit and the corresponding derivatives for an anion receptor 2 and a barbiturate receptor 4. Receptor 2 showed characteristic UV–vis changes and dramatic fluorescence quenc

Full text of DOI:10.1016/j.tetlet.2017.09.043

Accepted Manuscript
UV-vis and fluorescence detection by receptors based on an isophthalamide
bearing a phenylethynyl group
Shin-ichi Kondo, Kimihiro Endo, Jun Iioka, Keisuke Sato, Yuka Matsuta
PII:
S0040-4039(17)31170-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.043
TETL 49313
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2017
13 September 2017
15 September 2017
Please cite this article as: Kondo, S-i., Endo, K., Iioka, J., Sato, K., Matsuta, Y., UV-vis and fluorescence detection
by receptors based on an isophthalamide bearing a phenylethynyl group, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.09.043
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Tetrahedron Letters
UV-vis and fluorescence detection by receptors based on an isophthalamide
bearing a phenylethynyl group
Shin-ichi Kondo*, Kimihiro Endo, Jun Iioka, Keisuke Sato, and Yuka Matsuta
Department of Science, Faculty of Science, Yamagata University, Yamagata 990-8560, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We have successfully prepared 5-(2-phenylethynyl)isophathalilc acid as a signaling unit and the
corresponding derivatives for an anion receptor 2 and a barbiturate receptor 4. Receptor 2
showed characteristic UV-vis changes and dramatic fluorescence quenching upon the addition of
anions and receptor 4 showed UV-vis and an OFF-ON fluorescence changes upon the addition
of dibutylbarbituric acid based on the diphenylethyne moiety.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Isophthalamide derivatives
Anion recognition
Barbiturate receptor
UV-vis titrations
Fluorescence change
In the field of the molecular recognition, an isophthalamide
amide moiety has been a key component for construction of an
effective recognition site for guest species such as neutral
barbiturates1-3 and anions4-9 due to the convergent hydrogen
bonds formed by the cleft like structure. However,
isophthalamide spacer is less versatile for a chromophore and a
fluorophore due to the ineffective electronic perturbation on the
ground and excited states during the recognition process,
therefore a fluorescence signaling unit was generally appended to
a receptor as a peripheral group. In order to overcome this
disadvantage, an introduction of substituents on an isophthaloyl
skeleton to form a practical chromofluorophore would make
beneficial spacer to construct various kinds of receptors including
anion and barbiturate receptors. However, fluorescence spacer
groups bearing cleft-like bisamide have been less explored. Gale
et al. reported anthracene-1,3-dicarboxyamide as anion
phosphate selective receptors. We have also prepared an
isophthalamide-based receptor 1 bearing 1-pyrenylmethyl
moieties for the ratiometric detection by fluorescence spectral
changes for anions.22, 23 Receptor 1 showed potent binding ability
for anions by six hydrogen bonds with four amide N-H and two
hydroxy groups of serine residues.23 These receptors consist of
three parts, i.e. isophthalamide spacer, amino acids, and terminal
amide groups. All these parts can be decorated with substituents
to provide functionalities on the receptors. In this report, we
demonstrate the design and preparation of 5-(2-
phenylethynyl)isophthalamide and the derivatives as new class of
fluorophores. It should be pointed out that the phenylethynyl
group shows no photoisomerization unlike phenylethenyl and
phenyldiazenyl groups which show cis-trans photoisomerization
during photo irradiation. Receptor 2 based on this unit was
prepared and evaluated for anion receptors as shown in Scheme
1. Four amide N-H and two hydroxy groups of serine residues
would make effective binding site for anionic species as similar
receptors.10 Jurczak and co-workers reported that bisamides
based on azulene-1,3- and -5,7-dicarboxylic acids were used as
colorimetric anion receptors.11, 12 Berlin et al. reported synthesis
of Hamilton receptors bearing perylene diimides via ethyne as a
spacer.13 It is well known that 1,2-diphenylethyne (commonly
known as diphenylacetylene and tolan) and its derivatives show
fluorescence emission and widely applied to building blocks for
organic materials14-17 due to these easy preparation by well-
studied Sonogashira coupling.16 In addition, 5-
ethynylisophthalamide derivatives have been reported as
supramolecular materials.18, 19 We have designed and synthesized
receptors based on isophthalamide for anions as shown in
Scheme 1, for instance, isophthalamide-based receptors bearing
pyridyl,20 quinolyl, and isoquinolyl groups21 for dihydrogen
Scheme 1.

2
Tetrahedron
to receptor 1.23 As a result, UV-vis and drastic fluorescence
spectral changes of 2a suggesting weak interaction with these
responses of 2 can be observed during the binding process with
anions.
anions.
Diphenylethyne shows a structured fluorescence spectrum at
around 300–330 nm in 3-methylpentane.25 However, receptor 2
showed strong and structureless fluorescence at 355 nm in MeCN
excited at 301 mm, which is the isosbestic point described above,
in the absence of anions as shown in Figure 2a. The quantum
yield of 2 in MeCN was determined to be 0.075 by comparing
with quinine sulfate in 0.5 mol dm−3 sulfuric acid. The
A historical receptor 3 for barbiturate reported by Hamilton et
al. has also an isophthaloyl moiety for the construction of the
convergent binding site (Scheme 2).1 We also demonstrate
preparation and off-on fluorescence sensing of receptor 4 in
which diamidopyridine moieties was used as recognition sites for
barbiturates.
fluorescence intensity was gradually decreased and blue shifted
to 347 nm upon the addition of AcO− as shown in Figure 2a. In
the presence of excess amount of AcO−, fluorescence intensity of
Receptor 2 was successfully prepared as shown in Scheme 3.
Sonogashira coupling of dimethyl 5-bromoisophatalate24 with
ethynylbenzene by Pd(PPh3)4 in the presence of zinc chloride,
DBU, and NaI in DMF afforded a key intermediate, dimethyl 5-
(2-phenylethynyl)isophthalate 5 in 83% yield. After hydrolysis
by KOH in EtOH/water, the produced dicarboxylic acid 6 was
condensed with l-serine butyl amide trifluoroacetic acid salt in
the presence of WSCD, HOBt, and triethylamine in DMF to give
the target receptor 2 in 75% yield. The structure of 2 was
confirmed by 1H, 13C, COSY, HMQC, and HMBC NMR
techniques and HRMS.
−
2 was efficiently quenched (F/F0 ~ 0.2). Addition of H2PO4
caused the similar spectral changes with AcO−, however, Cl−
induced smaller spectral changes as shown in Figure 2b.
Interestingly, addition of Br− induced larger quenching, which
may due to bound Br− be able to act as effective quencher of 2.
Almost no fluorescence changes were observed upon the addition
a
b
3.0
2.0
1.0
0.0
0.6
0.4
0.2
0.0
The UV-vis spectrum of 2 in MeCN (typical solvent used for
anion recognition) showed typical structured but slightly red-
shifted spectrum for diphenylacetylene due to the intramolecular
charge transfer (ICT) of the phenylethylisophthaloyl moiety as
shown in Figure 1a. The absorbance maxima at 299.5 and 283.0
nm were slightly hypsochromic shifted to 298.5 and 282.0 nm,
respectively through an isosbestic point at 301 nm upon the
addition of AcO− (tetrabutylammonium was used as a counter
cation for all anionic guests). The similar shift was observed
0
2
4
6
260280300320340
Wavelength / nm
[Anion]/[2]
−
Figure 1. (a) UV-vis spectral titration of 2 with AcO− in MeCN. (b)
Absorbance change of 2 at 280 nm upon the addition of anions in MeCN.
AcO− (), H2PO4− (), Cl− (▲), and Br− (▼). [2] = 2.010−5 mol dm−3 at
298 K.
upon the addition of H2PO4 , and less significant shifts were also
observed by the addition of Cl− and Br−. Figure 1b shows UV-vis
spectral changes of 2a at 280 nm upon the addition of various
−
anions in MeCN. Addition of I−, NO3 , and ClO4− caused no
a
b
5x105
4
1.0
0.8
0.6
0.4
0.2
3
2
1
0
0
2
4
6
350 400 450 500
em / nm
[Anion]/[2]

Scheme 2.
Figure 2. (a) Fluorescence spectral titration of 2 with AcO− in MeCN. (b)
Fluorescence intensity changes of 2 at 358 nm upon the addition of anions in
MeCN. AcO− (), H2PO4− (), Cl− (▲), and Br− (▼). [2] = 1.010−5 mol
dm−3, λex = 301 nm at 298 K.
0
-5
-10
-15
-20
-25
0.0 0.2 0.4 0.6 0.8 1.0
[2]/([2]+[Anion])
Figure 3. Job plots of 2 with AcO− () and H2PO4− () in MeCN. [2] +
[anion] = 1.010−5 mol dm−3.
Scheme 3. (a) PhC≡CH, Pd(PPh3)4, ZnCl2, DBU, NaI, DMF, 83%; (b)
KOH, EtOH/H2O, 31%; (c) H2N-Ser-NHBu, WSCD·HCl, HOBt, Et3N,
DMF, 75%.

Table 1
a
b 0.20
The association constants of 2 with anions
1.2
0.8
0.4
0.0
K11 / mol−1 dm3
Fluorescenceb
0.15
Anion
AcO−
UV-vis a
5.42±0.50105
1.51±0.08105
ND c
4.96±0.43105
3.59±0.30105
ND c
0.10
0.05
0.00
−
H2PO4
−
NO3
−
ClO4
ND c
ND c
Cl−
Br−
I−
2.44±0.51104
4.15±0.62103
ND c
4.28±0.56104
1.16±0.19104
ND c
0
2
4
6
240 280 320 360
Wavelength / nm
[8]/[4]
a Measured in 0.3% DMSO–MeCN (v/v) at 298 K. [2] = 2.010−5 mol
dm−3. b Measured in 0.2% DMSO–MeCN (v/v) at 298 K. [2] = 1.010−5 mol
dm−3. λex = 301 nm. c Not determined due to small spectral changes.
Figure 4. (a) UV-vis spectral changes of 4 upon the addition of
dibutylbarbituric acid (8) in CHCl3. (b) Absorbance changes of 4 at 314 nm
upon the addition of 8 in CHCl3. [4] = 2.010−5 mol dm−3 at 298 K.
a250
b 12
200
150
100
50
8
4
0
0
0
10
[8]/[4]
20
30
300 400 500 600 700
em / nm

Scheme 4. Proposed structure of 2·AcO−.
−
of less basic anions, such as I−, NO3 , and ClO4− suggesting weak
Figure 5. (a) Fluorescence changes of 4 upon the addition of 8 in CHCl3.
(b) Fluorescence spectral changes of 4 at 472 nm upon the addition of 8 in
CHCl3. [4] = 5.010−6 mol dm−3, λex = 298 nm at 298 K.
interaction with 2. Job’s plot analyses of 2 with AcO− and
H2PO4− are shown in Figure 3. The minima at mole fraction 0.5
strongly suggest complexation of receptor 2 and these anions as
1:1 stoichiometries, respectively.
The association constants of 2 with anions were calculated
from the UV-vis and fluorescence titrations by non-linear curve
fitting analysis to the theoretical 1:1 complexation model and the
results are collected in Table 1. Basic oxoanions such as AcO−
and H2PO4− were strongly bound and less basic halogen anions
such as Cl− and Br− were weakly bound (one or two orders of
−
magnitude smaller than those for AcO− and H2PO4 ) with 2. The
−
association constants with other anions, including I−, NO3 , and
ClO4− were not determined due to the negligible spectral changes
even upon the excess addition of such anions. These association
constants for all anions were slightly smaller than those of 1 due
to the more flexible terminal butyl groups of 2 than rigid 1-
pyrenylmethyl groups of 1.
Scheme 5. Proposed structure of 4·8.
The isophthalic acid derivative 4 was also designed as another
example of fluororeceptor. Phenylethynyl moiety was attached to
the Hamilton’s receptor 3 to achieve an effective fluororeceptor
for barbiturates. The intermediate 6 can be easily converted to
diacylchloride with thionyl chloride and the produced diacyl
chloride was immediately condensed with 6-amino-2-
butyrylamidopyridine in THF gave receptor 4 in 51%. Receptor 4
showed broad absorption at around 300 nm in CHCl3. The UV-
vis spectra of 4 were slightly sharpen upon the addition of
dibutylbarbituric acid (8) through an isosbestic point at 298 nm
as shown in Figure 4. Receptor 4 showed low fluorescence
intensity (F = 0.0026) in the absence of guest excited at 298 nm,
however, the fluorescence intensity of 4 was gradually increased
upon the addition of 8 (Figure 5). The emission maximum of the
complex 4·8 was observed at 478 nm, which is longer
wavelength than that of 2 (355 nm, Figure 2a) due to the
conjugation of diphenylethyne and diamidopyridyl groups. The
titration curves showed typical 1:1 binding isotherms, therefore,
the association constants of 4 with dibutylbarbituric acid were
calculated to be 6.58±0.18104 and 5.98±0.27104 mol−1dm3
from UV-vis and fluorescence titrations, respectively. The
association constant of Hamilton’s receptor 3 with
The proposed structure of the complexation of 2 with AcO− is
shown in Scheme 4. The association constants with AcO− listed
in Table 1 suggest that the anion was coordinated by six point
hydrogen bonds, i.e. four amides and two hydroxy groups of
serine residues comparing with our previous studies.23 In
addition, a weak hydrogen bond with 2-CH of the isophthaloyl
group induced the reduction of electron-withdrawing nature of
the isophthaloyl moiety resulting in the diminishment of the
intramolecular charge transfer of the diphenylethynyl moiety.
Therefore, the UV-vis absorption of 2 was hypsochromic shift
and the fluorescence spectrum was also blue shifted during the
complexation with anions. TD-DFT calculations (B3LYP/6-
31+G(d) level of theory) of free 7 (butyl groups of 2 were replace
to methyl groups to reduce the computer resource), 7·Cl−, and
7·AcO− revealed that UV-vis absorption maxima at 312
(HOMO→LUMO), 307 (HOMO−2→LUMO), and 307 nm
(HOMO−2→LUMO), respectively (supplementary material) due
to the reduction of ICT nature of 2 by complexation with anionic
guest species support observed UV-vis spectral changes.
diethylbarbituric acid in the same solvent was reported to be

4
Tetrahedron
2.08104 mol−1dm3 by 1H NMR titrations,1 which is comparable
7.
Howe EN, Bhadbhade M, Thordarson P J. Am. Chem. Soc.
2014;136:7505.
8.
Rosano C Chem. Eur. J. 2014;20:1658.
to those of 4 suggesting the same binding mode of 4 for a
barbituric acid as shown in Scheme 5.
Cafeo G, Gattuso G, Kohnke FH, Papanikolaou G, Profumo A,
9.
Jarvis TS, Collins CG, Dempsey JM, Oliver AG, Smith BD J.
In conclusion, we have synthesized receptor 2 as an effective
anion receptor. Receptor 2 showed dramatic fluorescence
responses upon the addition of basic oxoanions such as AcO− and
Org. Chem. 2017;82:5819.
10.
Supramol. Chem. 2008;20:349.
11.
2005;46:6231.
12.
13.
Brooks SJ, Caltagirone C, Cossins AJ, Gale PA, Light M
−
H2PO4 . The key skeleton, 5-(2-phenylethynyl)isophthalamide
Zielinski T, Kedziorek M, Jurczak J Tetrahedron Lett.
can be used for construction of various kinds of receptors, for
instance barbituric acid receptor 4, which shows an OFF-ON
fluorescence response on the recognition events. Further
functionalization of isophthaloyl acid bearing phenylethynyl
group substituted by electron-donating, electron-withdrawing
groups, and polycyclic aromatic groups showing larger spectral
changes during the recognition is undertaken in our laboratory.
Zieliński T, Kędziorek M, Jurczak J Chem. Eur. J. 2008;14:838.
Handa NV, Shritcliff LD, Berlin KD Tetrahedron Lett.
2015;56:445.
14.
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Moore JS Acc. Chem. Res. 1997;30:402.
Zhang W, Moore JS Angew. Chem. Int. Ed. 2006;45:4416.
McFarland SA, Finney NS J. Am. Chem. Soc. 2002;124:1178.
Hong J-H, Atta AK, Jng K-B, Kim S-B, Heo J, Cho D-G Org.
Lett. 2015;17:6222.
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Wessendorf F, Grimm B, Guldi DM, Hirsch A J. Am. Chem. Soc.
Acknowledgments
2010;132:10786.
19.
Gtri R, Ouerfelli I, Efrit ML, Serein-Spirau F, Lère-Porte Jp,
Valvin P, Roisnel T, Bivaud S, Akdas-Kilig H, Fillaut J-L Organometallics
2014;33:665.
The authors would like to thank Professors Tatsuya
Nabeshima and Masaki Yamamura, University of Tsukuba for
measurements of HRMS (ESI) of the compounds. This work was
partially supported by a JSPS KAKENHI Grant Number
24550144 and YU-COE (C), Yamagata University.
20.
Kondo S-i, Hiraoka Y, Kurumatani N, Yano Y Chem. Commun.
2005:1720.
21.
22.
Kondo S, Takai R Org. Lett. 2013;15:538.
Kondo S, Nakajima S-i, Unno M Bull. Chem. Soc. Jpn.
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Kondo S, Matsuta Y Tetrahedron Lett. 2016;57:1113.
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Highlights
Isophthalamide based on 5-(2-
phenylethynyl)isophathalilc acid was prepared.
The corresponding receptors showed UV-vis and
fluorescence changes with guests.
The skeleton can be applied to various receptors.