Tuning the halide affinity of quinoline-based anion receptors

Article abstract of DOI:10.1002/ejoc.201201715

The binding behaviour of (thio)urea- and amide-functionalized quinoline-based anion receptors towards halide anions was investigated in detail in CDCl₃ and [D₆]DMSO solutions by using ¹H and ¹⁹F NMR spectroscopi

Full text of DOI:10.1002/ejoc.201201715

Job/Unit: O21715
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FULL PAPER
DOI: 10.1002/ejoc.201201715
Tuning the Halide Affinity of Quinoline-Based Anion Receptors
Zhan-Hu Sun,[a] Markus Albrecht,*[a] and Roland Fröhlich[b]
Keywords: Supramolecular chemistry / Receptors / Sensors / Anions / Halides
The binding behaviour of (thio)urea- and amide-function-
alized quinoline-based anion receptors towards halide
anions was investigated in detail in CDCl3 and [D6]DMSO
solutions by using 1H and 19F NMR spectroscopic methods.
The electronic, solvent, and fluoro-substitution effects were
studied. The (thio)urea- and amide-functionalized quinoline-
based anion receptors showed medium to strong anion affin-
ity and good selectivity in solution. Single crystals of key
compounds were obtained and studied by X-ray diffraction
spectroscopy.
co-workers synthesized a pentafluorobenzene derivative
and tried to use hydrogen bonding and anion···π interaction
to investigate its halide binding in solution.[5] The result
showed that it was possible to utilise anion···π interactions
in anion receptor design.
Our earlier studies were initiated by the observation that
two hydrogen atoms of 2-amido-8-hydroxyquinoline are
pointing to the front of the quinoline nitrogen atom (Fig-
ure 1).[6] Based on this finding, a series of quinoline recep-
tors were synthesized and successfully introduced into hal-
ide or nitrate binding studies.[7] The solid-state structures of
the receptors revealed that “acidic” hydrogen atoms create
a cavity that was well-suited for anion recognition.
Introduction
Supramolecular chemistry, “the chemistry beyond the
molecule”, focuses on molecular recognition and molecular
self-assembly based on noncovalent interactions.[1] Hereby,
due to the numerous functions in chemical and physiologi-
cal processes,[2] the selective recognition and sensing of
anions is becoming an increasingly fascinating branch of
supramolecular chemistry. Halide anions are ubiquitous in
nature. For instance, iodide is widely but unevenly distrib-
uted on Earth (found in the oceans at levels of ca. 50 μg/L)
and chloride is essential for us in daily food, and is involved
in many aspects of physiological processes. Malfunctions of
anion transport can lead to a variety of diseases or “chan-
nelopathies”, such as cystic fibrosis.[2c] In this context, it is
essential to search for effective receptors for anion recogni-
tion and sensing.[2d] Recently, Taylor and co-workers have
designed and prepared a series of anion receptors based on
halogen-bonding and combined hydrogen-/halogen-bond-
ing to sense anions.[3] Beer and co-workers have reported
the application of rotaxanes in anion sensing and recogni-
tion.[4]
Figure 1. The structure of a representative 2-amido-8-hydroxyquin-
oline derivative.
During the last decade, the weak noncovalent interaction
between anions and electron-deficient arenes has been dis-
cussed as a promising tool with which to develop innovative
anion receptors. The anion···π interaction has been in-
tensely studied by computational studies as well as in sin-
gle-crystal structures. However, as far as we know, only a
few attempts have been reported that use this kind of inter-
action for anion sensing in solution. In 2006, Johnson and
Herein, based on previous work on quinoline receptors,
novel anion receptors are reported that are based on a func-
tionalized quinoline backbone capable for halide binding
through hydrogen bonding. Electron-deficient aromatics
generate a cleft that should be ideal for the uptake of
anions, eventually with the help of anion···π interactions.
Urea as well as thiourea groups, particularly N,NЈ-substi-
tuted derivatives, represent the hydrogen-bond donor bind-
ing sites for anion recognition.[8] The preorganisation of the
receptor is enforced by intramolecular hydrogen bonding
between amide and (thio)urea units to the quinoline nitro-
gen lone pair. As an electron-deficient moiety, pentafluoro-
phenyl groups are attached to enhance the positive polarity
of the receptor binding sites and to introduce the possibility
of anion···π interaction.[9] Therefore, a series of quinoline-
[a] Institut für Organische Chemie, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
Fax: +49-241-8092385
E-mail: Markus.Albrecht@oc.rwth-aachen.de
Homepage: http://134.130.101.5/akalbrecht/index.html
[b] Organisch-Chemisches Institut, Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201715.
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Z.-H. Sun, M. Albrecht, R. Fröhlich
FULL PAPER
based halide receptors 1–10 (Figure 2) were successfully
synthesized, in which pentafluorophenyl groups are intro-
duced as electron-withdrawing π-acidic groups.
Figure 3. Synthesis of quinoline-based receptors and the assign-
ment of different acidic protons.
Figure 2. The structures of quinoline-based receptors.
distance of 2.263 Å and of the thiourea with a distance of
2.733 Å; thus the arrangement is suitable for anion recogni-
tion. The second hydrogen atom of the thiourea moiety and
the attached electron-deficient arene are turned away from
the front of the molecule.
Results and Discussion
Quinoline-based receptors were prepared by following
the processes depicted in Figure 3. Nitroquinoline carb-
oxylic acid was obtained from 2-nitroaniline according to
the procedure reported by Huc et al.[10] Two kinds of
amides, 11 and 12, were synthesized from appropriate
amines with nitroquinoline carboxylic acid in the presence
of DIPEA (N,NЈ-diisopropylethylamine), HOBT (N-hy-
droxybenzotriazole) and EDC·HCl [N-(3-dimethylamino-
propyl)-NЈ-ethylcarbodiimide hydrochloride]. The nitro
groups of the respective amides were reduced in the pres-
ence of Pd/C and hydrogen gas to afford the corresponding
amines in near quantitative yield. The latter reacted with
appropriate aryl isothiocyanates or aryl isocyanates to form
the (thio)urea receptors 1–6. The ether substituent at the
quinoline was introduced for synthetic reasons. However, it
also has the advantage of increasing the solubility of the
receptor.
Figure 4. Single crystal structure of receptor 4 (gray, C; white, H;
green, F; blue, N; red, O; yellow, S).
In addition, reaction of the amines with pentafluoro-
benzoyl chloride or benzoyl chloride in the presence of
TEA (triethylamine) in anhydrous acetonitrile afforded the
Furthermore, a single crystal of receptor 8 could be ob-
corresponding diamide receptors 7–10, possessing only two tained by slow evaporation of a solution of 8 in MeOH/
amides as hydrogen-bond donors bearing fluoro-substituted dichloromethane. Figure 5 shows the structure of receptor
or nonfluoro-substituted aromatic rings. All of the com- 8 in the crystal. Similar to 4, two hydrogen atoms of the
pounds were fully characterized by 1H, 19F (if possible), amides create a cleft that should be appropriate for the re-
13C NMR, IR, mass spectrum and elemental analysis. For cognition of anions. The distances between amide hydrogen
compounds 1, 3, 4, 6, 8, and 12, single crystals were ob- atoms and the quinoline nitrogen are 2.232 and 2.267 Å,
tained and analyzed by X-ray diffraction.
respectively. Interaction of one of the amide protons with
As a representative example, yellow crystals of receptor one ortho-fluorine atom of the C6F5-unit fixes the electron-
4 were obtained by slow evaporation of a solution of 4 in deficient unit in-plane with the quinoline (2.323 Å). The
MeOH/dichloromethane. Figure 4 displays the X-ray struc- conjugation between the C6F5-unit and the adjacent amide/
ture of receptor 4, which shows that the amide proton arene is likely to be the driving force that leads to this
points to the nitrogen atom of the quinoline moiety with a planar conformation.
2
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Tuning the Halide Affinity of Quinoline-Based Anion Receptors
shift as a function of molar ratio shows a 1:1 receptor/anion
stoichiometry. Subsequently, 1H NMR titration experi-
ments were performed in CDCl3 with a concentration of
0.01 m of receptor 4, successively adding Bu4N+Cl–. Fig-
ure 7 (top left) shows the titration curves; standard methods
of nonlinear regression[11] treatment of the obtained data
led to a binding constant K = 1.67ϫ104 m–1.
To evaluate the effect of fluorine substitution, the non-
fluorinated analogue 3 was synthesised and its titration ex-
periments with chloride were also carried out in CDCl3
(Figure 7). The corresponding binding constant was deter-
mined as K = 3.11ϫ103 m–1, again with a stoichiometry of
1:1 (Figure 7, bottom left and bottom right).
Figure 5. Single crystal structure of receptor 8 (gray, C; white, H;
green, F; blue, N; red, O).
1H NMR Studies in Solution
To obtain data for comparison of halide affinities of dif-
ferent thioureas, the interaction of receptor 2 with chloride
was also studied by H NMR titration in CDCl3 (see the
Interactions between (Thio)urea-Based Receptors and
Halide Anions
1
The change in the 1H NMR spectra of the new receptors
in CDCl3 and [D6]DMSO upon addition of chloride, brom-
ide and iodide ions was examined to study halide-binding
in detail. Tetrabutylammonium (Bu4N+) halide salts were
added as halide anion source. As a representative example,
the titration of 4 with Bu4N+Cl– is discussed in detail; sim-
ilar results were obtained for the other receptors. Upon ad-
dition of chloride, the signals of NH protons of the thiourea
and of the amide of 4 are significantly shifted downfield
(Figure 6) from 8.90, 8.49, and 6.76 ppm to 11.18, 10.72
and 10.92 ppm, respectively. This means that chloride ions
were tightly associated with the acidic hydrogen atoms. Af-
ter addition of 1.1 equiv. of Cl– salts, saturation was reached
and the chemical shift changed only slightly. This was con-
sistent with the Job plots results (see below).
Supporting Information).
A binding constant K Ͼ
5ϫ104 m–1 was estimated for a 1:1 binding situation. Com-
pared with receptor 4, the higher constant of receptor 2
probably results from a lower electron density in the bind-
ing pocket of the receptor. Secondary interactions between
the anions and the aromatic rings may somehow contribute
to the difference, in addition to hydrogen bonding.
1H NMR spectroscopic determinations of K are only re-
liable for binding constants in the range of 10–104 m–1. For
the data obtained in CDCl3, some are above the limit of 1H
NMR spectroscopy. To gain more reliable data for binding
1
constants from H NMR titration, we also investigated the
binding constants in [D6]DMSO; the data listed in Table 1
show a similar trend to that found in chloroform.
Titration of a solution of 4 was also performed in [D6]-
First, the stoichiometry for the binding of chloride DMSO, and a binding constant of K = 744 m–1 was deter-
anions to receptor 4 was obtained by the Job method (Fig- mined along with a 1:1 binding stoichiometry (Figure 8).
ure 7, top right). The variation of the weighted chemical For comparison, all binding constants of receptors 1–6 with
1
Figure 6. Partial H NMR spectra (CDCl3, 300 MHz, 298 K) of receptor 4 after successive addition of Bu4N+Cl– (for the assignment of
protons, see Figure 3).
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Z.-H. Sun, M. Albrecht, R. Fröhlich
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Figure 7. Titration curves of receptors 4 (left top) and 3 (bottom left) towards chloride anions in CDCl3 and the corresponding Job plots
in CDCl3 for receptors 4 (top right) and 3 (bottom right).
Table 1. Binding constants (K, m–1) of receptors 1–6 with halide
anions in CDCl3 and [D6]DMSO containing 0.5% water at 298 K.
1
The binding constants were determined by H NMR titration ex-
periments in CDCl3 and [D6]DMSO, and fitted according to a 1:1
binding ratio based on Job plots. Errors are estimated to be less
than 20%.
Cl–
Br–
I–
In CDCl3
1
2
3
4
5
6
969
218
65
Ͼ 5ϫ104
3.11ϫ103
1.67ϫ104
3.17ϫ104
3.52ϫ104
471
1.65ϫ103
106
3.22ϫ103
465
4.32ϫ103
593
[a]
[a]
[a]
–
–
–
In [D6]DMSO
[b]
1
2
3
4
5
6
600
845
831
744
408
809
87
21
66
50
62
73
–
–
–
–
–
–
[b]
[b]
[b]
[b]
[b]
Figure 8. Titration curves of receptor 4 towards chloride anion in
[D6]DMSO (top) and the corresponding Job plots in [D6]DMSO
(bottom).
[a] The receptor was not soluble in this solvent. [b] No significant
shift was observed.
halide anions (Cl–, Br– and I–) in CDCl3 and [D6]DMSO CDCl3, the fluorinated receptors have stronger binding af-
are also summarised in Table 1. finities for halide anions than the nonfluorinated receptors.
The obtained data reveal some trends in the anion bind- In [D6]DMSO the trend is not so clear and significant. An
ing of the (thio)urea/amide based quinoline receptors: (1) explanation for the differences in the measured K values
Each receptor, irrespective of whether it is fluorinated or might be the stronger solvation of receptors and anions in
not, shows a decreasing affinity for anions in the order Cl– [D6]DMSO than in CDCl3. Owing to the electron-deficient
Ͼ Br– Ͼ I– in CDCl3, as well as in [D6]DMSO. This is nature of the pentafluorophenyl group, the corresponding
expected from the decreasing basicity of the halide anions amide N–H is more acidic than the nonfluorinated deriva-
and the size of the receptor binding pocket.[7b] (2) In tives. In addition, anion···π interactions might be helpful
4
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Tuning the Halide Affinity of Quinoline-Based Anion Receptors
for binding in the case of the fluorinated receptors. (3) Re-
ceptor 2 interacts with halide anions more strongly than
receptor 4. In receptor 2, the pentafluorophenyl group is
directly bound to the thiourea moiety, whereas in receptor
4 the pentafluorophenyl group is attached to the thiourea
moiety through a methylene linker. Therefore, the induced
acidity at the thiourea moiety in receptor 4 is weaker than
in receptor 2. (4) Only in chloroform are dramatic differ-
ences found for the binding affinities of slightly modified
receptors, whereas in [D6]DMSO similar receptors showed
similar binding for a specific halide anion. No detectable
binding of iodide was observed in this polar solvent. (5) In
[D6]DMSO, binding constants are dramatically decreased
compared with those measured in CDCl3. The receptors
can bind iodide anions only in chloroform. In DMSO com-
petition between the anion and the solvent is too strong.
Interactions of Diamide-Based Receptors with Halide
Anions
1
Figure 9. H NMR titration curves of receptor 7 towards chloride
anions in CDCl3 (top, the fitted curves shown in the Supporting
Information) and the corresponding Job plots in CDCl3 (bottom).
In proteins, the amide units play an important role in the
binding of anions. Indeed, this unit is widely employed in
anion recognition and binding.[2,3] To minimize the poten-
tial of the binding site in the discussed receptors, two
amides were attached to a quinoline backbone to form a
Table 2. Binding constants (K, m–1) of receptors 7 and 8 with halide
anions in CDCl3 at 298 K. The binding constants were determined
1
preorganized bisamide cleft to bind halide anions. Associa- by H NMR titration experiments in CDCl3 and fitted according
1
to a 1:1 binding ratio. Errors are estimated to be less than 20%.
tion affinities were investigated in CDCl3 by the use of H
NMR spectroscopic titration with Bu4N+ halide salts. Fig-
ure 9 shows the titration curves for receptor 7 towards
chloride ions in CDCl3 and the corresponding Job plots.
The binding constant was K = 44 m–1 and the stoichiometry
was 1:1. Due to one fewer proton and the lack of better
hydrogen donor groups (urea/thiourea), the complexation
ability of amides is much weaker than that of (thio)ureas,
and the result is consistent with this. The determined bind-
ing constants of receptors 7 and 8 with halide anions in
CDCl3 are summarised in Table 2. Compounds 9 and 10
showed no detectable binding ability for halide anions in
CDCl3, so no data were obtained.
Cl–
Br–
I–
7
8
44
34
35
30
18
15
Solution Studies by 19F NMR Spectroscopic
Analysis
Interactions between (Thio)urea-Based Receptors and
Halide Anions
From these results we can conclude: (1) Both receptors 7
and 8 show a trend in halide anion binding in the order
Owing to its favourable nuclear properties and high natu-
Cl– Ն Br– Ͼ I– (considering the estimated errors), which is ral abundance, 19F NMR spectroscopic methods are widely
comparable to receptors 1–6. The receptors prefer some- used to analyse and determine the structures of organo-
what smaller halide anions over larger anions. (2) Receptor fluorine compounds. Recently, Metrangolo, Resnati, Taylor
7 shows a somewhat stronger binding affinity than receptor and co-workers[3a,12] used this method to investigate halo-
8. The fluoro substitution can account for this. The elec- gen bonding and/or anion sensing. To find the binding stoi-
tronic differences between receptors 7 and 8 resulting from chiometry between receptor 4 and chloride anions, 19F
the influence of the fluoro substituent on the pKa values of NMR based Job plots are were constructed (Figure 10, bot-
the N–H protons. In addition, anion···π interactions might tom). The results indicate a 1:1 binding stoichiometry,
occur. So far it is not clear which effect dominates. (3) It is which is consistent with the result of related proton NMR
of interest to note that the presence of the pentafluoro- studies. 19F NMR titration spectra of receptor 4 upon ad-
benzoyl substituent is essential for anion binding. Com- dition of a varying number of equivalents of Bu4N+Cl– are
pounds 9 and 10, which lack this group and only possess plotted in Figure 10 (top). Standard methods of nonlinear
the nonfluorinated analogue, show no detectable binding regression treatment of the obtained data leads to a binding
constants for anions.
constant K = 1.82ϫ104 m–1.
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Synthesis and Characterisation of Amide Precursor
N-Benzyl-4-isobutoxy-8-nitroquinoline-2-carboxamide (11): To an
anhydrous CH2Cl2 (20 mL) solution of a mixture of 4-isobutoxy-8-
nitroquinoline-2-carboxylic acid (290 mg, 1 mmol, 1.0 equiv.) and
benzylamine (0.22 mL, 2 mmol, 2 equiv.), successively DIPEA
(1.27 mL), HOBt (270 mg, 2 mmol, 2 equiv.), and EDC·HCl
(383 mg, 2 mmol) were added. The progress of the reaction was
monitored by TLC. Upon completion (stirring for 6 h under nitro-
gen at room temperature), the reaction mixture was washed with
saturated aqueous NH4Cl. The organic extract was dried with
Na2SO4 and filtered off. Solvent was evaporated to dryness and
the residue was purified on silica gel with dichloromethane or by
recrystallisation from dichloromethane/MeOH to allow isolation of
the compound as a yellow solid, yield 322 mg (85%), m.p. 142 °C.
1H NMR (400 MHz, CDCl3): δ = 8.54 (t, 1 H), 8.49 (dd, 1 H),
8.09 (dd, 1 H), 7.83 (s, 1 H), 7.61 (s, 1 H), 7.37 (m, 4 H), 7.28 (m,
1 H), 4.72 (d, 2 H), 4.13 (d, 2 H), 2.30 (m, 1 H), 1.15 (d, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 163.66, 163.20, 153.13, 147.70,
138.99, 137.98, 128.69, 127.55, 127.42, 126.67, 125.18, 125.03,
123.27, 100.07, 75.73, 43.57, 28.06, 19.14 ppm. IR (KBr): ν = 3382,
˜
3101, 2959, 2875, 1680, 1587, 1566, 1520, 1336, 1215, 1129, 1014,
865, 742, 696 cm–1. MS (ESI): m/z (%) = 402.14352 (100) [M +
Na]+, 380.16183 (10) [M + H]+. C21H21N3O4 (379.41): calcd. C
66.48, H 5.58, N 11.08; found C 66.36, H 5.44, N 11.04.
Figure 10. 19F NMR titration curves of receptor 4 towards chloride
anions in CDCl3 (top) and the corresponding Job plots in CDCl3
(bottom).
4-Isobutoxy-8-nitro-N-(pentafluorobenzyl)quinoline-2-carboxamide
(12): The synthesis of 12 was performed in a manner similar to that
used for 11. It was purified by recrystallisation from dichlorometh-
ane/MeOH to give a colourless solid, yield 422 mg (90%), m.p.
Conclusions
We have synthesized a series of quinoline derivatives 1–
10. Single-crystal structures reveal an appropriate pre-
organized structure for the recognition of anions. The bind-
ing ability towards halide anions was investigated by 1H
1
153 °C. H NMR (300 MHz, CDCl3): δ = 8.54 (t, 1 H), 8.47 (dd,
1 H), 8.12 (dd, 1 H), 7.76 (s, 1 H), 7.63 (m, 1 H), 4.78 (d, 2 H),
4.08 (d, 2 H), 2.29 (m, 1 H), 1.14 (d, 6 H) ppm. 19F NMR
(282 MHz, CDCl3): δ = –142.49 (dd, 2 F), –154.64 (t, 1 F), –161.67
and 19F NMR spectroscopic analysis in CDCl3 and [D6]- (m, 2 F) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.63, 163.30,
152.38, 147.64, 138.97, 126.72, 125.40, 125.24, 123.33, 99.91, 77.29,
DMSO solutions. Thereby, it was demonstrated that the
fluoro-substituted receptors are stronger binders than the
corresponding nonfluorinated derivatives. The reason is
probably the acidification of the amide and (thio)urea pro-
tons through the electron-withdrawing effect of the ap-
pended C6F5 group. However, anion···π-interactions effects
cannot be ruled out in this case.
76.97, 76.65, 75.78, 31.51, 28.01, 19.10 ppm. IR (KBr): ν = 3397,
˜
2960, 2878, 1690, 1591, 1498, 1362, 1144, 1120, 1011, 941, 868,
7 8 7, 75 8 c m– 1 . MS (E SI ): m/ z ( %) = 4 70 . 9 2 ( 100. 00).
C21H16F5N3O4 (469.37): calcd. C 53.74, H 3.44, N 8.95; found C
53.96, H 3.36, N 8.95. X-ray-quality crystals were obtained from
MeOH/dichloromethane: C21H16F5N3O4; Mr = 469.37; crystal size
0.23ϫ0.15ϫ0.10 mm3; monoclinic; space group P21/c (No. 14); a
= 5.2515(1) Å, b = 24.8800(5) Å, c = 15.5918(3) Å; β = 93.978 (1)°;
V = 2032.27(7) Å3; Z = 4; ρcal = 1.534 gcm–3; μ = 0.137 mm–1;
F(000) = 960; 12688 collected reflections (θmax = 27.87°) of which
Experimental Section
4750 were independent (Rint = 0.039); Tmax = 0.9864; Tmin
=
0.9691; T = 223(2) K; full-matrix least-square on F2 with 0 re-
straints and 303 parameters; GOF = 1.093; R1 = 0.0595 [IϾ2σ(I)];
ωR2(all data) = 0.1389; peak/hole ratio: 0.213/–0.199 eÅ–3.
General Methods: Commercially available reagents were used as re-
ceived. All solvents were used after distillation without further pu-
rification, unless otherwise indicated. After stirring with CaH2
overnight, dichloromethane and CH3CN were distilled for use. All
NMR spectra were recorded in CDCl3 or [D6]DMSO with a Varian
Mercury 300, Varian 400, or Varian 600 spectrometer. Mass spectra
were measured by using EI (70 eV) or ESI techniques with a Finni-
gan SSQ 7000 or Thermo Deca XP spectrometer. IR spectra were
obtained with a Perkin–Elmer FTIR spectrometer spectrum 100;
samples were measured in KBr (400–650 cm–1). Elemental analyses
were performed with a CHN-O-Rapid Vario EL instrument from
Heraeus. Melting points were obtained with a Büchi B-540 melting
point apparatus. Data sets for the X-ray analyses were collected
with a Nonius KappaCCD diffractometer, equipped with a rotating
anode generator. Programs used: data collection COLLECT[17]
(Nonius B.V., 1998), data reduction Denzo-SMN,[13] absorption
correction Denzo,[14] structure solution SHELXS-97,[15] structure
refinement SHELXL-97,[16] graphics SCHAKAL.[18]
Synthesis and Characterisation of (Thio)urea Receptors
N-Benzyl-4-isobutoxy-8-(phenylthioureido)quinoline-2-carboxamide
(1): A mixture of 11 (379 mg, 1 mmol, 1 equiv.) dissolved in CH2Cl2
(20 mL) and 10% Pd/C was stirred at room temperature under an
atmosphere of hydrogen (20 bar) overnight. The solution was fil-
tered through Celite and the filtrate was evaporated to dryness. The
residue was used directly in the next step.
A solution of 8-amino-N-benzyl-4-isobutoxyquinoline-2-carbox-
amide (1 mmol, 1 equiv.) and phenyl isocyanate (0.33 mL, 3 mmol,
3 equiv.) in dichloromethane (30 mL) was heated at reflux over-
night. After cooling to room temperature, the solvent was removed
in vacuo. The residue was purified by recrystallisation from di-
chloromethane/MeOH to allow isolation of a light-yellow solid,
1
yield 344 mg (71%), m.p. 194 °C. H NMR (600 MHz, CDCl3): δ
6
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Tuning the Halide Affinity of Quinoline-Based Anion Receptors
= 10.22 (s, 1 H), 9.48 (d, 1 H), 8.04 (s, 1 H), 7.89 (d, 1 H), 7.64 (s,
1 H), 7.52 (t, 1 H), 7.28 (m, 3 H), 7.20 (m, 5 H), 7.13 (d, 1 H), 7.04
(t, 1 H), 4.46 (d, 2 H), 3.96 (d, 2 H), 2.19 (m, 1 H), 1.04 (d, 6
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 177.16, 164.32, 163.51,
149.38, 138.57, 138.13, 136.39, 134.33, 130.07, 128.61, 127.27,
127.24, 126.94, 126.79, 125.03, 122.05, 118.52, 116.89, 99.78, 75.37,
1.049; R1 = 0.0677 [IϾ2σ(I)]; ωR2 (all data) = 0.1556; peak/hole
ratio: 0.215/–0.206 eÅ–3.
4-Isobutoxy-N-(pentafluorobenzyl)-8-(pentafluorobenzylthioureido)-
quinoline-2-carboxamide (4): The synthesis of 4 was performed in a
manner similar to that used for 1. It was purified by recrystalli-
sation from dichloromethane/MeOH to allow isolation of the com-
pound as a yellow solid, yield 366 mg (54 %), m.p. 196 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.99 (s, 1 H), 8.52 (t, 1 H), 8.03 (d,
2 H), 7.62 (s, 1 H), 7.53 (t, 1 H), 6.92 (t, 1 H), 4.96 (t, 2 H), 4.75
(d, 2 H), 3.99 (d, 2 H), 2.25 (m, 1 H), 1.12 (d, 6 H) ppm. 19F
NMR (282 MHz, CDCl3): δ = –142.22 (dd, 2 F), –142.58 (dd, 2
F), –153.88 (t, 1 F), –154.52 (t, 1 F), –161.41 (m, 2 F), –161.67 (m,
2 F) ppm. 13C NMR (75 MHz, CDCl3): δ = 181.31, 164.16, 163.53,
149.88, 147.21, 139.93, 133.81, 126.82, 123.05, 121.33, 119.02,
43.11, 28.10, 19.18 ppm. IR (KBr): ν = 3403, 3281, 3222, 2955,
˜
1664, 1528, 1346, 1227, 1160, 1051, 913, 861, 812, 755, 687 cm–1.
MS (ESI): m/z (%) = 507.18379 (100.00) [M + Na]+, 485.20196
(90.00) [C28H29N4O2S + H]+, 350.18738 (55.00) [C21H24N3O2]+.
C28H28N4O2S·1/2H2O (493.6): calcd. C 68.13, H 5.92, N 11.35;
found C 68.40, H 5.51, N 10.87. X-ray-quality crystals were ob-
tained from MeOH/dichloromethane: C28H28N4O2S; Mr = 484.60;
crystal size 0.27ϫ0.13ϫ0.05 mm3; monoclinic; space group P21/c
(No. 14); a = 8.0294(2) Å, b = 16.1218(4) Å, c = 19.8969(6) Å; β =
100.567 (1)°; V = 2531.94(12) Å3; Z = 4; ρcalcd. = 1.271 gcm–3; μ =
110.96, 99.63, 37.04, 31.56, 28.06, 19.12 ppm. IR (KBr): ν = 3320,
˜
3175, 2963, 1664, 1506, 1417, 1311, 1212, 1121, 1026, 965, 924,
763 cm– 1 . MS (ESI): m/z (%) = 679.17 (100) [M + H]+ .
C29H20F10N4O2S (678.54): calcd. C 50.33, H 2.97, N 8.26; found
C 51.22, H 2.96, N 8.25. X-ray-quality crystals were obtained from
MeOH/dichloromethane: C29H20F10N4O2S; Mr = 678.55; crystal
size 0.27ϫ0.13ϫ0.10 mm3; triclinic; space group P-1 (No. 2); a =
10.3605(3) Å, b = 12.1967(4) Å, c = 13.2370(4) Å; α = 108.120(1),
0.160 mm–1; F(000) = 1024; 7226 collected reflections (θmax
25.00°) of which 4340 were independent (Rint = 0.0251); Tmax
=
=
0.9920; Tmin = 0.9580; T = 223(2) K; full-matrix least-square on F2
with 0 restraint and 327 parameters; GOF = 1.057; R1 = 0.0573
[I Ͼ 2σ(I)]; ωR2(all data) = 0.1356; peak/hole ratio: 0.197/–
0.196 eÅ–3.
β = 108.706(2), γ = 99.221(3)°; V = 1441.59(8) Å3; Z = 2; ρcal
1.563 gcm–3; μ = 0.213 mm–1; F(000) = 688; 13439 collected reflec-
tions (θmax = 25.00°) of which 5000 were independent (Rint
=
4-Isobutoxy-N-(pentafluorobenzyl)-8-(pentafluorophenylthioureido)-
quinoline-2-carboxamide (2): The synthesis of 2 was performed in a
manner similar to that used for 1. The compound was purified by
recrystallisation from dichloromethane/MeOH to obtain a colour-
=
0.036); Tmax = 0.9790; Tmin = 0.9447; T = 223(2) K; full-matrix
least-square on F2 with 7 restraint and 426 parameters; GOF =
1.068; R1 = 0.0589 [IϾ2σ(I)]; ωR2 (all data) = 0.1496; peak/hole
ratio: 1.019/–0.518 eÅ–3.
1
less solid, yield 372 mg (56%), m.p. 167 °C. H NMR (300 MHz,
CDCl3): δ = 9.49 (s, 1 H), 8.55 (d, 1 H), 8.45 (t, 1 H), 8.08 (s, 1
H), 7.82 (d, 1 H), 7.44 (m, 2 H), 4.80 (d, 2 H), 3.86 (d, 2 H), 2.19
(m, 1 H), 1.09 (d, 6 H) ppm. 19F NMR (282 MHz, CDCl3): δ =
–142.72 (d, 2 F), –144.42 (d, 2 F), –154.08 (m, 1 F), –154.33 (t, 1
F), –161.56 (m, 2 F), –162.07 (d, 2 F) ppm. 13C NMR (75 MHz,
CDCl3): δ = 181.17, 165.17, 163.37, 149.80, 139.44, 133.71, 126.84,
122.37, 121.37, 118.95, 99.34, 31.66, 28.16, 19.04 ppm. IR (KBr):
N-Benzyl-4-isobutoxy-8-(phenylureido)quinoline-2-carboxamide (5):
The synthesis of 5 was performed in a manner similar to that used
for 1. The compound was purified by recrystallisation from di-
chloromethane/MeOH to allow isolation as a yellow solid, yield
314 mg (67%), m.p. 126 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
9.66 (s, 1 H), 9.63 (t, 1 H), 9.27 (s, 1 H), 8.52 (dd, 1 H), 7.72 (dd,
1 H), 7.66 (s, 1 H), 7.57 (t, 1 H), 7.49 (m, 2 H), 7.32 (m, 7 H), 6.98
(t, 1 H), 4.67 (d, 2 H), 4.11 (d, 2 H), 2.19 (m, 1 H), 1.07 (d, 6
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.46, 163.13,
152.67, 149.65, 139.64, 137.65, 136.50, 129.35, 128.84, 128.26,
127.62, 127.36, 118.95, 115.97, 113.68, 99.63, 75.08, 43.07, 28.09,
ν = 3369, 2949, 2234, 1713, 1611, 1502, 1464, 1324, 1197, 1134,
˜
1099, 993, 842, 750 cm–1. MS (ESI): m/z (%) = 665.58 (60) [M +
H]+, 440.85 (100) [C21H18F5N3O2 + H]+. C28H18F10N4O2S
(664.52): calcd. C 50.61, H 2.73, N 8.43; found C 50.56, H 2.79, N
8.39.
N-Benzyl-8-(benzylthioureido)-4-isobutoxyquinoline-2-carboxamide
(3): The synthesis of 3 was performed in a manner similar to that
used for 1. It was purified by recrystallisation from dichlorometh-
ane/MeOH to allow isolation of the compound as a light-yellow
19.38 ppm. IR (KBr): ν = 3324, 2964, 1646, 1523, 1416, 1313, 1198,
˜
1071, 1001, 752, 690 cm–1. MS (ESI): m/z (%) = 491.20361 (100)
[M + Na]+. C28H28N4O3·1/2H2O (477.6): calcd. C 70.42, H 6.12,
N 11.73; found C 70.70, H 5.98, N 11.76.
1
solid, yield 339 mg (68%), m.p. 163 °C. H NMR (400 MHz, [D6]-
DMSO): δ = 9.16 (s, 1 H), 8.43 (s, 1 H), 8.18 (s, 1 H), 7.89 (dd, 1
H), 7.60 (s, 1 H), 7.43 (t, 1 H), 7.17 (m, 9 H), 6.77 (s, 1 H), 4.71 4-Isobutoxy-N-(pentafluorobenzyl)-8-(pentafluorophenylureido)quin-
(d, 2 H), 4.52 (d, 1 H), 3.87 (d, 2 H), 2.16 (m, 1 H), 1.01 (d, 6 oline-2-carboxamide (6): The synthesis of 6 was performed in a
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 164.86, 163.38, 149.45,
manner similar to that used for 1. The compound was purified by
139.24, 137.62, 134.56, 128.64, 128.61, 127.80, 127.65, 127.44, recrystallisation from dichloromethane/MeOH to allow isolation as
127.20, 126.93, 122.60, 119.82, 117.30, 99.41, 75.12, 49.05, 43.39,
a colourless solid, yield 512 mg (79 %), m.p. 241 °C. 1H NMR
28.06, 19.13 ppm. IR (KBr): ν = 3289, 2084, 1647, 1544, 1460,
(400 MHz, [D6]DMSO): δ = 9.96 (s, 1 H), 9.53 (t, 1 H), 9.12 (s, 1
˜
1423, 1362, 1330, 1250, 1228, 1180, 1143, 1041, 857, 724, 692 cm–1. H), 8.46 (dd, 1 H), 7.79 (dd, 1 H), 7.64 (m, 2 H), 4.78 (d, 2 H),
MS (ESI): m/z (%) = 499.07 (99.68) [M + Na]+, 350.20 (100.00) 4.13 (d, 2 H), 2.21 (m, 1 H), 1.10 (d, 6 H) ppm. 19F NMR
[C21H24N3O2]+. C29H30N4O32S (978.62): calcd. C 69.85, H 6.06, N
(376 MHz, [D6]DMSO): δ = –142.41 (dd, 2 F), –146.17 (dd, 2 F),
11.24; found C 69.56, H 5.73, N 11.11. X-ray-quality crystals were –156.11 (t, 1 F), –159.31 (t, 1 F), –163.20 (m, 2 F), –163.85 (m, 2
obtained from MeOH/dichloromethane: C29H30N4O2S; Mr =
498.63; crystal size 0.37 ϫ 0.10 ϫ 0.06 mm3; monoclinic; space
group P21/c (No. 14); a = 8.2730(2) Å, b = 31.1994(4) Å, c =
20.2195(4) Å; β = 91.083(1)°; V = 5217.98(18) Å3; Z = 8; ρcalcd.
= 1.269 gcm–3; μ = 0.158 mm–1; F(000) = 2112; 16171 collected
F) ppm. IR (KBr): ν = 3310, 2969, 1685, 1644, 1561, 1501, 1461,
˜
1233, 1008, 980, 767, 745 cm–1. MS (ESI): m/z (%) = 649.00 (100)
[M + H]+. C28H18F10N4O3·H2O: calcd. C 50.46, H 3.03, N 8.41;
found C 50.71, H 3.19, N 8.57. X-ray-quality crystals were ob-
tained from DMSO: C28H18F10N4O3·(CH3)2SO; Mr = 726.59; crys-
tal size 0.53ϫ0.20ϫ0.10 mm3; monoclinic; space group P21/n (No.
14); a = 15.0156(3) Å, b = 9.5866(2) Å, c = 21.3804(5) Å; β =
92.722(1)°; V = 3074.21(11) Å3; Z = 4; ρcalcd. = 1.570 gcm–3; μ =
reflections (θmax = 25.00°) of which 9048 were independent (Rint
=
0.0491); Tmax = 0.9906; Tmin = 0.9440; T = 223(2) K; full-matrix
least-square on F2 with 0 restraint and 671 parameters; GOF =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O21715
/KAP1
Date: 10-04-13 17:57:11
Pages: 10
Z.-H. Sun, M. Albrecht, R. Fröhlich
FULL PAPER
0.210 mm–1; F(000) = 1480; 9631 collected reflections (θmax
25.00°) of which 5343 were independent (Rint = 0.0373); Tmax
=
=
4-Isobutoxy-8-(benzamido)-N-(pentafluorobenzyl)quinoline-2-carb-
oxamide (9): The synthesis of 9 was performed in a manner similar
to that used for 7. The compound was purified by recrystallisation
from dichloromethane/MeOH to obtain a colourless solid, yield
462 mg (85%), m.p. 215 °C. 1H NMR (400 MHz, CDCl3): δ =
10.13 (s, 1 H), 8.90 (dd, 1 H), 8.19 (t, 1 H), 7.95 (m, 2 H), 7.88
(dd, 1 H), 7.64 (s, 1 H), 7.52 (m, 4 H), 4.78 (d, 2 H), 4.01 (d, 2 H),
2.22 (m, 1 H), 1.07 (d, 6 H) ppm. 19F NMR (376 MHz, CDCl3): δ
= –143.02 (dd, 2 F), –154.02 (t, 1 F), –161.10 (m, 2 F) ppm. 13C
NMR (100 MHz, CDCl3): δ = 165.31, 164.15, 163.69, 148.87,
138.01, 135.21, 134.18, 132.10, 128.96, 127.89, 126.91, 122.20,
0.9793; Tmin = 0.8968; T = 223(2) K; full-matrix least-square on F2
with 68 restraint and 470 parameters; GOF = 1.059; R1 = 0.0630
[I Ͼ 2σ (I)]; ωR2 (all data) = 0.1451; peak/hole ratio: 0.358/–
0.386 eÅ–3.
4-Isobutoxy-8-(pentafluorobenzamido)-N-(pentafluorobenzyl)quinol-
ine-2-carboxamide (7): A mixture of 12 (469 mg, 1 mmol, 1 equiv.)
dissolved in CH2Cl2 (20 mL) and 10% Pd/C was stirred at room
temperature under an atmosphere of hydrogen (20 bar) overnight.
The solution was filtered through Celite and the filtrate was evapo-
rated to dryness. The residue was used in the next step without
purification.
117.92, 116.20, 99.35, 75.42, 31.26, 28.09, 19.16 ppm. IR (KBr): ν
˜
= 3380, 2975, 1660, 1528, 1501, 1417, 1328, 1259, 1017, 948, 761,
694 cm–1. MS (EI, 70 eV): m/z (%)
=
543.2 (100) [M]·+.
To a 100 mL round-bottomed flask equipped with a magnetic stir-
rer in N2, the amine (439 mg, 1 mmol, 1 equiv.) was added. Sub-
sequently, dried CH3CN (40 mL) and triethylamine (0.33 mL) were
successively added to the flask. After cooling the reaction to 0 °C,
pentafluorobenzoyl chloride (0.14 mL, 2.2 mmol, 2.2 equiv.) was
added dropwise by using a syringe. The suspension was allowed to
reach room temperature and stirred overnight. When the reaction
was complete, the solvent was evaporated and the residue was
washed with saturated aqueous NH4Cl. The organic extract was
dried with Na2SO4 and filtered off from the insoluble fraction. The
filtrate was evaporated to dryness, and the residue was purified by
crystallisation from MeOH/dichloromethane to allow isolation of 7
C28H22F5N3O3 (543.49): calcd. C 61.88, H 4.08, N 7.73; found C
61.47, H 3.77, N 7.65.
8-(Benzamido)-N-benzyl-4-isobutoxyquinoline-2-carboxamide (10):
The synthesis of 10 was performed in a manner similar to that
used for 7. The compound was purified by recrystallisation from
dichloromethane/MeOH to obtain a colourless solid, yield 245 mg
1
(54%), m.p. 191 °C. H NMR (400 MHz, CDCl3): δ = 10.19 (s, 1
H), 8.87 (dd, 1 H), 8.01 (t, 1 H), 7.90 (dd, 1 H), 7.78 (dd, 2 H),
7.71 (s, 1 H), 7.54 (t, 1 H), 7.44 (m, 1 H), 7.36 (m, 5 H), 7.22 (t, 2
H), 4.70 (d, 2 H), 4.04 (d, 2 H), 2.24 (m, 1 H), 1.08 (d, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 165.03, 164.20, 163.70, 149.53,
138.02, 137.90, 135.06, 134.12, 131.82, 129.01, 128.89, 127.82,
127.69, 126.79, 117.68, 116.19, 99.46, 43.92, 28.16, 19.22 ppm. IR
1
as a light-yellow solid, yield 456 mg (72%), m.p. 194 °C. H NMR
(300 MHz, CDCl3): δ = 9.98 (s, 1 H), 8.78 (dd, 1 H), 8.15 (t, 1 H),
7.95 (dd, 1 H), 7.65 (s, 1 H), 7.55 (t, 1 H), 4.76 (d, 2 H), 4.00 (d, 2
H), 2.22 (m, 1 H), 1.07 (d, 6 H) ppm. 19F NMR (376 MHz,
CDCl3): δ = –140.57 (d, 2 F), –143.54 (d, 2 F), –149.12 (m, 1 F),
–154.29 (t, 1 F), –159.82 (m, 2 F), –161.65 (d, 2 F) ppm. 13C NMR
(150 MHz, CDCl3): δ = 164.03, 163.67, 155.10, 149.41, 133.00,
127.50, 122.04, 118.85, 117.60, 99.53, 75.52, 31.31, 28.06,
(KBr): ν = 3379, 2971, 1673, 1650, 1532, 1421, 1331, 1229, 1028,
˜
911, 761, 697 cm–1. MS (ESI): m/z (%) = 454.27 (100) [M + H]+.
C28H27F5N3O3·1/2H2O (557.5): calcd. C 72.71, H 6.10, N 9.08;
found C 73.04, H 5.85, N 9.08.
CCDC-906526 (for 1), -906527 (for 3), -906528 (for 4), -906529 (for
6), -906530 (for 8) and -906525 (for 12) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
19.08 ppm. IR (KBr): ν = 3515, 3401, 2966, 1684, 1657, 1548, 1500,
˜
1420, 1331, 1123, 1060, 1012, 950, 764 cm–1. MS (ESI): m/z (%) =
634.13 (100) [M + H]+. C28H17F10N3O3 (633.44): calcd. C 53.09,
H 2.71, N 6.63; found C 53.38, H 2.87, N 6.18.
Supporting Information (see footnote on the first page of this arti-
N-Benzyl-4-isobutoxy-8-(pentafluorobenzamido)quinoline-2-carbox-
amide (8): The synthesis of 8 was performed in a manner similar
to that used for 7. The compound was purified by recrystallisation
from dichloromethane/MeOH to allow isolation as a light-yellow
solid, yield 332 mg (61 %), m.p. 197 °C. 1H NMR (600 MHz,
CDCl3): δ = 10.06 (s, 1 H), 8.83 (d, 1 H), 8.10 (s, 1 H), 8.02 (d, 1
H), 7.76 (s,1 H), 7.60 (t, 1 H), 7.34 (m, 5 H), 4.68 (d, 2 H), 4.09
(d, 2 H), 2.30 (m, 1 H), 1.13 (d, 6 H) ppm. 19F NMR (564 MHz,
CDCl3): δ = –140.28 (dd, 2 F), 149.20 (t, 1 F), –159.29 (m, 2
F) ppm. 13C NMR (150 MHz, CDCl3): δ = 164.04, 163.70, 154.99,
150.02, 137.82, 137.79, 133.08, 128.73, 127.69, 127.63, 127.40,
122.06, 118.79, 117.61, 99.71, 75.49, 43.86, 28.13, 19.18 ppm. IR
1
cle): H, 13C, and 19F NMR spectra and selected titration curves.
Acknowledgments
Z.-H. S. is thankful to the China Scholarship Council for financial
support.
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(KBr): ν = 3780, 3443, 3328, 2919, 2852, 1689, 1539, 1383, 1221,
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1040, 998, 756, 724 cm–1. MS (EI, 70 eV): m/z (%) = 543.2 (95.59)
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C28H22F5N3O3; Mr = 543.49; crystal size 0.30ϫ0.13ϫ0.06 mm3;
monoclinic; space group P21/c (No. 14); a = 16.1036(3) Å, b =
8.2664(2) Å, c = 19.9664(5) Å; β = 104.067(1)°; V = 2578.20(10) Å3;
Z = 4; ρcalcd. = 1.400 gcm–3; μ = 0.116 mm–1; F(000) = 1120; 10498
collected reflections (θmax = 25.00°) of which 4389 were indepen-
dent (Rint = 0.042); Tmax = 0.9931; Tmin = 0.9659; T = 223(2) K;
full-matrix least-square on F2 with 0 restraint and 360 parameters;
GOF = 1.097; R1 = 0.0651 [IϾ2σ(I)]; ωR2 (all data) = 0.1464;
peak/hole ratio: 0.216/–0.205 eÅ–3.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21715
/KAP1
Date: 10-04-13 17:57:11
Pages: 10
Tuning the Halide Affinity of Quinoline-Based Anion Receptors
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Published Online: ᭿
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9

Job/Unit: O21715
/KAP1
Date: 10-04-13 17:57:11
Pages: 10
Z.-H. Sun, M. Albrecht, R. Fröhlich
FULL PAPER
Anion Receptors
We have investigated in detail the binding
behaviour of (thio)urea- and amide-func-
tionalized quinoline-based anion receptors
towards halide anions in CDCl3 and [D6]-
DMSO solutions by using 1H and 19F
NMR spectroscopic methods. The elec-
tronic effects, solvent effects and fluoro-
substitution effects were studied. Single
crystals were obtained and analysed by X-
ray diffraction spectroscopy.
Z.-H. Sun, M. Albrecht,*
R. Fröhlich ...................................... 1–10
Tuning the Halide Affinity of Quinoline-
Based Anion Receptors
Keywords: Supramolecular chemistry / Re-
ceptors / Sensors / Anions / Halides
10
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