Anion receptors based on a quinoline backbone

Article abstract of DOI:10.1002/ejoc.200700130

2-Amido-8-urea substituted quinoline derivatives are potent receptors for the binding of halide or benzoate anions in chloroform. The selectivity and affinity of the receptors for fluoride can be tuned by variation of the substituents at the receptor side

Full text of DOI:10.1002/ejoc.200700130

FULL PAPER
DOI: 10.1002/ejoc.200700130
Anion Receptors Based on a Quinoline Backbone
Markus Albrecht,*[a] Triyanti,[a] Stefanie Schiffers,[a] Olga Osetska,[a] Gerhard Raabe,[a]
Thomas Wieland,[a] Luca Russo,[b] and Kari Rissanen[b]
Keywords: Anions / Quinoline / Receptors / Ab initio calculations / Fluorescence
2-Amido-8-urea substituted quinoline derivatives are potent
receptors for the binding of halide or benzoate anions in
chloroform. The selectivity and affinity of the receptors for
fluoride can be tuned by variation of the substituents at the
receptor side chains. Computational considerations show
that the cleft of the receptors provides space for effective
binding of F–, but not bigger anions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
anions. To gain some deeper insight into the interaction be-
tween anions and receptors, supporting computational
studies were performed.[8]
Introduction
Anions play an important role in many biological and
chemical processes.[1] For example, the disfunction of
anion-channel proteins can be the reason for cystic fibrosis,
a genetic disease.[2] Despite the importance of the specific
recognition and transport of anions, the molecular prin-
ciples of anion binding and recognition are not fully under-
stood.
Results and Discussion
Synthesis of the Receptors
The shape of anions is very often overestimated in bind-
ing modes; in only a few cases does it strictly follow the
lock-and-key principle.[3] Very often, anion binding occurs
only as a result of electrostatic attraction and entropic driv-
ing forces; shape usually only has a minor influence.[4]
To gain some deeper understanding on processes involv-
ing anions, it is necessary to thoroughly investigate the
anion binding properties of simple receptor molecules.
Therefore, this field of research became an important topic
of current supramolecular chemistry.
Quinoline derivatives 1 were prepared following the syn-
thetic procedure as described previously for 1a.[9] The syn-
thesis is depicted in Scheme 1. The reaction sequence starts
with Huc’s nitroquinoline carboxylic acid 2.[10] From 2,
amides 3 (a: RЈ = C6H13, b: R = Ph) were prepared by
coupling with an appropriate amine, H2N–RЈ, in the pres-
ence of carbonyl diimidazole (CDI) as the coupling reagent.
Hydrogenative reduction of the nitro group with Pd–C as
the catalyst afforded amine 4 (a: RЈ = C6H13, b: R = Ph) in
quantitative yield as the crude product. Even though this
A series of cationic anion receptors were developed,
which can bind simple inorganic but also sophisticated or-
ganic anions even in water.[5] Alternatively, neutral recep-
tors can be used to investigate anion binding mechanisms,
as demonstrated by the work of Sessler, Schmidtchen, Gale
and many others.[6] Recently, we reported a simple quino-
line derivative of type 1, which is able to bind halide anions
with moderate affinities in a 1:1 fashion; some selectivity
for the smaller anions was discovered.[7] On the basis of
those preliminary results, we now describe the synthesis of
a series of related quinoline-type receptors 1 and the op-
timisation of the halide binding properties. In addition, we
discuss their ability to bind simple organic (carboxylate)
[a] Institut für Organische Chemie, RWTH Aachen,
Landoltweg 1, 52072 Aachen, Germany
E-mail: markus.albrecht@oc.rwth-aachen.de
[b] Nanoscience Centre, Department of Chemistry, University of
Jyväskylä,
Scheme 1. Synthetic pathway for the preparation of quinoline de-
rivatives 1 (CDI = carbonyl diimidazole).
Survontie 9, 40014 Jyväskylä, Finland
2850
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2850–2858

Anion Receptors Based on a Quinoline Backbone
FULL PAPER
amine can be purified, it usually reacts with isocyanates contacts fix the molecule in a tweezer-type arrangement
without work up to form desired urea derivatives 1. with the hydrogen-bond donors pointing to the front of the
Following this approach, differently substituted com- molecule (Figure 2).
pounds 1a (R = C8H17, RЈ = C6H13), 1b (R = C8H17, RЈ =
Ph), 1c (R = C4H9, RЈ = Ph), 1d (R = Ph, RЈ = C6H13) and
1e (R = Ph, RЈ = Ph) were prepared in moderate-to-good
yields (56–85% overall yield starting from 2). The com-
pounds were characterised by standard spectroscopic meth-
ods (see Experimental Section) and the X-ray structure of
1c·CH3CN as well as 1e·DMSO (vide infra) could be ob-
tained.
Solid State Structures and Conformational Considerations
Figure 1 shows the result of the X-ray structure analysis
of the DMSO adduct of 5,7-dibromo-8-hydroxyquinoline-
2-carboxylic acid (5) from a weakly diffracting crystal. The
representation nicely shows the orientation of the two acidic
protons (phenol and carboxylic acid) towards the front of
the molecule. This front position is enforced by intramolec-
ular hydrogen bonding to the quinoline nitrogen atom,[11]
and owing to this, the hydrogen atoms are ideally predis-
posed for the tweezer-type interaction with hydrogen-bond
acceptors Ϫ in the present case DMSO. As shown earlier,
only weak binding of anions can be expected by derivatives
such as 5. However, by using the intramolecular interac-
tions such as those in 5·DMSO as a starting point, we de-
veloped and optimised anion receptors 1.
Figure 2. Solid-state structure of 1c·CH3CN (top) and 1e·DMSO
(bottom).
The two internal NH units provide the conformational
rigidity that positions the remaining NH to form a small
cleft. Therefore, this pyridine-bridged amido–urea unit is
predisposed to act as an anchor for the fixation of guest
species. In the solid phase, the carbonyl oxygen of a second
molecule of urea binds in the pocket, which leads to a 1D
hydrogen-bonded chain. Acetonitrile is not involved in the
H-bonding.
Involvement of solvent molecules in the hydrogen bond-
ing to the receptor is observed in the solid-state structure
of 1e·DMSO. The conformation of receptor 1e is very sim-
ilar to that described for 1c. However, now one molecule of
DMSO is bound to the three hydrogen-bond donors and it
shows long contacts to the internal hydrogen atoms with
the H···O bond lengths equal to 2.48 Å (amide), 2.21 Å
(urea) and a shorter one to the external urea proton of
Figure 1. X-ray structure of 5·DMSO.
Weakly diffracting crystals of 1c·CH3CN with only mod- 2.00 Å. In addition, one ortho proton of the phenyl ring
erate X-ray quality were also obtained. They show the for- that is attached to the amide is located at a distance of
mation of a hydrogen-donor binding pocket, in which, for 2.56 Å from the DMSO oxygen atom. This phenyl ring is in
example, anionic guest species can be introduced. Similar to the same plane as the amide and quinoline moieties, which
that observed for model 5, intramolecular hydrogen bonds probably introduces some steric hindrance, whereas the
between the quinoline N atom and a urea unit and between phenyl group at the urea is twisted out of plane and there-
the quinoline N atom and the amide NH are formed. These fore does not interfere with the binding guest. The DMSO
Eur. J. Org. Chem. 2007, 2850–2858
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2851

M. Albrecht et al.
FULL PAPER
molecule is located somewhat above the plane of the bind-
ing site owing to the size of the oxygen atom, which is too
big to allow binding inside the cavity.
Determination of Binding Affinities
In our earlier study, we used receptor 1a to determine its
binding affinities with fluoride, chloride, bromide and ni-
trate anions by NMR as well as fluorescence spectroscopy
in chloroform. Only in the case of fluoride did NMR spec-
troscopy not allow the determination of the binding con-
stants. With the other anions, only relative binding con-
stants could qualitatively be estimated because of self-ag-
gregation of the receptors at the concentration of the mea-
surement (0.0125 ).
Fluorescence spectroscopy, alternatively, was carried out
at a much lower concentration (1 µ) were no self-aggrega-
tion of the receptor could take place. Therefore, the ob-
served values are much higher, but they show similar trends
in their selectivities.
Following this, we investigated modified receptors 1b–e
to determine their anion binding abilities using both spec-
troscopic methods. In addition, benzoate as a bigger “or-
ganic” anion was studied.
NMR Spectroscopic Investigations
Before starting the titration experiments, we determined
the binding stoichiometry between receptors and anions by
Jobs method. It was found to be 1:1 (Figure 3).[12]
Titration experiments were performed at a receptor con-
centration of 0.0125  in CDCl3 by the successive addition
of tetrabutylammonium salts of the anions, and the amide
signals, as well as the urea NH signals, were followed. The
observation of three different signals allows to estimate the mined by H NMR spectroscopy in CDCl3 at a concentration of
error of the titration to be Ͻ25%. The titration curves (e.g.
Figure 3) were fitted by standard nonlinear regression
Figure 3. Representation of a selected example of the Jobs plot of
receptor 1d with chloride anions and the corresponding NMR ti-
tration curve observed for the amide NH. The solid line represents
the simulated curve.
Table 1. Binding constants Ka [–1] for the 1:1 binding of various
anions (as tetrabutyl ammonium salts) with receptors 1a–e deter-
1
0.0125  and 296 K. All data are the result of at least two indepen-
dent measurements. Errors are estimated to be Ͻ25%.
methods as described in the literature.[12] The results of the
NMR studies are summarised in Table 1. Again, no reliable
data could be obtained for fluoride by NMR spectroscopy.
All receptors 1 have a strong preference for the smaller
anions over the bigger ones. Therefore, decreasing binding
constants can be observed in the series chloride, bromide
and nitrate. However, a strong dependence of Ka on the
–
R
RЈ
Cl–
Br–
NO3
Benzoate
substituents at the receptor side chains can be observed.
Starting from our initial receptor 1a, we introduced a
phenyl group at the amide unit to obtain receptors 1b and
1c. This does not influence the binding of the anions signifi-
cantly. In 1d, we added a phenyl substituent to the urea
moiety. This led to a slight increase in the binding affinity
of the chloride anion. The most significant increase is found
1a
1b
1c
1d
1e
C8H17
C8H17
C4H9
Ph
C6H13
Ph
Ph
C6H13
Ph
1000
830
2110
3333
7700
500
260
353
337
1100
420
320
412
322
1100
450
4000
390
600
3000
Ph
for receptor 1e with two phenyl substituents. With chloride, ceptors 1a–e. Here, not only the binding of the anionic part
a Ka = 7700 –1 was found. This effect is probably due to is important, but it is additionally influenced by steric inter-
the increase in the acidity of the two protons close to the actions of the phenyl group with the receptor and by aro-
phenyl groups and is most effective with chloride, which, matic–aromatic interactions between the benzoate anion
because of its size, can come in close contact with the pro- and the receptors.
tons.
To summarise the NMR titration experiments, it is seen
In the case of benzoate binding,[13] the association con- that quinoline receptors 1a–e can be used for the binding
stants seem to unsystematically vary with the different re- of anions in chloroform, which shows some selectivity for
2852
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2850–2858

Anion Receptors Based on a Quinoline Backbone
FULL PAPER
smaller chloride anions over the larger halides. Introduction Table 2. Binding constants Ka [–1] for the 1:1 binding of various
anions (as tetrabutyl ammonium salts) with receptors 1a–e deter-
of phenyl groups increases the acidity of neighbouring NH
protons and thus increases the binding affinities of the
anions.
mined by fluorescence spectroscopy in CHCl3 at a concentration
of 1 µ at 296 K. All data are the result of at least two independent
measurements. Errors are estimated to be Ͻ25%. Excitation/emis-
sion wavelength [nm]: 403/471 (1a), 350/462 (1b), 387/461 (1c), 323/
438 (1d), and 299/456 (1e).
Fluorescence Spectroscopic Investigations[14]
As mentioned above, fluorescence spectroscopy has the
advantage that the measurements are performed at a con-
centration where no aggregation of the receptor can occur.
This can be shown by concentration-dependent fluores-
cence studies. In addition, fluoride anion binding can be
investigated.
The addition of halide or nitrate anions to receptors 1a–
–
R
RЈ
F–
Cl–
Br–
NO3 Benzoate
e leads in all cases to fluorescence enhancement (Figure 4).
Only with benzoate quenching occurs probably by the aro-
matic carboxylate.
1a C8H17 C6H13 14400
1b C8H17 Ph
1c C4H9
1d Ph
1e Ph
3100 640
7700 340
400
6000
14300
5000
1510 4700
4630 1050 1630 5080
10380 1887 1672
Ph
C6H13 150000
Ph
receptor is light unstable
Computational Considerations
Quantum-chemical calculations were performed to ac-
quire some insight into the size-complementarity between
model receptor A and different halide anions. Although the
applied method is appropriate to gain an impression of the
geometry of the interaction between host and guest, it does
not allow an estimation of entropic influences or solvent
effects.
Unconstrained optimisation for all structures were ini-
tially carried out at the Hartree–Fock level of ab initio
theory by using the 6-31++G** basis set (HF/6-31++G**).
Calculation and diagonalisation of the corresponding force
constant matrices showed that all resulting structures were
Figure 4. Enhancement of the fluorescence intensity of receptor 1d
(concentration: 1 µ) in chloroform upon addition of tetrabutyl
ammonium chloride (excitation wavelength: 323 nm, emission
wavelength: 438 nm).
As a disadvantage, no reliable titration curves could be local minima. Starting from these geometries, we then per-
obtained for easily photooxidised receptor 1e. formed final optimisations at the correlated level by em-
The results of the fluorescence titrations are summarised ploying Møller–Plesset perturbation theory to the second
in Table 2. Without competition of receptor self-aggrega- order and the 6-31+G* basis set (MP2/6-31+G*). The
tion, the obtained Ka’s are usually higher than the ones ob- Gaussian03 suite of quantum-chemical routines[15] running
tained by NMR spectroscopy. The relative selectivities of on the facilities of the Computing and Communication
chloride, bromide and nitrate anion binding by 1a–d are in Centre of the RWTH Aachen was used for all of the calcu-
the same range as observed by NMR spectroscopy (see for lations. Selected structural parameters of the minima are
comparison Table 1).
given in Table 3, and the structures optimised at the MP2
The fluoride anion already shows a moderately high level of theory are shown in Figure 5.
binding with receptor 1a (Ka = 14400 –1) as well as with
The –C(=O2)–N4H2 segment of free receptor molecule A
1b (Ka = 14300 –1). The Ka = 5000 –1 of 1c with fluoride has a significantly pyramidalised amino group; it is distinc-
seems to be very low, but can be reproduced.
tively turned out of the plane defined by the atoms of the
Receptor 1d, in contrast, shows a very high affinity for condensed ring system. Except for a pyramidalisation of the
the small fluoride anion with Ka = 150000 –1. This is prob- N4H2 group, the complex A·F– (Figure 5, a) is essentially
ably due to the fact that F– is the ideal size to fit in the planar. Whereas the structural features of the host unit are
cavity of the receptor. In this case, enhancement of the acid- widely retained in A·Cl–, the chlorine atom lies significantly
ity at the urea moiety increases the binding affinity because (1.114 Å) above the least-squares plane defined by the non-
of the close contact to the anion. Enhancement of the acid- hydrogen atoms of the acceptor part of the complex (cf.
ity at the amide moiety (receptor 1b/1c) does not lead to Table 3). Elevation of the halogen atom from this plane is
related effects. This binding unit is blocked by the intramo- even stronger in A·Br– (1.674 Å), where rotation of the N3–
lecular hydrogen bonding to the quinoline nitrogen atom. C(=O)–N4H2 side chain about the bond to the ring system
Unfortunately we were not able to obtain association con- is more pronounced than in the other complexes. The
stants of the biphenylated receptor 1e with fluoride.
H1a···X···H4a bond angles decrease in the order F Ͼ Cl Ͼ
Eur. J. Org. Chem. 2007, 2850–2858
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2853

M. Albrecht et al.
FULL PAPER
Table 3. Selected structural parameters for A·F–, A·Cl– and A·Br– Bernardi.[16] These corrections are small at the Hartree–
obtained at the MP2/6-31+G* level (HF/6-31++G** values in pa-
rentheses) (Interatomic distances measured in Å, angles in °). The
values are most likely too negative as a result of an overpol-
parameter h is the largest perpendicular distance of an atom (϶X–)
Fock level (cf. Table 4), and although the calculated ∆Eb
arisation of the molecules at the Hartree–Fock level, strong
from the least-squares plane defined by the non-hydrogen atoms
electrostatic and polarisation components are likely to con-
tribute to the total binding energy. As to be expected, the
counterpoise corrections are significantly larger when MP2
corrections are included in single-point calculations at the
Hartree–Fock-optimised geometries (MP2/6-311++G**//
HF/6-31++G**).
of the host part of the complex. The parameter hЈ is the largest
perpendicular distance of the halide anion from the same plane.
A·F–
A·Cl–
A·Br–
H1a···X
1.663(1.718)
1.758(1.826)
1.728(1.753)
2.491(2.559)
93.4(92.4)
69.5(68.2)
162.9(160.6)
2.216(2.418)
2.401(2.834)
2.195(2.283)
2.779(2.833)
73.9(64.7)
54.9(48.9)
123.8(113.3)
72.9(73.6)
2.416(2.560)
2.534(3.059)
2.403(2.426)
2.822(2.840)
69.5(59.9)
51.7(45.3)
111.6(105.2)
73.7(73.9)
H3···X
H4a···X
H1a···H3[a]
H1a···X···H3
H3···X···H4a
H1a···X···H4a
Table 4.Energy changes associated with the reaction A + X–
Ǟ
A·X– (∆Eb; all energies in kcalmol–1); ZPE is the zero-point vi-
brational energy.
H1a···N2···H3[b] 66.4(67.4)
A·F– A·Cl–
A·Br–
N4···C···N3···C[d] –177.0(179.8)
178.7(178.1)
0.418(0.101)
1.114(0.332)
–173.4(–179.9)
0.585(0.002)
1.674(0.003)
h[c]
hЈ
0.355(0.013)
0.064(0.007)
HF/6-311++G**//HF/6-31++G**
HF/6-311++G**//HF/6-31++G**[a]
MP2/6-311++G**//HF/6-31++G**
MP2/6-311++G**//HF/6-31++G**[a]
MP2/6-31+G*//MP2/6-31+G*
–66.56 –40.67 –35.60
–65.16 –40.04 –35.48
–55.73 –34.21 –28.76
–50.46 –28.21 –24.39
–62.34 –40.97 –40.38
–61.84 –41.94 –36.32
–53.78 –32.61 –26.80
[a] 2.744 Å in acceptor molecule A. [b] 75.30° in acceptor molecule
A. [c] 0.886 Å in acceptor molecule A. [d] 173.8° in acceptor mole-
cule A.
MP2/6-311++G**//MP2/6-31+G*
ZPE+MP2/6-311++G**//HF/6-31++G**
ZPE+MP2/6-311++G**//HF/6-31++G**[a] –48.51 –26.61 –22.43
ZPE+MP2/6-31+G*//MP2/6-31+G*
ZPE+MP2/6-311++G**//MP2/6-31+G*
–60.39 –39.37 –38.42
–59.89 –40.34 –34.36
[a] Including a counterpoise correction.[16]
NBO calculations[17,18] with the 6-31G** basis set at the
HF/6-31++G**- and the MP2/6-31+G*-optimised geome-
tries were performed to elucidate binding between the
anions and the acceptor molecule. Independent of the ge-
ometry and the halogen atom, the NBO results are qualita-
tively the same for all three complexes in that this analysis
of the molecular wave function does not give classical
bonds between X and the host unit of the complex. Each
of the anions carries four lone pairs (n) with occupation
numbers between 1.910 and 2.000 e. These lone pairs
strongly interact predominantly with the σNH* orbitals of
the receptor unit, whereas the interaction of highly occu-
pied σ orbitals of the host molecule with Rydbergs of the
halogen atoms are very weak and can safely be neglected.
Figure 5. Calculated structures (MP2, top view and side view) of
simplified receptor A (a), and its host–guest complex with fluoride
A·F (b), chloride A·Cl (c) and bromide A·Br (d).
(2)
The energy lowering due to the nǞσ* interaction (∆Enσ*
)
can be estimated by using an energy expression derived from
(2)
second-order perturbation theory ∆Enσ* = –qn·͗n|F|σ*͘2/
(εσ*-εn), where F is the Fock operator of the molecule and qn
is the occupation number of the lone pair. The parameters
εσ* and εn are the NBO orbital energies of the σ* and non-
bonding orbital n, respectively.[17,18] The corresponding
values are given in Table 5.
Br. The bond lengths between the atoms of the heavy-atom
skeletons obtained at the MP2/6-31+G* level are very sim-
ilar in all three complexes. Except for the side chains where
the C–NH2 and the C=O bonds are about 0.020 Å shorter
and 0.013 Å longer than in the acceptor molecule, the
bonds in A and A·X– are of comparable lengths.
Table 5.Natural atomic charges q(X–), charge transfer energies
(∆Ect) and ∆Enσ* calculated at the HF/6-31G**//MP2/6-31+G*
level. The numbers in parentheses were obtained at the HF/6-
At all levels of accuracy, bonding is the strongest for X
= F, followed by X = Cl and finally X = Br.
The energies of the reaction A + X– Ǟ A·X– [∆Eb
=
31G**//HF/6-31++G** level (charges in
e
and energies in
Etot(A·X–) – Etot(A) – Etot(X–)] obtained at different levels
of theory are given in Table 4. The interactions between the
halogen anions and A are stabilising even at the HF level.
To roughly estimate how much of ∆Eb might be due to a
basis set superposition error (BSSE), we applied counter-
poise corrections using the method suggested by Boys and
kcalmol–1).
X–
q(X–)
∆Ect
∆Enσ*
(2)
F–
–0.8304(–0.8492) –105.1(–91.1)
–0.8870(–0.9283) –53.5(–31.8)
–0.8868(–0.9211) –47.7(–32.4)
–108.5(–91.4)
–61.8(–35.4)
–52.2(–33.4)
Cl–
Br–
2854
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2850–2858

Anion Receptors Based on a Quinoline Backbone
FULL PAPER
At –108.5 kcalmol–1, the nǞσ* interactions are the prevents the determination of reliable data for fluoride an-
strongest for X = F, significantly weaker for X = Cl ionic binding by NMR spectroscopy. In our computational
(–61.8kcalmol–1) and the weakest for
X
=
Br calculations, this process was not taken into account and
(–52.2kcalmol–1). As to be expected, these energies are sim- only binding of the fluoride anion to the pocket of the re-
ilar to the energies associated with charge transfer from X– ceptor was considered.
to acceptor molecule A upon formation of the complex
In an additional preliminary study, the binding of car-
(charge-transfer energy, ∆Ect). The charge-transfer energy boxylate anions to the receptors can be shown, which opens
was obtained as the difference between the SCF energy of up a way for organocatalytic reactions. Therefore, we are
the complex (A·X–) calculated with the full Fock matrix and now preparing enantiomerically pure chiral derivatives of 1.
the total energy obtained in a single iteration after deletion
of the Fock matrix elements between the donor orbitals of
X and the acceptor orbitals of A.[17] The amount of charge
transferred to the acceptor molecule (∆q) is relatively small
(F: 0.1696 e, Cl = 0.1130 e and Br: 0.1132 e), and the largest
transfer occurs from the fluoride anion, which also gives
the most negative charge-transfer energy. Owing to similar
geometries for A·F– at the Hartree–Fock and the MP2
Experimental Section
NMR spectra were recorded with a Varian Mercury 300 or Inova
400 spectrometer. FTIR spectra were recorded with a Perkin–Elmer
FTIR 1760 spectrometer (KBr). MS were measured with a Varian
MAT 212 spectrometer. Elemental analyses are obtained with a
Heraeus CHN-O-Rapid analyser. Melting points were measured
with a Büchi B-540 apparatus and are uncorrected. Fluorescence
measurements were performed with a Perkin–Elmer LS 50-B spec-
trofluorometer.
(2)
levels, ∆q, ∆Ect and ∆Enσ* are not too different for both
sets of structural parameters. The structural differences be-
tween the geometries obtained with the HF and MP2 meth-
ods are larger for A·Cl– and A·Br–. Consequently, the values
CCDC-633847 to -633849 contain the supplementary crystallo-
graphic 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.
(2)
that were obtained for ∆q, ∆Ect and ∆Enσ* for both geo-
metries differ much more for these two molecules than they
do for A·F–. In general, more negative values of ∆Ect and
(2)
5,7-Dibromo-8-hydroxyquinoline-2-carboxylic Acid (5): 5,7-Di-
bromo-8-hydroxyquinoline-2-carboxaldehyde[20] (0.25 g, 0.72 mmol)
was dissolved in formic acid (10 mL, 0.26 mol, 1 equiv.) and the
suspension was cooled to 0 °C. Cold hydrogen peroxide (16 mL;
30% solution in water, 0.52 mol, 2 equiv.) was slowly added, and
the mixture was warmed to room temperature. After stirring for
3 d, water (200 mL) was added, the precipitate was collected by
filtration, washed with cold water and dried. The first recrystalli-
sation from DMF/iPrOH allowed the recovery of 0.06 g (24%) of
the starting material; the second recrystallisation from methanol
provided 5 as a yellow solid. Yield: 0.096 g (37%). M.p. 265 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 13.00 (br. s, 1 H), 11.07 (br. s,
1 H), 8.55 (d, J = 7.0 Hz, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 8.15 (s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.70 (C), 151.70
(C), 146.15 (C), 138.29 (CH), 137.34 (C), 136.03 (CH), 128.06 (C),
∆Enσ* and a more positive ∆q value are obtained for the
structures optimised at the correlated level.
Conclusions
Starting from solid-state structures such as 5·DMSO,
which show the host–guest behaviour of 2-acid substituted
8-hydroxyquinolines, we developed an efficient and selective
receptor for the fluoride anion in chloroform. Substitution
of the amide moiety for an acid functionality and a urea
group instead of the hydroxy group in 5 led to potent halide
receptors 1a–c. However, variation of the substituents at the
amide group as well as at the urea caused an enhancement
in the acidity of the NH protons and an enhancement in
the binding of fluoride anions in chloroform at room tem-
perature to Ka = 150000 –1 for 1d.
Computational considerations using model A indicate
that the binding of the anion is mainly electrostatic and
show that receptors 1a–e provide a cavity that is most ap-
propriate for the binding of the small fluoride. The larger
halides (chloride and bromide) do not fit in the provided
cavity and therefore have to be located above the plane of
receptor molecule A.
122.23 (CH), 109.29 (C), 106.08 (C) ppm. IR (KBr): ν = 3309,
˜
1706, 1613, 1572, 1451, 1376, 1245, 1194, 936, 839 cm–1. MS (EI):
m/z = 346.8 [M + H]+. C10H5Br2NO3·CH3OH (379.01): calcd. C
34.86, H 2.39, N 3.70; found C 35.09, H 2.68, N 4.08. X-ray quality
crystals were obtained from DMSO: Crystal data (C10H5NO3Br2)-
(SC2H6O): FW = 425.10, plate, 0.20ϫ0.10ϫ0.04 mm3, triclinic,
¯
space group P1, a = 8.6570(17) Å, b = 10.524(2) Å, c = 17.694(4) Å,
α= 96.72(3)°, β = 102.80(3)°, γ = 109.81(3)°, V = 1446.1(5) Å3, Z
= 4, Dcalcd. = 1.952 gcm–3, F(000) = 832, Mo-Kα radiation, λ =
0.71073 Å, µ = 5.761 mm–1, T = 173(2) K, 2θmax = 55.0°, 12587
reflections collected, 3638 unique (Rint = 0.1006), 2158 with Io
Ͼ
2σ(Io). Solved by using SHELXS and refined with SHELX-97,[21]
full-matrix least-squares on F2, 392 parameters, 492 restraints, GoF
= 1.128, R1 = 0.1800, wR2 = 0.2391 (all reflections), 1.24 Ͻ ∆ρ Ͻ
–1.24 eÅ–3.
From our comparative studies by NMR and fluorescence
techniques, we can see that fluorescence at lower concentra-
tions leads to more accurate data than the corresponding
NMR spectroscopic methods. However, NMR spec-
troscopy allows an estimation of relative affinities for dif-
ferent anions, if measurements are performed at the same
concentration of the receptor.
4-Isobutoxy-8-nitroquinoline-2-carboxylic Acid Hexylamide (3a): A
solution of 4-isobutoxy-8-nitroquinoline-2-carboxylic acid (2; 0.6 g,
2.07 mmol, 1.0 equiv.) and carbonyl diimidazole (0.57 g, 3.5 mmol,
1.75 equiv.) in chloroform (20 mL) was heated at reflux for 1.5 h
under an atmosphere of Ar. A solution of n-hexylamine (0.32 g,
3.18 mmol, 1.5 equiv.) in chloroform (2 mL) was added, and the
As pointed out,[19] deprotonation of the receptors by a
fluoride anion always has to be considered as a competitive
process to the binding of this anion with high basicity. This mixture was heated at reflux for an additional 2 d. After cooling
Eur. J. Org. Chem. 2007, 2850–2858
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2855

M. Albrecht et al.
FULL PAPER
to room temperature, the organic phase was washed with water and
dried (MgSO4), and the solvent was removed in vacuo. After col-
umn chromatography (silica gel, CH2Cl2) 3a was obtained in 92%
[C11H8N2O3]+, 187 (10) [C10H7N2O2]+, 160 (27) [C9H6NO2]+, 130
(4) [C9H6O]+, 100 (9) [C8H4]+, 77 (1) [C6H5]+, 57 (1) [C4H9]+.
C20H29N3O2·1/2H2O (352.47): calcd. C 68.15, H 8.58, N 11.92;
(0.71 g) as a yellow solid. M.p. 97 °C. 1H NMR (400 MHz, CDCl3): found C 68.17, H 8.67, N 11.82.
δ = 8.48 (dd, J = 1.5, 8.5 Hz, 1 H), 8.20 (s, NH), 8.11 (dd, J = 1.5,
4-Isobutoxy-8-amine-quinoline-2-carboxylic Acid Phenylamide (4b):
7.5 Hz, 1 H), 7.81 (s, 1 H), 7.62 (t, J = 8.5 Hz, 1 H), 4.11 (d, J =
6.6 Hz, 2 H), 3.47 (q, J = 7.5 Hz, 2 H), 2.30 (m, 1 H), 1.67 (m, 2
H), 1.37 (m, 2 H), 1.33 (m, 4 H), 1.14 (d, J = 6.6 Hz, 6 H), 0.90
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.4, 163.1,
153.4, 126.7 (2 C), 124.9 (2 C), 124.8 (2 C), 123.1, 99.8, 75.6, 39.7,
A mixture of nitro precursor 3a dissolved in CH2Cl2 (20–30 mL)
and 10% Pd/C was stirred at ambient temperature under an atmo-
sphere of hydrogen (5 bar) for 1 d. The solution was filtered
through Celite. The solution was used in the next step without iso-
lation of the amine.
31.6, 29.7, 28.1, 26.7, 22.5, 19.1, 14.0 ppm. IR (KBr): ν = 3301 (s),
˜
4-Isobutoxy-8-(3-octylureido)quinoline-2-carboxylic Acid Hexyl-
amide (1a): A solution of 8-amino-4-isobutoxyquinoline-2-car-
boxylic acid hexylamide (4a; 0.53 g, 1.55 mmol, 1.0 equiv.) and n-
octyl isocyanate (0.51 g, 3.29 mmol, 1.5 equiv.) in chloroform
(30 mL) was heated at reflux for 3 h. After cooling to room tem-
perature, the solvent was removed in vacuo. After column
chromatography (silica gel, CH2Cl2), 1a was obtained as a yellow
solid. Yield: 0.66 g (1.32 mmol, 85%). M.p. 135 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.69 (s, NH), 9.23 (s, NH), 8.73 (d, J =
7.7 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.67 (s, 1 H), 7.49 (t, J =
8.2 Hz, 1 H), 6.37 (s, NH), 3.98 (d, J = 6.6 Hz, 2 H), 2.32 (q, J =
6.7 Hz, 2 H), 2.25 (m, 1 H), 1.64 (s, 4 H), 1.39 (m, 4 H), 1.15 (d, J
= 6.6 Hz, 6 H), 1.10 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.0, 163.5, 163.2, 137.4, 136.3, 127.9,
123.5, 121.9, 100.2, 98.4, 76.1, 40.2, 31.6, 31.4, 30.4, 30.2, 29.2,
2959 (s), 2928 (s), 2859 (m), 1667 (vs), 1539 (vs), 1501 (m), 1465
(m), 1354 (s), 1240 (m), 1142 (m), 1014 (s), 873 (m), 758 (m), 729
(m) cm–1. MS (EI, 70 eV): m/z (%) = 373 (7) [M, C20H27N3O4]+,
355 (92) [C20H25N3O3]+, 300 (22) [C18H26N2O]+, 282 (17)
[C17H20N3O]+, 246 (100) [C13H14N2O3]+, 230 (40) [C13H12NO3]+,
217 (14) [C12H11NO3]+, 200 (12) [C12H8O3]+, 190 (21) [C9H6-
N2O3]+, 173 (6) [C9H5N2O3]+, 144 (5) [C9H6NO]+, 57 (9) [C4H9]+.
C20H27N3O4 (373.45): calcd. C 64.32, H 7.29, N 11.25; found C
64.60, H 7.63, N 11.71.
4-Isobutoxy-8-nitroquinoline-2-carboxylic Acid Phenylamide (3b): A
solution of 4-isobutoxy-8-nitro-quinoline-2-carboxylic acid (2;
0.2 g, 0.69 mmol, 1.0 equiv.) and carbonyl diimidazole (0.196 g,
1.21 mmol, 1.75 equiv.) in chloroform (20 mL) was heated at reflux
for 1.5 h under an atmosphere of Ar. A solution of aniline (0.01 g,
0.76 mmol, 1.1 equiv.) in chloroform (2 mL) was added, and the
mixture was heated at reflux for an additional 2 d. After cooling
to room temperature, the organic phase was washed with water and
dried (MgSO4), and the solvent was removed in vacuo. After col-
umn chromatography (silica gel, CH2Cl2), 3b was obtained in 80%
(0.2 g) as a white solid. M.p. 188.5 °C. 1H NMR (400 MHz,
CDCl3): δ = 10.18 (s, NH), 8.52 (dd, J = 1.4, 8.5 Hz, 1 H), 8.19
(dd, J = 1.4, 7.4 Hz, 1 H), 7.88 (s, 1 H), 7.81 (d, J = 7.4 Hz, 2 H),
7.66 (t, J = 7.9 Hz, 1 H), 7.42 (t, J = 7.9 Hz, 2 H), 7.19 (t, J =
7.4 Hz, 1 H), 4.15 (d, J = 6.7 Hz, 2 H), 2.33 (m, 1 H), 1.17 (d, J =
29.1, 28.2, 26.9, 26.7, 22.5, 22.4, 19.0, 14.0, 13.8 ppm. IR (KBr): ν
˜
= 3348 (vs), 2928 (vs), 2858 (s), 1646 (s), 1528 (vs), 1460 (m), 1416
(m), 1384 (w), 1360 (m), 1321 (m), 1274 (m), 1224 (m), 1144 (w),
1045 (m), 865 (w), 817 (w), 762 (m), 725 (w), 544 (w) cm–1. MS
(EI, 70 eV): m/z (%) = 498 (7) [M, C29H46N4O3]+, 370 (22)
[C21H30N4O2]+, 343 (100) [C20H29N3O2]+, 314 (10) [C19H28N3O]+,
242 (42) [C15H20N3]+, 216 (53) [C12H20N2]+, 185 (12) [C10H5-
N2O2]+, 159 (13) [C9H5NO2]+, 100 (11) [C8H4]+, 85 (1) [C6H13]+,
57 (4) [C4H9]+. C29H46N4O3·1/2H2O (509.71): calcd. C 68.60, H
9.33, N 11.04; found C 68.83, H 9.03, N 10.90.
6.7 Hz, 6 H) ppm. IR (KBr): ν = 3743 (m), 3350 (w), 2958 (m),
˜
8-(3-Octylureido)-4-isobutoxy-quinoline-2-carboxylic Acid Phenyl-
amide (1b): A solution of 4-isobutoxy-8-aminoquinoline-2-car-
boxylic acid phenylamide (4b; 0.28 g, 0.89 mmol, 1.0 equiv.) and n-
octyl isocyanate (0.179 g, 1.155 mmol, 1.5 equiv.) in dichlorometh-
ane (30 mL) was heated at reflux for 1 d. After cooling to room
temperature, the solvent was removed in vacuo. After column
chromatography (silica gel, CH2Cl2), 1b was obtained as a yellow
solid. Yield: 0.302 g (0.62 mmol, 80%). M.p. 155 °C. 1H NMR
(300 MHz, CDCl3): δ = 10.02 (s, NH), 8.95 (s, NH), 8.58 (dd, J =
1.0, 8.0 Hz, 2 H), 7.74 (dd, J = 1.0, 6.7 Hz, 2 H), 7.67 (s, NH), 7.43
(t, J = 8.0 Hz, 1 H), 7.21 (t, J = 7.4 Hz, 2 H), 7.04 (t, J = 7.4 Hz,
1 H), 5.87 (s, 1 H), 3.95 (d, J = 6.5 Hz, 2 H), 3.11 (m, 2 H), 2.23
(q, J = 6.7 Hz, 1 H), 1.33 (m, 2 H), 1.19 (m, 10 H), 1.09 (d, J =
6.5 Hz, 6 H), 0.83 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 155.8, 148.9, 137.3, 135.7, 134.9, 128.6 (2 C), 127.7, 124.4, 122.0,
120.5 (2 C), 116.0 (2 C), 113.9, 98.8, 75.1, 40.5, 31.7 (2 C), 30.1,
2361 (vs), 2339 (vs), 1692 (s), 1525 (vs), 13674 (m), 1110 (m), 1018
(m), 752 (m), 669 (m) cm–1. MS (EI, 70 eV): m/z (%) = 365 (85)
[M, C20H19N3O4]+, 309 (7) [C16H13N3O4]+, 280 (2) [C15H12-
N3O3]+, 262 (5) [C16H10N2O2]+, 246 (40) [C13H14N2O3]+, 190 (100)
[C9H6N2O3]+, 173 (4) [C9H5N2O2]+, 143 (3) [C9H5NO]+, 115 (5)
[C8H5N]+, 93 (3) [C6H5O]+, 77 (4) [C6H5]+, 57 (5) [C4H9]+.
C20H19N3O4 (365.39): calcd. C 65.75, H 5.21, N 11.5; found C
65.37, H 5.73, N 11.96.
8-Amino-4-isobutoxyquinoline-2-carboxylic Acid Hexylamide (4a):
A mixture of nitro precursor 3a (0.6 g, 1.66 mmol) dissolved in
EtOAC (20–30 mL) and 10% Pd/C was stirred at ambient tempera-
ture under an atmosphere of hydrogen (5 bar) for 4 h. The solution
was filtered through Celite, and the solvent was evaporated.
1
Yield:0.55 g (1.60 mmol, 98%). M.p. 121 °C. H NMR (300 MHz,
CDCl3): δ = 8.10 (s, NH), 7.67 (s, 1 H), 7.60 (dd, J = 1.0, 8.2 Hz,
1 H), 7.36 (t, J = 8.2 Hz, 1 H), 6.99 (dd, J = 1.0, 6.9 Hz, 1 H), 4.91
(br. s, 2 H), 4.05 (d, J = 6.5 Hz, 2 H), 3.52 (q, J = 6.9 Hz, 2 H),
2.27 (m, 1 H), 1.69 (m, 2 H), 1.36 (m, 4 H), 1.13 (d, J = 6.5 Hz, 6
H), 0.92 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.8,
164.8, 163.1 (2 C), 148.9, 143.7, 127.5, 111.3, 110.6, 108.4, 98.8,
75.0, 39.7 (2 C), 31.6, 29.8, 28.2, 26.7, 22.6, 19.2, 14.0 ppm. IR
29.2 (2 C), 28.1, 26.9, 22.6, 19.2 (2 C), 14.0 ppm. IR (KBr): ν =
˜
3746 (w), 3335 (s), 2928 (s), 1686 (s), 1643 (m), 1526 (vs), 1449 (m),
1320 (m), 1042 (m), 755 (m), 695 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 490 (9) [M, C29H38N4O3]+, 361 (36) [C21H21N4O2]+, 335 (100)
[C19H19N4O2]+, 306 (3) [C17H14N4O2]+, 279 (14) [C15H11N4O2]+,
242 (13) [C12H10N4O2]+, 216 (5) [C11H8N2O3]+, 186 (11)
[C10H6N2O2]+, 160 (9) [C9H6NO2]+, 130 (2) [C9H6O]+, 99 (4)
[C8H3]+, 55 (3) [C4H7]+. C29H38N4O3·1/2H2O (499.65): calcd. C
69.71, H 7.87, N 11.21; found C 69.31, H 7.03, N 11.10.
(KBr): ν = 3491 (m), 3332 (s), 3257 (m), 2957 (s), 2926 (s), 2851
˜
(m), 1650 (s), 1614 (m), 1510 (m), 1510 (vs), 1469 (m), 1422 (m),
1355 (m), 1275 (m), 1150 (m), 1065 (m), 1012 (m), 878 (m), 747 (s)
cm–1. MS (EI, 70 eV): m/z (%) = 343 (82) [M, C20H29N3O2]+, 300
(1) [C18H26N3O]+, 286 (4) [C18H26N2O]+, 272 (8) [C17H24N2O]+, 8-(3-Butylureido)-4-isobutoxy-quinoline-2-carboxylic Acid Phenyl-
258 (3) [C16H22N2O]+, 243 (5) [C13H11N2O3]+, 216 (100)
amide (1c): A solution of 4-isobutoxy-8-aminoquinoline-2-car-
2856
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2850–2858

Anion Receptors Based on a Quinoline Backbone
FULL PAPER
boxylic acid phenylamide (4b; 0.3 g, 0.89 mmol, 1.0 equiv.) and n-
butyl isocyanate (0.133 g, 1.335 mmol, 1.5 equiv.) in dichlorometh-
ane (30 mL) was heated at reflux for 1 d. After cooling to room
temperature, the solvent was removed in vacuo. After column
chromatography (silica gel, CH2Cl2), 1c was obtained as a yellow
solid. Yield: 0.29 g (0.69 mmol, 75%). M.p. 210 °C. 1H NMR
solid. Yield: 0.21 g, (0.46 mmol, 77%). M.p. 236 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.62 (s, NH), 9.18 (s, NH), 8.54 (d, J =
7.9 Hz, 1 H), 8.00 (s, NH), 7.64 (d, J = 8.5 Hz, 4 H), 7.50 (s, 1 H),
7.48 (d, J = 7.9 Hz, 1 H), 7.30 (t, J = 8.5 Hz, 1 H), 7.13 (t, J =
7.8 Hz, 2 H), 7.06 (t, J = 7.8 Hz, 2 H), 6.93 (t, J = 7.4 Hz, 1 H),
6.87 (t, J = 7.4 Hz, 1 H), 3.83 (d, J = 6.4 Hz, 2 H), 2.18 (m, 1 H),
(300 MHz, CDCl3): δ = 9.93 (s, NH), 8.83 (s, NH), 8.53 (dd, J = 1.06 (d, J = 6.4 Hz, 6 H) ppm.13C NMR (100 MHz, CDCl3): δ =
1.0, 7.2 Hz, 2 H), 7.72 (dd, J = 1.0, 7.4 Hz, 2 H), 7.64 (s, NH), 7.43
(t, J = 8.0 Hz, 1 H), 7.24 (t, J = 7.2 Hz, 2 H), 7.07 (d, J = 8.0 Hz,
163.0, 162.8 (2 C), 153.3, 148.8, 137.8, 137.4.136.8, 134.8, 128.9 (2
C), 128.5, 127.4, 124.5, 123.9, 121.7, 121.0, 120.7, 116.8, 114.4,
1 H), 5.57 (s, NH), 3.94 (d, J = 6.5 Hz, 2 H), 3.20 (m, 2 H), 2.23 98.6, 75, 28.1, 19.1 (2 C) ppm. IR (KBr): ν = 3909 (w), 3851 (m),
˜
(m, 1 H), 1.41 (m, 2 H), 1.21 (m, 2 H), 1.10 (d, J = 6.5 Hz, 6 H), 3737 (vs), 3448 (s), 2940 (w), 2856 (w), 2361 (vs), 1843 (w), 1649
0.83 (t, J = 7.4 Hz, 3 H) ppm. IR (KBr): ν = 3681 (s), 3441 (vs),
(s), 1542 (vs), 1315 (w), 667 (vs) cm–1. MS (EI, 70 eV): m/z (%) =
˜
2961 (s), 2360 (vs), 1687 (m), 1650 (m), 1532 (s), 1458 (w), 1388 454 (1) [M, C27H26N4O3]+, 362 (64) [C21H20N3O3]+, 363 (15)
(w), 1322 (w), 1043 (m), 754 (m), 668 (m) cm–1. MS (EI, 70 eV): [C21H21N3O3]+, 335 (21) [C20H21N3O2]+, 306(29) [C19H20N3O]+,
m/z (%) = 434 (15) [M, C25H30N4O3]+, 361 (39) [C21H21N4O2]+,
278 (7) [C16H12N3O2]+, 242 (7) [C13H12N3O2]+, 216 (4)
335 (100) [C19H19N4O2]+, 306 (5) [C17H14N4O2]+, 279 (23) [C11H10N3O2]+, 186 (21) [C10H6N2O2]+, 160 (17) [C9H6NO2]+, 130
[C15H11N4O2]+, 242 (19) [C12H10N4O2]+, 216 (7) [C11H8N2O3]+,
187 (5) [C10H7N2O2]+, 160 (17) [C9H6NO2]+, 130 (3) [C9H6O]+,
104 (1) [C8H8]+, 57 (2) [C4H9]+. C25H30N4O3·1/2H2O (443.54):
calcd. C 67.70, H 7.04, N 12.63; found C 67.45, H 6.95, N
12.53. X-ray quality crystals were obtained from acetonitrile:
(6) [C9H6O]+, 119 (100) [C7H3O2]+, 93 (61) [C6H5O]+, 77 (5)
[C6H5]+, 64 (23) [C5H5]+, 51 (10) [C4H3]+. C27H26N4O3·1/2H2O
(463.53): calcd. C 69.96, H 5.87, N 12.08; found C 70.14, H
5.55, N 11.26. X-ray quality crystals were obtained from DMSO:
Crystal data (C27H26N4O3)(C2H6SO): FW
= 532.65, block,
Crystal data (C25H30N4O3)(CH3CN): FW
=
475.58, plate,
0.20ϫ0.10ϫ0.10 mm3, monoclinic, space group P 21/n, a =
9.3881(19) Å, b = 11.631(2) Å, c = 13.968(3) Å, α = 109.68(3)°, β
0.60ϫ0.15ϫ0.03 mm3, monoclinic, space group P 21/n, a =
15.454(3) Å, b = 8.2659(17) Å, c = 21.183(4) Å, β = 105.44(3)°, V
= 101.96(3)°, γ = 100.26(3)°, V = 1353.2(5) Å3, Z = 2, Dc
=
= 2608.2(9) Å3, Z = 4, Dcalcd. = 1.211 gcm–3, F(000) = 1016, Mo- 1.307 gcm–3, F(000) = 564, Mo-Kα radiation, λ = 0.71073 Å, µ =
Kα radiation, λ = 0.71073 Å, µ = 0.081 mm–1, T = 173(2) K, 2θmax
= 55.0°, 6723 reflections collected, 2641 unique (Rint = 0.0650),
1020 with Io Ͼ 2σ(Io). Solved by using SHELXS[21] and refined
with SHELX-97, full-matrix least-squares on F2, 317 parameters,
0 restraints, GoF = 1.070, R1 = 0.2447, wR2 = 0.3109 (all reflec-
tions), 0.29 Ͻ ∆ρ Ͻ –0.28 eÅ–3.
0.162 mm–1, T = 173(2) K, 2θmax = 55.0°, 4689 reflections col-
lected, 4689 unique (Rint = 0.0710, before merging), 3793 with Io
Ͼ 2σ(Io). Solved by using SHELXS[21] and refined with SHELX-
97, full-matrix least-squares on F2, 343 parameters, 0 restraints,
GoF = 1.081, R1 = 0.0769, wR2 = 0.1251 (all reflections), 0.22 Ͻ
∆ρ Ͻ –0.31 eÅ–3.
4-Isobutoxy-8-(3-phenylureido)quinoline-2-carboxylic Acid Hexyl-
amide (1d): A solution of 8-amino-4-isobutoxyquinoline-2-car-
boxylic acid hexylamide (4a; 0.22 g, 0.59 mmol, 1.0 equiv.) and
phenyl isocyanate (0.11 g, 0.89 mmol, 1.5 equiv.) in chloroform
(30 mL) was heated at reflux for 3 h. After cooling to room tem-
perature, the solvent was removed in vacuo. After column
chromatography (silica gel, CH2Cl2), 1d was obtained as a yellow
solid. Yield: 0.15 g (0.32 mmol, 56%). M.p. 153 °C. 1H NMR
(300 MHz, CDCl3): δ = 9.83 (s, NH), 8.76 (d, J = 7.2 Hz, 1 H),
8.35 (s, NH), 7.81 (d, J = 7.7 Hz, 1 H), 7.76 (s, 1 H), 7.54 (t, J =
8.03 Hz, 1 H), 7.35 (d, J = 7.7 Hz, 2 H), 7.15 (t, J = 7.67 Hz, 2 H),
6.96 (t, J = 7.15 Hz, 1 H), 3.94 (d, J = 6.43 Hz, 2 H), 2.22 (m, 1
H), 1.35 (m, 3 H), 1.07 (d, J = 6.70 Hz, 6 H), 0.73 (m, 4 H), 0.51
(m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.0, 163.7,
163.4 (2 C), 137.4, 136.3, 131.6, 128.8 (2 C), 128.2, 121.9, 113.9,
100.2, 98.6, 75.2, 40.4 (2 C), 31.3, 30.5, 29.2, 28.1, 26.7, 22.3, 19.1
Acknowledgments
Financial support by the DFG, the Fonds der Chemischen Indus-
trie, COST D31, and the Academy of Finland (proj. no. 205729;
K. R. and L. R.) is gratefully acknowledged. We thank Prof. E.
Weinhold and M. Bahr for their help with the fluorescence spec-
troscopy.
[1] a) I. Stibor (Ed.), Topics in Current Chemistry Vol. 255: Anion
Sensing, Springer, Heidelberg, 2005; b) P. D. Beer, P. A. Gale,
Angew. Chem. 2001, 113, 502; Angew. Chem. Int. Ed. 2001, 40,
486; c) A. Bianchi, K. Bowman-James, E. Garcia-Espana
(Eds.), Supramolecular Chemistry of Anions, Wiley-VCH, New
York, 1997; d) K. Gloe (Ed.), Macrocyclic Chemistry, Springer,
Berlin, 2005.
(2 C), 14.2, 13.7 ppm. IR (KBr): ν = 3328 (m), 2958 (m), 2929 (m),
˜
[2] S. M. Rowe, S. Miller, E. J. Sorscher, New Engl. J. Med. 2005,
2869 (m), 1642 (m), 1602 (m), 1531 (vs), 1499 (m), 1440 (m), 1418
(m), 1315 (s), 1269 (w), 1198 (m), 1072 (m), 1014 (m), 966 (w), 894
(w), 754 (m), 696 (m) cm–1. MS (EI, 70 eV): m/z (%) = 462 (7) [M,
C27H34N4O3]+, 370 (100) [C21H30N4O2]+, 343 (18) [C20H29N3O2]+,
314 (30) [C19H28N3O]+, 242 (9) [C15H20N3]+, 216 (24)
[C12H20N2]+, 185 (14) [C10H5N2O2]+, 159 (7) [C9H5NO2]+, 100 (5)
[C8H4]+. C27H34N4O3·1/4H2O (467.09): calcd. C 69.43, H 7.44, N
11.99; found C 69.42, H 7.26, N 11.95.
352, 1992.
[3] K. Bowman-James, Acc. Chem. Res. 2005, 38, 671.
[4] R. Herges, A. Dikmans, U. Jana, F. Köhler, P. G. Jones, I. Dix,
T. Fricke, B. König, Eur. J. Org. Chem. 2002, 3004.
[5] a) G. Müller, J. Riede, F. P. Schmidtchen, Angew. Chem. 1988,
100, 1574; Angew. Chem. Int. Ed. Engl. 1988, 27, 1516; b) A.
Metzger, V. M. Lynch, E. V. Anslyn, Angew. Chem. 1997, 109,
911; Angew. Chem. Int. Ed. Engl. 1997, 36, 862; c) C. Schmuck,
Chem. Commun. 1999, 843; d) C. Schmuck, Chem. Eur. J. 2000,
6, 709; e) R. Martinez-Manez, F. Sancanon, Chem. Rev. 2003,
103, 4419; f) J. Yoon, S. K. Kim, N. J. Singh, K. S. Kim, Chem.
Soc. Rev. 2006, 35, 355.
[6] a) P. J. Gale, J. L. Sessler, V. Kral, V. Lynch, J. Am. Chem. Soc.
1996, 118, 5140; b) F. P. Schmidtchen, Org. Lett. 2002, 4, 431;
c) J. L. Sessler, D. E. Gross, W.-S. Cho, V. M. Lynch, F.-P.
Schmidtchen, G. W. Bates, M. E. Light, P. A. Gale, J. Am.
Chem. Soc. 2006, 128, 12281; d) J. M. Llinares, D. Powell, K.
4-Isobutoxy-8-(3-phenylureido)quinoline-2-carboxylic Acid Phenyl-
amide (1e): A solution of 4-isobutoxy-8-aminoquinoline-2-car-
boxylic acid phenylamide (4b; 0.2 g, 0.6 mmol, 1.0 equiv.) and
phenyl isocyanate (0.1 g, 0.9 mmol, 1.5 equiv.) in dichloromethane
(30 mL) was heated at reflux for 1 d. After cooling to room tem-
perature, the solvent was removed in vacuo. After column
chromatography (silica gel, CH2Cl2), 1e was obtained as a white
Eur. J. Org. Chem. 2007, 2850–2858
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2857

M. Albrecht et al.
FULL PAPER
Bowman-James, Coord. Chem. Rev. 2003, 204, 57; e) K. Kaval-
lieratos, S. R. de Gala, D. J. Austin, R. H. Crabtree, J. Am.
Chem. Soc. 1997, 119, 2325; f) K. Kavallieratos, C. M. Bertao,
R. H. Crabtree, J. Org. Chem. 1999, 64, 1675; g) P. A. Gale,
Acc. Chem. Res. 2006, 39, 465.
M. Albrecht, Triyanti, M. de Groot, M. Bahr, E. Weinhold,
Synlett 2005, 2095.
a) H. Jiang, J.-M. Leger, P. Guionneau, I. Huc, Org. Lett. 2004,
6, 2985; b) H.-Y. Hu, C.-F. Chen, Tetrahedron Lett. 2006, 47,
175.
M. Albrecht, K. Witt, E. Wegelius, K. Rissanen, Tetrahedron
2000, 56, 591.
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratch-
ian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C.
Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dap-
prich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick,
A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q.
Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin,
D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayak-
kara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Revision
D.02, Gaussian, Inc., Wallingford, CT, 2004.
[7]
[8]
[9]
[10]
H. Jiang, J.-M. Leger, C. Dolain, P. Guionneau, I. Huc, Tetra-
hedron 2003, 59, 8365.
[16] S. F. Boys, F. Bernardi, Mol. Phys. 1970, 19, 553.
[17] A. E. Reed, L. A. Curtiss, F. Weinhold, Chem. Rev. 1988, 88,
899.
[18] E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold,
NBO 3.0 Program Manual, Theoretical Chemistry Institute
and Department of Chemistry, University of Wisconsin, Madi-
son, Wisconsin.
[19] V. Amendola, M. Bonizzoni, D. Esteban-Gomez, L. Fabbrizzi,
M. Licchelli, F. Sancenon, A. Taglietti, Coord. Chem. Rev.
2006, 250, 1451.
[20] M. Hassani, W. Cai, D. C. Holley, J. P. Lineswala, B. R. Mah-
arjan, G. R. Ebrahimian, H. Seradj, M. G. Stocksdale, F. Mo-
hammadi, C. C. Marvin, J. M. Gerdes, H. D. Beall, M. Behfor-
ouz, J. Med. Chem. 2005, 48, 7733.
[11] a) P. Roychowdury, P. N. Das, B. S. Basak, Acta Crystallogr.,
Sect. B 1978, 34, 1047; b) T. Banerjee, N. N. Saha, Acta Crys-
tallogr., Sect. C 1986, 42, 1408; c) M. Albrecht, K. Witt, R.
Fröhlich, O. Kataeva, Tetrahedron 2002, 58, 561.
[12] a) K. A. Connors, Binding Constants, Wiley, New York, 1987;
b) C. S. Wilcox in Frontiers in Supramolecular Chemistry and
Photochemistry (Eds.: H.-J. Schneider, H. Dürr), Wiley-VCH,
Weinheim, 1991, p. 123.
[13] A. Tejeda, A. I. Oliva, L. Simon, M. Grande, M. C. Caballero,
J. R. Moran, Tetrahedron Lett. 2000, 41, 4563.
[14] O. S. Wolfbeis, Fluorescence Spectroscopy: New Methods and
Applications, Springer, Berlin, 1993.
[15] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr, T. Vreven,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
[21] G. M. Sheldrick, SHELXTL 6, Bruker AXS Inc., Madison,
Wisconsin, USA.
Received: February 13, 2007
Published Online: April 17, 2007
2858
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2850–2858