Fluorescent anion sensing by bisquinolinium pyridine-2,6-dicarboxamide receptors in water

Article abstract of DOI:10.1039/c3ra44363a

Dicationic N-methylated at quinolyl moieties derivatives of three isomers of N,N′-bis(quinolyl)pyridine-2,6-dicarboxamide, and respective N-methyl quinolinium benzamides as reference compounds, have been prepared and characterized by crystal structures, s

Full text of DOI:10.1039/c3ra44363a

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Fluorescent anion sensing by bisquinolinium
pyridine-2,6-dicarboxamide receptors in water†
Cite this: RSC Adv., 2014, 4, 455
Alejandro Dorazco-Gonzalez,a Marcos Flores Alamo,b Carolina Godoy-Alcantar,c
´
´
c
b
*
Herbert Hopfl and Anatoly K. Yatsimirsky
¨
Dicationic N-methylated at quinolyl moieties derivatives of three isomers of N,N0-bis(quinolyl)pyridine-
2,6-dicarboxamide, and respective N-methyl quinolinium benzamides as reference compounds, have
been prepared and characterized by crystal structures, spectral and acid–base properties in water. First
pKa values of dicarboxamides between 8.1 and 9.3 determined spectrophotometrically are unusually low
for amides. Dicarboxamide derivatives of 3- (1) and 6-aminoquinoline (2) undergo efficient fluorescence
quenching by halide, acetate, pyrophosphate and nucleotide anions but the derivative of
5-aminoquinoline (3) shows very small quenching effects. The shape of Stern–Volmer plots for
dicarboxamides indicates the existence of ground state complexation with anions, which is absent for
related benzamides. Association constants, KA, with anions were calculated from analysis of
concentration profiles of the quenching effects on the fluorescence of 1 and 2. Quenching by
nucleoside triphosphates is much more efficient than by inorganic anions. Efficient binding of even
simple inorganic anions by neutral amide N–H donors in water is attributed to high acidity of amides and
preorganized rigid structure of the receptors.
Received 14th August 2013
Accepted 4th October 2013
DOI: 10.1039/c3ra44363a
www.rsc.org/advances
the system prompted us to test their anion recognition prop-
erties in water. In order to have receptors with more advanced
Introduction
optical properties potentially suitable for sensor applications we
have prepared for this study the analogous compounds 1–3 with
uorescent quinolinium instead of pyridynium groups, Scheme
1. Also, a series of respective quinolinium benzamides 4–6 was
prepared as reference compounds lacking the bisamide poten-
tial anion binding site.
Among these receptors compound 1 was reported previously
as selective G-quadruplex ligand.6 It also was structurally char-
acterized and studied as an anion receptor in MeCN where it
showed high selectivity toward chloride.5 The purpose of
preparing additional isomeric compounds 2 and 3 with differ-
ently positioned N–Me+ center in respect to the amide group
was to modify the electronic and optical properties of the
receptors in order to optimize their function.
Anion recognition by H-bond donor receptors is mostly
restricted to non-aqueous media.1,2 This seriously limits their
practical applications as sensors or selectors and for this reason
the search for receptors capable to function in water is an
important current trend in this area.3,4 Recently we reported
highly efficient anion recognition by dicationic N-methylated at
pyridyl moieties derivatives of N,N0-bis(pyridyl)pyridine-2,6-
dicarboxamide in MeCN.5 Tight and selective anion binding by
these receptors was achieved by the presence of two convergent
and strongly acidied amide NH donors, which in principle
may operate also in water. The positive charge of receptors is
strongly delocalized and does not contribute signicantly to the
observed affinity even in low polar acetonitrile solvent,5 but
makes the receptors sufficiently water soluble. These features of
Quinolinium derivatives nd many applications in sensing
and molecular recognition. They are used as intercalators,7
uorescent pH-sensors,8,9 signaling components of receptors
for antibiotics,10 proteins,11 heparin,12 saccharides,13 uoride
and cyanide ions.14 Perhaps the most important application is
using them as uorescent indicators for measurement of
intracellular chloride concentration based on dynamic
quenching of quinolinium uorescence by chloride.15,16 Both
selectivity and sensitivity of this method could be improved by
adding to quinolinium ions the receptor properties toward
chloride. Recently reported tripodal tris-quinolinium receptors
designed for this purpose indeed show markedly increased
a
´
´
Centro Conjunto de Investigacion en Quımica Sustentable, UAEM-UNAM, Carretera
´
´
Toluca-Atlacomulco Km 14.5, C. P. 50200, Toluca, Estado de Mexico, Mexico
b
´
´
´
´
Facultad de Quımica, Universidad Nacional Autonoma de Mexico, 04510 Mexico D.F.,
´
Mexico. E-mail: anatoli@unam.mx; Fax: +52 55 5616 2010; Tel: +52 55 5622 3813
c
´
´
Centro de Investigaciones Quımicas, Universidad Autonoma del Estado de Morelos,
´
Av. Universidad 1001, C.P. 62209 Cuernavaca, Mexico
† Electronic supplementary information (ESI) available: Crystallographic data for
compounds 2–6; absorption spectra of compounds 1–6 at pH 6.5; superimposed
Stern–Volmer plots for 1 and 4 at pH 6.5; quenching data and Stern–Volmer
constants for 3 and 6; spectrophotometric titration of 1 with ATP; 1H and 13C
NMR spectra of compounds 2–6. CCDC 941790–941794. For ESI and
crystallographic data in CIF or other electronic formats see DOI:
10.1039/c3ra44363a
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Scheme 1 Pyridine-2,6-dicarboxamide receptors and respective N-quinolyl benzamides employed in this study.
quenching by anions in MeCN,17,18 but the effect disappears in between the pyridine plane and the planes of le and right
water,18 and this is what typically happens with hydrogen- quinolinium rings are 9.6ꢁ and 11.52ꢁ respectively; they
bonding receptors when you attempt to use them in aqueous become 38.61ꢁ and 11.47ꢁ in 2 and nally 39.48ꢁ and 31.12ꢁ in
solutions.
3. The binding of anions in these receptors is expected to
In this paper we demonstrate that receptors 1–3 conserve occur via hydrogen bonding to N–H proton donors of amide
reduced, but still noticeable, affinity to anions in water with the groups and to ortho-C–H donors of cationic aromatic rings.5
same selectivity to chloride among halide anions as in MeCN Obviously the C–H bonds have the optimum orientation for
and show fairly strong binding to nucleoside triphosphate intracavity anion binding when the quinolinium rings are co-
anions. The positional isomers appeared to possess signi- planar with the pyridine dicarboxamide fragment as in 1,
cantly different conformations strongly affecting both spectral which is therefore the most preorganized receptor for small
and recognition properties of the receptors.
spherical anions like chloride.
This loss of co-planarity seems to be principally electronic
rather than steric effect. This conclusion is supported by
comparison with crystal structures of simple benzamides 4–6 as
shown in Fig. 2. Like in the case of dicarboxamides, quinoli-
nium rings are progressively less co-planar with amide groups
on going from 3- to 6- and to 5-aminoquinoline isomers. Thus
the angles between the planes of amide and quinolinium
groups are 11.21ꢁ for 4, 24.50ꢁ for 5 and 32.66ꢁ for 6. Such
variability is not unusual for benzamides: dihedral angles
between aromatic groups in reported structures of N-aryl
Results and discussion
Structures and acid–base properties of receptors
Iodide salts of 1–3 were prepared by reacting 2,6-pyr-
idinedicarbonyl dichloride with respective isomers of amino-
quinoline and subsequent prolonged treatment with MeI under
reux. The respective triates were obtained by treatment with
silver triate in MeCN. Compounds 4–6 were prepared similarly
with benzoyl chloride instead of 2,6-pyridinedicarbonyl
dichloride as the acylating reagent.
Crystal structures were determined for the triates of 2, 3,
4, 6, and iodide of 5 (Table 1S, ESI†). The crystal structures of
dicationic receptors 1–3 are shown in Fig. 1. In all dications
amide groups are coplanar with the central pyridine ring and
their N–H bonds are turned inside the cle toward each
other. The distances between the protons increases from
˚
˚
˚
2.953 A in 3 to 3.131 A in 1 and to 3.207 A in 2. Counter-ion
binding involves multiple short contacts/H-bonds with N–H
and C–H donors in the case of 1, only N–H donors for 3, and
in the case of 2, the cle between amide groups is lled with a
cluster of 3 water molecules to which the counter-ions are
bound. The properties of amide group are essentially the
same in all three isomers with average C–N bond length
˚
1.356 ꢀ 0.008 A corresponding to the length of Csp2–Nsp2
19
˚
bond 1.355 A. The most signicant structural difference in
this series of receptors is the progressive loss of co-planarity
between the central pyridine dicarboxamide structure and
Fig. 1 Perspective views of the molecular structures of triflates of 1–3.
The structure of 1 was reported previously5 and is shown for
N-methyl quinolinium rings. In compound 1 the angles comparison with other isomers.
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Fig. 2 Perspective views of the molecular structures of triflates of 4 and 6 and of iodide of 5.
benzamides vary from nearly 0 to as large as 80ꢁ, although no statistical factor. Second pKa values expectedly are higher, but
general trend has been established yet.20
still are rather low for amide groups.
The acid dissociation constants of 1–6 were determined by
Fluorescence spectra of 1–6 are shown in Fig. 4a and the
UV-vis and uorometric pH-titrations. Absorption maxima of respective emission maxima are given in Table 1. In the series of
1–6 at pH 6.5 collected in Table 1 (Fig. 1S in ESI† shows the benzamides the emission maxima are shied to longer wave-
complete spectra) are in the range typically observed for qui- lengths with concomitant decrease in the uorescence intensity
nolinium salts.8 A long wavelength absorption band around on going from 4 to 5 and to 6. The latter can be attributed to the
340–350 nm observed in some of compounds 1–6 as a shoulder progressive increase in the dihedral angle between quinoline
is attributed to n / p* transition.8 On increasing pH the and amide groups causing increased intramolecular charge
absorbance at shorter wavelengths decreases while that at transfer quenching. A similar although less pronounced trend
longer wavelengths it increases for all compounds. Fig. 3 shows is observed for dicarboxamides 1–3.
as an example of the results for 1 and 4. In the case of 4 all
The pH-proles of uorescence intensity are shown in
spectra pass through four clear isosbestic points indicating the Fig. 4b. For monoamides 4 and 6 one observes essentially the
co-existence of only two differently absorbing species, initial same pKa values as from spectrophotometric titrations (Table
cationic amide and its deprotonated zwitter-ionic form (Scheme 1), but in the case of 5 besides one pKa in basic range of pH,
2). In the case of 1 there are no strict isosbestic points indicating which is close to spectrophotometrically determined pKa, one
more than two differently absorbing species at equilibrium. observes an additional 4.6 units lower pKa in a neutral solution
Indeed, for a bisamide one expects two consecutive deproto- (Table 1). Such a situation indicates deprotonation of the
nation processes (Scheme 2) generating differently absorbing excited state of the uorophore, which is a stronger acid than its
mono- and diprotonated forms.
ground state.22 This second pKa cannot be considered as a true
Insets in Fig. 3a and b illustrate the tting of the proles of excited state pKa* however because in neutral solutions
absorbances at a single wavelength vs. pH to the respective the concentration of protons is too low to protonate back the
theoretical equations and Table 1 collects the pKa values deprotonated form of the excited state during its lifetime and
calculated from the tting procedure. Monoamides 4–6 are the equilibrium cannot be achieved.22 Thus the observation of a
more acidic than ordinary amides due to strong electron second reduced pKa in uorometric titration prole just indi-
accepting effect of the quinolinium group. Calculated with ACD cates a signicant acidication of 5 in the excited state leading
soware,21 pKa values 8.89; 10.84 and 10.14 for 4, 5 and 6, to its partial quenching due to the excited state proton transfer.
respectively, are not too far from the experimental values and In all cases the deprotonated forms of the amides are not
follow a similar trend 4 < 6 < 5. First pKa values of dicarbox- uorescent.
amides 1–3 are even lower due to stronger electron accepting
The uorometric titrations of bisamides 1–3 are consistent
properties of pyridyl as compared to phenyl group and to a with two consecutive pKa values, which are approximately 2
Table 1 Absorption and emission maxima (nm) at pH 6.5 and pKa values of compounds 1–6 in water (the number in parentheses is the standard
error in the last significant digit)
UV-vis titrations
Fluorometric titrations
labs (log 3)
lem
pKa1
pKa2
pKa1
pKa2
1
2
3
4
5
6
275 (4.59); 344 (4.10)
270 (4.54); 342 sh (3.85)
239 (4.71); 319 (4.08); 340 sh (3.64)
243 (4.50); 270 (4.52); 347 (3.87)
268 (4.54); 324 (3.76); 350 sh (3.62)
239 (4.54); 319 (3.86); 340 sh (3.63)
403
453
515
405
461
533
9.17a
8.1(1)
9.29(8)
10.56(3)
12.25(2)
10.65(3)
11.5a
11.18(2)
11.40(5)
7.61(4)
7.55(2)
7.31(4)
10.33(2)
7.22(8)
10.63(2)
9.41(6)
10.25(5)
9.59(8)
11.82(9)
a
Ref. 5.
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Fig. 3 UV-vis pH titration of 0.02 mM 1 (a) and 4 (b).
Anion quenching and complexation studies
Interactions of receptors 1–6 with anions were studied by uo-
rometric titrations because the spectrophotometric response to
anion binding was very weak. As a rst step simple inorganic
anions were tested. No interaction was observed with sulfate,
nitrate, phosphate and perchlorate anions at concentrations up
to 0.05 M. Halide anions, pyrophosphate (PPi) and acetate in
most cases induced noticeable quenching.
Quenching effects of inorganic anions and acetate on the
uorescence of 1 and 4 (inset) are shown in Fig. 5a in Stern–
Volmer coordinates (I0/I vs. quencher concentration, where I0
Scheme
compounds.
2 Acid dissociation equilibria for mono and bisamide
units smaller than those determined by spectrophotometric and I are the uorescence intensities in the absence and in the
titrations (Table 1) indicating the excited state acidication of presence of the quencher, respectively). For the monoamide 4,
amide bonds for all isomers. The assignment of these apparent simple linear plots with the Stern–Volmer constant KSV given in
pKa values is rather uncertain. The only clear conclusion is that Table 2 were observed. The KSV values follow the typꢂical for
below pH 7 all receptors are in dicationic non-dissociated form quinolinium salts in the order Fꢂ ꢃ Clꢂ < Brꢂ < Iꢂ > AcO .23 The
both in ground and excited states and for this reason their plot for iodide shows a very small upward curvature (see Fig. 2S
interactions with anions were studied at pH 6.5.
in ESI† for an extended plot) observed when both dynamic and
Fig. 4 (a) Fluorescence emission spectra of 5 mM 1–6 at pH 6.5 (excitation at 350 nm); (b) pH-titration profiles observed at emission maximum of
each compound.
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Fig. 5 Stern–Volmer plots for quenching of fluorescence by inorganic anions and acetate at pH 6.5 (a) for 1 and 4 (inset) (excitation at 350 nm,
emission at 400 nm), (b) for 2 and 5 (inset) (excitation at 350 nm, emission at 400 nm).
attributed to a statistical factor since 1 contains two quinoli-
nium groups. Interactions with pyrophosphate (PPi), Clꢂ and
AcOꢂ show different features, however (Fig. 2S in ESI† shows
superimposed plots for 1 and 4, which makes the differences
more evident). The quenching plots are downwardly curved at
low concentrations, but become linear at higher concentrations
of anions. The proles of this type are oen observed for
compounds possessing uorophores of different accessibility to
the quencher, e.g., tryptophan residues in different positions in
a protein,24 but for a single uorophore it indicates simulta-
neous dynamic and static quenching when the ground state
complexation does not quench the uorescence completely and
the uorophore–quencher complex still possesses some
reduced by a factor r uorescence intensity.17 The respective
equation takes the form of eqn (2).17 Parameters found by tting
the results to eqn (2) are given in Table 2.
Table 2 Binding and quenching parameters for receptors 1–6 with
inorganic anions and acetate at pH 6.5 (relative errors less or equal
ꢀ10%)
1
Anion KA
F
2
3
4
5
6
KSV
r
KA
KSV
r
KSV KSV KSV KSV
0.3(1)
52
4.4
6.3 0.57
3.6
0
0.68 18
0
6.1 2.5
Cl
120 12
0.64
110
1000 150
180
690
510
17 2.4
34 57
0
0.93
Br
I
18 87
130 36a 100 21
0
PPi
AcO
300 11
210 4.8
0.62
0.82
6
13
0.65
21 4.9b
0
3.0
0.68 7.4 5.0 12
a
b
KA ¼ 7.2 Mꢂ1
.
KA ¼ 106 Mꢂ1, r ¼ 0.81.
static quenching contribute simultaneously to the observed
effect.24 The respective equation for the quenching effect takes
in this case the form (1) where [Q] is the quencher concentration
and KA is the ground state association constant of the quencher
with the uorophore.
I0 ð1 þ KA½QꢄÞð1 þ KSV½QꢄÞ
¼
(2)
I
1 þ rKA½Qꢄ
Eqn (2) is approximate because it assumes similar quench-
ing with a single KSV value for both free and complexed forms of
the uorophore as well as equal rates of photoexcitation of free
and complexed forms. A more exact equation can be found in
ref. 27 but it contains larger number of adjustable parameters,
which cannot be reliably determined from the tting of plots
like those shown in Fig. 5. Another limitation of eqn (2) is that
when r ¼ 1 it takes the form of classical Stern–Volmer eqn (3)
and the association constant cannot be calculated. In practice
we found that already with r > 0.9 the tting to eqn (2) gives very
large relative errors in KA and KSV exceeding 100% and in such
cases (e.g., quenching of 1 by Brꢂ) the results were tted to eqn
(3). Thus the association constant can be reliably calculated
only if the static quenching is sufficiently strong, that is more
than by 10%.
I0/I ¼ (1 + KSV[Q])(1 + KA[Q])
(1)
Fitting of the plot in Fig. 5a for 4 and Iꢂ gives a small asso-
ciation constant KA ¼ 7.2 Mꢂ1, which can be attributed to weak
ion pairing of iodide with the quinolinium cation by analogy
with known weak association of voluminous anions with
quaternary ammonium cations in water driven by the hydro-
phobic effect.25 In addition there may be some contribution
from a charge-transfer interaction reported for Iꢂ and N-alkyl-
pyridinium cations.26
The quenching of 1 by Brꢂ and Iꢂ has the same character-
istics as that of 4. With Brꢂ one observes a simple linear plot
with increased KSV and with Iꢂ an upwardly curved plot, which
follows eqn (1) with also increased KSV and KA values. All
constants increase by a factor of about 2, which can be
I0/I ¼ (1 + KSV[Q])
(3)
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The dynamic quenching of quinolinium salts by anions stable complexes with basic acetate and pyrophosphate anions
reected in the Stern–Volmer constant takes place through and among halides prefers larger bromide over smaller chloride
various mechanisms, such as intersystem crossing and charge- anion.
transfer quenching.28,23 The static quenching is related to
The behavior of the last isomer 3 was rather unexpected. It
complex formation of anions with dicarboxamide receptors, does not show any quenching by Clꢂ and PPi, very weak
which occurs via hydrogen bonding to NH and aromatic CH quenching by Brꢂ and no indication of complex formation with
proton donors,5 as outlined in Scheme 3. It has been proposed anions (Fig. 3Sa, Table 2S, ESI†). Since its monoamide analog
for several analogous systems that bind in such a way that 6 also shows very weak anion quenching (Fig. 3Sb, Table 2S,
anions induce quenching by promoting the intramolecular ESI†), this behavior seems to be caused by electronic rather than
photoinduced electron transfer (PET) from the electron donor possible conformational effects.
atoms of a substituent involved in hydrogen bonding to the
Previously reported anion complexation by 1 in MeCN shows
anion to the excited state of the uorophore.29 The effect can be a similar selectivity (Fꢂ < Clꢂ > Brꢂ ꢅ Iꢂ < AcOꢂ), but much
interpreted as a consequence of increased negative charge on higher affinity with KA values in the range of 104–106 Mꢂ1
.
5
the amide groups due to the shi of the proton inside the anion- However, being rather modest the association constants of
HN hydrogen bond toward the anion and is in line with the monoanions with 1 and 2 in water are signicantly larger and
observation of total uorescence quenching induced by show different trends than those reported for these anions with
complete deprotonation of the receptor (see above). Also typical simple organic dications such as diprotonated polyamines.30
for this mechanism is a very small complexation-induced For instance, KA values or Fꢂ, Clꢂ and AcOꢂ with diprotonated
change in the absorption spectrum of the receptor.29 The effi- ethylenediamine, 1,4-diaminobutane and spermidine extrapo-
ciency of this complexation-induced quenching is expressed in lated to zero ionic strength show little variation with the poly-
terms of parameter r in eqn (2): the smaller r values correspond amine structure and are equal on average to 100, 4 and 20 Mꢂ1
.
to a stronger quenching. A general mechanism of complexation Binding of Brꢂ and Iꢂ was not detected. These data correspond
and quenching phenomena in this system is outlined in the to a “normal” order of affinity Fꢂ > AcOꢂ > Clꢂ > Brꢂ > Iꢂ
Scheme 3.
determined by size and basicity of anions, but with receptors 1
Fig. 5b shows similar data for quenching of 2 and 5. Again and 2 we see much higher binding constants with clear peak
quenching of the monoamide 5 follows simple linear depen- selectivity for Clꢂ and Brꢂ among halides, which have a similar
dence, but for the dicarboxamide 2 one observes with Clꢂ, Brꢂ, affinity as acetate. More basic and highly negatively charged
AcOꢂ and PPi non-linear plots indicative of complexation with pyrophosphate forms expectably very stable complexes with
these anions. With the most basic PPi some curvature is dications of polyamines with KA values about 105 Mꢂ1 30 but has
,
observed even for 5. Receptor 2 differs from 1 in two aspects: it just a bit larger affinity to 1 and 2 than acetate clearly illus-
is more acidic (see Table 2) and has a larger and more open trating the minor contribution of simple Coulombic attraction
cavity (see Fig. 1). In line with these features it forms more to association free energy with these receptors. Thus binding of
anions to dicarboxamide receptors is governed by the amount to
which they complement the receptor cle rather than by
electrostatics.
Relatively high affinity of receptors 1 and 2 to PPi prompted
us to study interaction of these receptors with nucleotide
triphosphates. For comparison also di- and monophosphates
were included. The results are shown in Fig. 6a and b.
The quenching efficiency of nucleotides toward dicarbox-
amide receptors 1 and 2 is much larger than that of similarly
charged pyrophosphate and also it is much larger than that
toward monoamides 4 and 5. Another important aspect is that
for quenching of 1 and 2 one observes non-linear Stern–Volmer
plots indicative of complex formation, but the quenching of 4
and 5 follows a linear dependence. These qualitative observa-
tions clearly show the importance of both dicarboxamide
structure of the receptor and the presence of a nucleobase for
nucleotide recognition. For the quantitative analysis the results
for 1 and 2 were tted to the eqn (2) and the tting parameters
are collected in Table 3 together with KSV values for receptors 4
and 5.
Analyzing the results for monoamides 4 and 5 one
observes that quenching by adenine nucleotides is approxi-
mately twice as strong as that by adenosine. This effect
can be attributed to electrostatic attraction of nucleotides
Scheme 3 Quenching mechanism of dicarboxamide receptors by
anions.
to cationic uorophore. The quenching efficiency for
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Fig. 6 Stern–Volmer plots for quenching of the fluorescence by nucleotides and adenosine at pH 6.5 (a) for 1 and 4 (inset), (b) for 2 and 5 (inset).
Therefore with KA ¼ 5400 Mꢂ1 and r ¼ 0.25 for ATP the
Table 3 Binding and quenching parameters for receptors 1, 2, 4 and 5
with nucleotides at pH 6.5. (Relative errors less or equal ꢀ10%)
additional contribution to quenching will be equal to 4000
Mꢂ1, which represents a 40-fold increase in the quenching
efficiency as compared to that for 4. The nucleobase selec-
tivity both in dynamic and static quenching of 1 is the same
as in the case of 4, G > A > C. In the series of adenine
nucleotides the quenching efficiency decreases in the order
ATP > ADP > AMP. For AMP the Stern–Volmer plot is linear,
but signicantly larger KSV for AMP than for adenosine as
well as for AMP and 4 indicates that some binding between
AMP and 1 should occur.
1
2
4
5
KSV
Anion
KA
KSV
r
KA
KSV
r
KSV
GTP
CTP
ATP
ADP
AMP
Ade
5500
2100
5400
1600
160
36
130
150
470
94
0.20
0.35
0.25
0.24
4700
1900
6000
4800
1600
200
21
190
570
380
180
0.21
0.44
0.17
0.64
0.72
120
—
74
83
75
32
230
28
180
120
105
62
a
a
To prove that the observed association is a true ground
state reaction and KA found from uorescence data is not
affected by possible excited state association,27 the binding
constant of ATP to 1 was determined also spectrophotomet-
Fluorescence enhancement was observed.
nucleotides with different nucleobases follows the order G >
A > C. Quenching by nucleobases proceeds via PET mecha-
nism31 and the relative quenching efficiency of nucleobases
depends on the direction of the electron transfer:31 when the
nucleobase serves as the electron acceptor the order is C > A >
G, but when the excited state of the uorophore serves as the
electron acceptor, which is more likely for quinolinium u-
orophores, the order is G > A > C as observed in our case. The
ground-state association oen observed between nucleo-
sides or nucleotides with aromatic compounds is not
detected at concentrations below 10 mM employed in these
experiments.
rically (Fig. 4S, ESI†) and a reasonably close value of KA
¼
6100 ꢀ 400 Mꢂ1 was obtained. The binding constant for ATP is
ca. 20 times larger and r value is 2.5 times smaller than those
for pyrophosphate. Both stronger binding and stronger static
quenching effect can be explained if adenine nucleobase can
interact with quinolinium rings of receptor simultaneously
with trapping of nucleotide phosphate by dicarboxamide cle
as sketched in Scheme 4. A bent conformation of ATP with
terminal phosphate positioned near adenine required for this
binding mode was found in some ATP–protein complexes.32 In
The dicarboxamide receptor 1 undergoes much stronger
quenching by nucleotides as compared to monoamide 4. For
instance, 5 mM ATP reduces the uorescence intensity of 4 by
a factor of 1.4, but the same effect with 1 is observed already
with 0.1 mM ATP. However, the dynamic quenching of 1
occurs with approximately the same efficiency, as is evident
from comparison of KSV values for both receptors. The
enhanced quenching can be attributed therefore to associa-
tion between 1 and nucleotides inducing strong static
quenching. It follows from eqn (2) that the initial slope of the
plot of I0/I vs. [Q] at low quencher concentration is given by
eqn (4).
Scheme
4
Proposed binding mode of ATP to dicarboxamide
d(I0/I)/d[Q] ¼ KSV + KA(1 ꢂ r)
(4) receptors.
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terms of this model higher quenching efficiency of ATP as
compared to ADP and AMP can result from better t of
terminal phosphate and nucleobase to the respective sites
of the receptor allowed by the longer polyphosphate chain of
ATP.
Similar behavior was observed with 2. Spectrophotometri-
cally determined KA ¼ 7200 ꢀ 600 Mꢂ1 for ATP is again
reasonably close to KA found from uorescence results (Table
3). We used this more soluble in water receptor also for 1H and
31P NMR studies of interaction with ATP. Fig. 7a shows the
aromatic region of 1H NMR spectra of 2, ATP and their
mixture. Evidently signals of both components undergo
signicant up-eld shis by 0.2–0.6 ppm in the mixture
indicating mutual contact of aromatic groups of host and
guest. A similar picture was observed, e.g., in 1H NMR spectra
of ATP complexes with acridine bearing macrocyclic poly-
amine receptors.33
Experimental section
Materials
Solvents were puried and dried using standard procedures.
Other reagents and components of buffer solutions MES, MOPS
and CHES all from Aldrich, were used as supplied. Buffer
solutions were prepared by adjusting pH of 0.01 M free acids
with concentrated NaOH to desired values.
N,N0-Di(3-N00-methylquinolinium)pyridine-2,6-dicarboxamide
triuoromethanesulfonate (1)
The compound was synthesized as was reported previously.5
N,N0-Di(6-N00-methylquinolinium)pyridine-2,6-dicarboxamide
triuoromethanesulfonate (2)
A mixture of 6-amino-quinoline (1.4 g, 9.50 mmol) and
Fig. 7b illustrates titration of ATP by 2 monitored by 31P 2,6-pyridinedicarbonyl dichloride (1.00 g, 4.75 mmol) in 40 mL
NMR. The signal, which belongs to terminal g-phosphate group of dry toluene was stirred under reux for 5 h. The yellow
of ATP undergoes a characteristic down-eld shi observed in precipitate was collected by ltration and washed with acetone
ATP complexes with polycations34,35,36a and attributed to a and 5% NaHCO3 solution to give N,N-bis-(6-quilonyl)pyridine-
decreased degree of protonation of the phosphate group (at pH 2,6-dicarboxamide (1.86 g) in 90% yield, which was reacted
6.5 ATP is present in a monoprotonated form) in the complex.34b with 10 equiv. of CH3I in DMF–acetone (1 : 1 v/v, 50 mL) for 1
Thus results of NMR titrations conrm the binding mode day. The resulting yellow powder was ltered and washed with
proposed in Scheme 4.
cold MeOH to give the iodide salt. The iodide salt (0.30 g, 0.42
There are many examples of receptors for nucleotide mmol) was dissolved in 200 mL of hot H2O then 2 equiv. of
recognition containing aromatic groups linked to proton- silver triate (0.22 g, 0.85 mmol) were added. The mixture was
ated polyazamacrocyles36 or other polycations37 operating stirred overnight at room temperature. The precipitate was
through simultaneous stacking interactions of nucleobases ltered off and the solvent was removed under reduced pres-
and electrostatic binding of phosphate moiety. A new feature sure to produce the product (0.28 g) in 90% yield. 1H NMR (300
of receptors 1 and 2 is that they provide for the binding of MHz, DMSO-d6) d 11.64 (s, 2H), 9.42 (d, J ¼ 5.6 Hz, 2H), 9.34 (d,
phosphate moiety neutral amide N–H donors working in J ¼ 8.4 Hz 2H), 9.22 (s, 2H), 8.67 (m, 4H), 8.55 (d, J ¼ 7.6 Hz,
water. Association constants of about 5 ꢆ 103 Mꢂ1 found 2H), 8.44 (t, J ¼ 7.6 Hz, 1H); 8.18 (dd, J ¼ 5.7 Hz, 2H), 4.67 (s,
with these receptors are of the same order of magnitude as 6H); 13C NMR (75 MHz, DMSO-d6) d 162.5, 148.6, 148.2, 146.4,
reported for, e.g., tetracationic anthracene derivatives37 or 140.6, 138.8, 135.4, 130.2, 129.7, 126.2, 122.8, 122.5, 120.1,
protonated azamacrocycles with incorporated dipyridine or 117.6, 45.3; MS (FAB, m/z) 598 [M + Tf]+; IR (KBr) 3330, 3088,
terpyridine fragments.36d
1685, 1539, 1251, 1223, 1154 cmꢂ1
;
anal. cal. for
Fig. 7 (a) The aromatic region of 1H NMR spectra of 2 mM 2 (top), and ATP (bottom, red peaks) and their 1 : 1 mixture at pH 6.5 in D2O; (b) 31
NMR spectra of 1 mM ATP alone (bottom) and in the presence of 1 equivalent of 2 in D2O at pH 6.5.
P
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N-(5-N0-methylquinolinium)benzamide
triuoromethanesulfonate (6)
C29H23F6N5O8S2 (747.643): C, 46.59; H, 3.10; N, 9.37. Found: C,
46.51; H, 3.12; N, 9.34.
It was obtained following the same procedure as for (4) from
5-aminoquinoline instead 3-aminoquinoline. The yields were
87%. 1H NMR (300 MHz, DMSO-d6) d 10.97 (s, 1H), 9.51 (d, J ¼
5.5 Hz, 1H), 9.27 (d, J ¼ 8.7 Hz, 1H), 8.51 (d, J ¼ 9.0 Hz, 1H), 8.32
(t, J ¼ 7.6 Hz, 1H), 8.13 (m, 4H), 7.64 (m, 3H), 4.66 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) d 166.7, 150.4, 143.5, 138.8, 136.4,
135.0, 133.6, 132.3, 128.5, 128.1, 126.2, 125.2, 122.8, 121.1,
118.5, 116.6, 45.8; MS (FAB, m/z) 263 [M]+; IR (KBr) 3298, 3114,
1675, 1517, 1358, 1247, 1224, 1148 cmꢂ1; anal. cal. for
N,N0-Di(5-N00-methylquinolinium)pyridine-2,6-dicarboxamide
triuoromethanesulfonate (3)
It was obtained following the same procedure as for 2 from
5-amino-quinoline instead of 6-amino-quinoline with 70%
yield. 1H NMR (300 MHz, DMSO-d6) d 11.78 (s, 2H), 9.57 (d, J ¼
5.5 Hz, 2H), 9.46 (d, J ¼ 8.6 Hz, 2H), 8.53 (m, 4H), 8.42 (m, 3H),
8.25 (m, 4H), 4.69 (s, 6H); 13C NMR (75 MHz, DMSO-d6) d 163.0,
150. 7, 148.0, 143.7, 140.4, 138.9, 135.4, 135.1, 127.0, 126.1,
125.5, 122.7, 121.4, 118.5, 117.5, 45.9; MS (FAB, m/z) 598 [M +
C
18H15F3N2O4S (412.4): C, 52.43; H, 3.67; N, 6.79. Found: C,
Tf]+; IR (KBr) 3275, 3097, 1684, 1517, 1241, 1160, 1027 cmꢂ1
;
52.48; H, 3.69; N, 6.76.
anal. cal. for C29H23F6N5O8S2 (747.64): C, 46.59; H, 3.10; N, 9.37.
Found: C, 46.57; H, 3.11; N, 9.35.
X-ray crystallography
Crystals of the triate salts of all compounds suitable for X-ray
diffraction were grown by slow evaporation from the MeOH–
water solutions (1 : 1 vol) except for the iodide salt 5 that was
grown from DMF solution.
Single-crystals of 2, 3 and 4 were studied with Oxford
Diffraction Gemini “A” diffractometer with a CCD area detector
N-(3-N0-methylquinolinium)benzamide
triuoromethanesulfonate (4)
A mixture of 3-aminoquinoline (1.0 g, 6.9 mmol) and benzoyl
chloride (0.49 g, 3.45 mmol) in 30 mL of dry toluene was
stirred under reux for 3 h. The white precipitate was
collected by ltration and washed with acetone and 5%
NaHCO3 to give N-(3-quinolinyl)benzamide in 92% yield,
which was reacted with 3 equiv. of CH3I in DMF–acetone
(1 : 1 v/v, 50 mL) for 1 day. The resulting yellow powder was
ltered and washed with cold MeOH–H2O to give the iodide
salt. The iodide salt (0.39 g, 1.0 mmol) was dissolved in 100
mL of hot H2O then one equiv. of silver triate (0.26 g, 1.0
mmol) was added, the mixture was stirred overnight at room
temperature. The precipitate was ltered off and the solvent
was removed under reduced pressure to produce the product
(0.38 g) in 92% yield. 1H NMR (300 MHz, DMSO-d6) d 11.32 (s,
1H), 9.87 (s, 1H), 9.38 (s, 1H), 8.48 (d, J ¼ 8.7 Hz, 2H), 8.18 (t,
J ¼ 6.2 Hz, 1H), 8.08 (d, J ¼ 7.0 Hz, 2H), 8.04 (m, 1H), 7.67 (m,
3H), 4.7 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 166.2, 144.8,
135.4, 134.1, 133.7, 133.3, 133.0, 132.8, 130.2, 129.8, 129.1,
128.8, 127.9, 122.8, 119.0, 118.5, 46.2; MS (FAB, m/z) 263 [M]+;
IR (KBr) 3343, 3098, 1681, 1550, 1373, 1262, 1151 cmꢂ1; anal.
cal. for C18H15F3N2O4S (412.4): C, 52.43; H, 3.67; N, 6.79.
Found: C, 52.38; H, 3.69; N, 6.75.
˚
(lCuKa ¼ 1.5418 A, monochromator: graphite) source equipped
with a sealed tube X-ray source. Unit cell constants were
determined with a set of 15/3 narrow frame/runs (1ꢁ in u) scans.
Data sets consisted of 1201, 671 and 1193 frames of intensity
data collected for 2, 3 and 4, respectively, with a frame width of
1ꢁ in u, and a crystal-to-detector distance of 55.00 mm. The
double pass method of scanning was used to exclude any noise.
The collected frames were integrated by using an orientation
matrix determined from the narrow frame scans.
CrysAlisPro RED soware packages38 were used for data
collection and data integration. Analysis of the integrated data
did not reveal any decay. Final cell constants were determined
by a global renement of 4291, 5594 and 6907 reections (q <
67.99ꢁ) for 2, 3 and 4, respectively. Collected data were corrected
for absorbance by using analytical numeric absorption correc-
tion39 using a multifaceted crystal model based on expressions
upon the Laue symmetry using equivalent reections.
Structure solution and renement were carried out with the
program SHELXS97.40 Full-matrix least-squares renement was
2
2 2
carried out by minimizing (Fo ꢂ Fc ) . All non-hydrogen atoms
were rened anisotropically. The H atoms of the water group
(H–O) and amine group (H–N) were located in a difference map
and rened isotropically with Uiso (H) ¼ 1.5 and 1.2 Ueq for (O)
N-(6-N0-methylquinolinium)benzamide
triuoromethanesulfonate (5)
It was obtained following the same procedure as for (4) from and (N), respectively. H atoms attached to C atoms were placed
6-aminoquinoline instead 3-aminoquinoline. The yields in geometrically idealized positions and rened as riding on
were 93%. 1H NMR (300 MHz, DMSO-d6) d 10.97 (s, 1H), their parent atoms, with C–H ¼ 0.93–0.98 A with Uiso (H) ¼ 1.2
˚
9.35 (d, J ¼ 5.7 Hz, 1H), 9.24 (d, J ¼ 8.5 Hz, 1H), 9.02 (s, 1H), Ueq (C) for aromatic groups, and Uiso (H) ¼ 1.5 Ueq (C) for methyl
8.51 (dd, J ¼ 9.0 Hz, 2H), 8.11 (t, J ¼ 5.9 Hz, 1H), 8.04 (d, J ¼ groups.
6.7 Hz, 2H), 7.61 (m, 3H), 4.60 (s, 3H); 13C NMR (75 MHz,
For single-crystals of 5 and 6, X-ray diffraction studies were
DMSO-d6)
d 166.4, 148.2, 146.3, 140.0, 132.3, 130.2, performed on a Bruker-APEX diffractometer with a CCD area
˚
129.3, 128.6, 127.9, 122.8, 122.3, 120.0, 118.5, 116.9, 45.2, detector (lCuKa ¼ 0.71073 A, monochromator: graphite). Frames
MS (FAB, m/z) 263 [M]+; IR (KBr) 3345, 3074, 1678, 1555, were collected at T ¼ 100 K via u/4-rotation at 10 s per frame
1251, 1237, 1226, 1160 cmꢂ1, anal. cal. for C18H15F3N2O4S (SMART).41a The measured intensities were reduced to F2 and
(412.4): C, 52.43; H, 3.67; N, 6.79. Found: C, 52.43; H, corrected for absorption with SADABS (SAINT-NT).41b Correc-
3.68; N, 6.75.
tions were made for Lorentz and polarization effects. Structure
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solution, renement, and data output were carried out with the
SHELXTL-NT program package.41c,d
Acknowledgements
Non-hydrogen atoms were rened anisotropically. C–H
hydrogen atoms were placed in geometrically calculated posi-
tions, using a riding model. O–H and N–H hydrogen atoms have
been localized by difference Fourier maps and rened xing the
We gratefully acknowledge the CONACyT (project no.101699)
´
for support of this work. Alejandro Dorazco-Gonzalez thanks
CONACyT for the repatriation fellowship.
˚
bond lengths to 0.84 and 0.86 A, respectively; the isotropic
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