Multiple Recognition of Barbiturate Guests by Hamilton-Receptor-Functionalized Dendrimers

Article abstract of DOI:10.1002/chem.200305461

The well-known unsubstituted "Hamilton receptor" was monofunctionalized with an amino group and attached at the periphery of poly(propyleneamine) dendrimers through the use of an activated ester. Four generations of Hamilton-receptor-functionalized dendri

Full text of DOI:10.1002/chem.200305461

FULL PAPER
Multiple Recognition of Barbiturate Guests by Hamilton-Receptor-
Functionalized Dendrimers
Anouk Dirksen,[a] Uwe Hahn,[b] Frank Schwanke,[b] Martin Nieger,[c] Joost N. H. Reek,[a]
Fritz Vˆgtle,*[b] and Luisa De Cola*[a]
Abstract: The well-known unsubstitut-
ed ™Hamilton receptor∫ was mono-
functionalized with an amino group
and attached at the periphery of poly-
(propyleneamine) dendrimers through
the use of an activated ester. Four gen-
erations of Hamilton-receptor-function-
alized dendrimers (HR-dendrimers)
were synthesized and characterized by
1H and 13C NMR spectroscopy and
MALDI-TOF mass spectrometry. The
photophysical properties of the HR-
dendrimers were investigated by UV/
Vis as well as with steady-state and
time-resolved fluorescence spectrosco-
py. The dendrimers were used as multi-
valent hosts for the barbiturate guests
Barbital (7) and [Re(Br)(CO)3(barbi-
bpy)] (8; barbi-bpy=5-[4-(4’-methyl)-
2,2’-bipyridyl]methyl-2,4,6-
the barbiturate guests 7 and 8 were in-
vestigated by 1H NMR spectroscopy
and photophysical methods. The bind-
ing constants of the barbiturate guests
for binding to reference compound 2
(with a single receptor unit) in chloro-
form were found to be 1.4î103 mÀ1 and
1.5î105 mÀ1 for 7 and 8, respectively.
Binding of 7 to the dendrimers enhan-
ces the weak emission of the Hamilton
receptor. This increase in emission is
also generation dependent; it was
found to be most pronounced in the
case of 2 and the least in the case of
the fourth-generation dendrimer 6. The
unexpected increase in the quantum
yield of emission from the HR-den-
drimers with increasing generation
could be caused by the rather rigid
conformation of the Hamilton recep-
tors in later-generation compounds,
which is a result of intramolecular ag-
gregation and steric hindrance at the
periphery of the dendrimer. The photo-
induced energy transfer from the excit-
ed state of the HR-dendrimers to the
lower-lying excited state of the guest 8
was used to probe the formation of
host guest complexes. The rate of
energy transfer was calculated to be
3.6î1010 sÀ1. Energy transfer in 2ꢀ8
only occurred in the presence of a
strong base, which shows that the basic
amine core in the HR-dendrimers is
crucial for this photoinduced process.
The binding of 8 to the dendrimers is
completely reversible: 8 can be ex-
changed with a competitive guest such
as 7 and the emission of the HR-den-
drimer is restored.
Keywords: barbiturate receptors ¥
(1H,3H,5H)-pyrimidinetrione).
The
dendrimers
¥
energy transfer
¥
stable adducts formed between the
dendritic architectures (the hosts) and
host guest systems ¥ rhenium
Introduction
An important area of supramolecular chemistry is the as-
sembly of multiple components in a predefined way to
[a] Dr. A. Dirksen, Dr. J. N. H. Reek, Prof. Dr. L. De Cola
Institute of Molecular Chemistry
Universiteit van Amsterdam, Nieuwe Achtergracht 166
1018 WV Amsterdam (The Netherlands)
Fax : (+31)20-5256454
enable them to perform specific functions, such as photoin-
18]
duced energy or electron transfer processes.[1
Generally,
self-assembly and molecular recognition involve the use of a
mono- or bifunctionalized host or guest. Multibinding
events within the same molecule are very rare in artificial
systems, especially when hydrogen bonds are used to glue
the complementary components together. Dendrimers have
E-mail: ldc@science.uva.nl
[b] Dr. U. Hahn, Dr. F. Schwanke, Prof. Dr. F. Vˆgtle
Kekulÿ-Institut f¸r Organische Chemie und Biochemie
der Universit‰t Bonn
Gerhard-Domagk Strasse 1, 53121 Bonn (Germany)
Fax : (+49)228-735662
E-mail: voegtle@uni-bonn.de
proven to be suitable supramolecular hosts for guest mole-
40]
cules.[19
As a result of their monodispersed, highly
[c] Dr. M. Nieger
branched three-dimensional structure, a microenvironment
is created within each dendrimer in which guest molecules
can be encapsulated through topological entrapment (hydro-
Institut f¸r Anorganische Chemie
der Universit‰t Bonn
Gerhard-Domagk Strasse 1, 53121 Bonn (Germany)
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DOI: 10.1002/chem.200305461
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2036 2047
34]
philic/hydrophobic interactions).[19
Such nonbonding in-
ular assemblies containing barbiturates, even in solvents that
compete for the receptor site.[54]
teractions are unspecific and even the encapsulation of sol-
vent molecules can be considered as a form of topological
entrapment.
Herein we report the synthesis and characterization of
four generations (Gx, x=1,2,3,4) of poly(propyleneamine)
dendrimers (3 6) substituted at the periphery with barbitu-
rate receptors, which we will call ™Hamilton receptors∫
(Scheme 2). We discuss the photophysical properties of the
Hamilton receptor itself in detail for the first time, as well
as the photophysical properties of the Hamilton-receptor-
functionalized dendrimers (HR-dendrimers).
Since dendrimers can be built up very regularly, it is possi-
ble to incorporate receptor sites into the core, into the
branches, or at the periphery.[19
40] These receptors might
24,35
recognize their targets based on acid base, electrostatic, or
hydrogen-bonding interactions. The organization of binding
sites in specific parts of a dendritic structure allows the for-
mation of multiple, stable host guest systems within one
molecule.
The creation of large structures that can selectively bind a
certain class of compounds contributes to the development
of artificial systems closely resembling those found in pro-
Two barbiturate derivatives were also prepared and were
studied as guests, namely Barbital[55] (7) and [Re(Br)(CO)3-
(barbi-bpy)] (8; barbi-bpy=5-[4-(4’-methyl)-2,2’-bipyridyl]-
methyl-2,4,6-(1H,3H,5H)-pyrimidinetrione),[53] which are
both able to form host guest complexes with the HR-den-
drimers, as depicted in Scheme 3. The binding constants for
binding of the barbiturate guests 7 and 8 to the Hamilton re-
43]
teins.[41
Particularly interesting are host guest systems in
which the binding of a guest can promote new functions,
such as energy, electron, and proton transfer processes. The
use of dendrimers containing multiple chromophoric units
or receptor sites is extremely appealing since there is a great
need for well-characterized systems in which it is possible to
simultaneously perform sensor functions and immobilize bi-
ological substrates.[44]
Herein we discuss poly(propyleneamine) ™POPAM∫ (also
called poly(propylenimine), or PPI)[24] dendrimers substitut-
ed at the periphery with receptors that can bind barbiturates
and their derivatives through six hydrogen bonds.[45] Such a
receptor, whose target binding is based on multiple hydro-
gen bonds and which contains 2,6-diaminopyridine, was in-
troduced in 1988 by Hamilton et al. (Scheme 1).[45]
1
ceptor could be determined by H NMR and fluorescence
spectroscopy, respectively.
Finally, we showed that the receptor itself can be used as
a chromophore and upon excitation can transfer energy to
the guest across hydrogen bonds. Compound 8 is very suita-
ble for this purpose as it has a triplet excited state, a metal-
to-ligand charge transfer state (3MLCT state), at lower
energy than the excited state of the Hamilton receptor. The
energy transfer process was studied by both steady-state and
time-resolved fluorescence spectroscopy.
Results and Discussion
Synthesis and characterization of the HR-dendrimers: Four
generations of HR-dendrimer were synthesized as shown in
Scheme 4.
In the first step of the synthesis, the hitherto unknown
monomeric receptor 12, which has an amino group at the 5-
position of the isophthalic acid unit, was prepared. This
functionalized receptor was subsequently allowed to react in
a 1:1:1 ratio with the diacid dichloride 14 and pentafluoro-
thiophenol (PTFE, 13). The PTFE ester 15 obtained by this
synthetic route was used instead of the free acid chloride to
ensure full substitution of the periphery of the dendrimers, a
strategy used previously by Meijer et al. for the preparation
of functionalized POPAM dendrimers.[56] The complete
functionalization of the dendrimers can be confirmed by
MALDI-TOF spectrometry, as demonstrated for
5 in
Figure 1. All generations of dendrimers were characterized
1
by using H and 13C NMR spectroscopic and mass spectro-
metric techniques.
Scheme 1. The barbiturate receptor 1 published in 1988 by Hamilton
et al.[45]
Determination of the association constants (Kass): To gain
more insight into the association of the host guests systems,
titrations were performed on 2 to determine its association
constants (Kass) with Barbital (7) and [Re(CO)3(Br)(barbi-
bpy)] (8). The association constant of 2ꢀ7 (in CDCl3) was
Since then, several papers have appeared reporting the
ability of this receptor to substract barbiturates from
50]
serum[46,47] and its use as a model for enzyme catalysis,[48
as a building block in supramolecular materials,[51] and as a
receptor in photoactive hydrogen-bond-based assem-
blies.[11,52,53] From these studies it is clear that the receptor
can be a powerful tool for the creation of stable supramolec-
determined by using H NMR spectroscopy. A Kass value of
1
1.4î103 mÀ1 was calculated from the change in chemical shift
of selected proton signals of 2 upon addition of 7. The asso-
ciation constant of 2ꢀ8 (in CHCl3) could be determined by
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F. Vˆgtle, L. De Cola et al.
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Scheme 2. A schematic representation of the HR-dendrimers 3 6 and the structures of 2 (reference compound) and 4.
using fluorescence spectroscopy and exciting 8 at 435 nm.
From the changes in the emission intensity of 8 upon addi-
tion of 2, the association constant was calculated to be 1.5î
105 mÀ1. The association constants found for 7 and 8 are in
good agreement with those found previously by Isied et al.,
for nondendritic Hamilton receptors, who ascribed the large
difference in binding constants to the ability of the barbitu-
rate to form a keto-enol-enolate equilibrium.[57] The associa-
tion constants of the dendritic host guest systems cannot be
determined exactly because of the wide variety of equili-
brating species. However, based on their identical behavior
in fluorescence titration experiments (see below), we
assume that the binding constant is similar for each receptor
site and resembles that of 2.
Photophysical properties of 2 and the HR-dendrimers 3 6:
Several studies have focused on the Hamilton receptor and
its complexation of barbiturates and their derivatives. In
particular, the assembly of the two units has been investigat-
ed by X-ray crystallography and by NMR, UV/Vis, and fluo-
53]
rescence spectroscopies.[11,44
However, the photophysical
properties of the receptor itself have never been studied in
detail. Hamilton et al. reported an absorption maximum in
the UV/Vis spectrum at 303 nm for the Hamilton receptor
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Receptor-Functionalized Dendrimers
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Scheme 3. Formation of host guest complexes between the HR-dendrimers 3 6 and the guest molecules 7 and 8.
Figure 1. MALDI-TOF mass spectrum of 5 (mass calcd. for 5: 13292.0).
and an emission maximum at 461 nm.[52] A binding-induced
increase in both the absorption and the emission bands of
the receptor was also reported.[52]
Like reference compound 2, which contains a single re-
ceptor, the HR-dendrimers 3 6 have an absorption maxi-
mum at 302 nm in CHCl3 (Figure 2a). The molar extinction
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Scheme 4. Synthesis of HR-dendrimers 3 6: i) NEt3, tetrahydrofuran (THF), RT, 12 h; ii) PtO2¥H2O, EtOH, 4 bar, RT, 24 h.
coefficient is linearly related to the number of Hamilton re-
ceptors attached to the periphery of the poly(propylenea-
mine) dendrimer. However, the molar extinction coefficient
of the Hamilton receptor within the HR-dendrimers 3 6
was found to be significantly lower per Hamilton unit than
that within 2 (Table 1). Excitation of the dendrimers at
310 nm gives a dual emission, with a maximum at 440 nm
and a shoulder at lower energy centered at about 500 nm
for all dendrimers. In the case of 2, a distinguishable band is
observed at 540 nm, although the emission intensity is much
lower for 2 than for 3 6 (Figure 2b). All the photophysical
data are summarized in Table 1.
(Table 1). Remarkably, the quantum yield of emission is
larger for the later-generation than for the earlier-generation
compounds (Table 1). This trend is probably related to the
aggregation of the Hamilton receptors at the periphery of
the dendrimer. Steric hindrance becomes greater with in-
creasing dendrimer generation number since the periphery
of the molecule becomes more crowded with receptor moi-
eties. The number of possibilities for receptor intra- or inter-
molecular interaction therefore becomes greater with in-
creasing generation of dendrimer. At the low concentrations
used in our experiments, (10À5 m receptor concentration), we
can assume that intramolecular processes are predominant.
Aggregation introduces rigidity to the Hamilton receptor,
which results in a higher quantum yield of emission since ra-
diationless deactivation is reduced.
The emission shows a double exponential decay for all
generations of dendrimer in CHCl3, with a short lifetime
component of 400 ps and
a longer lifetime of 1.5 ns
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Receptor-Functionalized Dendrimers
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tions of the receptor; one in
which the receptor arms are not
in the same plane (long life-
time), and another in which the
receptor arms are in the same
plane (short lifetime). The
three possible conformations of
the receptor in 2, namely cis-cis,
cis-trans, and trans-trans, are de-
picted in Scheme 5. Detailed
theoretical calculations of such
cis-trans behavior in meta-sub-
stituted benzenes and 2,6-sub-
stituted pyridines were carried
out within the frame of our in-
vestigations into template syn-
theses of molecular knots (kno-
tanes) in cooperation with the
Theoretical Chemistry Depart-
ment of the University of
Bonn.[58,59] Upon binding of a
barbiturate guest, the receptor
is always forced into an in-
plane cis-cis configuration.
Figure 2. Absorption (a) and emission (b) spectra (lexc =310 nm) of 2 6 in CHCl3.
Interestingly, an increase in
emission and a slight shift of
the emission maximum to lower
energy is also observed for the
HR-dendrimers 3 6 upon bind-
ing of 7. This effect becomes
smaller with increasing den-
drimer generation (Figure 3b).
This trend can only be ex-
plained if the Hamilton recep-
tors already have restricted
conformational freedom in the
Table 1. The photophysical properties of 2 6 in CHCl3.
[b]
[d]
Sample
n[a]
e [mÀ1 cmÀ1
]
Ratio e[c]
Fem
t1 [psÀ1
]
t2 [ns][d]
2
3
4
5
6
1
4
8
16
32
32900
99000
198000
377000
785000
1.3
4
8
15.2
31.7
0.0024
0.0103
0.0151
0.0180
0.0211
374
408
408
369
429
1.46
1.51
1.57
1.48
1.38
[a] n=number of Hamilton receptors. [b] Calculated at the maximum at 302 nm. [c] Ratio e=ratio between
the e values correlated to the number of chromophores. [d] lexc =356 nm and lprobe =480 nm.
Since conformational evidence to support these findings is
so far lacking, the binding of guest molecules was used as an
alternative strategy to rigidify the structure of the Hamilton
receptor to allow validation of the concept described above.
The binding of a barbiturate guest such as 7 ™fixes∫ the
Hamilton receptor in a certain conformation and in this way
reduces the degrees of freedom of the chromophore. Since 7
is an ™innocent∫ guest (i.e. no absorption or emission from 7
occurs at the excitation wavelength used), all changes in the
emission of the receptors as a result of the addition of 7 can
be attributed to conformational changes of the receptor
upon binding the guest.
As can be seen in Figure 3a, the quantum yield of emis-
sion from 2 increases dramatically upon addition of 7, and
the maximum shifts to lower energy (450 nm). Such a shift
can be explained by considering that the insertion of 7 into
2 causes planarization of the receptor and greater delocali-
zation within the system. As a result of the binding of 7 (a
large excess of 100 equiv was used because of the low bind-
ing constant), the long-lived component (1.5 ns) of the excit-
ed-state lifetime of 2 disappears, so that only the 400-ps
component remains (Figure 4). This result indicates that the
two different lifetimes belong to two different conforma-
later-generation dendrimers as a result of the aggregation or
steric hindrance at the periphery of the dendrimer.
Energy transfer in the complexes 2ꢀ8, 3ꢀ8, 4ꢀ8, 5ꢀ8, and
6ꢀ8: Metal complexes such as [Ru(bpy)3] and [Os(bpy)3],
but also [Re(CO)3(X)(bpy)] (X=Cl, Br, I), are often used
as energy or electron donors or acceptors in photoinduced
65]
processes.[60
The use of these complexes is often dictated
by their photophysical and redox properties, which are suita-
ble for the study of photoinduced processes. In the complex
[Re(CO)3Br(bpy)], the lowest excited state is a luminescent
triplet metal-to-ligand charge transfer state. In a separate
study, we have shown that [Re(CO)3(Br)(barbi-bpy)] (8)
forms a stable host guest complex with the Hamilton recep-
tor.[53] Comparison of the energy levels of the HR-dendrim-
ers 3 6 with those of the rhenium guest shows that the
3MLCT state of 8 is at lower energy (17730 cmÀ1, 564 nm)
than the lowest excited state of the HR-dendrimers
(27397 cmÀ1, 365 nm). As a result of the different absorption
properties of the separate components of the dendrimer 8
complexes (Figure 5), it is possible to selectively excite the
HR-dendrimers. Excitation at 330 nm predominantly excites
the Hamilton receptor. At this excitation wavelength, the
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Figure 3. a) Titration of 2 with 7 as observed by fluorescence spectroscopy (in CHCl3; lexc =330 nm); a binding-induced increase in the emission of 2 can
be seen. b) The binding-induced increase in the emission (in CHCl3; lexc =330 nm) of HR-dendrimers 3 6 as a result of the addition of 7, plotted relative
to the original emission (E0).
Figure 4. The emission decay (probed at 480 nm) of 2 in the absence and
in the presence of a large excess of 7 (100 equiv in CH2Cl2; lexc
=
324 nm).
Figure 5. The absorption spectra of 4 (scaled to e per HR) and 8 in
CHCl3.
contribution of 8 to the overall absorption is around 15% in
an equimolar solution.
The association of the two components is expected to
lead to a very exergonic photoinduced energy transfer
(DG=À1.20 eV) from the selectively excited (lexc =330 nm)
Hamilton receptor to 8 (Figure 6b). Indeed, upon addition
of the guest, quenching of the excited state (lmax =450 nm)
of the Hamilton receptor, as well as sensitization of the rhe-
nium emission (lmax =564 nm) was observed, as shown for
dendrimer 4 in Figure 6a. No isosbestic point was observed,
which indicates that two different processes occur simultane-
ously. The first process is the quenching of the excited state
of the Hamilton receptor by 8 through energy transfer. The
second process, discussed in detail below, is the deprotona-
tion of the barbituric acid moiety attached to the bipyridine
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Receptor-Functionalized Dendrimers
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upon binding of 8. A long-lived
component is also present in
the emission of the complex as
a result of the population of the
3MLCT state (t=109 ns) of 8
through energy transfer. From
this quenched lifetime, the rate
of energy transfer from the
Hamilton receptors at the pe-
riphery of the dendrimer to 8
was calculated to be 3.6î
1010 sÀ1. The same rate was
found for this photoinduced
process in all generations of
dendrimer (3 6), as expected.
A schematic overview of the
photophysical processes occur-
ring in 3ꢀ8, 4ꢀ8, 5ꢀ8, and 6ꢀ8
is given in Scheme 6.
Upon complexation of 8 with
HR-dendrimers 3 6, the 8-
based emission is blue-shifted
from 610 nm to 564 nm. This
shift in the emission of 8 can be
attributed to deprotonation of
the barbituric acid to produce
its enolate form, which is nega-
tively charged. Since the bipyri-
dine ligand is involved in the
MLCT as an electron acceptor,
the presence of the electron-
rich barbiturate would cause
the MLCT state to rise to a
higher energy. The addition of
third-generation poly(propyle-
neamine) dendrimer (DAB-
dendr-Am16; DAB=diaminobu-
tane, dendr=dendrimer, Am=
amine), which can only act as a
Scheme 5. The structures of the cis-cis, cis-trans, and trans-trans configurations of 2.
base, to
a solution of 8 in
CHCl3 causes the same shift in
emission. Furthermore, an in-
crease in the quantum yield of
emission from 8 was observed
upon complexation. This result
is in accordance with the
™Energy Gap Law,∫ which
states that if the energy differ-
ence between the lowest excit-
ed state and the ground state
increases, nonradiative decay to
the ground state decreases. In
the case of the dendrimer 8
complexes, an increase in the
Figure 6. a) Titration of 4 with 8 as observed by fluorescence spectroscopy (in CHCl3; lexc =330 nm); an
energy transfer from the excited state of 4 to 8 occurs. b) A schematic representation of the energy diagram.
ligand of 8, which causes a blue shift (from 610 to 564 nm)
and an increase in intensity of the emission of 8.
Time-resolved fluorescence spectroscopy revealed that
the emission lifetime of 400 ps, which corresponds to the ex-
cited state of the Hamilton receptor, was reduced to 30 ps
energy gap between the ground state and the lowest excited
state (3MLCT state) of 8 upon binding would cause a blue
shift and an increase in emission from 8. Another possible
explanation for the increased quantum yield of emission
from 8 lies in the change in conformation of 8 upon depro-
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Figure 7. Titration of 8ꢀ5 with 7 in CHCl3, as observed by fluorescence
spectroscopy (lexc =330 nm). The exchange of 8 with 7 results in the re-
covery of the emission of 5 and a decrease in the emission of 8.
Scheme 6. A schematic representation of the energy transfer between
HR-dendrimers 3 6 and guest compound 8.
tonation. The barbiturate ring in deprotonated 8 lies in-
plane with the bipyridine ring as a result of the change in
hybridization of the deprotonated carbon atom from sp3 to
sp2, which improves the conjugation between the binding
moiety and the rhenium complex.
emission of the Hamilton receptors at 450 nm was restored,
while the emission from 8 at 564 nm decreased (at the exci-
tation wavelength almost no direct excitation of the rhenium
complex was possible). These results show clearly that 8 was
replaced by 7 (Figure 7). The exchange of guests is a clean
and reversible process, as demonstrated by the presence of
an isosbestic point at 512 nm.
The deprotonation of the barbituric acid moiety of 8
proved to be essential for the energy transfer from the excit-
ed state of the receptor to the excited state of 8. No energy
transfer was observed within the host guest complex 2ꢀ8;
only an increase in the quantum yield of emission from 2
was caused by guest binding. Upon addition of a strong
base, such as DAB-dendr-Am16, the receptor emission was
quenched and strong emission from 8 was observed. This
result proves that the presence of the basic poly(propylenea-
mine) core is absolutely necessary for the energy transfer to
occur, even though the energy gap between the lowest excit-
ed state of the receptor and the lowest excited state of 8
does not increase, but rather decreases upon binding, reduc-
ing the driving force for the energy transfer process (see
above). The reason for the occurrence of the efficient
energy transfer must therefore be an improvement in elec-
tronic coupling between the receptor and 8. The excited
state of the receptor is very short-lived (only 400 ps), so that
a strong electronic coupling between the energy donor and
the energy acceptor is crucial for fast energy transfer to occur.
Conclusion
The results presented herein show that the new ™Hamilton-
receptor∫-functionalized dendrimers synthesized in this
study can be used as multiple-emitting sensors to probe the
presence of barbiturates. The emission from the Hamilton
receptor is strongly related to the rigidity of the chromo-
phoric system. The emission quantum yield was found to be
dependent on the dendrimer generation (dendritic effect).
The emission intensity increases with dendrimer generation
because of the increasing aggregation of receptors and steric
hindrance at the periphery of the dendrimers. The binding
of an ™innocent∫ guest, such as Barbital (7), forces the re-
ceptor into a ™fixed∫ conformation, which results in an in-
crease in its emission. Binding of the barbiturate guest [Re-
(CO)3(Br)(barbi-bpy)] (8), which has an excited state at a
lower energy than those of the HR-dendrimers, results in an
energy transfer from the Hamilton receptors to 8 at a rate
of 3.6î1010 sÀ1. The emission of 8 shifts towards higher
energy upon binding to the HR-dendrimers as a result of
deprotonation of the barbituric acid attached to the bipyri-
dine ligand. Deprotonation is necessary to obtain good elec-
tronic coupling between the receptor and 8 to allow an effi-
cient and fast energy transfer. Exchange of 8 with 7 results
Competition between 8 and 7: To show that the binding of 8
to the Hamilton receptor causes a photoinduced energy
transfer and that the exchange of guest molecules is a clean
and reversible process, a competition experiment was per-
formed with compounds 8 and 7.
Upon addition of a large excess of 7 to a solution contain-
ing 3ꢀ8, 4ꢀ8, 5ꢀ8, and 6ꢀ8 (Hamilton receptor:8, 1:1), the
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Receptor-Functionalized Dendrimers
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of Gx dendrimer (3 mL, 1î10À5 m HR) and 8 (1 equiv per HR) in CHCl3.
Fluorescence spectra were recorded with excitation at 330 nm.
in the recovery of the receptor emission and a decrease in
the emission of 8.
5-Nitroisophthaloyl dichloride (9): A solution of 5-nitroisophthalic acid
(18.0 g, 85.0 mmol) in thionyl chloride (30 mL) and N,N’-dimethylform-
amide (five drops) was refluxed for 6 h under dry conditions with subse-
quent vacuum distillation of the thionyl chloride excess. The residue was
dried under high vacuum and yielded a colorless solid (21.1 g, 100%):
1H NMR (CDCl3): d=8.68 (s, 1H; Har), 8.70 ppm (s, 2H; Har); 13C NMR
([D6]dimethyl sulfoxide): d=127.1, 133.0, 134.8, 148.1, 164.5 ppm.
By using the Hamilton receptor as a binding motif at the
periphery of poly(propyleneamine) dendrimers, stable
supramolecular host guest complexes can be formed in
which photophysical processes such as energy transfer can
be observed. The emission of the Hamilton receptor was
successfully used in binding studies to probe the complexa-
tion of guest molecules and can be regarded as a multiple
sensor for barbiturates. Careful design of the interior of the
dendrimer could allow the assembly of different guests in
desired parts of the dendritic structure. Such a structure
would make intradendritic processes possible and could
allow a more complicated function of the molecule, such as
the release of one of the guests induced by light excitation.
N-(6-Aminopyridin-2-yl)-3,3-dimethylbutyramide (10): A solution of 3,3-
dimethylbutyryl chloride (12.7 g, 91.6 mmol) in dry THF (50 mL) was
added to a solution of 2,6-diaminopyridine (10.0 g, 91.6 mmol) and trie-
thylamine (12.8 mL, 91.6 mmol) in dry THF (100 mL) at 08C under an
argon atmosphere over a period of 2 h. The solution was stirred for 60 h
at RT, the residue filtered off, and the solvent removed under reduced
pressure. Purification by column chromatography on silica gel (CH2Cl2/
ethyl acetate (4:1) as eluent) gave a colorless solid (8.7 g, 46%): M.p.:
114 1158C; 1H NMR (CDCl3): d=1.05 (s, 9H; (C(CH3)3), 2.18 (s, 2H;
4
(CH2C(CH3)3), 4.35 (brs, 2H; NH2), 6.23 (dd, 1H, 3JH,H =7.88, JH,H
=
3
0.74 Hz; Hpy), 7.42 (dd, 1H, 3JH,H =7.88 Hz; Hpy), 7.55 (d, 1H, JH,H
=
7.88 Hz; Hpy), 7.77 ppm (brs, 1H, CONH); 13C NMR (CDCl3): d=29.8,
31.3, 51.6, 103.3, 104.2, 140.2, 149.9, 157.1, 170.3 ppm; EI: m/z (%): 207
(15), 192 (5), 151 (4), 136 (8), 109 (100), 82 (19).
Experimental Section
Solvents and starting materials: All reagents were obtained from com-
mercial sources and used without additional purification unless otherwise
indicated. Solvents were dried according to known procedures. Deuterat-
ed solvents were used as obtained from Merck KGaA. CDCl3 was freshly
distilled from CaH2 onto 4-ä molecular sieves prior to use in the binding
study.
N,N’-Bis[6-(3,3-dimethylbutyrylamino)pyridin-2-yl]-5-nitro-isophthal-
amide (11): A solution of diacid dichloride 9 (2.74 g, 9.6 mmol) in dry
THF (40 mL) was added dropwise to a solution of monosubstituted dia-
minopyridine 10 (4.0 g, 19.3 mmol) and triethylamine (2.7 mL,
19.3 mmol) in dry THF (40 mL) at 08C under an argon atmosphere. The
solution was stirred at RT for 12 h, the residue filtered off, and the sol-
vent removed under reduced pressure. Purification by column chroma-
tography on silica gel (CH2Cl2/ethyl acetate (2:1) as eluent) gave a yel-
lowish solid (5.4 g, 97%): M.p.: 1848C; Rf =0.7 (CH2Cl2/ethyl acetate
(2:1 v/v)); 1H NMR (CDCl3): d=1.10 (s, 18H; C(CH3)3), 2.29 (s, 4H;
COCH2), 7.71 (t, 3JH,H =8.0 Hz, 2H; Hpy), 7.88 (d, 3JH,H =8.0 Hz, 2H;
Hpy), 7.95 (d, 3JH,H =8.0 Hz, 2H; Hpy), 7.98 (brs, 2H; CONH), 8.74 (m,
3H; Har), 8.82 ppm (brs, 2H; CONH); 13C NMR (CDCl3): d=29.8, 31.4,
51.5, 109.9, 110.8, 125.2, 131.6, 136.4, 140.9, 148.5, 148.7, 149.9, 162.2,
170.8 ppm. FAB: m/z: 590 (100), 492 (12), 394 (14). X-ray structure anal-
Instrumentation: 1H NMR and 13C NMR spectra were recorded on
Bruker WM 250, DPX 300, and DPX 400 spectrometers. The 1H NMR
binding study was performed on a Varian Inova500 spectrometer at
499.86 MHz. EI spectra were recorded on an AEI MS-30 or MS-50 spec-
trometer, positive-ion FAB mass spectra were collected on a Kratos Con-
cept 1H spectrometer, and MALDI-TOF mass spectra were collected on
a Micromass TofSpec E spectrometer. Melting points were recorded on a
B¸chi SMP 20 apparatus. Thin-layer chromatography (TLC) was carried
out on DC-Fertigplatten Kieselgel 60 F254 from Merck KGaA. Column
chromatography was performed on silica gel 60, 40 63 mesh, or silica gel
100, 63 100 mesh from Merck KGaA. UV/Vis absorption spectra were
recorded on a diode-array HP8453 spectrophotometer at 293 K. Fluores-
cence spectra were recorded on a SPEX fluorometer. The lifetime of the
emission of the HR-dendrimers was determined by single photon count-
ing with a picosecond laser.
ysis of 11: C30H41N7O9 (C30H35N7O6¥3H2O): colorless crystals, crystal di-
3
≈
mensions 0.10î0.30î0.50 mm ; Mr =643.70; triclinic, space group P1
(no. 2), a=9.3024(1), b=13.3131(2), c=14.1360(3) ä, a=105.161(1), b=
103.689(1), g=100.292(1)8, V=1586.79(4) ä3, Z=2, m(MoKa)=
0.101 mmÀ1, T=123(2) K, F(000)=684. 10711 reflections up to 2qmax
=
508 were measured on a Nonius KappaCCD diffractometer with MoKa ra-
diation, 5572 of which were independent and used for all calculations.
The structure was solved by direct methods and refined to F2 anisotropi-
cally; the H atoms were refined with a riding model. The final quality co-
efficient wR2(F2) for all data was 0.2032, with a conventional R(F) value
of 0.0782 for 446 parameters and 16 restraints.[66]
Determination of the quantum yields of emission: The quantum yields of
emission of the HR-dendrimers in CHCl3 were determined with quinine
sulfate in 0.05m H2SO4 (aq) as a reference. The solutions were optically
dilute, that is, they had an absorption between 0.05 and 0.15 at the excita-
tion wavelength (lexc =310 nm).
Determination of the binding constant for binding of 7 to 2 by 1H NMR
spectroscopy: A solution of 7 (28 mm) in CDCl3 was added in aliquots of
10 mL (0.2 equiv 7) to a solution of 2 (1 mL, 2.5 mm) in CDCl3. The bind-
ing constant could be calculated from the change in chemical shift of se-
lected proton signals of 2 upon addition of 7 by using a Scatchard plot.
5-Amino-N,N’-bis[6-(3,3-dimethylbutyrylamino)pyridin-2-yl]isophthal-
amide (12): Platinum(iv) oxide hydrate (100 mg) was added to a solution
of the nitrocompound 11 (5.4 g, 9.2 mmol) in dry ethanol (100 mL). The
suspension was hydrogenated at RT and 4.0 bar with stirring for 24 h.
The catalyst was filtered off over celite and the solvent removed under
reduced pressure. Recrystallization from ethanol gave a yellowish solid
(5.0 g, 97%): M.p.: 191 1928C; Rf =0.72 (ethyl acetate); 1H NMR
(CDCl3): d=1.11 (s, 18H; C(CH3)3), 2.23 (s, 4H; CH2C(CH3)3), 4.17 (s,
2H; NH2), 7.08 (brs, 2H; Har), 7.52 (brs, 1H; Har), 7.72 (brs, 2H; Hpy),
7.79, 7.85 (brs, 4H; Hpy), 8.52 (s, 2H; CONH), 8.54 ppm (s, 2H; CONH);
13C NMR (CDCl3): d=29.8, 31.4, 51.0, 109.6, 110.5, 114.9, 117.2, 135.5,
140.6, 147.8, 149.1, 150.0, 171.8, 174.4 ppm; FAB: m/z (%): 560 (100), 503
(6), 462 (8), 353 (19).
Determination of the binding constant for binding of 8 to 2 by fluores-
cence spectroscopy: A solution of 2 (1.2 mm) in CHCl3 was added in ali-
quots of 5 50 mL (5 mL contains 0.2 equiv 2) to a solution of 8 (3 mL, 1î
10À5 m) in CHCl3. The fluorescence intensity at the emission maximum
(lmax =618 nm) of 8 was probed, with excitation at 435 nm. The binding
constant could be calculated from the decrease in emission intensity by
using a Scatchard plot.
Energy transfer study of Gx (x=1,2,3,4) dendrimers complexed with 8:
A solution of Gx dendrimer (1î10À5 m HR) in CHCl3 and a solution of
Gx dendrimer (1î10À5 m HR) and 8 (2î10À5 m) in CHCl3 were mixed in
various ratios. In this way, solutions were obtained containing Gx den-
drimer (1î10À5 m HR) and increasing amounts of 8 per HR. Fluores-
cence spectra were recorded with excitation at 330 nm and corrected for
the small increase in absorption caused by the addition of 8.
9-{3,5-Bis[6-(3,3-dimethylbutyrylamino]-pyridin-2-ylcarbamoyl]-3-phenyl-
carbamoyl}nonanethioic acid pentafluorophenyl ester (PFTP ester; 15):
A solution of the amine-functionalized receptor 12 (3.0 g, 5.4 mmol) and
pentafluorothiophenol 13 (1.07 g, 5.4 mmol) in dry THF (150 mL) and a
solution of sebacoyl dichloride 14 (1.29 g, 5.4 mmol) in dry THF
(150 mL) were added simultaneously to
a solution of triethylamine
Competition experiment with 7 and 8: A solution of 7 (15 mm) in CHCl3
was added in aliquots of 5 10 mL (10 mL contains 5 equiv 7) to a solution
(1.5 mL, 10.8 mmol) in dry THF (150 mL) over 12 h under an argon at-
mosphere. The suspension was stirred for 12 h at RT, the residue filtered
2045
Chem. Eur. J. 2004, 10, 2036 2047
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

F. Vˆgtle, L. De Cola et al.
FULL PAPER
off, and the solvent removed under reduced pressure. Purification by
column chromatography on silica gel (petroleum ether/ethyl acetate/
methanol (50:50:1) as eluent) gave a yellowish solid (1.50 g, 30%): M.p.:
1188C; Rf =0.51 (petroleum ether/ethyl acetate (1:1 v/v)); 1H NMR
(CDCl3): d=1.06 (s, 18H; (CH3)3), 1.22 (brs, 8H; CH2(CH2)4CH2), 1.62
(brs, 4H; CH2CH2CO), 2.35 (s, 4H; CH2C(CH3)3), 2.43 (m, 2H;
Synthesis of the guest molecules: Barbital[55] (7) and [Re(Br)(CO)3(barbi-
bpy)][53] (8) were synthesized according to literature procedures.
Acknowledgment
CH2CO), 2.63 (t, 3JH,H =7.4 Hz, 2H; CH2CO), 7.51 (t, 3JH,H =8.3 Hz, 2H;
3
We thank Cornelis J. Kleverlaan and Derk J. Stufkens for valuable discus-
sions, S. Bitter and S. Buschbeck for measurement of the MALDI-TOF
spectra, and Jeroen van Heyst and Renÿ M. Williams for their contribu-
tion to the photophysical measurements. This work was financially sup-
ported by the Council for the Chemical Sciences of the Netherlands Or-
ganization for Scientific Research (CW-NWO) and a Cooperation in the
Field of Scientific and Technical Reasearch (COST) grant (Grant no.:
D11/0007).
H
py), 7.69 (d, JH,H =7.1 Hz, 2H; Hpy), 7.83 (brs, 2H; Hpy), 7.90 (brs, 1H;
Har), 8.28 (brs, 3H; Har + CONH), 8.89 (brs, 2H; CONH), 8.96 ppm
(brs, 2H; CONH); 13C NMR (CDCl3): d=25.3, 25.4, 28.7, 29.0, 29.1,
1
29.2, 29.8, 31.5, 37.6, 43.6, 50.9, 109.4, 110.6, 121.5, 137.8 (d, JC,F
=
1
247 Hz; Car F), 139.3, 140.2 (d, 1JC,F =240 Hz; Car F), 146.9 (d, JC,F
=
À
À
À
243 Hz; Car F), 148.8, 150.1, 171.9, 173.5, 192.4 ppm; FAB: m/z (%): 926
(100).
N,N’-Bis-[6-(3,3-dimethyl-butyrylamino)-pyridin-2-yl]-5-octanoyl-amino-
isophthalamide (2): Octanoylchloride (0.087 mL, 0.509 mmol) was added
dropwise to a solution of the amine-functionalized receptor 12 (300 mg,
0.536 mmol) and triethylamine (0.074 mL, 0.536 mmol) in dry dichloro-
methane (15 mL) at 08C under an argon atmosphere. The solution was
stirred for 3 h at RT and the solvent removed under reduced pressure.
Purification by column chromatography on silica gel (CH2Cl2/MeOH
(100:1, 50:1, and 20:1) as eluent) gave 2 (250 mg, 72%) as a light-yellow
[1] J.-M. Lehn, Science 2002, 295, 2400 2403.
[2] D. N. Reinhoudt, M. Crego-Calama, Science 2002, 295, 2403 2407.
[3] C. J. Chang, J. D. K. Brown, M. C. Y. Chang, E. A. Baker, D. G.
Nocera in Electron Transfer in Chemistry Vol. 3 (Ed.: V. Balzani),
Wiley-VCH, Weinheim, Germany, 2001, p. 409.
[4] Supramolecular Chemistry (Eds.: V. Balzani, F. Scandola), Horwood,
Chichester, England, 1991.
[5] A. D. Hamilton in Advances in Supramolecular Chemistry (Ed.:
G. W. Gokel), JAI, London, England, 1990, p. 1.
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Vol. 10 (Ed.: D. N. Reinhoudt), Pergamon, Oxford, England, 1996,
p. 687.
1
solid: M.p.: 231 2328C; Rf =0.56 (CH2Cl2/methanol (20:1 v/v)); H NMR
3
(CDCl3): d=0.82 (t, 3H, JHH =7.1 Hz; CH2CH3), 1.06 (s, 18H; C(CH3)3),
1.20 1.39 (m, 8H; CH2), 1.68 (dt, 2H, 3JH,H =7.5, 3JH,H =7.5 Hz;
CH2CH2CH2CO), 2.22 (s, 4H; CH2C(CH3)3), 2.40 (t, 2H, 3JH,H =7.5 Hz;
3
3
CH2CH2CO), 7.62 (t, 2H, JH,H =8.1 Hz; Hpy), 7.72 (d, 2H, JH,H =8.1 Hz;
H
3
py), 7.83 (d, 2H, JH,H =8.2 Hz; Hpy), 8.11 (s, 1H; Har), 8.20 ppm (s, 2H;
Har); 13C NMR (CDCl3/CD3OD (10:1 v/v)): d=15.1, 23.8, 26.9, 30.3, 30.5,
30.8, 32.5, 33.0, 38.3, 52.1, 111.1, 111.2, 123.2, 123.7, 137.0, 140.7, 141.5,
151.3, 151.6, 167.0, 173.2, 175.1 ppm; FAB: m/z (%): 686.4 (100).
Typical procedure for dendrimers containing Hamilton receptors (5):
Triethylamine (0.03 mL, 0.22 mmol) was added to a solution of DAB-
dendr-Am16 (22 mg, 0.013 mmol) in chloroform (10 mL). A solution of
the PFTP ester 15 (200 mg, 0.22 mmol) in chloroform (5 mL) was added
slowly over a period of 5 minutes. The solution was stirred for four days
under an argon atmosphere. The product was precipitated by dropwise
addition of n-hexane, filtered, and dried in vacuo to yield 5 (150 mg,
[7] J.-M. Lehn, Supramolecular Chemistry, Wiley-VCH, Weinheim, Ger-
many, 1995.
[8] Molecular Self-Assembly. Organic versus Inorganic Approaches.
Structure and Bonding Vol.96 (Ed.: M. Fujita), Springer, Berlin,
Germany, 2001.
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Davies, D. D. MacNicol, F. Vˆgtle), Pergamon/Elsevier, Oxford,
England, 1996.
1
85%) as a brownish product. M.p.: 1408C; H NMR (CDCl3): d=1.03 (s,
288H; C(CH3)3), 1.47 (brs, 192H; CH2), 1.58 (brs, 60H; CH2CH2N), 2.10
(s, 84H; NCH2), 2.32 (s, 64H; CH2C(CH3)3), 2.60 (m, 64H; COCH2),
3.11 (brs, 32H; CONCH2), 7.45 (brs, 48H; Har), 7.67 (brs, 32H; Hpy),
7.82 (brs, 64H; Hpy), 8.29 (brs, 64H; CONHCpy), 9.12 ppm (brs, 32H;
CONH); 13C NMR (CDCl3): d=10.5, 29.1, 29.3, 29.8, 29.9, 30.9, 31.4,
37.3, 45.9, 51.1, 110.1, 111.2, 121.1, 136.8, 140.3, 149.3, 150.8, 172.9,
176.1 ppm; MALDI-TOF MS: calcd for C728H1024N142O96: 13292.0; found:
13291.1.
[10] J. L. Sessler, M. Sathiosatham, C. T. Brown, T. A. Rhodes, G. Wie-
derrecht, J. Am. Chem. Soc. 2001, 123, 3655 3660.
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122, 1233 1234.
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10902 10911.
[13] A. Osuka, R. Yoneshima, H. Shiratori, T. Okada, S. Tanigushi, N.
Mataga, Chem. Commun. 1998, 1567 1568.
3: M.p.: 1808C; 1H NMR (CDCl3): d=1.03 (s, 72H; C(CH3)3), 1.45 (s,
48H; CH2), 1.55 (brs, 12H; CH2CH2N), 2.05 (s, 12H; NCH2), 2.35 (s,
16H; CH2C(CH3)3), 2.65 (m, 16H; COCH2), 3.15 (brs, 8H; CONCH2),
7.45 (brs, 12H; Har), 7.71 (brs, 8H; Hpy), 7.85 (brs, 16H; Hpy), 8.30 (brs,
16H; CONHCpy), 9.10 ppm (brs, 8H; CONH); 13C NMR (CDCl3): d=
10.5, 25.8, 26.2, 29.0, 29.8, 31.4, 37.0, 46.0, 50.8, 109.6, 111.6, 121.7, 122.1,
136.0, 140.6, 149.1, 150.5, 163.5, 171.9, 175.4, 177.8 ppm; MALDI-TOF
MS: calcd for C176H244N34O24: 3217.9; found: 3219.2.
4: M.p.: 1358C; 1H NMR (CDCl3): d=1.03 (s, 144H; C(CH3)3), 1.40
(brm, 96H; CH2), 1.60 (brs, 20H; CH2CH2N), 2.05 (s, 36H; NCH2), 2.35
(s, 32H; CH2C(CH3)3), 2.90 (m, 32H; COCH2), 3.10 (brs, 16H;
CONCH2), 7.47 (brs, 24H; Har), 7.68 (brs, 16H; Hpy), 7.82 (brs, 32H;
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Angew. Chem. 1997, 109, 2216 2219; Angew. Chem. Int. Ed. Engl.
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9230 9236.
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Curr. Chem. 2000, 210, 261 308.
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124, 11541 11551.
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182.
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Curr. Chem. 2001, 212, 81 135.
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77.
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F. Vˆgtle), Wiley-VCH, New York, 2001 and references therein.
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H
py), 8.33 (brs, 32H; CONHCpy), 9.08 ppm (brs, 16H; CONH);
13C NMR (CDCl3): d=8.8, 25.6, 29.0, 29.3, 29.8, 31.4, 37.3, 45.7, 51.6,
109.8, 111.1, 122.1, 136.1, 140.8, 149.0, 150.9, 172.7, 176.5 ppm; MALDI-
TOF MS: calcd for C360H504N70O48: 6575.9; found: 6577.2.
1
6: M.p.: 2208C; H NMR (CDCl3): d=1.03 (s, 576H; C(CH3)3), 1.48 (brs,
384H; CH2), 1.58 (brs, 124H; CH2CH2N), 2.10 (s, 180H; NCH2), 2.32 (s,
128H; CH2C(CH3)3), 2.62 (m, 128H; COCH2), 3.11 (brs, 64H;
CONCH2), 7.45 (brs, 96H; Har), 7.66 (brs, 64H; Hpy), 7.81 (brs, 128H;
Hpy), 8.29 (brs, 128H; CONHCpy), 9.09 ppm (brs, 64H; CONH);
13C NMR (CDCl3): d=10.6, 29.2, 29.3, 29.8, 29.9, 31.4, 37.1, 41.5, 45.9,
51.0, 109.8, 111.2, 136.6, 136.8, 140.6, 148.3, 150.8, 172.9 ppm.
2046
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 2036 2047

Receptor-Functionalized Dendrimers
2036 2047
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Received: August 18, 2003
Revised: November 24, 2003 [F5461]
2047
Chem. Eur. J. 2004, 10, 2036 2047
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim