Four generations of water-soluble dendrimers with 9 to 243 benzoate tethers: Synthesis and dendritic effects on their ion pairing with acetylcholine, benzyltriethylammonium, and dopamine in water

Article abstract of DOI:10.1002/chem.200701607

Water-soluble benzoate-terminated dendrimers of four generations (from G₀ with 9 branches to G₃ with 243 branches) were synthesized and fully characterized. They form water-soluble assemblies by ion-pairing interactions with three ca

Full text of DOI:10.1002/chem.200701607

FULL PAPER
DOI: 10.1002/chem.200701607
Four Generations of Water-Soluble Dendrimers with 9 to 243 Benzoate
Tethers: Synthesis andDendritic Effects on Their Ion Pairing with
Acetylcholine, Benzyltriethylammonium, andDopamine in Water
Elodie Boisselier,[a] Cµtia Ornelas,[a] Isabelle Pianet,[b] Jaime Ruiz Aranzaes,[a] and
Didier Astruc*[a]
1
Abstract: Water-soluble benzoate-ter-
minated dendrimers of four genera-
tions (from G0 with 9 branches to G3
with 243 branches) were synthesized
and fully characterized. They form
water-soluble assemblies by ion-pairing
interactions with three cations of me-
dicinal interest (acetylcoline, benzyl-
triethylammonium, and dopamine),
which were characterized and investi-
any significant shift of H NMR signals
with the monomeric benzoate anion.
The calculated association constants
confirm that the dendritic carboxylate
termini reversibly form ion pairs and
aggregates. Diffusion coefficients and
hydrodynamic diameters of the den-
drimers, as well as changes thereof on
interaction with the cations, were eval-
uated by DOSY experiments. The lack
of increase of dendrimer size on addi-
tion of the cations and the upfield
shifts of the 1H NMR signals of the
cation indicate encapsulation within
the hydrophobic dendrimer interiors
together with probable backfolding of
the benzoate termini.
Keywords: aggregation · cations ·
dendrimers · ion pairs · supramolec-
ular chemistry
1
gated by H NMR spectroscopy, where-
as such interactions do not provoke
Introduction
es) with acetylcholine.[9] We have nowextended this study
to four generations of benzoate-terminated dendrimers
(from G0 with 9 branches to G3 with 243 branches) and their
supramolecular interactions with three cations of medicinal
interest: acetylcholine (AC), benzyltriethylammonium
(BTEA), and dopamine.
An attractive property of dendrimers is their supramolecular
facet,[1] and they have indeed been used as unimolecular mi-
celles,[2] molecular boxes,[3] exoreceptors,[4] and sensors.[5]
Applications of water-soluble dendrimers as drug vectors
are most promising.[6,7] Polycationic dendrimers are consid-
ered to be toxic, but polyanionic dendrimers usually exhibit
acceptable biocompatibility.[8]
Acetylcholine chloride is produced naturally by the nerv-
ous system. It is also used as an active ingredient in some
drugs, but it is not very active on oral ingestion because of
hydrolysis in the digestive tract. Therefore, transport by den-
drimers may be useful. Acetylcholine chloride has various
pharmacological properties: it can be used as a parasympa-
thomimetic,[10a] a peripheral vasodilator, an antihypertensive,
a myotic, or a coronarodilator.[10b] Its muscarinic parasympa-
thomimetic action consists of contracting the smooth fiber
in the digestive tract,[10c] the eye, and the bronchi.[10d] It is
used in a drug marketed as a parasympathomimetic prepara-
tion for an intraocular use, although aqueous solutions are
unstable and must thus be prepared just before use.[11]
As a quaternary ammonium compound, benzyltriethylam-
monium chloride shows a variety of physical, chemical, and
biological properties. It can disrupt the cell processes of mi-
croorganisms, and it is used as a phase-transfer catalyst, an-
timicrobial agent, emulsifying agent, and pigment disperser.
We have reported, in preliminary form, the ionic interac-
tion of a single benzoate-terminated dendrimer (81 branch-
[a] E. Boisselier, C. Ornelas, Dr. J. R. Aranzaes, Prof. D. Astruc
Nanosciences and Catalysis Group
Institut des Sciences MolØculaires, UMR CNRS N8 5255
UniversitØ Bordeaux 1
351, Cours de la LibØration, 33405 Talence Cedex (France)
Fax : (+33)5-4000-6994
E-mail: d.astruc@ism.u-bordeaux1.fr
[b] I. Pianet
CESAMO
UniversitØ Bordeaux 1
351, Cours de la LibØration, 33405 Talence Cedex (France)
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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5577

Its interaction with dendrimers may allow it to be stabilized
in various formulations.[12,13] Moreover, together with alkyl-
dimethylbenzylammonium chloride, it belongs to a large cat-
egory of chemical compounds whose surface-active and bio-
cidal properties are widely used in the pharmaceutical in-
dustry.
Results andDiscussion
Water-soluble polyanionic dendrimers with 3n+2 benzoate
termini (generation number n=0–3) were synthesized as de-
scribed below, and their assembly with AC, BTEA, and dop-
amine was investigated by 1H NMR spectroscopy, as were
their solubility properties and ion-pair behavior in water. Ti-
tration of the three compounds with each generation of den-
drimers (i.e., twelve complexes is described and analyzed.
Diffusion ordered spectroscopy (DOSY), dipolar correlation
ROESY experiments, and a titration by 13C NMR are pro-
vided for the interaction between 81-benzoate G2 and AC.
Dopamine is a natural catecholamine formed by decar-
boxylation of 3,4-dihydroxyphenylalanine (DOPA). It is a
precursor to norepinephrine in noradrenergic nerves and is
also a neurotransmitter in certain areas of the central nerv-
ous system.[14] Dopamine produces positive chronotropic
and inotropic effects on the myocardium, which result in in-
creased heart rate and cardiac contractility.[15,16] Dopamine
hydrochloride is indicated for the correction of hemodynam-
ic imbalances present in the Shock syndrome.[17] The half-
life of dopamine in plasma is about two minutes when it is
intravenously administrated. Use of a dendrimer/dopamine
assembly might lead to a longer half-life that would allow
dopamine to better penetrate the target area. Supramolec-
ular interactions of the newbenzoate dendrimers with AC,
BTEA, and dopamine in water were investigated by
1H NMR spectroscopy, and the calculated association con-
stants and dendritic effects, that is, comparison of the influ-
ence of benzoate monomer and dendrimers and that of the
dendritic generation, are discussed.
Synthesis of benzoate-terminated dendrimers: For dendri-
mer construction, we used the 1!3C connectivity pioneered
by Newkome et al.[18] (Schemes 1 and 2). It starts with the
known nonaallylation of [FeCp(h6-mesitylene)]
[PF6] (1),
A
which quantitatively yields nonaallyl dendritic core 1,3,5-
[C(CH2CH=CH2)3]3C6H3 (2) on a large scale after to visible-
light photolysis to removes the metal moiety.[19] Hydrosilyla-
tion of terminal olefinic bonds, pioneered in dendrimer syn-
thesis by van Leeuwen et al.,[20] was carried out on 2 by
using chloromethyldimethylsilane and Karstedt catalyst to
regioselectively give a nonakis(chloromethyldimethylsilyl)
intermediate that reacts with NaI to form nonaiodide 3.
Scheme 1. Synthesis of water-soluble nonabenzoate G0 dendrimer 6. FE=[h5-CpFe]+ [PF6]À. a) CH2=CHCH2Br, KOH, THF, RT, 3 days; b) hnvis, MeCN;
A
c) HSiMe2CH2Cl, Karsted cat., RT, 1 day; d) NaI, butanone, 808C, 16 h; e) HOC6H4COOCH3, K2CO3, DMF, 808C, 2 days; f) NaOH, dioxane/water
(9:1), 608C, 16h, HCl; g) H2O, NaOH.
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Chem. Eur. J. 2008, 14, 5577 – 5587

Water-Soluble Dendrimers with Benzoate Tethers
FULL PAPER
We functionalized nine-branch G0 dendrimer 3 with car-
boxylate termini to solubilize it in water. This was achieved
in two steps: 1) Williamson reaction of dendri-9-iodide (den-
drimer with 9 iodide termini) 3 with methyl 4-hydroxyben-
zoate yielded dendri-9-benzoate 4, which was characterized
by its molecular peak at 2520.21 [M+Na]+ in the MALDI-
TOF mass spectrum (calcd for C135H192O27Si9Na: 2522.71);
2) basic hydrolysis of dendri-9-benzoate 4 to form dendri-9-
acid 5, which was characterized by its molecular peak at
2394.44 [M+Na]+ in the MALDI-TOF mass spectrum
(calcd for C126H174O27Si9Na: 2396.47). Dendrimer 5 was
easily solubilized in water as its sodium carboxylate form 6
in the presence of a stoichiometric amount of NaOH
(Scheme 1).
We investigated the supramolecular interactions of the
three cations with the four generations of benzoate den-
drimers to evaluate the role of dendrimer size and number
of carboxylate groups at the periphery. The major advantage
of these dendrimers is that they all become water-soluble on
addition of a stoichiometric amount of NaOH relative to
the number of acid groups. Thus, the supramolecular inter-
actions can be tested at a pH close to neutrality, a condition
for applications in biological systems (here pH 7.6 at c=
10À3 m for all sodium carboxylate dendrimers).
The dendrimer with nine sodium carboxylate groups re-
versibly reacts with AC chloride to form water-soluble
supramolecular assemblies whose structure can be examined
by 1H NMR spectroscopy.[21] The interaction between
dendri-9-carboxylate and AC is characterized in the
1H NMR spectrum by a large upfield shift of the four AC
signals. The dendrimer signals also move, but to a lesser
extent; the average shift is Dd=0.06 ppm in water for pe-
ripheral protons H5–H8 (see Figure 2 for numbering
scheme). Indeed, the protons at the periphery of the den-
drimers that are detectable by 1H NMR spectroscopy are
too far away from the carboxylate groups, and this small
shift is not representative of the interaction. The titration of
AC was performed to quantify the number of AC molecules
that can possibly be transported by dendri-9-carboxylate.
When the first equivalent of AC is added, the AC signals
shift from d=4.56 to 4.33 ppm for CH2CH2N proton H3,
from d=3.75 to 3.30 ppm for CH2N protons H2, from d=
3.23 to 3.03 ppm for the CH3N protons H1, and from d=
2.16 to 2.00 ppm for the CH3COO protons. These results
correspond to an average displacement of Dd=0.26 ppm.
The four signals of AC shift during this titration because of
interactions of the whole molecule with dendri-9-carboxyl-
ate. When AC interacts with this dendrimer, the ammonium
AC group should be located at the dendrimer periphery,
where it reversibly forms a contact ion pair and aggregates
with the carboxylate ion (see Figure 2).
Dendritic progression was achieved by using the known
“phenoltriallyl” dendronic brick p-HOC4H4C(CH2CH=
CH2)3, obtained by one-pot reaction of [FeCp(h6-p-chloroto-
luene)]PF6 with allyl bromide and tBuOK (Scheme 2).[19]
The same synthetic strategy was then applied to G1 with
27 branches, G2 with 81 branches, and G3 with 243 branches.
All newdendrimers were fully characterized by 1H, 13C, and
29Si NMR spectroscopy, mass spectrometry (except G3), and
elemental analysis. The MALDI-TOF mass spectra show
molecular peaks of the products (see Figure 1 and Support-
ing Information): dendri-27-COOCH3 7 (found: 9265.44
[M]+; calcd for C504H732O90Si36: 9264.98), dendri-27-COOH 8
(found: 8886.4 [M]+; calcd for C477H678O90Si36: 8886.3), and
dendri-81-COOCH3
C
9
(found: 29 471 [M]+; calcd for
1611H2352O279Si117: 29469.75). The 1H NMR spectra of the
benzoate dendrimers in MeOD showall the expected sig-
nals and thus confirm their structure. However, the
1H NMR spectra of the higher generations in D2O only
showthe peripheral proton signals. The synthesis of water-
soluble 81-benzoate G2 dendrimer 10 is shown in Scheme 2.
1H NMR experiments anddetermination of association con-
stants: Intermolecular interactions in solution play a key
role in molecular recognition. NMR spectroscopy is a very
useful technique to analyze them, because it allows the esti-
mation of the association constants. It also gives information
on the formation of aggregates, ion pairing, encapsulation,
and size variations. This technique was used here to analyze
three compounds that all contain ammonium moieties: AC,
BTEA, and dopamine.
The number n of AC molecules bound to the dendrimer
is determined as a function of the variation Dd of chemical
shifts according to Equation (1)[21]
1
Dd ¼ = Ddmax ½ð1 þ Kd=n½D0Š þ ½ACŠ=n½D0ŠÞ
Àfð1 þ Kd=n½D0Š þ ½ACŠ=n½D0ŠÞ À4 ½ACŠ=n½D0Šg
2
ð1Þ
2
1=2
Š
where [D0] is the total concentration of dendrimer, [AC] the
total concentration of acetylcholine, and Kd the dissociation
constant.
The data fit best with dendri-9-carboxylate interacting on
average (equilibrium) with 18Æ2 molecules of AC. The first
nine molecules interact electrostatically at the dendrimer
periphery. The first dissociation constant Kd1 of (20Æ2)”
10À3 m involves an equilibrium with nine AC molecules. A
second weaker interaction in equilibrium with nine other
AC molecule is obtained from the best fit, with a second dis-
sociation constant Kd2 of 1Æ0.1m [Eq. (2); R=dendrimer,
R’=Ac].
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D. Astruc et al.
Scheme 2. Synthesis of the water-soluble G2 dendri-81-benzoate 10. FE=[h5-CpFe]+ [PF6]À. a) CH2=CHCH2Br, KOH, THF, RT, 3 days; b) hnvis, MeCN;
A
c) HSiMe2CH2Cl, Karsted cat., RT, 1 day; d) NaI, butanone, 808C, 16 h; e) HOC6H4C(CH2CH=CH2)3, K2CO3, DMF, 808C, 2 days; f) NaOH, dioxane/
water (9:1), 608C, 16h, HCl; g) H2O, NaOH.
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Water-Soluble Dendrimers with Benzoate Tethers
FULL PAPER
The interactions of AC with dendrimers of higher genera-
tions are similar and were also analyzed, as were the inter-
actions of all dendrimers with BTEA and dopamine
(Table 1).
For the three cations, Ddmax varies with dendrimer genera-
tion and has the largest value for dendri-81-carboxylate. The
Ddmax value is 0.6 for AC, 1.16 for BTEA, and 0.54 ppm for
dopamine. These values showthe large change in environ-
ment of each cation when it is in the presence of a dendri-
mer terminated by benzoate groups.
All AC proton signals are shielded upfield as the dendri-
mer concentration increases. This is best taken into account
by incoming electron density near these AC protons due to
the negatively charged carboxylate groups and by penetra-
tion of AC into the hydrophobic interior of the dendrimer,
that is, AC is encapsulated in the dendrimer near its periph-
ery.[22] A similar situation is found for the ammonium pro-
tons of the two other cations.
Figure 1. MALDI-TOF mass spectrum of G1 dendri-27-benzoic acid 8.
We can distinguish two different interactions, one for AC
and BTEA (Figure 3a), and another for dopamine (Fig-
1
ure 3b). The evolution curves of the H NMR signals have
different shapes and thus reflect different interactions. In
the cases of AC and BTEA, the cation interacts with the
dendrimer in two steps, with a first association constant Ka1
for a first number of molecules n1 and a second association
constant a1 for a second number of molecules n2 (Table 1).
The observed behavior of the dendrimer/cation assembly
is best taken into account by reversible formation of ionic
bonds between the dendrimers and the three cations located
near the dendrimer periphery but inside the dendrimer.[23]
The second stage most probably involves agglomeration of
additional charges of chloride salt to reversibly form an ag-
gregate at each tether terminus that is backfolded into the
dendrimer interior.
This should be due to the dual location of the anionic
charge delocalized on both carboxylate oxygen atoms of the
carboxylate group, which can form a five-component aggre-
gate (one chloride anion in addition to the two oxygen
atoms and the two cations, see Figures 4 and 5).
This reasoning is also valid for AC and BTEA. The first
association constant increases with increasing dendrimer
generation, from 50 to 77mÀ1 for AC, and from 125 to 200mÀ1
for BTEA. The association constants are slightly smaller for
AC than for BTEA, that is, the dendrimer/BTEA assembly
is more strongly bound than the dendrimer/AC assembly.
There is no significant difference between Ka2 values of the
two cations, which are both between 1 and 12mÀ1.
Dopamine has only one association constant that de-
scribes the interaction between a molecule of dopamine and
a carboxylate group (Figure 6). Each dendrimer interacts
with a number of dopamine molecules equal to the number
of dendrimer carboxylate groups, and the association con-
stant also increases from 2000mÀ1 to 5000mÀ1 with increasing
dendrimer generation. This corresponds to a positive den-
dritic effect, which is observed in both cases.
Figure 2. 1H NMR titration of dendri-81-carboxylate with AC. AC proton
signals: a) dendri-81-carboxylate+20 equivalents of AC; b) dendri-81-
carboxylate+40 equivalents of AC; c) dendri-81-carboxylate+60 equiva-
lents of AC; d) dendri-81-carboxylate+80 equivalents of AC; e) dendri-
81-carboxylate+100 equivalents of AC; f) dendri-81-carboxylate+
200 equivalents of AC; g) dendri-81-carboxylate+300 equivalents of AC;
h) AC alone.
Kd1
À
þ
0
þ
À
½RCO ÀR0NþMe3Š
ƒƒ!
ƒƒ
½RCO2 Na Š þ ½R N Me Cl Š
3
2
H2O
Kd2
þ½NaðH2OÞxþClðH2OÞy
þ½NaðH2OÞx ClðH2OÞy
Š
½RCO ÀðR0NþMe3Þ2ClÀŠ
À
ƒ!
ð2Þ
ƒ
2
þ
À
Š
As AC is added to a D2O solution of dendri-9-carboxyl-
1
ate, the H NMR signals of the dendrimer benzoate termini
progressively broaden, in confirmation of a reversible ex-
change interaction, and the signals of AC followthe same
trend when the dendrimer is progressively added to a solu-
tion of AC (Figure 2).
The Ddmax value observed in each case confirms the exis-
tence of the interaction, and the evolution of Dd leads to an
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D. Astruc et al.
Table 1. Results obtained from 1H NMR titration of the three cations with the benzoate-terminated dendrim-
ers.
estimation of the association
constants. By comparison, mon-
omeric sodium benzoate hardly
shows any interaction with the
three cations (Dd<0.1 ppm),
which demonstrates a positive
dendritic effect (i.e., compari-
son of the dendrimers with the
monomer). Moreover, a study
on a carboxylate dendrimer and
the neutral amine benzylamine
did not reveal any interaction
that could be characterized by
1H NMR spectroscopy.
[a]
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Supramolecular assembly
Ddmax
[ppm]
c2
n1
Kd1
[m]
Ka1
n2
Kd2
[m]
Ka2
G
[mÀ1
]
[mÀ1
]
Dendri-9-carboxylate+AC
Dendri-27-carboxylate+AC
Dendri-81-carboxylate+AC
0.32
0.35
0.60
0.46
0.9
1.1
1.16
0.6
0.35
0.37
0.54
0.41
0.06
0.02
0.03
0.08
0.007
0.02
0.03
9
20”10À3
18”10À3
17”10À3
13”10À3
8”10À3
7”10À3
6”10À3
5”10À3
5”10À4
4”10À4
3”10À4
2”10À4
50
56
59
9
10”10À1
1
1
4
12
3
3
3
3
–
–
27
81
243
9
27
81
243
9
27
81
243
9
27
81
243
–
8
23”10À2
8”10À2
3”10À1
3”10À1
3”10À1
3”10À1
–
Dendri-243-carboxylate+AC
Dendri-9-carboxylate+BTEA
Dendri-27-carboxylate+BTEA
Dendri-81-carboxylate+BTEA
Dendri-243-carboxylate+BTEA
Dendri-9-carboxylate+dopamine
Dendri-27-carboxylate+dopamine
Dendri-81-carboxylate+dopamine
Dendri-243-carboxylate+dopamine
77
125
143
167
200
2000
2500
3333
5000
0.08
0.009
0.007
0.009
0.002
27
81
243
–
–
–
–
–
–
–
–
[a] Ddmax is the maximum observed chemical shift variation. [b] c2 is the difference between the experimental
points and the numerical values extracted from a theoretical curve. [c] n1 is the number of cationic molecules
revealed by the first association constant. [d] Kd1 is the first dissociation constant. [e] Ka1 is the first association
constant. [f] n2 is the number of cationic molecules involved with the second association constant. [g] Kd2 is the
second dissociation constant. [h] Ka2 is the second association constant. The attenuated maximum error for all
the values of this table is Æ10%.
In conclusion, in the studies
on association constants, the
data fits clearly showa plateau
for dopamine, that is, the ben-
Figure 3. a) Titration of dendri-27-carboxylate with BTEA. b) Titration
of dendri-27-carboxylate with dopamine.
Figure 5. Representation of the ionic aggregates of carboxylate dendrim-
ers with two BTEA molecules.
zoate terminus interacts with a single dopamine molecule.
Such a plateau is not found in titrations with AC and BTEA
cations, for which the best fit is a sinusoidal curve involving
two distinct association constants, the second of which very
weak and thus only significant in its order of magnitude.
These association constants are small, because water mole-
cules also strongly interact with these ions. It is their order
of magnitude that is informative, while their exact values
have little meaning given that they are small. It is remark-
able that dopamine behaves so differently from the two
other cations given the similar structures of BTEA and dop-
amine. The association constant of the dendrimers with dop-
amine are indeed about 20 times larger that those with
BTEA and 50 times larger than those with AC. In addition,
the data only fit single 1:1 association between the benzoate
Figure 4. Representation of the ionic aggregates of carboxylate dendrim-
ers with two AC molecules (close contacts between the whole AC groups
and benzoate are omitted for clarity).
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Chem. Eur. J. 2008, 14, 5577 – 5587

Water-Soluble Dendrimers with Benzoate Tethers
FULL PAPER
where D is the diffusion coeficient, kB the Boltzman con-
stant, T the absolute temperature, h the solvent viscosity,
and rH the hydrodynamic radius of the species.
Figures 7–9 showthe DOSY spectra of free dendri-81-car-
boxylate, free AC, and dendri-81-carboxylate/AC. Free
dendri-81-carboxylate in water has a diffusion coefficient of
(4.4Æ0.2)”10À11 m2 sÀ1 and a hydrodynamic diameter of
11Æ1 nm. The AC, BTEA, and dopamine molecules have
diffusion coefficients of (5.9Æ0.03)”10À10
,
(5.0Æ0.04)”
10À10, and (5.0Æ0.03)”10À10 m2 sÀ1, and hydrodynamic diam-
eters of 1.2Æ0.1, 1.0Æ0.1, and 1.0Æ0.1 nm, respectively.
When dendri-81-carboxylate is bound to 162 AC, 162
BTEA, or 81 dopamine molecules, it has diffusion coeffi-
cients of (5.0Æ0.1)”10À11, (5.4Æ0.1)”10À11, and (7.0Æ0.1)”
10À11 m2 sÀ1, and its hydrodynamic diameter is to (9.8Æ0.1),
(9.0Æ0.1), and (7.0Æ0.1) nm, respectively. The diffusion co-
Figure 6. Representation of the ion pair between dopamine and carboxyl-
ate-terminated dendrimers.
termini and dopamine. Clearly, this completely specific be-
havior of dopamine is due to the fact that it is a primary am-
monium compound, whereas the two other cations are qua-
ternary ammonium compounds. Thus, dopamine has acidic
hydrogen atoms on the ammonium center that can form hy-
drogen bonds with benzoate groups in synergy with the elec-
trostatic attraction between the two oppositely charged ions.
We knowfrom recognition studies with ATP that synergistic
interactions between two oppositely charged ions is consid-
erably strengthened by such favorable hydrogen bonding.[4]
Although the hydroxyl protons of the catechol moiety of
dopamine are less acidic than the ammonium protons, they
may also be involved in hydrogen bonding with one or two
oxygen atoms of the bidentate carboxylate group. However,
distinction between these two possible modes of hydrogen
bonding is not feasible at this stage.
Figure 7. The four signals on the top line represent lgD for the dendri-
81-carboxylate, and the last signal belowthe line lg D for water. Dd =
(4.4Æ0.1)”10À11 m2 sÀ1 and RH,d =5.517 nm, where Dd is the diffusion co-
efficient of the dendri-81-carboxylate, and RH,d its hydrodynamic radius.
DOSY experiments to determine diffusion coefficients and
13C NMR experiments: DOSY experiments were carried out
for the dendrimer/cation assemblies involving dendri-81-car-
boxylate and the three cations in order to followthe evolu-
tion of the diffusion coefficient of the free dendrimer on ad-
dition of each cation. The main goal of these experiments
was to measure the diffusion coefficient D by 1H NMR spec-
troscopy. The D value allows the hydrodynamic diameter of
1
a molecule to be calculated. In the H NMR experiment dif-
fusion is mathematically treated as a DOSY (diffusion-or-
dered spectroscopy) process in order to obtain the equiva-
lent of “spectral” chromatography. The objective is thus
double: measuring the size of the free and bound molecules
1
in solution by H NMR, and obtaining a DOSY spectrum
that reflects the purity of the assembly.
Dendri-81-carboxylate is regarded as a spherical molecu-
lar object and characterized by an apparent diffusion coeffi-
cient. The Stokes–Einstein law[Eq. (3)] gives an estimate
for the diameter of the molecule
Figure 8. The four signals on the line (top) represent lgD of one molecule
of acetylcholine (AC), and the last signal belowthe line represents lg D
for water. DAC = (5.9Æ0.1)”10À10 m2 sÀ1, RH,AC =0.59 nm.
D ¼ kBT=6phrH
ð3Þ
Chem. Eur. J. 2008, 14, 5577 – 5587
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5583

D. Astruc et al.
The DOSY experiments showthe evolution of the diffu-
sion coefficients of each molecule and of the assembly. The
dendrimer and the AC cation have their own diffusion coef-
ficients in the free state that reflect their molecular weight.
When a complex is formed with fast exchange on the NMR
timescale, however, the observed diffusion coefficient is a
weighted average of the diffusion coefficients for the free
and bound species.
The diffusion coefficient of AC decreases at a a lowcon-
centration of AC, and then increases up to a concentration
corresponding to 162Æ5 AC molecules per dendrimer (i.e.,
[AC]=28 mm), which shows the interaction between the
two species, before stagnating at higher AC concentrations.
In the beginning of AC addition to the dendrimer, the diffu-
sion coefficient of AC becomes close to that of the dendri-
mer. Then, it becomes close to its initial value in the free
state, as the amount of excess AC increases. The two other
cations (BTEA and dopamine) followapproximately the
same trend.
Figure 9. Four lines are identifiable from to bottom: the four signals on
the first line (top) represent lgD for the free dendri-81-carboxylate; the
four other signals on the same line (top) represent lgD for dendri-81-car-
boxylate bound to AC; the four signals on the second line represent lgD
for an AC molecule bound to the dendrimer; the four signals on the
third line represent lgD for a free molecule of AC. The last signal on the
line belowrepresents lg
H,d =4.902 nm.
D
for water. Dd =(4.998Æ0.1)”10À11 m2 sÀ1
,
An increase in diffusion coefficient on titration is found
for all three cations, but it is more pronounced for dopa-
mine, which interacts more strongly with the dendrimers
than the other two cations, as indicated by association con-
stants that are one order of magnitude larger than those of
AC and BTEA. These observations are in accord with the
proposed encapsulation of the guest cations deduced from
the shielding of their protons on interaction with the den-
drimers. This encapsulation on ionic bonding forces the ben-
zoate branch termini to be more strongly backfolded as the
strength of this interaction increases. The free dendrimer is
surrounded by a layer of hydrogen-bonded water molecules,
and it appears that this layer is significant given the rather
large hydrodynamic diameter of 11 nm. The decreased di-
ameter of the dendrimers in the presence of cationic guests
may not only signify backfolding of the dendrimer branch
termini, but possibly also significant decrease of the water
layer around the dendrimer, which is involved in the hydro-
dynamic diameter. This smaller surrounding water layer
would itself be also due to the bakfolding of the ionic ben-
zoate groups. Altogether, backfolding of the benzoate termi-
ni that is enforced by encapsulation of the ammonium guest
most probably makes the dendrimers more compact.
R
efficient of dendri-81-carboxylate increases on titration, that
is, dendrimer size decreases in the dendrimer/guest assem-
blies. This is in accord with our above interpretation of Dd
in terms of encapsulation. For instance, although the diffu-
sion coefficient of AC significantly increases on titration up
to a concentration of 27.9 mm, which corresponds to 162 AC
molecules per dendrimer, it stagnates at higher concentra-
tions (plateau in Figure 10). This confirms interaction be-
tween the AC molecules and the dendrimer up to a molar
ratio of 162 AC molecules per dendrimer. After this stage,
the diffusion coefficient observed is an average between
free AC and AC bound to the dendrimer, and its value
slowly approaches that of free AC when the proportion of
AC increases.
Supramolecular interactions were investigated by
13C NMR only for the single case of dendri-81-carboxylate
and AC, because the 13C NMR technique requires a consid-
1
erably longer recording time than H NMR and is thus im-
practical. In 1H NMR spectra, the shifts of the dendrimer
protons describing the effect of the dendrimer interaction
are rather small (d=0.06 ppm), because the closest protons
are four bonds away from the carboxylate group that inter-
acts with the AC molecules.
In the 13C NMR experiment, when 81 equivalents of AC
are added to dendri-81-carboxylate, the signal of the carbon
atom of the carboxylate group shifts from d=174.4 to
173.3 ppm, whereas the other carbon signals of the dendri-
mer do not move. Under the same conditions, the AC sig-
nals shift from d=60.9 to 57.9 (CH2CH2N), from 67.2 to
^
Figure 10. Evolution of the diffusion coefficients of AC ( ) and dendri-
&
81-carboxylate 10 ( ) as a function of their concentration in water.
5584
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Chem. Eur. J. 2008, 14, 5577 – 5587

Water-Soluble Dendrimers with Benzoate Tethers
FULL PAPER
64.2 (CH2N), from 56.5 to 53.5 (CH3N), from 23 to 20
(CH3COO), and from 175.7 to 172.4 ppm (COO). These re-
sults correspond to an average shift of Dd=3 ppm. The five
signals of AC shift during titration because of interactions of
the whole molecule with dendri-81-carboxylate, consistent
with encapsulation of AC in the dendrimer.
association constants, the same trend is observed. Thus, the
dendritic effect for the three ammonium cations is positive,
that is, the Ddmax and association constant increase as the
dendrimer generation increases up to the dendri-81-carbox-
ylate.
When 81 additional equivalents are added, the AC signals
always show an average shift of Dd=3 ppm, and the signal
of the carboxylate group of the dendri-81-carboxylate shifts
from d=174.4 to 172.0 ppm. These results confirm those ob-
Experimental Section
General: All reactions were carried out by Schlenk techniques or in a ni-
trogen-filled Vacuum Atmosphere drylab. 1H NMR spectra were record-
ed at 258C with a Brucker AC 250 (250 MHz) spectrometer. 13C NMR
spectra were obtained in pulsed FT mode at 62.0 MHz with a Brucker
AC 250 spectrometer, and 29Si NMR spectra were obtained at 59.6 MHz
with a Brucker AC 300 spectrometer. All chemical shifts d are reported
in parts per million (ppm) relative to Me4Si (TMS). The MALDI-TOF
mass spectra were recorded with a PerSeptive Biosystems Voyager Elite
(Framingham, MA) time-of-flight mass spectrometer. Elemental analyses
were performed by the Center of Microanalyses of the CNRS at Lyon
Villeurbanne, France. Syntheses of the precursor iodomethyltrimethylsilyl
dendrimers were described previously.[19]
1
tained in the H NMR experiments and the fact that the am-
monium group of AC should be located at the dendrimer
periphery. It forms an ion pair and aggregates with the car-
boxylate ion, which backfolds into the dendrimer interior so
that the guest be encapsulated.
Conclusions
New water-soluble dendrimers were synthesized, character-
ized, and used as sensors of three cations of biological inter-
est. The supramolecular interactions between the two enti-
Synthesis of dendri-9-benzoate 4: Nonaiodide dendrimer
0.482 mmol), methyl 4-hydroxybenzoate (1.32 g, 8.68 mmol), K2CO3
(6.10 g, 43.4 mmol), and dry DMF (30 mL) were introduced into
3 (1.1 g,
a
Schlenk flask. The reaction mixture was stirred at 808C for 48 h. DMF
was removed, and the crude product was dissolved in dichloromethane
(30 mL) and washed with water to remove K2CO3. The organic layer was
dried with Na2SO4, filtered, and the solvent was removed in vacuo. The
product was washed with methanol and precipitated twice in CH2Cl2/
methanol to remove excess methyl 4-hydroxybenzoate. Nonabenzoate
dendrimer 4 was obtained as a colorless waxy material in 90% yield
1
ties were investigated by H NMR spectroscopy.
The protons of dendritic benzoate tethers are deshielded
(downfield shifts) on addition of any ammonium cation due
to decreased electron density in ion-pairing interactions.
Those of the ammonium cations are all shielded (upfield
shift) due to encapsulation within the hydrophobic dendri-
mer interior.
The Ddmax value observed in each case confirms the exis-
tence of the reversible interaction, and the evolution of Dd
led to an estimate of the association constants. By compari-
son, the monomeric sodium benzoate hardly shows any in-
teraction with the three cations (Dd<0.1 ppm), and this
demonstrates a positive dendritic effect.
Two distinct cases were found: AC and BTEA on the one
hand, and dopamine on the other. In the former case, the
dendrimer acts in two steps: it first equilibrates with a stoi-
chiometric number of cations by ionic association, and then
form aggregates with the same number of cations with much
weaker association. Dopamine has only one association con-
stant characterizing the interaction between a dopamine
molecule and a carboxylate group (i.e., 9 molecules of dopa-
mine for the dendri-9-carboxylate, 27 for the dendri-27-car-
boxylate, 81 for the dendri-81-carboxylate, and 243 for the
dendri-243-carboxylate). This interaction between dopamine
and the dendrimers is much stronger than those between
the dendrimers and AC and BTEA, as shown by the relative
values of the association constants, because for dopamine
hydrogen-bonding between the primary ammonium protons
and the carboxylate termini acts in synergy with ion paring,
which is not the case with the two other ammonium cations,
which are quaternary.
1
(1.089 g). H NMR (CDCl3, 250 MHz): d=7.93 and 6.88 (d, 18H, arom.),
7.01 (s, 3H, arom. core), 3.86 (s, 27H, COOCH3), 3.50 (s, 18H, SiCH2O),
1.65 (s, 18H, CH2CH2CH2Si), 1.13 (s, 18H, CH2CH2CH2Si), 0.57 (s, 18H,
CH2CH2CH2Si), 0.040 ppm (s, 54H, Si
(CH3)2); 13C NMR (CDCl3,
G
62 MHz): 165.8 (COOCH3), 164.2 (arom. CqO), 144.8 (CH, arom. core),
130.4 and 112.7 (CH, arom.), 121.2 (CqCOOCH3, arom.), 59.7 (SiCH2O),
50.7 (COOCH3), 42.9 (CH2CH2CH2Si), 41.0 (CqCH2), 16.8
(CH2CH2CH2), 13.6 (CH2CH2CH2Si), À5.6 ppm (Si
C
7.56; IR: n˜ =1719 (nC O) cmÀ1
.
=
Synthesis of dendri-9-benzoic acid 5: Dendri-9-benzoate
4 (0.50 g,
0.20 mmol) was dissolved in dioxane (40 mL), and an aqueous solution of
NaOH (10 mL, 18 mmol, 10 equiv per branch) was added. The reaction
mixture was stirred at 608C for 48 h. Dioxane was removed under
vacuum, and the aqueous solution was acidified with HCl. The dendri-9-
acid precipitated as a white powder. The solution was filtered, and the
powder was washed twice with diethyl ether. The product was recovered
from the filter by dissolving it with methanol. Methanol was removed in
vacuo, and the product was obtained as a white powder in 72% yield.
1H NMR (MeOD, 250 MHz): d=7.93 and 6.91 (d, 18H, arom.), 7.06 (s,
3H, arom. core), 3.52 (s, 18H, SiCH2O), 1.64 (s, 18H, CH2CH2CH2Si),
1.16 (s, 18H, CH2CH2CH2Si), 0.54 (s, 18H, CH2CH2CH2Si), À0.003 ppm
(s, 54H, Si
(CH3)2); 13C NMR (MeOD, 62 MHz): d=169.8 (COOH),
U
166.7 (arom. CqO), 147.2 (CH, arom. core), 132.9 and 115.0 (CH, arom.),
123.0 (arom. CqCOOCH3), 61.9 (SiCH2O), 45.2 (CH2CH2CH2Si), 43.3
(CqCH2), 19.3 (CH2CH2CH2), 15.9 (CH2CH2CH2Si), À4.1 ppm (Si-
A
(MALDI-TOF): m/z calcd for C126H174O27Si9Na: 2 396.47; found: 2 394.44
[M+Na]+; elemental analysis (%) calcd for C126H174O27Si9: C 63.76, H
7.39; found: C 62.71, H 7.22; IR: n˜ =1686 (nC O) cmÀ1 1H NMR of 6
;
=
For dendrimers of different generations, Ddmax increases
in all the cases with increasing generation number up to the
dendri-81-carboxylate, then slightly decreases from the
dendri-81-carboxylate to the dendri-243-carboxylate. For the
(D2O+NaOH, 250 MHz): d=7.82 and 6.79 (d, 18H, arom.), 7.08 (s, 3H,
arom. core), 3.41 (s, 18H, SiCH2O), 1.68 (s, 18H, CH2CH2CH2Si), 1.16 (s,
18H, CH2CH2CH2Si), 0.52 (s, 18H, CH2CH2CH2Si), À0.045 ppm (s, 54H,
Si(CH3)2).
A
Chem. Eur. J. 2008, 14, 5577 – 5587
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5585

D. Astruc et al.
Synthesis of dendri-27-benzoate 7: Dendri-27-iodide (0.1 g, 0.016 mmol),
methyl 4-hydroxybenzoate (0.134 g, 0,882 mmol), K2CO3 (0.609 g,
4.40 mmol), and dry DMF (20 mL) were introduced into a Schlenk flask.
The reaction mixture was stirred at 808C for 48 h, then DMF was re-
moved, the crude product was dissolved in 30 mL of dichloromethane
and washed with water to remove K2CO3. The organic layer was dried
with Na2SO4, filtered, and the solvent removed in vacuo. The product
was washed with methanol and precipitated twice in CH2Cl2/methanol to
remove excess methyl 4-hydroxybenzoate. The dendri-27-benzoate was
obtained as a colorless waxy material (0.140 g, 92% yield). 1H NMR
(CDCl3, 250 MHz): d=7.94 and 6.88 (d, 54H, outer arom.), 7.10 and 6.80
(d, 18H, inner arom.), 3.84 (s, 81H, COOCH3), 3.51 (s, 72H, SiCH2O),
1.60 (s, 72H, CH2CH2CH2Si), 1.11 (s, 72H, CH2CH2CH2Si), 0.55 (s, 72H,
Synthesis of dendri-243-benzoate 11: Dendri-243-iodide (0.10 g,
0.001 mmol), methyl 4-hydroxybenzoate (0.088 g, 0.576 mmol), K2CO3
(0.398 g, 2.88 mmol), and dry DMF (20 mL) were introduced into a
Schlenk flask. The reaction mixture was stirred at 808C for 48 h. DMF
was removed, and the crude product dissolved in dichloromethane
(30 mL) and washed with water to remove K2CO3. The organic layer was
dried with Na2SO4, filtered, and the solvent was removed in vacuo. The
product was washed with methanol and precipitated twice in CH2Cl2/
methanol to remove excess methyl 4-hydroxybenzoate. Dendri-81-ben-
zoate was obtained as a colorless waxy material (0.289 g, 89% yield).
1H NMR (CDCl3, 250 MHz): d=7.94 and 6.88 (d, 486H, outer arom.),
7.10 and 6.80 (d, 234H, inner arom.), 3.79 (s, 729H, COOCH3), 3.47 (s,
720H, SiCH2O), 1.59 (s, 720H, CH2CH2CH2Si), 1.10(s, 720H,
CH2CH2CH2Si), 0.53 (s, 720H, CH2CH2CH2Si), À0.012 ppm (s, 2160H,
CH2CH2CH2Si), 0.025 (s, 216H, Si
(CH3)2). 13C NMR (CDCl3, 62 MHz):
G
Si
(CH3)2); 13C NMR (CDCl3, 62 MHz): d=165.7 (COOCH3), 164.2
U
165.8 (COOCH3), 164.2 (outer arom. CqO), 158.1 (inner arom. CqO),
130.4 and 112.8 (CH, arom.), 121.1 (arom. CqCOOCH3), 59.7 (SiCH2O),
50.7 (COOCH3), 41.9 (CH2CH2CH2Si), 41.9 (CqCH2), 16.6
(outer arom. CqO), 159.4 (inner arom. CqO), 130.4 and 112.8 (CH,
arom.), 121.1 (arom. CqCOOCH3), 59.6 (SiCH2O), 50.7 (COOCH3), 42.0
(CH2CH2CH2Si),
(CH2CH2CH2Si), À5.7 ppm (Si
d=0.47 ppm (SiCH2O); IR: n˜ =1719 (nC O) cmÀ1
40.9
(CqCH2),
16.6
(CH2CH2CH2),
13.5
(CH2CH2CH2), 13.5 (CH2CH2CH2Si), À5.5 ppm (Si
C
AHCTREUNG
.
=
calcd for C504H732O90Si36: 9264.9816; found: 9265.4374; IR: n˜ =1719 (nC
=
O) cmÀ1
.
Synthesis of dendri-243-benzoic acid 12: Dendri-243-benzoate (0.06 g,
0.0007 mmol) was dissolved in dioxane (45 mL), and an aqueous solution
of NaOH (5 mL, 2.5 mmol, 15 equiv per branch) was added. The reaction
mixture was stirred at 608C for 48 h. Dioxane was removed under
vacuum, and the aqueous solution was acidified with HCl. Dendri-81-
acid precipitated as a white powder. The solution was filtered, and the
powder was washed twice with diethyl ether. The product was recovered
from the filter by dissolving in methanol. The methanol was removed in
vacuo, and the product was obtained as a white powder in 67% yield.
1H NMR (MeOD, 250 MHz): d=7.94 and 6.84 (d, 486H, outer arom.),
7.08 and 6.75 (d, 234H, inner arom.), 3.36 (s, 720H, SiCH2O), 1.62 (s,
720H, CH2CH2CH2Si), 1.10 (s, 720H, CH2CH2CH2Si), 0.54 (s, 720H,
Synthesis of dendri-27-benzoic acid 8: Dendri-27-benzoate 7 (0.070 g,
0.007 mmol) was dissolved in dioxane (45 mL), and an aqueous solution
of NaOH (5 mL, 2.5 mmol, 12 equiv per branch) was added. The reaction
mixture was stirred at 608C for 48 h. Dioxane was removed under
vacuum, and the aqueous solution was acidified with HCl. Dendri-81-
acid precipitated as a white powder. The solution was filtered, and the
powder was washed twice with diethyl ether. The product was recovered
from the filter by dissolving in methanol. The methanol was removed in
vacuo, and the product was obtained as a white powder in 67% yield.
1H NMR (MeOD, 250 MHz): d=7.91 and 6.86 (d, 54H, outer arom.),
7.10 and 6.79 (d, 18H, inner arom.), 3.48 (s, 81H, SiCH2O), 1.60 (s, 72H,
CH2CH2CH2Si), 1.15 (s, 72H, CH2CH2CH2Si), 0.53 (s, 72H,
CH2CH2CH2Si), À0.020 ppm (s, 2160H, Si
C
CH2CH2CH2Si), À0.056 ppm (s, 216H, Si
C
14.3 (CH2CH2CH2Si), À5.3 ppm (Si
T
(CH3)2); 29Si NMR (MeOD,
General procedure for titration: In an NMR tube, carboxylate dendrimer
(3 mg) was introduced into D2O (0.4 mL), then one of the cations was
progressively added. Titrations spanned from 0 to the 2x equivalents of
the cation per dendrimer, where x is the number of carboxylate groups in
each dendrimer.
14.4 (CH2CH2CH2Si), À4.9 ppm (Si
59.62 MHz) d=1.57 ppm (SiCH2O); MS (MALDI-TOF): m/z calcd for
C477H678O90Si36: 8886.3; found: 8886.4; IR: n˜ =1686 (nC O) cmÀ1
Synthesis of dendri-81-benzoate 9: Dendri-81-benzoate 9 was synthesized
from dendri-81-iodide (0.30 g, 0.011 mmol) following the same procedure
as for the synthesis of 4, in 89% yield. 1H NMR (CDCl3, 250 MHz): d=
7.94 and 6.88 (d, 162H, exterior arom.), 7.10 and 6.80 (d, 72H, interior
arom.), 3.84 (s, 243H, COOCH3), 3.51 (s, 234H, SiCH2O), 1.60 (s, 234H,
CH2CH2CH2Si), 1.11 (s, 234H, CH2CH2CH2Si), 0.55 (s, 234H,
Synthesis of all dendrimers and detailed 1H NMR, 13C NMR, DOESY,
and ROESY spectra and data are available as Supporting Information.
CH2CH2CH2Si), 0.034 ppm (s, 702H, Si
(CH3)2); 13C NMR (CDCl3,
G
62 MHz): d=167.2 (COOCH3), 164.2 (exterior arom. CqO), 159.4 (inte-
rior arom. CqO), 131.8 and 114.2 (CH, arom.), 122.5 (arom. CqCOOCH3),
61.1 (SiCH2O), 52.2 (COOCH3), 43.4 (CH2CH2CH2Si), 42.3 (CqCH2),
Acknowledgements
18.0 (CH2CH2CH2), 14.9 (CH2CH2CH2Si), À4.3 ppm (Si
C
We are grateful to the referees for helpful comments, to the Fundażo
para a CiÞncia e a Tecnologia (FCT), Portugal (Ph.D. grant to C.O.), the
Institut Universitaire de France (IUF, DA), the CNRS, and the Univer-
sitØ Bordeaux 1 for financial support.
H 8.04; IR: n˜C O =1719 cmÀ1
.
=
Synthesis of dendri-81-benzoate 10: Dendri-81-acid 10 was synthesized
from dendri-81-benzoate 9 (0.20 g, 0.0068 mmol) by the same procedure
as for the synthesis of 5, in 67% yield. 1H NMR (MeOD, 250 MHz): d=
7.90 and 6.83 (d, 162H, exterior arom.), 7.08 and 6.75 (d, 72H, interior
arom.), 3.43 (s, 234H, SiCH2O), 1.58 (s, 234H, CH2CH2CH2Si), 1.10 (s,
234H, CH2CH2CH2Si), 0.49 (s, 234H, CH2CH2CH2Si), À0.056 (s, 702H,
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(CH3)2). 13C NMR (MeOD, 62 MHz): 169.9 (COOH), 166.8 (exterior
G
arom. CqO), 160.5 (interior arom. CqO), 133.0 and 115.1 (CH, arom.),
123.8 (arom. CqCOOCH3), 61.8 (SiCH2O), 44.3 (CH2CH2CH2Si), 43.4
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.
=
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Chem. Eur. J. 2008, 14, 5577 – 5587

Water-Soluble Dendrimers with Benzoate Tethers
FULL PAPER
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Received: October 11, 2007
Revised: January 31, 2008
Published online: April 2, 2008
Chem. Eur. J. 2008, 14, 5577 – 5587
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5587