Supramolecular dendrimer chemistry: Using dendritic crown ethers to reversibly generate functional assemblies

Article abstract of DOI:10.1016/S0040-4020(03)00468-X

A series of crown ether derivatives functionalised with dendritic branching based on L-lysine repeat units has been synthesised. The ability of these receptors to interact with cationic guests has been investigated using NMR and mass spectrometric techniques. Binding constants have been evaluated, some using competitive binding assays, and these indicate that the strength of interaction between the encapsulated crown-ether and cationic guests decreases with increasing dendritic functionalisation. The interaction of these dendritic branches with ditopic ammonium cation functionalised templates has been investigated, and Job plot analysis indicates the formation of 2:1 (branch/template) stoichiometric complexes in MeOH solution. These supramolecular assemblies have been disassembled by the addition of potassium cations, hence achieving controlled release of the template back into solution. This process has been investigated by NMR methods and the effect of counteranion on these studies is reported. The use of ditopic ammonium cations possessing long alkyl spacer chains as templates has also been investigated, and in this case, the 2:1 assembly that forms, goes on to achieve higher order levels of organisation, hence gelating the solvent. This particular system is therefore a rare example in which discrete, characterisable dendritic supermolecules possess an inherent potential for further supramolecular assembly, to yield new materials.

Full text of DOI:10.1016/S0040-4020(03)00468-X

Tetrahedron 59 (2003) 3999–4009
Supramolecular dendrimer chemistry: using dendritic crown
ethers to reversibly generate functional assemblies
*
Graham M. Dykes and David K. Smith
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 22 November 2002; revised 23 December 2002; accepted 10 January 2003
Abstract—A series of crown ether derivatives functionalised with dendritic branching based on L-lysine repeat units has been synthesised.
The ability of these receptors to interact with cationic guests has been investigated using NMR and mass spectrometric techniques. Binding
constants have been evaluated, some using competitive binding assays, and these indicate that the strength of interaction between the
encapsulated crown-ether and cationic guests decreases with increasing dendritic functionalisation. The interaction of these dendritic
branches with ditopic ammonium cation functionalised templates has been investigated, and Job plot analysis indicates the formation of 2:1
(
branch/template) stoichiometric complexes in MeOH solution. These supramolecular assemblies have been disassembled by the addition of
potassium cations, hence achieving controlled release of the template back into solution. This process has been investigated by NMR
methods and the effect of counteranion on these studies is reported. The use of ditopic ammonium cations possessing long alkyl spacer chains
as templates has also been investigated, and in this case, the 2:1 assembly that forms, goes on to achieve higher order levels of organisation,
hence gelating the solvent. This particular system is therefore a rare example in which discrete, characterisable dendritic supermolecules
possess an inherent potential for further supramolecular assembly, to yield new materials. q 2003 Elsevier Science Ltd. All rights reserved.
1
. Introduction
advantage when binding biologically important macro-
molecules, where the individual binding interactions are
4
Dendrimer chemistry has developed rapidly since its
1
inception during the 1980s. In general, synthetic chemists
weak. Multiple binding events at a dendritic surface have
also been shown to dramatically alter the solubility profile
5
now have an excellent degree of control over the covalent
synthesis of dendritic superstructures using a wide range of
organic and inorganic methodologies. Recently, attention
has increasingly turned to the construction of dendritic
structures using supramolecular synthetic methods—in
other words, synthesising dendrimers which are held
of the dendrimer, as the supramolecular assembly gener-
ated by this process is surface modified, and it is this
modified surface which interacts with the surrounding bulk
solvent environment.
Distinct from the surface, the core of spherical dendrimers
has been used in supramolecular chemistry to act as an
encapsulated binding site. In such cases, the dendritic shell
has been shown to have an impact on both the strength and
selectivity of guest binding in an analogous way to the
manner in which the tertiary structure of a protein can
2
together by non-covalent (or supramolecular) interactions.
Such systems are easy to construct, with components being
simply mixed in solution. In addition, chemical information
can easily be programmed into the different building blocks
used in the construction of the assembly. Finally, because
the connections between the building blocks are non-
covalent, they are reversible, and can, in principle, be
broken at a precise moment of choice.
6
control binding at the active site. A variety of receptors
7
8
such as dendritic porphyrins, dendroclefts and dendro-
9
phanes have been used to bind diverse guests. This
approach has also been used to assemble multiple spherical
1
0
Both fully formed spherical dendrimers and individual
dendritic branches (or dendrons) have been of interest for
their application in supramolecular dendrimer chemistry.
Molecular recognition at the multiple surface groups of a
spherical dendrimer has been used to achieve multivalent
dendrimers. In a keynote example, Diederich and co-
workers used a dendrophane receptor to interact with a
ditopic guest containing one steroid attached to each end of
a rigid molecular rod. This gave rise to a 2:1 supramolecular
assembly, with the length of the rod being crucial in
controlling the thermodynamics of the assembly process.
Dendritic cyclodextrins have been used to generate
3
binding. It has been shown that such multivalent recog-
nition offers enhanced binding strength, providing a clear
1
1
supramolecular assemblies in a similar way.
Keywords: crown ethers; dendrimers; gels; supramolecular chemistry; self
assembly.
Individual dendritic branches (or dendrons) are of increas-
ing interest in supramolecular assembly processes, in part
due to the wide variety of structures that can readily be
*
Corresponding author. Tel.: þ44-1904-434181; fax: þ44-1904-432516;
e-mail: dks3@york.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00468-X

4000
G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
synthesised. Zimmerman and co-workers illustrated that
well-designed branches could self-assemble through hydro-
gen bond formation to form a hexameric rosette type
ditopic ammonium cation guests. These supramolecular
assemblies could then be disassembled by the addition of
potassium cations, providing us with a means of achieving
reversible dendritic encapsulation. This paper reports
further details of these investigations, in particular,
additional binding data, mass spectral evidence for com-
plexation, the effect of counteranion on the disassembly
process and the ability of some of the assembled systems to
form novel gel-phase materials.
1
2
structure. This hydrogen bond mediated approach to
dendritic assembly has also been applied by other
1
3
researchers. Meanwhile, Percec and co-workers have
exploited the ability of dendrons to assemble into
cylindrical and spherical structures with liquid crystalline
properties—an approach also exploited by numerous other
1
4
groups. Dendritic branches have also been shown to
1
assemble in solution to give gel phase materials.
5
2. Results and discussion
In addition to these dendron-only processes, however, it is
also possible to direct the assembly of dendrons through the
use of a template (see Figure 1). This approach requires that
the focal point of the dendritic branch is capable of
interacting with a functional group on the template. Several
2.1. Synthesis
Target molecules G1(Crown), G2(Crown) and G3(Crown)
were synthesised as illustrated in Scheme 1. Commercially
1
6
0
quantitative yield according to literature methodology
groups have employed hydrogen bonds for this purpose,
1
available 4 -nitrobenzo-[18]crown-6 was reduced in near
24
7
others have used ligand–metal interactions, and yet
another example cites the use of electrostatically attractive
with Pd/C and H in EtOH. The resultant amine was then
2
coupled to L-lysine derived dendritic branches with a
carboxylic acid group at the focal point (Gn(COOH)), the
synthesis of which has been described by us previously.
For the first generation dendritic branch (G1(COOH)), this
coupling reaction could be performed using the classic
peptide coupling conditions of DCC/HOBt. The product
G1(Crown) was obtained in an excellent yield of 87%.
1
8
interactions. Gibson and co-workers have recently
employed interactions between [24]crown-8 and protonated
secondary amine groups to construct supramolecular
dendrimers via the formation of rotaxane-type inter-
2
1b
1
9
actions. Stoddart and co-workers have also generated
supramolecular dendritic structures using a similar
2
5
2
0
approach.
We have recently exploited acid–amine interactions to
assemble dendritic superstructures. We illustrated that the
acid functionalised dendritic branches were able to
solubilise and transport hydrophilic amine functionalised
2
1
dyes into and through non-polar solvents. Enhanced
solubilisation was achieved by higher generation dendri-
mers, and furthermore, the optical properties of the dye were
also controlled by the degree of dendritic encapsulation. In a
2
2
separate paper, we also indicated that certain assemblies
of dendritic branch and aliphatic diamines were able to
assemble yet further in solution, generating gel phase
materials.
However, acid–amine interactions are relatively weak, and
the assemblies generated were not particularly well defined
or easy to characterise. In order to improve on this, we have
developed dendritic crown ethers. In a recent preliminary
2
3
communication we described the ability of these dendritic
crowns to bind cationic guest species, in particular, their
ability to assemble into supramolecular dendrimers with
Scheme 1. Synthesis of the crown ether functionalised dendritic branches:
N, EtOAc, 87%; (b) G2(COOH), HATU,
N, EtOAc, 63%.
Figure 1. Schematic of a supramolecular dendrimer with individual
dendritic branches (dendrons) assembled around a molecular template.
(a) G1(COOH), DCC, HOBt, Et
3
Et N, EtOAc, 91%; (c) G3(COOH), HATU, Et
3
3

G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
4001
However, for the second generation dendritic branch
G2(COOH)), the coupling reaction became sluggish, and
branching generates a microenvironment at the focal point,
2
an effect often seen in dendritic systems.
7
(
the yield was poor (40%). For third generation dendritic
branch (G3(COOH)), the reaction was incomplete and the
desired product, present in about 20% yield, could not be
purified. This is a common problem associated with
Further characterisation data, including IR, [a] , R , mp and
f
HRMS (where appropriate) can be found in Section 4.
D
1
e
convergent coupling methodology, in which the bulk of
the dendritic branches effectively buries the focal point,
hence decreasing its reactivity. Consequently, more strongly
2.3. Binding studies with cationic guests
In the first instance, we were interested in the ability of these
dendritic crown ethers to bind simple un-functionalised
cationic guests. Given the high affinity and selectivity of
2
6
activating conditions using HATU as coupling reagent
were employed, and this approach gave rise to the target
second (G2(Crown)) and third (G3(Crown)) generation
dendritic crown ethers in excellent yields of 91 and 63%,
respectively. Even still, the synthesis of G3(Crown)
required heating and a prolonged reaction time. During
2
8
þ
[18]crown-6 derivatives for potassium ions, we chose K
as a suitable target. As described in Section 1, there has been
considerable interest in the ability of an encapsulated
binding site to recognise guest species, with the effect of
the synthesis of all three dendritic crown ethers, an excess of
0
encapsulation on the binding strength being of key
7–9
4
-aminobenzo-[18]crown-6 was employed. This was to
interest.
Surprisingly, however, to the best of our
ensure that there was no remaining Gn(COOH) in the
reaction mixture. It would have been very difficult to
separate Gn(Crown) from unreacted Gn(COOH) on the
basis of molecular size using gel permeation chromato-
graphy as they have similar molecular masses, whereas
knowledge, this is the first occasion that the ability of a
single dendritically encapsulated binding site to bind a
single charged guest ion has been described.
1
H NMR titrations in methanolic solution allowed us to
Gn(Crown) could easily be separated from the excess of
4
unambiguously assign the stoichiometry of binding as 1:1,
with clear titration profiles for the aromatic resonances of
Gn(Crown) indicating saturation of the receptor on the
0
SX-1, 90:10, CH Cl –MeOH). Hence the novel dendritic
crown ethers were obtained in pure form.
-aminobenzo-[18]crown-6 using this approach (Biobeads,
2
2
þ
addition of one equivalent of K (Fig. 2). The binding
stoichiometry was independent of dendritic generation.
However, the binding constants were too large to be
determined by regression analysis of the data. Nonetheless,
it was clear that the aromatic protons of G1(Crown), were
more strongly perturbed by K than those of G2(Crown),
which in turn were shifted further than those of G3(Crown).
2
.2. Characterisation
Characterisation of the novel dendritic crowns was achieved
using all standard techniques. Mass spectrometry, which is
particularly important for dendritic systems, was performed
using electrospray ionisation, and the ions were observed for
þ
[
MþNa]þ for G1(Crown) and G2(Crown)—no significant
In order to determine accurate binding strengths, we
developed a new calibrated competitive binding assay, the
fragment peaks or impurities were present. The detection
limit of our apparatus was m/z 2000, and hence G3(Crown)
was observed as a doubly charged ion corresponding to
2
9
full details of which have been reported elsewhere. It is
well-known that competitive binding experiments allow the
elucidation of binding constants for strongly bound com-
2
þ
[
Mþ2Na] . The isotope distributions observed for the
3
0
mass spectral ions of the larger molecules were consistent
with data calculated from isotopic abundances.
plexes. In this case, we used dibenzo-[18]crown-6 as a
þ
competing receptor for K ions, and hence determined the
binding constants for G1(Crown), G2(Crown) and
G3(Crown) (Table 2).
1
13
H and C NMR spectra were also fully consistent with the
proposed structures. It is interesting to note that the peaks
corresponding to the aromatic ring were perturbed by the
presence of the dendritic branching, an effect particularly
1
3
noticeable for the C NMR resonances (Table 1), especially
with third generation branching. A similar, but less marked
effect could be observed for the CH –O resonances of the
2
crown ether ring. This is the first indication that the dendritic
branching does indeed have an impact on the binding site
located at the focal point—in other words the dendritic
13
Table 1. C NMR data (ppm, MeOD) for the resonances of the aromatic
ring of Gn(Crown) indicating the effect of dendritic generation on NMR
shift
G1(Crown)
G2(Crown)
G3(Crown)
1
1
1
1
1
1
08.7
14.3
15.7
33.6
47.1
50.3
108.5
114.2
115.5
133.5
146.9
150.2
106.0
112.1
113.8
133.1
145.4
148.4
Figure 2. NMR titration curves for G1(Crown), G2(Crown) and
G3(Crown) with K , monitoring the shift of the aromatic peak (at ca.
þ
6
.9 ppm).

4002
G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
1
Table 2. Binding constants (log K
a
, MeOD, T¼300 K) elucidated by
H
NMR competition experiments and titration methods for 1:1 complexes of
cally disfavoured process due to the relatively low
micropolarity of the internal dendritic microenvironment
when compared to the more polar bulk solvent environ-
þ
21
3
dendritic crown ethers with K and 1 (K
in K values is ^10%)
a
: units mol dm , estimated error
a
3
1
ment.
Receptor
Guest
log K
a
Ddsat (ppm)
Binding studies were then performed with a simple,
commercially available benzylammonium guest cation (1,
Figure 3), also in methanol solution. It is well known that
[18]crown-6 forms strong complexes with protonated
primary amines, with the complex formed having three
þ
a
b
G1(Crown)
G2(Crown)
G3(Crown)
G1(Crown)
G2(Crown)
G3(Crown)
K
5.01
0.070
þ
a
b
K
K
4.86
0.050
þ
a
b
4.40
0.038
c
d
1
1
1
3.58
0.115
c
d
3.28
0.104
c
d
þ
32
2.31
0.108
N –H· · ·O hydrogen bonds (Fig. 4). In this case, we
followed the binding of dendritic crown ethers to the
a
Determined by calibrated competitive method as described in the text.
Saturation shift in the aromatic peak (at ca. 6.9 ppm) of the benzo crown
ether induced by the addition of potassium cations.
b
c
d
ammonium cation by monitoring the shift of the Ar–CH2
protons of the ammonium cation on the addition of
increasing amounts of Gn(Crown). Titration curves were
obtained, and binding constants determined using
Determined by NMR titration methods with regression analysis of the
33
data using HYPNMR.
Saturation shift in the CH
by the addition of the dendritic crown ether.
2
(benzyl) peak (at 4.10 ppm) on guest 1 induced
3
3
HYPNMR (Table 2). The binding constants were
approximately two orders of magnitude less than for the
þ
[18]crown-6, and is primarily a consequence of the very
The assay developed involved the careful calibration of the
recognition process between a reference receptor (dibenzo-
simple K cation. This is also the case for unfunctionalised
þ
þ
Interestingly, as for the binding of K , it was again observed
[
18]crown-6) and K . This allowed the determination of a
high binding affinity of this type of crown for K ions.
þ
straight-line relationship connecting the concentration of
the reference complex and the NMR shift of the aromatic
protons of dibenzo-18-crown-6 induced by K . Once the
calibration had been performed, an NMR spectrum was then
measured of a solution containing equimolar concentrations
of Gn(Crown), dibenzo-[18]crown-6 and K . The induced
NMR shift of the aromatic protons of the reference receptor
was observed, with the presence of Gn(Crown) diminishing
this shift, because it competes for the guest cation. The
straight-line relationship previously generated then allowed
the concentration of the reference complex in the presence
of an equimolar amount of competitive Gn(Crown) to be
determined. From this concentration, and the known
that the binding constant decreased with the increasing
degree of dendritic functionalisation—it might be expected
that this is at least partially due to steric effects.
þ
þ
To support these NMR investigations, binding studies were
also performed between Gn(Crown) and compound 1 using
mass spectrometric techniques. It is possible to perform
quantitative mass spectral studies in order to obtain binding
3
4
constant data, however, in this case a qualitative approach
was applied to see whether the proposed complexes could
be detected by this method.
literature value of the binding constant (K ) between
a
dibenzo-[18]crown-6 and K , the unknown binding con-
þ
After mixing an equimolar amount of Gn(Crown) and
ammonium cation 1, an electrospray mass spectrum was
determined. In the case of G1(Crown), the major peak in the
mass spectrum corresponded to the complex
þ
stant between Gn(Crown) and K could be calculated using
straightforward thermodynamic relationships. In summary,
this method allowed us to determine binding constants for
each of the novel receptors using a single NMR spectral
measurement. This new competitive assay is ideal for rapid
screening of large numbers of potential receptors (e.g.
combinatorial libraries) and full details can be found
þ
[G1(Crown)þ1] (Table 3). For G2(Crown), however,
this peak had decreased in intensity relative to the peak
for [G2(Crown)þNa] . For G3(Crown), doubly charged
þ
2
9
elsewhere.
Interestingly, the binding constants indicate that as the
extent of dendritic functionalisation of the crown ether
þ
increases, so the strength of K binding decreases, with an
order of magnitude difference between G1(Crown) and
G3(Crown). There are several potential reasons for this
negative dendritic effect: (a) donor atoms in the dendritic
þ
branching are also able to interact with K and compete
Figure 3. Ammonium cation guests.
with the crown ether for the guest; (b) steric hindrance of the
crown ether cavity is provided by the dendritic branches,
hence hindering guest binding; (c) the micro-environment
generated by the dendritic branching is apolar and therefore
less favourable for a charged entity than the surrounding
bulk solvent, which in this case is relatively polar methanol.
Which of these reasons is dominant in this case could not be
determined, but it is interesting to note there is a direct
parallel with investigations of encapsulated redox probes,
the overwhelming majority of which indicate that the build
up of charge inside dendritic structures is a thermodynami-
Figure 4. Interaction between 18-crown-6 and an alkylammonium cation.

G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
4003
Table 3. Major mass spectral peaks [with intensities] observed on
electrospray MS determination of equimolar amounts of Gn(Crown) and
compound 1 in methanol
Table 4. Major mass spectral peaks [with intensities] observed on
electrospray MS determination of equimolar amounts of G1(Crown) and
compound 2 in methanol
Compounds
Major mass spectral peaks [intensity]
Compounds
Major mass spectral peaks [intensity]
þ
þ
G1(Crown)þ1
G2(Crown)þ1
G3(Crown)þ1
763 [100%] [G1(Crown)þ1]
G1(Crown)þ2
1447 [11%] [2£G1(Crown)þ2–H]
þ
þ
6
78 [10%] [G1(Crown)þNa]
1333 [20%] [2£(G1Crown)þNa]
þ
þ
2þ
1219 [100%] [G2(Crown)þ1]
792 [100%] [(G1Crown)þ2–H]
þ
1
135 [22%] [G2(Crown)þNa]
724.5 [50%] [2£(G1Crown)þ2]
2
þ
þ
1120 [32%] [G3(Crown)þ2£1]
678 [48%] [G1(Crown)þNa]
2
þ
2þ
1
1
1
078 [97%] [G3(Crown)þ1þNa]
036 [100%] [G3(Crown)þ2£Na]
397 [27%] [G1(Crown)þ2]
2
þ
2
þ
024 [27%] [G3(Crown)þNaþH]
grounds of the increased steric crowding experienced on the
formation of the 2:1 assembly.
2þ
ions were observed, with the peak for [G3(Crown)þ2Na]
being dominant over those which included compound 1.
This qualitative result agrees with the NMR investigations
that illustrate that with increasing dendritic functionalisa-
tion, cationic guest 1 becomes less strongly bound.
Convincing evidence for the formation of a 2:1 complex
was found by performing a Job plot for G2(Crown) and
compound 2, and comparing it to that for G2(Crown) and
compound 1 (Fig. 5). The maximum of this plot occurs at
0.5 for compound 1, whereas it occurs at 0.33 for compound
2.4. Binding studies with a ditopic guest cation—
assembly of a supramolecular dendrimer
2. This clearly indicates the formation of complexes with
1:1 and 2:1 stoichiometries respectively. This proves that
under the concentration regime of the NMR experiments
performed, supramolecular dendrimers (2:1 assemblies) are
indeed present.
In order to extend the binding studies, we investigated the
ability of these novel dendritic crown ethers to assemble
around a ditopic guest cation: 1,4-bis(aminomethyl)
benzene dihydrochloride (2, Figure 3). Compound 2 was
prepared by the treatment of commercially available 1,4-
bis(aminomethyl) benzene with HCl(g) in Et O. NMR
2
binding titration experiments were performed in methanol,
with G2(Crown) being added to a solution of compound 2
Finally, mass spectrometry was used to investigate whether
these supramolecular dendrimers could be observed. The
mass spectral peaks are tabulated (Table 4). Mass spectral
ions for the doubly charged 1:1 and 2:1 complexes were
observed, as were the corresponding singly charged ions in
which a proton had been lost. These peaks indicated a
mixture of 1:1 and 2:1 complexes. This may be due to
partial complexation, or fragmentation of the 2:1 assembly
under electrospray ionisation conditions. These results are
therefore in broad agreement with what would have been
expected from the NMR investigations. Peaks correspond-
ing to one and two equivalents of G1(Crown) complexed to
sodium were also observed.
and the NMR shift of the Ar–CH protons being followed
2
(
Fig. 5). The profile was relatively uninformative, however,
it could be fitted to a mixture of 1:1 and 2:1 (G2(Crown):2)
stoichiometries using HYPNMR and binding constants of
log K ¼2.06 (0.37) and log K ¼1.27 (0.16) were
1
1
21
obtained. Given the poor NMR profile, there is some
doubt about these values. It is, however, interesting to note
that the first binding event (K ) is weaker than that for
1
1
G2(Crown) binding compound 1 (log K ¼3.28 (0.23)).
1
1
This is perhaps surprising, however, this could be a
consequence of the dendritic branching and the fact that it
disfavours the build up of charge within the superstructure.
2.5. Disassembly of the supramolecular assemblies
Perhaps the major advantage of using supramolecular
chemistry to assemble dendrimers, apart from its relative
ease, is the fact that the process is a reversible one, and the
interaction between template and dendritic branch can, in
principle, be broken at a controlled moment of choice. This
opens the possibility of dendritically encapsulating a
template molecule in a supramolecular manner, modifying
its behaviour, and then releasing it again into solution. There
are two potential strategies for the disassembly of the
supramolecular dendrimers formed above. The first
approach is to add a base to the solution, a concept
previously suggested by Gibson and co-workers for related
Log K21 is lower than log K , as would be expected on the
11
1
9b
systems. This would release the template as the free base,
rather than in the protonated form. The second approach is
to use potassium ions as competitive species. This method
would release the protonated template into solution. As
þ
shown above, K ions bind 2–3 orders of magnitude more
þ
strongly than the NH functionalised templates, and hence
3
1
Figure 5. Job plot determined by H NMR indicating the 2:1 stoichiometry
of the complex formed between G2-crown and compound 2 (circles), and
the 1:1 stoichiometry of the complex formed between G2-crown and
compound 1 (triangles).
should be able to displace them from the assembly. In this
way, controlled encapsulation and release of the template
species would be achieved.

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G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
Figure 7. Disassembly of the supramolecular dendrimer induced by the
addition of KPF
6
.
2
Figure 6. NMR shift of the ArCH peak (at 4.10 ppm) of guest 1 on the
addition of G2-crown followed by the addition of KPF
6
.
supramolecular dendrimer and into solution (Fig. 7). On this
occasion, the NMR shift of the Ar–CH peak returned to
2
In order to monitor this encapsulation–release process,
NMR experiments were performed with G2(Crown) and
compound 1 in methanol (Fig. 6). Firstly, 5 equiv. of
7.547 ppm, having started at 7.303 ppm. This difference was
again rationalised as the effect of excess KPF on the NMR
spectrum of template 2, and this was proven by the
appropriate control experiment.
6
G2(Crown) were added to compound 1, and the downfield
1
H NMR shift of the Ar–CH peaks of 1 reported on the
2
formation of the molecular complex (as described above).
Potassium ions were then added to the solution in the form
of KPF . The NMR peaks of compound 1 were again
monitored, and this time an upfield shift of the protons was
observed. This indicates that the complex is being
disassembled, and cation 1 released into solution (Fig. 6).
This experiment illustrates that supramolecular assembly is
a reversible process, and furthermore indicates that the
NMR properties of the template are modified by the
encapsulation/release process. We are now extending this
research to reversibly modify the behaviour of other
functional templates. This will hopefully allow this type
of supramolecular dendrimer to be used for the reversible
storage of information on a molecular scale.
6
It was observed that the NMR shift for the Ar–CH peak did
2
not quite return to its original value (4.097 ppm), returning
instead to 4.114 ppm. It was proposed that this was the
result of the presence of an excess of KPF . The original
2.6. Gel formation with supramolecular dendrimers
6
counter-ion to compound 1 was chloride, but in the presence
of an excess of KPF , the counter ion will predominantly be
In order to extend the scope of this methodology, we
decided to investigate the complexes formed between
G2(Crown) and protonated long chain aliphatic diamine 3.
This ammonium salt was prepared by treating 1,12-
6
hexafluorophosphate. In order to check this was indeed the
reason, 50 equiv. of KPF were added to compound 1 at
6
1
NMR titration concentrations and the H NMR shift of the
Ar–CH peak was monitored. As expected, the peak was
diaminododecane with HCl(g) in Et O. From our previous
2
2
investigations of supramolecular dendrimers constructed
using acid–base interactions, we knew that the combination
of G2(COOH) with 1,12-diaminododecane in organic
solvents led to the formation of new two-component gel-
shifted from 4.097 ppm to 4.114 ppm, confirming our
hypothesis. It is possible that this could simply be an ionic
strength effect induced by KPF , but it is more likely that the
6
2
1
reason for the effect is a consequence of the ability of
phase materials (Fig. 8). These gel phase materials form
because the dendritic supermolecule has the inherent
potential to assemble yet further, creating networks running
through the solvent. Both the length of the hydrophobic
spacer, and hydrogen bond interactions between the peptidic
branches have been shown to be important for the formation
of strong gel phase materials.
chloride anions to interact with NH3 better than the PF62
þ
anion can, hence modifying the NMR shift of the adjacent
CH protons.
2
The same experiment to monitor assembly followed by
potassium ion induced disassembly was then performed
using compound 2, but this time 10 equiv. of G2(Crown)
were added to ensure formation of the 2:1 complex. Once
1
Given this precedent for dendrimers with a similar
supramolecular structure to form gels, and the general
interest in the structure activity relationships of gel-phase
again, the addition of KPF had a dramatic effect on the H
6
NMR spectrum of encapsulated template 2, indicating that
the template was being released from the interior of the
1
5,35
materials,
we were therefore very interested to know

G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
4005
þ
Figure 8. Two-component supramolecular dendritic gels based on either acid–amine or crown-NH
3
interactions between the components.
whether the combination of G2(Crown) with cationic 3
would have the same effect. G2(Crown) was dissolved in
organic solvents (30 mM), and 1 mL of the resultant
solution was added to solid bis-ammonium cation 3
toluene, which is a poor hydrogen bond donor or acceptor.
This indicates that hydrogen bond interactions between the
peptidic groups of the dendritic branching in adjacent
complexes may play a key role in allowing further
assembly. Furthermore, the addition of small amounts of
hydrogen bond competitive solvents to the gels destroyed
them, once again indicating the importance of hydrogen
bonds in maintaining the assembly.
(
14 mg). This experiment was performed in several
different solvents—dichloromethane, toluene and
methanol.
In toluene, the dendritic branch on its own formed a very
weak gel which could be broken by lightly shaking
It should be pointed out that such two-phase supramolecular
3
7–40
(
behaviour not previously observed with G2(COOH)). It
organogelators are still comparatively rare.
therefore very pleasing that our expectations were fulfilled,
It was
has been previously reported that crown ethers can lead to
some hierarchical ordering of dendritic systems, and
þ
and that the complexes formed through crown-NH3
3
6
presumably that is occurring in this case. Compound 3
was insoluble in toluene. On the addition of G2(Crown),
however, the bis-ammonium cation was solubilised. A
similar effect on the solubility of diaminododecane caused
interactions did indeed assemble further into gel-phase
networks. This indicates that the structural motif discovered
2
2
in our previous investigations (Fig. 8) is of general
applicability in the development of novel dendritic gelation
systems.
2
2
by dendritic carboxylic acids was reported previously. As
before, the result in this case was a strong gel, which could
not be broken on shaking. This indicates that the two-
components when combined form a complex which is
capable of forming a hierarchical network that rigidifies the
solvent. In this way, the two individual components act in a
synergistic way. In dichloromethane, however, the mixture
did not form a gel-phase material, and in methanol, both
components were freely soluble at the outset, and once
again, no gel-phase material resulted.
Further studies to elucidate other structure–activity
properties of these assemblies have thus far been limited
by lack of material, but work is currently ongoing to fully
evaluate the behaviour and potential applications of this
type of tunable two-component gel phase system. These
materials clearly illustrate the ability of supramolecular
assemblies of dendrimers to demonstrate behaviour that is
more than the sum of their individual parts. This system is
therefore a rare example in which discrete, characterisable
dendritic supermolecules possess an inherent potential for
further supramolecular assembly on the mesoscale, to yield
new materials. In addition, these gel phase materials should
The results in different solvents indicate that the solvent
plays a key role in mediating the interactions between the
individual components that allow the hierarchical assembly
of individual supramolecular dendrimers to take place,
hence forming a gelated network. The solvent in which
strong gelation of the two-component mixture occurred was
þ
be reversibly broken down simply by the addition of K
ions—a property which may give rise to interesting
applications.

4006
G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
0
3. Conclusions
4.1.1. G1(Crown). 4 -Aminobenzo-[18]crown-6 (0.274 g,
.839 mmol, 1.5 equiv.) was dissolved in ethyl acetate
0
A series of dendritic crown ethers has been synthesised, and
their ability to bind simple cationic guests has been
investigated. It has been shown that increasing the extent
of dendritic functionalisation decreases the strength of the
host–guest complex. These dendritic crowns have also been
used to assemble supramolecular dendrimers around bis-
ammonium cations. These supramolecular dendrimers can
be disassembled by the addition of potassium ions, a process
investigated by NMR methods. Disassembly achieves
controlled release of the template into solution and indicates
the potential of this system for reversible encapsulation and
release of functional species. In the case where the template
(25 mL). Triethylamine (0.12 mL, 0.839 mmol) and
G1(COOH) (0.194 g, 0.559 mmol, 1.0 equiv.) were added
and the solution stirred under nitrogen for 2 min, before
being cooled to 08C. Hydroxybenzotriazole (HOBt, 0.076 g,
0.559 mmol) and dicyclohexylcarbodiimide (DCC, 0.115 g,
0.559 mmol, 1 equiv.) were then added simultaneously as a
mixture of solids. The reaction mixture was allowed to
warm to room temperature and stirred for 40 h. The solvent
was removed by rotary evaporation and the mixture purified
by gel permeation chromatography (Biobeads, 90:10,
CH Cl –MeOH) to give the product with a yield of
2
2
0.318 g (0.485 mmol, 87%). White solid; mp 140–1418C;
2
93
bis-ammonium cation has a long aliphatic chain between the
þ
R 0.47 (CH Cl –MeOH 80:20); [a] ¼219.3 (c¼1.0,
f
2
2
D
NH groups, the supramolecular assemblies which form
3
CHCl ); HRMS (FAB) C H N O Na calcd 678.3578,
3 32 53 3 11
þ
100%), 679 (30%); d (500 MHz, CD OD) 7.29 (1H, br s,
give rise to gel phase hierarchical assemblies in non-
hydrogen bond competitive solvents, indicating the ability
of such assemblies to behave as more than the sum of their
individual parts.
found 678.3575; m/z (ESI) (M ¼678.8) 678 ([MþNa] ,
r
H
3
ArH), 7.04 (1H, dd, J¼8.5, 2.5 Hz, ArH), 6.88 (1H, d,
J¼8.5 Hz, ArH), 4.13–4.10 (5H, m, CH O, CHCONH),
2
3.88–3.84 (4H, m, CH O), 3.73–3.70 (4H, m, CH O),
2 2
We are currently extending this research through the
encapsulation of functional templates, the supramolecular
synthesis of dendrimers with a variety of three dimensional
shapes and structures, and the further determination of the
key factors controlling the gelation process for this type of
supramolecular dendrimer.
3.69–3.67 (4H, m, CH O), 3.65 (4H, s, CH O), 3.06–3.03
2 2
(2H, m, CH CH NH), 1.90–1.30 (24H, m, CH , CH ); d
C
2
2
2
3
(125 MHz, CD OD) 173.3 (CONH), 158.6 (NHCOBoc),
3
157.9 (NHCOBoc), 150.3, 147.1, 133.6, 115.7, 114.3, 108.7
(Ar£6), 80.7 (OC(CH ) ), 79.9 (OC(CH ) ), 71.8, 71.8,
3
3
3 3
71.7, 71.7, 71.7, 71.7, 70.8, 70.7, 70.6, 70.1 (CH O£10),
2
5
6.7 (CHCONH), 41.0 (CH CH NH), 33.3 (CH ), 30.7
2
2
2
(
CH ), 28.8 (CCH ), 28.7 (CCH ), 24.2 (CH ). n
2
(KBr
max
3
3
2
disc) 3343s, 3326s, 2971w, 2932m, 2867w, 1681s, 1660s,
1604w, 1517s, 1456w, 1365m, 1130s, 1248s, 1169s, 1056m.
4. Experimental
0
.839 mmol, 1.5 equiv.) was dissolved in ethyl acetate
4
.1. General
4.1.2. G2(Crown). 4 -Aminobenzo-[18]crown-6 (0.274 g,
0
Solvents and reagents were used as supplied. Thin layer
chromatography was performed on commercially available
Merck aluminium backed silica plates. Preparative gel
permeation chromatography (GPC) was carried out using a
(25 mL). Triethylamine (0.12 mL, 0.839 mmol) and
G2(COOH) (0.449 g, 0.559 mmol, 1.0 equiv.) were added.
The solution was stirred under nitrogen for 2 min, before
0
0
being cooled to 08C. O-(7-Azabenzotriazol-1-yl)-N,N,N ,N -
tetramethyl uronium hexafluorophosphate (HATU, 0.256 g,
0.672 mmol, 1.2 equiv.) was then added and the reaction
mixture was stirred at room temperature for 40 h. The
solvent was removed by rotary evaporation and the mixture
purified by gel permeation chromatography (Biobeads,
90:10, CH Cl –MeOH) to give the product with a yield
2
m glass column packed with Biobeads SX-1, supplied by
Biorad. Analytical GPC traces were recorded using a
Waters instrument incorporating two Shodex columns in
series (KF-802.5 and KF-803) using THF as eluent. Proton
and carbon NMR spectra were recorded on either a Jeol EX-
1
13
2
(
70 ( H 270 MHz, C 67.9 MHz) or a Bruker AMX-500
13
H 500 MHz, C 125 MHz) at 258C. Chemical shifts (d)
2
2
1
of 0.564 g (0.507 mmol, 91%). White solid; melting range
93
2
are quoted in parts per million, referenced to residual
solvent. Coupling constant values (J) are given in Hz. DEPT
90–1108C; R 0.08 (CH Cl –MeOH 90:10); [a] ¼þ21.1
f
2
2
D
(c¼1.0, CHCl ); HRMS (FAB) C H N O Na calcd
3 54 93 7 17
1
3
experiments were used to assist in the assignment of
C
1134.6520; found 1134.6526; m/z (ESI) (M ¼1135.36)
r
þ
NMR spectra. Melting points were measured on an
Electrothermal IA 9100 digital melting point apparatus
and are uncorrected. Optical rotation was measured as [a]D
on a JASCO DIP-370 digital polarimeter. Positive ion
electrospray mass spectra were recorded on a Finnigan LCQ
mass spectrometer. Positive ion fast atom bombardment
mass spectra were recorded on a Fisons Instruments
Autospec mass spectrometer. The isotope distributions
observed for mass spectral ions of the larger molecules
are consistent with data calculated from isotopic abun-
dances. Infra-red spectra were recorded using an ATI
Mattson Research Series 1 FTIR spectrometer. Compound
G1(COOH) was prepared according to a literature
1134.5 ([MþNa] , 100%), 1135.5 (65%), 1136.6 (20%);
d (270 MHz, CD OD) 7.31 (1H, d, J¼2.5 Hz, ArH), 7.08
H
3
(1H, dd, J¼8.5, 2.5 Hz, ArH), 6.88 (1H, d, J¼8.5 Hz, ArH),
4.45–4.41 (1H, br s, COCH(R)NH), 4.14–4.10 (4H, m,
CH O), 4.07 (1H, br s, COCH(R)NH), 3.96 (1H, br s,
2
COCH(R)NH), 3.89–3.86 (4H, m, CH O), 3.72–3.69 (8H,
2
m, CH O), 3.65 (4H, s, CH O), 3.21–3.18 (2H, m,
2
2
CH CH NH), 3.04–2.99 (4H, m, CH CH NH), 1.90–1.40
2
2
2
2
(54H, m, CH , CH ); d (67.9 MHz, CD OD) 175.3, 175.1,
3
2
3
C
172.0 (CONH£3), 158.5, (NHCOBoc), 158.1, (NHCOBoc),
158.0, (NHCOBoc), 157.7 (NHCOBoc), 150.2, 146.9,
133.5, 115.5, 114.2, 108.5 (Ar£6), 80.8 (OC(CH ) ), 80.6
3
3
(OC(CH ) ), 79.8 (OC(CH ) £2), 71.7, 71.7, 71.6, 71.6,
3
3
3 3
4
1
method, as were dendritic branches G2(COOH) and
2
G3(COOH).
71.6, 71.6, 70.8, 70.6, 70.4, 70.0 (CH O£10), 56.3
2
1b
(COCH(R)NH), 56.2 (COCH(R)NH), 55.1 (COCH(R)NH),

G. M. Dykes, D. K. Smith / Tetrahedron 59 (2003) 3999–4009
4007
þ
þ
3
4
1.0 (CH CH NH£2), 40.0 (CH CH NH), 33.2 (CH ), 32.9
CH NH ); 1.69 (4H, qn, J¼7.5 Hz, CH CH NH ); 1.42–
2
2
2
2
2
2
3
2
2
(
CH ), 32.7 (CH ), 30.6 (CH ), 29.9 (CH ), 28.9 (CCH £6),
1.32 (16H, m, CH ).
2
2
2
2
2
3
2
disc) 3335m, 2976m, 2936m, 2870w, 1688s, 1655s, 1604w,
9.8 (CCH £6), 24.2 (CH £2), 24.0 (CH £2). n
(KBr
max
3
2
2
1
517s, 1457w, 1366m, 1124m, 1250m, 1171s.
Acknowledgements
0
.839 mmol, 3.0 equiv.) was dissolved in ethyl acetate
25 mL). Triethylamine (0.12 mL, 0.839 mmol) and
G3(COOH) (0.480 g, 0.280 mmol, 1.0 equiv.) were added.
The solution was stirred under nitrogen for 2 min, before
being cooled to 08C. HATU (0.213 g, 0.559 mmol,
4
0
(
.1.3. G3(Crown). 4 -Aminobenzo-[18]crown-6 (0.274 g,
We would like to acknowledge the EPSRC and ICI
Technology for a CASE award (G. M. D.) to support this
research.
2
.0 equiv.) was then added and the reaction mixture was
References
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.0 equiv.), and the reaction was heated at 458C until TLC
indicated completion (42 h). The solvent was then removed
by rotary evaporation and the mixture purified by gel
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2
2
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f
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2
2
93
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C H N O Na (M ¼2071.6—observed as dipositive
9
8
173 15 29
2
r
2
þ
036.0 (60%), 1036.5 (25%); d (500 MHz, CD OD) 7.47–
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4
3
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.98–3.95 (2H, m, COCH(R)NH), 3.91–3.88 (4H, m,
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2
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(
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3 3
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2
(
COCH(R)NH£7), 41.0 (CH CH NH£4), 40.0 (CH CH -
2
2
2
2
NH£3), 33.2, 32.6, 32.4, 30.6, 29.9 (all CH ), 28.8
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(
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(KBr disc) 3420s, 2977m,
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251m, 1170s.
3
2
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2
1
4.1.4. Protonated diamines 2 and 3. 1,4-Bis(amino-
methyl)benzene or 1,12-diaminododecane was dissolved
in Et O and stirred. An excess of HCl(g) was bubbled
2
through the solution, with a white precipitate being formed.
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1
and dried to give products 2 or 3 as a white solid. H NMR
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(
(
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2

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