Cyclohexane-based low molecular weight hydrogelators: A chirality investigation

Article abstract of DOI:10.1002/chem.200500007

Seven new 1,3,5-cyclohexyl-tricarboxamide-phenylalanine derivatives were synthesized in order to investigate the effect of the amino acid chirality on the gelating properties of these small molecules in water. Gelation tests have shown that enantiomerical

Full text of DOI:10.1002/chem.200500007

FULL PAPER
Cyclohexane-Based Low Molecular Weight Hydrogelators:
A Chirality Investigation
Arianna Friggeri,*[a] Cornelia van der Pol,[a] Kjeld J. C. van Bommel,[a] AndrØ Heeres,[a]
Marc C. A. Stuart,[b] Ben L. Feringa,[b] and Jan van Esch*[b]
Abstract: Seven new 1,3,5-cyclohexyl-
tricarboxamide-phenylalanine deriva-
tives were synthesized in order to in-
vestigate the effect of the amino acid
chirality on the gelating properties of
these small molecules in water.Gela-
tion tests have shown that enantiomeri-
cally pure homochiral 1,3,5-cyclohexyl-
in contrast to the logarithmic curves
generally observed for gels derived
from low molecular weight gelators
(LMWGs).Such sigmoidal behaviour
can be related to interactions between
fibre bundles, which give rise to inter-
twined bundles of fibres.Transmission
electron microscopy (TEM) images of
lld and ddl gels show a network of
thin, unbranched, fibre bundles with di-
ameters of 20 nm.Right-handed twist-
ed fibre bundles are present in the lld
gel, whereas left-handed structures can
be found in the ddl gel.Each bundle
of fibres consists of a finite number of
primary fibres.Gels consisting of mix-
tures of gelators, lld and ddl, and
nongelators (lll or ddd) were investi-
gated by means of Tgs measurements,
CD spectroscopy and TEM.Results
show that the incorporation of nonge-
lator molecules into gel fibres occurs;
this leads to higher Tgs values and to
changes in the helicity of the fibre bun-
dles.Furthermore, it was found that pe-
ripheral functionalization of the homo-
chiral derivatives lll or ddd by means
of a second amino acid or a hydrophilic
moiety can overcome the effect of chir-
ality; this process in turn leads to good
hydrogelators.
tricarboxamide-l-phenylalanine is
a
non-hydrogelator as it crystallizes from
water, whereas the heterochiral deriva-
tives with either two l-phenylalanine
moieties and one d-phenylalanine
(lld), or vice versa (ddl), are very
good hydrogelators.Concentration-de-
pendent gel-to-sol transition-tempera-
ture (Tgs) curves for lld or ddl gels
show a sigmoidal behaviour, which is
Keywords: amino acids · chirality ·
cyclohexane · gels · self-assembly
Introduction
sulting in their characteristic consistency.[1] Such materials
are of considerable interest since they are intermediates be-
tween liquids and solids and as such combine properties of
both of these states, as well as presenting new properties of
their own.[1,2] Recently, LMWG hydrogel matrices have
shown great potential in the field of drug delivery as con-
trolled release systems,[3,4] as scaffolds providing cell storage
as well as directionality for cellular differentiation[5] and for
the construction of protein microarrays compatible with
enzyme assays.[6] A class of particularly interesting LMWGs
is based on the 1,3,5-benzene- and 1,3,5-cyclohexyltricarbox-
amide cores.A variety of 1,3,5-benzenetricarboxamide de-
rivatives synthesized by Meijer and co-workers have shown
interesting behaviour in organic polar and apolar solvents.
In both media chiral columnar aggregates can form,[7] and in
some cases the so-called “sergeants-and-soldiers” effect
could be observed for gelators with relatively small periph-
eral substituents (C8-alkyl chains).[8] Furthermore, deriva-
tives with polymerizable peripheral moieties can undergo
photoinitiated polymerization, forming very stable colum-
Low molecular weight gelators (LMWGs) can self-assemble
in water leading to the formation of hydrogels; these gels
are jelly-like materials usually consisting of intertwined fi-
brous structures, in which water remains entrapped, thus re-
[a] Dr.A.Friggeri, C.van der Pol, Dr.K.J.C.van Bommel,
Dr.A.Heeres
Biomade Technology Foundation
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Fax : (+31)50-363-4429
E-mail: friggeri@biomade.nl
[b] Dr.M.C.A.Stuart, Prof.B.L.Feringa, Dr.J.van Esch
Laboratory for Organic Chemistry, Stratingh Institute
University of Groningen, Nijenborgh 4
9747 AG Groningen (The Netherlands)
Fax : (+31)50-363-4296
E-mail: j.van.esch@chem.rug.nl
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the authors.
Chem. Eur. J. 2005, 11, 5353 – 5361
DOI: 10.1002/chem.200500007
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nar, mesoscopic objects.[9,10] The gelation capabilities of
alkyl-substituted 1,3,5-cyclohexyltricarboxamide derivatives
in organic solvents were initially investigated by Hanabusa
et al.[11] More recently we showed that amino acid substitut-
ed derivatives function as gelators for water.[12] Moreover,
peripheral functionalization of such molecules with pH-sen-
sitive moieties leads to responsive gels that can be switched
reversibly from gel to sol by changing the pH, thus making
these materials particularly interesting for controlled drug-
delivery systems.[12]
Both 1,3,5-benzenetricarboxamide- and 1,3,5-cyclohexyl-
tricarboxamide derivatives make excellent scaffolds for the
study of chiral supramolecular architectures in protic sol-
vents.To obtain well-defined architectures of synthetic mol-
ecules in such media the right balance between forces of
limited directionality, such as hydrophobic forces, and more
directional but less stable interactions, such as hydrogen
bonds, has to be found.For natural proteins, the possibility
of creating stable hydrogen bonds, even in aqueous media,
derives from the presence of hydrophobic regions within the
protein where such interactions can take place.Similarly, for
1,3,5-cyclohexyltricarboxamide amino acid based gelators,
the hydrophobic moieties of the amino acid substituents are
needed for the protection of the hydrogen-bonding network
from the surrounding solvent, allowing self-assembly and
subsequently gelation in water to take place.[12] In some
cases, as has often been observed with many other gelator
systems, very slight changes to the gelator structure can in-
fluence the gelation behaviour dramatically.[13] Chirality, for
example, often determines whether a compound will func-
tion as a gelator or not.Whereas racemic mixtures are
sometimes less efficient gelators than the corresponding
enantiomerically pure products,[14,15] the opposite effect has
been observed in other cases.[13,16,17] Very recently, Hirst
et al.have shown that changing the chirality of one amino
acid of a dendritic organogelator can lead to changes in the
gelation behavior in organic solvents.[18]
Scheme 1.Molecular structure of amino acid substituted 1,3,5-cyclohexyl-
tricarboxamide derivatives.
gelating capability of 1,3,5-cyclohexyltricarboxamide-phenyl-
alanine, this effect can be counteracted.For nongelating ho-
mochiral derivatives, substitution at the acid terminus of the
amino acid with a second amino acid or with hydrophilic R
groups generally leads to the formation of very good hydro-
gelators.
Results
Synthesis: The synthesis of enantiomerically pure homochi-
ral 1,3,5-cyclohexyltricarboxamide-phenylalanine (either lll
or ddd) was carried out according to literature proce-
dures.[12] The products were obtained in good yield.Protect-
ing-group chemistry (Scheme 2) was used for the synthesis
of the heterochiral compounds (lld and ddl).Reaction of
l-phenylalanine methyl ester with 7 (obtained via mono-
Herein we report that changes in chirality effect the gela-
tion behaviour of amino acid-substituted 1,3,5-cyclohexyltri-
carboxamide derivatives in water (Scheme 1), which lead to
novel hierarchical self-assembled systems.In particular, we
show that the enantiomerically pure homochiral 1,3,5-cyclo-
hexyltricarboxamide-phenylalanine derivative (lll or ddd)
is a non-hydrogelator that can be transformed into a good
gelator for water simply by changing the chirality of one of
the three substituents (lld or ddl).The consequences of
the chirality changes made to the structure of this cyclohex-
yltricarboxamide derivative are not only reflected in the ge-
lation behaviour of the system, but are also apparent at the
microscopic level through changes in the gel fibre morphol-
ogy.CD spectroscopy, transmission electron microscopy
(TEM) and gel-to-sol transition-temperature measurements
demonstrate that interactions between homochiral and het-
erochiral derivatives can take place, thus leading to changes
in supramolecular chirality and thermostability of the gels.
Furthermore, we show that although the chirality of the
amino acid plays a very important role in determining the
functionalization
of
cis,cis-1,3,5-cyclohexyltricarboxylic
acid), deprotection to the cyclohexanecarboxylic acid 9, sub-
sequent reaction with d-phenylalanine methyl ester, and fi-
nally hydrolysis of the three methyl esters gave lld-product
11.Switching the l- and d-amino acids in this synthetic
route results in the isolation of the heterochiral ddl-product
12.
Gelation experiments: Gelation tests were carried out by
dissolving the compound of interest in water by heating, and
subsequently allowing the sample to cool.Owing to the pH-
sensitive nature of the synthesized compounds, gelation tests
could also be performed by first dissolving the compound of
interest with 0.1n NaOH, and subsequently adding 0.2n
HCl to cause gelation.The enantiomerically pure homochi-
ral compounds, lll and ddd, did not show gelation behav-
iour in water, nor in a variety of organic solvents, up to a ge-
lator concentration of 15 mm (1 wt%).Soft gels could only
be obtained in ethanol and 2-propanol; in all other solvents
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Hydrogelators
FULL PAPER
Scheme 2.Synthesis of lld.a) Benzyl alcohol, CDI, DMSO/ethyl acetate; b) H- l-Phe-OMe·HCl, Et3N, DMT-MM, MeOH; c) Pd/C, H2, MeOH/iPrOH/
CH2Cl2; d) H-d-Phe-OMe·HCl, Et3N, DMT-MM, MeOH; e) NaOH (aq)/MeOH.CDI: 1,1 ’-carbonyldiimidazole, DMT-MM: 4-(4,6-dimethoxy-1,3,5-tri-
azin-2-yl)-4-methylmorpholinium chloride.
tested, including water, formation of a crystalline needle-
like precipitate could be observed with the naked eye.The
heterochiral compounds, lld and ddl, on the other hand,
are very good gelators for water, yielding clear, homogene-
ous gels which become slightly opaque at high gelator con-
centrations.These compounds possess a critical gelation
concentration (cgc) of 0.5 mm (0.04 wt%) (Figure 1).[19] All
gels displayed very good stability over time, as no changes
were observed in these systems for more than one year.No-
ticeably, the shape of the curve depicting Tgs (that is the
temperature at which the gel turns into a solution) as a func-
tion of the gelator concentration is sigmoidal, whereas for
LMWGs such curves are usually logarithmic.At low gelator
concentrations (0.5–2.0 mm) the phase-transition tempera-
tures are between 20 and 408C, whereas at high gelator con-
centrations (3.0–6.0 mm) Tgs values are around 1208C.This
seems to indicate that distinct gelator aggregates form at
these two different concentration levels.Since a difference
in the clarity of the samples was also observed, turbidity
measurements as a function of the gelator concentration
were performed to see if the parallel between phase transi-
tion temperature changes and aggregation could further be
substantiated.A small but significant jump in turbidity was
observed at around 2 mm (Figure 2), which corresponds
quite well to the concentration at which the large change in
Figure 1.Gel-to-sol transition temperatures ( Tgs) as a function of gelator
Figure 2.Concentration dependent absorption (at 700 nm) of lld gels in
&
^
(
: lld, : ddl) concentration in water.
water.
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A.Friggeri, J.van Esch et al.
Tgs occurred.The presence of different gelator aggregates
was furthermore confirmed by cryo-TEM images of low
(1.0 mm) and high (4.0 mm) gelator concentration gels (see
below).
Mixtures of lld with ddl, lll or ddd, and of ddl with
lll and ddd, of different ratios, respectively, were also
tested for gelation in water.The appearance of the gels ob-
tained was investigated (Table 1).Gels consisting of either
lld or ddl compounds were homogeneous and did not con-
tain any crystalline material at all ratios of the two compo-
nents.On the contrary, mixtures of lld with lll or ddd
(and of ddl with lll or ddd) led to the formation of clear
gels at high percentages of the heterochiral component (i.e.,
the gelator), and to gels containing more and more needle-
like crystals as the percentage of the homochiral component
Figure 3.Gel-to-sol transition temperatures ( Tgs) as a function of gelator
^
concentration for ddl (&) and 1:1 mixtures of ddl and ddd ( ), ddl and
~
lld (”), or ddl and lll ( ) in water.
sample, which can only be ach-
ieved if the non-hydrogelator is
also incorporated into the gel
fibres.
Table 1.Aggregation state and appearance (app). of mixtures of ddl with lll or ddd, and of lld with lll,
ddd, or ddl, at room temperature (RT) in water (total concentration of each sample: 4.5 mm).[a]
lll
App.RT
ddd
App.
lll
ddd
App.RT
ddl
ddl (%)
RT
lld (%)
RT
App.RT
App.
77
71
53
48
32
30
21
g
g
t
t
g
g
c
c
79
64
52
34
32
30
22
g
g
c
c
g
t
g
g
g
g
g
g
g
o
Although the amino acid
chirality in 1,3,5-cyclohexyltri-
carboxamide phenylalanine de-
termines the gelating properties
of the product, this effect can
be overcome by simple changes
to the molecular structure.
Scheme 1 shows a variety of ge-
lators based on 1,3,5-cyclohex-
cg
cg
cg
cg
cg
cg
w
w
w
w
w
w
o
o
o
o
o
o
cg
cg
cg
cg
cg
w
w
w
w
w
cg
cg
cg
cg
cg/p
w
w
w
w
w
cg
cg
cg
cg
cg/p
w
w
w
w
w
[a] g: gel, cg: gel containing crystalline material, p: precipitate, c: clear, t: turbid, w: white, o: opaque.
(i.e., the nongelator) increased. For lld samples containing
lll or ddd, the lowest percentage of lll, which led to the
formation of a gel containing crystalline material, was ap-
proximately 48%; the lowest percentage of ddd was about
36%.These results provide a strong indication that nongela-
tors lll and ddd are the cause of crystallization in the
mixed samples, as presented in Table 1.[20]
yltricarboxamide-l-phenylalanine with the R group being
either a hydrophilic moiety or a second amino acid.All of
these molecules (1–6) are good hydrogelators (Figure 4),
even though the three phenylalanines are of l chirality.[12] In
particular, the gelation tests carried out on compounds 3–6
show that, although some differences in Tgs values occur be-
tween the different gelators, the chirality, or non-chirality, of
the second amino acid does not strongly influence the gela-
tion capability of these molecules.
To determine whether gels containing two components
consist of self-assembled aggregates (generally fibres) in
which both components are present, or of a mixture of ag-
gregates of the individual components, the temperatures at
which the gels turn into solutions (Tgs) were measured.Such
measurements can provide an indication of molecular inter-
actions in LMWG gels.[4,21] Tgs values of mixtures of ddl
and ddd, lld, or lll, as depicted in Figure 3, show that at
low concentrations of ddl the mixed gels exhibit much
higher Tgs values than the pure ddl gel.Analogous results
were obtained with mixtures of lld and ddd or lll (data
not shown).Higher Tgs values are generally obtained for
LMWGs upon increasing the gelator concentration, whereby
a greater number, longer or thicker gel fibres are formed,
making the gel network thermally more stable.However, it
is remarkable that at comparable gelator concentration, for
example, 1.5 mm, the samples that also contain non-hydroge-
lator show much higher Tgs values than the sample contain-
ing only ddl (Figure 3).Therefore, a larger number of gel
fibres, longer or thicker fibres, must be present in the mixed
Circular dichroism studies: CD measurements were per-
formed to determine if the chirality of the different 1,3,5-cy-
Figure 4.Gel-to-sol transition temperatures ( Tgs) as a function of gelator
~
&
^
(1: ”, 2: , 3: À, 4: &, 5: , 6: ) concentration in water.
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Hydrogelators
FULL PAPER
clohexyltricarboxamide phenylalanine compounds is reflect-
ed in the self-assembled gelator aggregates. lld and ddl
gels in water present opposite CD absorptions (as was to be
expected) at 227–228 nm,[22] and a gel consisting of a 1:1
mixture of the two didnꢁt give any CD absorption in this
region (Figure 5).Variable-temperature CD performed on a
cause the sample though liquid still contained some small
gelator aggregates.[24]
CD spectroscopy of gel samples of lld or ddl mixed with
lll and ddd was carried out to determine if interactions be-
tween the gelator and nongelator molecules can be detected
by using this technique.Interestingly, 1:1 gels of gelator lld
and of nongelator lll showed a modest positive CD signal,
whereas both lld and lld + ddd gels gave rise to negative
signals (Figure 7).[25] In a similar fashion, gels of gelator ddl
Figure 5.CD spectra of 24. m m gels of ddl, lld, and ddl+lld 1:1 in
water.
2.40 mm gel of lld showed that the intensity of the CD
signal decreases upon heating of the sample, that is, upon
going from a gel to a solution (Figure 6).The CD signal ob-
Figure 7.CD spectra of 24. m m lld + lll (a) and lld + ddd (c)
hydrogels in 1:1 ratios (inset: spectrum of 2.4 mm lld gel).
with nongelator ddd gave a negative CD signal, whereas
gels of ddl only, or of ddl + lll, gave positive peaks (see
Supporting Information for figure).[25] CD sign inversions
have previously been observed by Shinkai and co-workers
for cholesterol-based gelators in organic solvents, and they
were related to the variable cooling speeds of samples
during gel preparation.[23] However, in this case, all samples
were prepared and handled identically and the CD sign in-
versions observed for duplicate samples were found to be
reproducible.Therefore, these results prove that interactions
are taking place at the molecular level in the gels between
gelators lld and ddl, and non-hydrogelators lll and ddd,
respectively.Such interactions most probably derive from
the incorporation the nongelator molecules into the gel
fibres, as was also suggested from the Tgs measurement re-
sults, thus leading to a change in the morphology of the gels.
With respect to eventual molecular interactions taking place
in a gel containing lld and ddd (or ddl and lll), no
changes in CD sign were observed in the spectra.Such re-
sults are indicative of either a lack of molecular interactions
between these particular gelator and nongelator combina-
tions, which seems highly improbable due to the large
changes observed in the Tgs measurements, or of the fact
Figure 6.Temperature dependent CD spectra of a 2.4 m m lld hydrogel.
served for the gel therefore derives from the chirality of the
self-assembled aggregates making up the gel, and not from
the chirality of the individual gelator molecules.[7,23] Com-
plete loss of the CD signal did not occur even at 908C, be-
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A.Friggeri, J.van Esch et al.
that the CD sign of the mixed gelator/nongelator samples is
determined by the nongelator; that is, mixed samples con-
taining the nongelator lll lead to a positive CD sign, while
samples containing the nongelator ddd lead to a negative
CD sign.The gels were investigated by TEM to clarify this
matter further.
as well as some right-handed
helical fibres, while for a lld +
lll gel left-handed helical
fibres are visible (Figure 10).
Such a change in handedness,
brought about by mixing the
lll component with the lld ge-
lator, confirms the change in
CD sign observed for the same
system (see above).In the case
of ddl, mixing with lll did not
cause changes in the fibre helic-
ity, whereas mixing with ddd
led to the formation of right-
handed helical fibres.There-
fore, it seems that the presence
of the nongelator lll leads to
left-handed helical fibres, and
vice versa for the nongelator
ddd.Interestingly, this behav-
iour has been observed in other
peptide-based aggregates.The
l-chirality of such peptides, al-
Transmission electron microscopy studies: TEM was em-
ployed to obtain visual insight into the gel structure mor-
phology, and to shed light on the interactions between the
different derivatives of 1,3,5-cyclohexyltricarboxamide phe-
nylalanine in the gels.Gels of lld or ddl (2.0 mm) consist
mainly of very long, thin fibre bundles with very uniform di-
ameters of approximately 20 nm (Figure 8).A few thicker
Figure 9.Cryo-TEM images of
1.0 mm (a) and 4.0 mm (b, c)
though the structure is quite lld hydrogels (scale bars:
500 nm).
different from that of 1,3,5-cy-
Figure 8.TEM images 20. m m lld (a, b) and ddl (c, d) hydrogels (scale
bars a and c: 1 mm, b and d: 500 nm).
bundles, 50–80 nm, which seem to arise from the intertwin-
ing of thinner bundles are also present (Figure 8c); fibre
branching was not observed.Considering that each gelator
molecule is approximately 14–15 Š wide, the cross-section
of a gel fibre bundle 20 nm in diameter should therefore
consist of 13–15 monomolecular-thick fibres (primary
fibres).Furthermore, several right-handed fibres can be dis-
tinguished in the Pt-shadowed electron micrographs of the
lld gel (Figure 8a and b), whereas left-handed helices are
present in the ddl gel (Figure 8c and d).To determine
whether gelator concentration affects gel morphology, 1.0
and 4.0 mm gels of lld were investigated by cryo-TEM.Fig-
ure 9a shows that in the 1.0 mm gel fibre bundles of approxi-
mately 15 nm in diameter are mainly present, whereas in the
4.0 mm gel 100–200 nm bundles, deriving from intertwined
thinner bundles, can predominantly be found (Figure 9b and
c).The presence of such larger intertwined bundles at high
gelator concentrations is in excellent agreement with the
higher turbidity and Tgs values observed for these gels.
Figure 10.TEM images of 24. m m lld+ddd (a) and lld+lll (b) hydro-
gels in 1:1 ratios (scale bars: 250 nm).
clohexyltricarboxamide-phenylalanine gelators, leads to b-
sheet ribbons with an intrinsically left-handed twist.[26] Final-
ly, a gel containing the two gelators lld and ddl is observed
to consist mainly of straight, non-helical fibres (see Support-
ing Information for figure), which agrees with the fact that
no signal was observed in the corresponding CD spectrum.
Such a lack of specific fibre handedness could be due to in-
corporation of the two types of gelator molecules, lld and
ddl, within the same fibre.
Discussion
These results highlight the importance of different types of
interactions and their relative contributions with respect to
the gelating capability of a compound in water.In the case
of the homochiral 1,3,5-cyclohexyltricarboxamide-phenylala-
nine (lll or ddd) compounds, molecular interactions occur
Mixing of gelators lld and ddl with nongelators lll and
ddd led to detectable changes in gel fibre morphology that
reflect the results obtained with CD spectroscopy.TEM
images of a gel containing lld + ddd show straight fibres
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Hydrogelators
FULL PAPER
not only in a one-dimensional fashion, but also in two and
three dimensions, thereby causing precipitation of the com-
pound in water.Although a crystal structure of this com-
pound could not be obtained, that of 1,3,5-cyclohexyltricar-
boxamide-l-tyrosine was solved (Figure 11).[12] It can there-
to the intrinsic chirality of their system.They showed that
aggregation occurs via increasingly complex structures and
leads to the formation of fibre bundles (referred to as fi-
brils) of finite width due to the competition stemming from
the free energy gain from the attraction between primary
fibres, and the energy loss from the elastic distortion that
occurs when the twisted fibres aggregate into a bundle of
fibres.In this paper, we have furthermore shown that lld
gels consist of larger fibre bundles deriving from intertwined
thinner bundles (cryo-TEM) at high gelator concentrations.
The transition from the thinner aggregates to the larger
ones follows a sigmoidal relationship as a function of the ge-
lator concentration (see Figures 1 and 2: dropping ball and
turbidity measurements).Such sigmoidal behaviour is simi-
lar to that generally encountered in concentration depen-
dent studies of surfactant solutions, where the cooperative
formation of micelles occur.[27] Evidently, once fibres bun-
dles are formed in lld gels, interactions between bundles
arise that lead to the formation of larger intertwined aggre-
gates.Apparently, a certain bundle concentration is needed
to make the formation of large intertwined bundles more fa-
vourable, in analogy to micellar systems.
Figure 11.X-ray crystal structure of 1,3,5-cyclohexyltricarboxamide- l-ty-
rosine: a) view along the a axis showing the packing of the individual
stacks (arrow: disordered carbonyl, solid circle: hydrophobic area,
dashed circle: hydrophilic area); b) side view of a single stack showing
the intermolecular triple hydrogen bonding motif.
fore be assumed that 1,3,5-cyclohexyltricarboxamide-l-phe-
nylalanine molecules would be arranged in a similar fashion.
The molecules stack through the formation of a triple chain
of intermolecular hydrogen bonds and the individual stacks
are packed hexagonally, giving rise to hydrophobic areas in
which the phenyl rings of neighbouring tyrosines (or phenyl-
alanines) come together.[12] Changing the chirality of one
phenylalanine from l to d causes the molecules to lose their
symmetry, thus assuming a different overall shape.However,
their ability to aggregate in a stack-like fashion remains un-
impaired.The loss of molecular symmetry, or the fact that
the resulting fibres can be constituted of stacked molecules
with either matching (d on d) or different (d on l) chiral
centres above and below each other, gives rise to a more
disordered system which makes crystallization unfavourable,
and thus causes gelation to occur.Similarly, the peripheral
substituents (R groups) of compounds 1–6 also inhibit
strong 2D and 3D interactions from taking place, making
these 1,3,5-cyclohexyltricarboxamide-l-phenylalanine deriv-
atives good hydrogelators in spite of the fact that all three
amino acid have the same chirality.
In the case of homochiral derivatives lll and ddd crystal-
lization occurs independently of concentration; this indicates
that the interactions between the stacks of molecules (in the
second and third dimensions) are energetically favourable.
However, for the heterochiral derivatives lld and ddl, pri-
mary gel fibres form at low gelator concentrations, reflecting
the fact that one-dimensional aggregation is in this case en-
ergetically more favourable than 2D and 3D interactions.
These primary fibres subsequently aggregate into bundles
with very monodisperse diameters of approximately 20 nm.
The formation of such monodisperse aggregates by self-as-
sembling peptides was recently ascribed by Boden et al.[26]
Conclusion
In summary, we have shown how the gelation behaviour of
1,3,5-cyclohexyltricarboxamide phenylalanine derivatives in
water can be controlled by either varying the chirality of
one of the amino acids, or by peripheral functionalization of
the compound with a second amino acid or a hydrophilic
moiety.Whereas homochiral 1,3,5-cyclohexyltricarboxamide
phenylalanine does not gelate water, its heterochiral var-
iants are good hydrogelators.The chiral nature of the inves-
tigated gelators is reflected microscopically in their CD ac-
tivity, and at a macroscopic level in the helical fibre mor-
phologies observed by TEM.These two techniques, as well
as gel-to-sol transition temperature measurements, have
made it possible to conclude that heterochiral gelator and
homochiral nongelator molecules interact with each other
within individual gel fibres.Such interactions can lead to
changes in the gel fibre helicity, and in the gel-to-sol transi-
tion temperatures of the materials.Furthermore, once the
fibre bundles are formed, interactions between them can
also take place.These interactions lead to large intertwined
bundles; their concentration-dependent formation is strik-
ingly analogous to the formation of micelles in surfactant
solutions.The straightforward design of amino acid substi-
tuted 1,3,5-cyclohexyltricarboxamide-based molecules has
enabled us to investigate the apparently serendipitous effect
of chirality on gelation in a methodical fashion, thus obtain-
ing a better understanding of these hierarchical self-assem-
bled architectures.
Chem. Eur. J. 2005, 11, 5353 – 5361
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
5359

A.Friggeri, J.van Esch et al.
tion of the CH2Cl2 resulted in the precipitation of pure 8 as a white solid
(2.80 g, 45%). 1H NMR: d=1.05–1.35 (brm, 3H; CHex), 1.55, 1.70, 1.85
(3”brm, 3”1H; CHex), 2.1–2.4 (brm, 3H; CHex), 2.8–3.1 (m, 4H;
CH2Ar), 3.57, 3.58 (2”s, 2”3H; OMe), 4.43 (m, 2H; CH), 5.08 (s, 2H;
OCH2Ar), 7.17 (m, 10H; Ar), 7.35 (m, 5H; Ar), 8.19, 8.23 (2”d, J=
3.7 Hz, 2”1H; NH); 13C NMR: d=29.7, 35.5, 39.9, 40.6, 40.8, 50.8, 52.1,
52.3, 64.5, 125.4, 126.8, 127.0, 127.1, 127.4, 128.0, 135.1, 136.2, 136.3,
171.1, 172.7, 172.8, 172.9; elemental analysis calcd (%) for C36H40N2O8: C
68.77, H 6.41, N 4.46; found: C 68.55, H 6.43, N 4.72; EI-MS: m/z: calcd
for C36H40N2O8: 628.3; found: 627.4 [MÀH]À.
Experimental Section
General: All chemicals were purchased from Aldrich or Fluka and used
without further purification.NMR experiments were performed by using
a Varian Gemini NMR spectrometer operating at 200 MHz, or a Varian
VXR NMR spectrometer operating at 300 MHz.All spectra were record-
ed in [D6]DMSO unless stated otherwise.MS spectra were measured on
a JOEL JMS-600H or a Science API 3000 mass spectrometer.
Synthesis: The syntheses of compounds 1–3 were carried out according to
literature procedures.[12] Yields were not optimized.
Similarly, with H-d-Phe-OMe·HCl, CHex(Am-d-Phe-OMe)2(COOBz)
was obtained as a white solid (4.00 g, 64%). elemental analysis calcd (%)
for C36H40N2O8: C 68.77, H 6.41, N 4.46; found: C 68.50, H 6.49, N 4.66.
CHex(Am-l-Phe-l-Ala)3 (4): Compound 4 was synthesized according to
literature procedures,[12] by using H-l-Phe-l-Ala-OMe·xTFA (4.8 g,
13 mmol).After the reaction was completed, the precipitate was filtered
off, washed with MeOH, and dried in vacuo to give 4 (0.54 g, 24%).
1H NMR: d=1.03–1.32 (m, 2H), 1.27 (d, 3J=7.3 Hz, 3H; CH3), 2.12
(brm, 1H), 2.68 (t, 1H; CH2), 2.98 (d, 3J=13.9 Hz, 1H; CH2), 4.19 (m,
1H; CH), 4.48 (m, 1H; CH), 7.20 (m, 5H; Ar), 7.97 (d, 3J=9.2 Hz, 1H;
NH), 8.37 (d, 3J=7.0 Hz, 1H; NH); 13C NMR: d = 17.19, 37.54, 42.06,
47.63, 53.34, 126.17, 127.93, 129.17, 138.01, 171.31, 174.01; elemental anal-
ysis calcd (%) for C45H54N6O12·5H2O: C 56.24, H 6.71, N 8.74; found: C
56.38, H 6.51, N 8.60; EI-MS: m/z: calcd for C45H54N6O12: 870.38; found
434.1 [MÀ2)/2]2À, 870.5 [M]À.
CHex(Am-l-Phe-d-Ala)3 (5): Compound 5 was synthesized similarly to 4
by using H-l-Phe-d-Ala-OMe·xTFA (4.8 g, 13 mmol); yield: 0.54 g, 24%;
1H NMR: d=1.08–1.39 (m, 2H), 1.18 (d, 3J=7.3 Hz, 3H; CH3), 2.15
(brm, 1H), 2.72 (t, 1H; CH2), 2.90 (q, 1H; CH2), 4.17 (m, 1H; CH), 4.53
(m, 1H; CH), 7.18 (m, 5H; Ar), 7.92 (d, 3J=9.2 Hz, 1H; NH), 8.28 (d,
3J=7.7 Hz, 1H; NH); 13C NMR: d = 17.47, 31.15, 42.11, 47.38, 53.33,
126.26, 127.93, 129.23, 137.72, 170.95, 173.91; elemental analysis calcd
(%) for C45H54N6O12·4.25H2O: C 57.04, H 6.65, N 8.87; found: C 56.70, H
6.10, N 8.68; EI-MS: m/z: calcd for C45H54N6O12: 870.38; found: 893.5
[M+Na]+.
CHex(Am-l-Phe-OMe)2(COOH) (9): 10% Pd/C (ca.100 mg) was added
to a solution of 8 (2.4 g, 3.82 mmol) in MeOH/iPrOH/CH2Cl2 (100 +
100 + 200 mL); after the addition the mixture was degassed and subse-
quently stirred vigorously under a H2 atmosphere for 3 d.After removal
of the catalyst by filtration (double paper filter) the resulting solution
was evaporated to dryness to give pure 9 as a white solid (2.00 g, 97%).
1H NMR: d=1.1–1.3 (brm, 3H; CHex), 1.55, 1.70, 1.85 (3”brm, 3”1H;
CHex), 2.1–2.3 (brm, 3H; CHex), 2.75–3.1 (m, 4H; CH2Ar), 3.6 (s, 6H;
OMe), 4.42 (m, 2H; CH), 7.20 (m, 10H; Ar), 8.23 (m, 2H; NH), 12.2
(brs, 1H; COOH); 13C NMR: d=24.4, 29.8, 35.5, 40.9, 50.8, 52.3, 125.4,
127.1, 128.0, 136.2, 171.1, 173.0, 174.7; elemental analysis calcd (%)
C29H34N2O8: C 64.66, H 6.37, N 5.20; found: C 64.56, H 6.41, N 5.40; EI-
MS: m/z: calcd for C29H34N2O8: 538.2; found: 539.3 [M+H]+.
Similarly, CHex(Am-d-Phe-OMe)2(COOH) was obtained as
a white
solid (3.13 g, 95%). elemental analysis calcd (%) for C29H34N2O8·1= H2O:
4
C 64.14, H 6.40, N 5.16; found: C 64.13, H 6.52, N 5.19.
CHex(Am-l-Phe-OMe)2(Am-d-Phe-OMe) (10): DMT-MM (0.95 g,
3.60 mmol) was added to a solution of 9 (1.85 g, 3.44 mmol), H-d-Phe-
OMe·HCl (0.78 g, 3.60 mmol), Et3N (0.50 g, 5.00 mmol) in MeOH
(50 mL).The mixture was stirred overnight after which the formed pre-
cipitated was filtered off, washed with MeOH (3”30 mL), and dried to
CHex(Am-l-Phe-b-Ala)3 (6): Compound 6 was synthesized similarly to 4
by using H-l-Phe-b-Ala-OMe ·xTFA (4.6 g, 13 mmol); yield: 1.18 g,
80%; H NMR: d = 1.03–1.40 (m, 2H), 2.14 (m, 1H), 2.32 (m, 2H), 2.71
1
give pure 10 as a white solid (1.09 g, 45%). H NMR: d=1.05–1.80 (brm,
1
6H; CHex), 2.15 (brm, 3H; CHex), 2.75–3.10 (m, 6H; CH2Ar), 3.58 (s,
9H; OMe), 4.43 (brm, 3H; CH), 7.19 (s, 15H; Ar), 8.20 (brs, 3H; NH);
13C NMR: d=30.0, 35.5, 41.1, 50.8, 52.2, 125.4, 127.1, 128.0, 136.2, 171.1,
(t, 1H; CH2), 2.89 (d, 1H; CH2), 3.23 (m, 2H), 4.40 (m, 1H; CH), 7.19
(m, 5H; Ar), 7.94 (d, 3J=8.4 Hz, 1H; NH), 8.07 (s, 1H; NH), 12.24
(brm, 1H); 13C NMR: d = 31.11, 33.79, 34.80, 37.89, 42.14, 53.60, 126.20,
127.95, 129.14, 137.90, 171.30, 172.87, 173.94; elemental analysis calcd
(%) for C45H54N6O12·2H2O: C 59.01, H 6.49, N 9.17; found: C 58.92, H
6.38, N 8.91; EI-MS: m/z: calcd for C45H54N6O12: 870.38; found: 869.3
[MÀH]À.
173.1; elemental analysis calcd (%) for C39H45N3O9·1= H2O: C 66.09, H
2
6.54, N 5.93; found: C 66.16, H 6.48, N 5.99; EI-MS: m/z: calcd for
C39H45N3O9: 699.3; found: 700.2 [M+H]+.
Similarly, CHex(Am-d-Phe-OMe)2(Am-l-Phe-OMe) was obtained as a
white solid (1.64 g, 54%). Elemental analysis calcd (%) for
CHex(COOH)2(COOBz) (7): CDI (37.5 g, 0.24 mol) was added to a solu-
tion of cis,cis-1,3,5-cyclohexanetricarboxlic acid (50 g, 0.24 mol) in a mix-
ture of DMSO (250 mL) and ethyl acetate (1 L).The solution was stirred
for an additional 2 h. Benzyl alcohol (24.8 g, 0.24 mol) was subsequently
added and the mixture was stirred overnight.The main part of the sol-
vent was removed in vacuo.To the remaining viscous solution water
(500 mL) was added and the aqueous fraction was extracted with ethyl
acetate (3”300 mL).The aqueous layer was brought to pH 1 by using 2 n
HCl (aq).The acidified aqueous layer was extracted with ethyl acetate
(3”300 mL) and the combined organic layers were washed with brine,
dried with Na2SO4, and evaporated to dryness to give pure 7 as a white
solid (38.16 g, 52%). 1H NMR: d=1.26 (m, 3H; CHex), 2.09 (m, 3H;
CHex), 2.25–2.65 (m, 3H; CHex), 5.09 (s, 2H; CH2Ar), 7.35 (m, 5H;
Ar), 12.27 (brs, 2H; COOH); 13C NMR: d = 29.3, 29.5, 39.5, 64.5, 126.8,
127.0, 127.4, 135.2, 172.8, 174.5; elemental analysis calcd (%) for
C39H45N3O9·1= H2O: C 66.09, H 6.54, N 5.93; found C 66.00, H 6.41, N
2
5.91.
CHex(Am-l-Phe-OH)2(Am-d-Phe-OH) (11, lld): A suspension of 10
(0.90 g, 1.29 mmol) in a mixture of MeOH (50 mL) and 2n NaOH (aq)
(50 mL) was stirred for 2 d, after which the now-clear solution was fil-
tered, added to H2O (100 mL), and subsequently acidified to pH 1 by
using concentrated HCl (aq).The formed gel precipitate was filtered off,
washed with H2O (3”50 mL), and dissolved in hot MeOH/H2O (5:1, ap-
proximately 400 mL).This solution was evaporated to dryness, the re-
maining solvent was stripped off using a mixture of toluene and MeOH
(1:1, 3”50 mL), and the solid was dried in vacuo to give pure 11 as a
white solid (0.63 g, (74%). 1H NMR: d=1.05–1.70 (m, 6H; CHex), 2.13
(m, 3H; CHex), 2.75–3.10 (m, 6H; CH2Ar), 4.36 (brm, 3H; CH), 7.18 (s,
15H; Ar), 8.04 (m, 3H; NH), 12.6 (brs, 3H; COOH); 13C NMR: d=30.1,
35.5, 41.1, 52.1, 125.3, 127.0, 128.0, 136.7, 172.1, 173.0; elemental analysis
(%) calcd for: C36H39N3O9·2H2O: C 62.33, H 6.25, N 6.06; found: C
62.22, H 5.94, N 6.03; EI-MS: m/z: calcd for C36H39N3O9: 657.3; found:
656.5 [MÀH]À.
C16H18O6·1= H2O: C 60.93, H 6.08; found C 60.94, H 6.01; EI-MS: m/z:
2
calcd for C16H18O6: 306.1; found 306.0 [M]+.
CHex(Am-l-Phe-OMe)2(COOBz) (8):
A
solution of
7
(3.06 g,
10.0 mmol), H-l-Phe-OMe·HCl (4.73 g, 22.0 mmol), Et3N (3.03 g,
30.0 mmol), and DMT-MM[28] (6.08 g, 22.0 mmol) in MeOH (50 mL) was
stirred overnight at room temperature.The resulting precipitate was fil-
tered off, rinsed with MeOH (50 mL), and dissolved in CH2Cl2 (200 mL).
The organic layer was washed with 0.5n HCl (3”100 mL), brine
(100 mL), dried with MgSO4, and evaporated to dryness.The crude prod-
uct was dissolved in CH2Cl2 and MeOH (75 + 110 mL).Slow evapora-
Similarly, CHex(Am-d-Phe-OH)2(Am-l-Phe-OH) (12, ddl) was obtained
as a white solid (0.83 g, 59%). Elemental analysis for C36H39N3O9·H2O: C
63.99, H 6.12, N 6.22; found: C 63.85, H 6.11, N 6.13.
Gelation tests: Gelation was considered to have occurred when a homo-
geneous substance was obtained which exhibited no gravitational flow
upon inversion of the container (generally a glass vial) in which it was
5360
ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 5353 – 5361

Hydrogelators
FULL PAPER
ˇ
found.Gel-to-sol transition temperatures ( Tgs) were determined by using
the “dropping ball” method, which consisted of carefully placing a steel
ball (65 mg, 2.5 mm in diameter) on top of prepared gels in 2 mL glass
vials and subsequently placing these vials in a heating block.[4] The tem-
perature of the heating block was increased by 58ChÀ1 and the Tgs was
defined as the temperature at which the steel ball reached the bottom of
the vial, as observed by a CCD camera.All Tgs measurements were car-
ried out in duplicate or triplicate.The error on Tgs values was Æ58C.All
gels were allowed to stand at room temperature for one week before any
measurements/characterization was carried out.
Caplar, M.Z inic, -JL. .Pozzo, F.Fages, G.Mieden-Gundert, F.
Vçgtle, Eur. J. Org. Chem. 2004, 4048–4059.
[14] J-H. .Fuhrhop, P.Schnieder, J.Rosenberg, E.Boekema,
Chem. Soc. 1987, 109, 3387–3390.
[15] K.Hanabusa, K.Okui, K.Karaki, M.Kimura, H.Shirai,
Interface Sci. 1997, 195, 86–93.
[16] Y.Watanabe, T.Miyasou, M.Hayashi,
1550.
J. Am.
J. Colloid
Org. Lett. 2004, 6, 1547–
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Angew. Chem.
2001, 113, 633–636; Angew. Chem. Int. Ed. 2001, 40, 613–616.
[18] A.R.Hirst, D.K.Smith, M.C.Feiters, H.P.M.Geurts,
J. 2004, 10, 5901–5910.
Chem. Eur.
CD spectroscopy: CD spectra were measured using a JASCO J-715 spec-
tropolarimeter.Gel samples were prepared in closed vials and after
standing at room temperature for one week the gels were transferred to
an optical cell (0.5 mm optical path length) for measurement. Variable-
temperature CD on a 2.28 mm lld gel was carried out by increasing the
temperature in steps of 58C, allowing ample equilibration time, to a max-
imum of 968C to prevent drying out of the samples due to water evapo-
ration.All measurements were carried out in duplicate.No contribution
from linear dichroism was observed, as no change in absorption was mea-
sured when the sample cell was rotated by 908.
[19] The cgc is the lowest concentration of gelator molecules capable of
gelling a liquid at room temperature.[1]
[20] The racemic mixture that was obtained by carrying out the synthesis
with racemic phenylalanine, was also capable of gelating water with
a cgc similar to that of the pure heterochiral gelators lld and ddl.
However, the appearance of the gels was turbid to white, depending
on the concentration, due to the presence of needle-like crystalline
material from the homochiral components, lll and ddd.Such crys-
talline material was observable with the naked eye and was birefrin-
gent when observed by optical microscopy.
[21] H.Kobayashi, K.Koumoto, J.Hwa Jung, S.Shinkai,
PerkinTrans. 2 2002, 1930–1936; A.Friggeri, O.Gronwald, K.J.C.
van Bommel, S.Shinkai, D.N.Reinhoudt, J. Am. Chem. Soc. 2002,
124, 10754–10758; H.Kobayashi, M.Amaike, J.Hwa Jung, A.Frig-
TEM measurements: Samples were prepared by taking a piece of the gel,
placing it on a carbon-coated copper grid (400 mesh), and removing most
of it after 1 min.Samples were shadowed with platinum at a 30 8 angle.
All samples were examined using a JEOL 1200 EX transmission electron
microscope operating at 100 kV.For cryo-TEM measurements, a few mi-
croliters of gel were deposited on a bare 700 mesh copper grid.After
blotting away the excess of liquid the grids were rapidly plunged into
liquid ethane.Frozen hydrated specimens were mounted in a cryo-holder
(Gatan, model 626) and observed in a Philips CM 120 electron micro-
scope, operating at 120 KV.Micrographs were recorded under low-dose
conditions on a slow-scan CCD camera (Gatan, model 794).
J. Chem. Soc.
geri, S.Shinkai, DN. .Reinhoudt,
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[22] The spectra of lld and ddl showed slight differences around the
200–225 nm due to noise that can occur in this spectral region.
[23] K.Murata, M.Aoki, T.Suzuki, T.Harada, H.Kawabata, T.Komori,
F.Ohseto, K.Ueda, S.Shinkai, J. Am. Chem. Soc. 1994, 116, 6664–
6676.
[24] The Tgs of a 2.40 mm lld sample as measured by the dropping ball
method should be between 60 and 1208C.Temperature-dependent
CD spectroscopy was attempted with 3 mm samples, however, no
effect was observed due to the very high temperature necessary to
melt the gel.Experiments at gelator concentrations below 2 m m
were not carried out due to the very small temperature range avail-
able for the measurement. lld solutions did not give rise to CD sig-
nals.
[25] All CD spectroscopy experiments, excluding temperature-dependent
experiments, were carried out at three different concentrations: 1.5,
2.4, and 5.3 mm; however, no significant differences were observed
in the obtained spectra.For mixed gel samples containing gelators
(lld or ddl) and nongelators (lll or ddd) the CD signal intensities
were considerably lower than for samples containing only gelators
(lld or ddl) due to increased turbidity of the mixed samples with
respect to the pure gelator samples.
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Chem. Eur. J. 2005, 11, 5353 – 5361
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
5361