Cyclohexane bis-urea compounds for the gelation of water and aqueous solutionst

Article abstract of DOI:10.1039/b500837a

A new class of efficient hydrogelators has been developed by a simple modification of the peripheral substituents of cyclohexane bis-urea organogelators with hydrophilic hydroxy or amino functionalities. These bis-urea hydrogelators were synthesised in tw

Full text of DOI:10.1039/b500837a

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A R T I C L E
Cyclohexane bis-urea compounds for the gelation of water
and aqueous solutions†
Maaike de Loos,a Arianna Friggeri,b Jan van Esch,*a Richard M. Kellogga and
Ben L. Feringa*a
a Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of
Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
E-mail: J.H.van.Esch@rug.nl, B.L.Feringa@rug.nl
b BiOMaDe Technology Foundation, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Received 19th January 2005, Accepted 3rd March 2005
First published as an Advance Article on the web 21st March 2005
A new class of efficient hydrogelators has been developed by a simple modification of the peripheral substituents of
cyclohexane bis-urea organogelators with hydrophilic hydroxy or amino functionalities. These bis-urea hydrogelators
were synthesised in two or three steps using an alternative procedure to the common isocyanate method. Gelation
was obtained with organic solvents, water and strongly basic aqueous solutions like 25% ammonia. Hydrogelation
was found to depend on a delicate balance between the hydrophobicity of the alkyl chains, hydrophilicity of the
terminal substituents and the enantiomeric purity of the compound. The hydrogels consisted of a network of fibers,
in which all urea groups are involved in intermolecular hydrogen bonding. Most likely, gelation is driven by
hydrophobic interactions of the methylene units, whereas hydrogen bond formation between the urea groups provides
the necessary anisotropy of the aggregation and the high thermal stability of the gels.
Introduction
Hydrogels find broad applications in, for instance, foods,
pharmaceuticals, biomaterials, cosmetics and personal care
products, and have therefore been studied extensively.1 Most
of the hydrogels reported so far are based on polymers.1
However, as a result of recent developments in the field of low
molecular weight (LMW) organogelators,2 the gelation of water
and aqueous solutions by small molecules has been a topic of
great current interest.3 Examples of LMW hydrogelators include
compounds based on saccharides,4 bile acids,5 amino acids,6
nucleotides,7 nucleosides,8 gemini surfactants9 and dendritic
compounds.10 Most of these compounds are derived from
Fig. 1 Design features for the conversion of a cyclohexyl bis-urea
organogelator into a hydrogelator.
naturally occurring molecules and contain hydrophilic moieties
together with aromatic groups or long hydrophobic alkyl chains.
Owing to these structural properties, many of the hydrogelators
reported so far are amphiphilic. Apart from a few examples,
most of these hydrogelators were found by serendipity rather
than by design.3b Focusing on a more rational approach, we
decided to design a LMW hydrogelator, without the use of
natural building blocks and clear-cut amphiphilic structures,
by exploiting the self-assembling properties of the well-studied
and highly efficient cyclohexane bis-urea organogelators.2b,11
These compounds were developed based on the principle that
gel formation is favoured by anisotropic self-assembly.2b Their
molecular structure can roughly be divided into two parts: the
cyclohexane bis-urea unit, designed to self-assemble in one-
dimensional anisotropic stacks, and the peripheral substituents
(Fig. 1). The peripheral substituents can be varied without
disturbing the self-assembling ability and it is envisioned that
these substituents partly determine the scope of gelated solvents.
So far cyclohexane bis-urea compounds have only been reported
to gelate organic solvents. However, if indeed the peripheral
substituents determine the solvent scope, it should be possible to
convert this typical organogelator into a hydrogelator by simply
modifying these substituents with hydrophilic functionalities X,
such as hydroxy groups, carboxylic acids or amines. A short
hydrophobic spacer between the urea and the hydrophilic groups
might facilitate the formation of intermolecular urea hydrogen
bonds by shielding the urea from the aqueous phase.
In this article we report on the development of hydrogelators
based on these design principles. The synthesis of cyclohexane
bis-urea dialkanols and diaminoalkanes using a method alter-
native to the common isocyanate approach is described. The
gelation behaviour of these compounds will be discussed as well
as the properties of the corresponding gels.
Results and discussion
Synthesis
In general, cyclohexane bis-urea derivatives are prepared by re-
action of trans-1,2-cyclohexanediamine with the corresponding
isocyanate.11,12 The isocyanate in turn can be prepared from the
carboxylic acid via a Curtius rearrangement.13 However, this
synthesis strategy is not suitable for the preparation of cyclohex-
ane bis-urea derivatives with terminal hydroxy or amino groups,
since preparation of the required amino and hydroxy isocyanates
at the reaction temperatures required for the Curtius rearrange-
ment immediately leads to the formation of (poly-)carbamates
and urea.12,14 Recently, the preparation of a,x-isocyanato alka-
nols from amino alcohols has been reported.15 However the
required reagent is not commercially available16 and the obtained
isocyanate could not be isolated because in situ polymerisation
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra for compounds 2a and b, 3a and b, 5a and b. See http://
www.rsc.org/suppdata/ob/b5/b500837a/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9
1 6 3 1
©

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Table 1 Gelation properties of compounds 2–5 in organic solventsa
into polycarbamates readily occurs. These problems could be
circumvented by the use of protected alcohols or amines,
however, this requires additional reaction steps.
Solvents
2a 2b 3a 3b 4a
4b 5a 5b
As an alternative to the reaction of 1,2-cyclohexanediamine
with the desired isocyanato alcohol or amine, the reaction
of an amino alcohol or diamine with trans-1,2-cyclohexa-
nediisocyanate could also be considered. The synthesis of
1,2-cyclohexanediisocyanate under mild conditions has been
reported, however, the desired diisocyanate was isolated in
only 20% yield, whereas a large amount of a cyclic urea by-
product is formed.15a Furthermore, the required reagent is not
commercially available but has to be synthesised using the highly
toxic gas phosgene.
To prevent the formation of the cyclic urea by-product,
the isocyanates can be masked with alcohols in the form of
their corresponding carbamates. It has been known for several
decades that these form urea upon reaction with amines.17
Recently, an extensive study resulted in a mild reaction procedure
in which phenyl carbamates and a variety of amines are em-
ployed with DMSO as solvent.17d Interestingly, the aminolysis of
phenyl carbamates is compatible with numerous functionalities,
including hydroxy groups. This offers the possibility of applying
this reaction in a more direct synthesis of the desired 1,2-
cyclohexane bis-urea alkanols and aminoalkanes.
Hexadecane
p-Xylene
i
i
i
i
i
p
p
p
s
p
p
i
s
i
i
i
10
i
10
20
gp pg
sb
20 gp
s
p
p
i
5
i
i
5
i
p
r
i
—
p
p
Tetraline
p
p
p
p
s
p
p
10 10 20
n-Butyl acetate
Cyclohexanone
1,2-Dichloroethane
DMSO
1-Octanol
i-Propanol
5
p
5
s
p
s
p
p
10
s
p
s
5
pg
p
s
gp (>10)
gp (>10)
r
—
sc
sc
a Abbreviations used: digits: gel formation with minimal gelation
concentration in mg ml−1; i: insoluble at solvent reflux temperature;
p: precipitates; s: soluble at room temperature (solubility >20 mg ml−1);
gp: gel-like precipitate; pg: partial gel; r: reaction with the solvent.
b Precipitation above 20 mg ml−1 c Solubility below 1 mg ml−1
. .
Gelation of organic solvents
At room temperature compounds 2–5, like many other
organogelators, were found to be sparingly soluble in common
organic solvents like ethanol, acetone or chloroform. The
gelation properties were studied by first dissolving them by
heating in the appropriate solvent, followed by cooling to room
temperature. For several of the solid–solvent combinations, the
formation of a gel was observed. The results are shown in Table 1,
in which the solvents are arranged in order of increasing polarity
according to their ET(30)-values.
From Table 1, it can be seen that the gelation of organic
solvents by the dialkanol compounds 2 and 3 exhibits straight-
forward behaviour: compound 2 (pentyl spacer) does not gelate
any of the solvents tested but forms precipitates, whereas
compound 3 (hexyl spacer) forms gels with solvents like tetraline
and 1,2-dichloroethane. Furthermore, both compounds are
soluble in DMSO, a solvent known to break up hydrogen
bonds.18
Apparently, introduction of only one extra carbon atom in the
side chains increased the compatibility of the compound with
the organic solvents to such an extent that gel formation was
obtained in some cases.19 The observed differences in gelation
behaviour could also be due to an odd–even effect,20 however,
preliminary results on dialkyl cyclohexane bis-amides are not
in accord with such an effect.19 Compared to the cyclohexane
bis-urea dialkyl compounds, the gelation ability for organic
Following this strategy, the desired cyclohexane bis-urea
derivatives were synthesised in only two or three straightfor-
ward steps starting from commercially available compounds
(Scheme 1). First the bis-phenyl carbamate 1 was prepared by
reaction of trans-1,2-cyclohexanediamine with phenyl chloro-
formate. The modest yield is compensated by the possibility to
perform the reaction on a large scale (>44 mmol) yielding multi-
gram amounts of 1. Furthermore, compound 1 is very stable and
can be stored at low temperatures for months. Subsequent reac-
tion with the appropriate amino alcohols yielded cyclohexane
bis-urea dialkanols 2 and 3. Unfortunately, the amino derivative
5 could not be obtained via direct reaction of the diamine with
the carbamate, due to difficulties in the separation of the desired
product from the excess diamine employed. However, the use of
a commercially available mono-protected diamine, followed by
one additional deprotection step, did yield bis-urea 5. For all bis-
urea compounds the yields are good, isolation and purification
of the products is straightforward and the reactions can easily be
scaled up. The bis-urea compounds were obtained as white solids
1
and were characterised by H NMR, 13C NMR and elemental
analysis or mass spectrometry.
Scheme 1 Synthesis of the cyclohexane bis-urea dialkanols and diaminoalkanes 2, 3 and 5.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9
1 6 3 2

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solvents has decreased as can be expected upon introduction
of hydrophilic moieties.11
The minimal gelation concentrations for 2a and 3b are
comparable to those reported for other hydrogelators.3 Remark-
ably, compound 3b was able to gelate both water and organic
solvents, a property that was also observed for some other
hydrogelators.4a,d,e,5a,6d,9a
This is supported by the fact that the even more hydrophilic
bis-aminoalkane compound 5 displays a decreased gelation
ability compared to both the cyclohexane bis-urea dialkyl
compounds11 and the dialkanol compound 3. In most solvents
tested, the amino compounds were not soluble and only with p-
xylene was a turbid gel formed. On the other hand, its precursor
4, which contains a hydrophobic t-butyl group as the peripheral
substituent, was able to gelate aromatic solvents, n-butyl acetate
and 1,2-dichloroethane. Furthermore, with the polar solvents, in
most cases aggregation was observed and instead of a gel only
a gel-like precipitate or a partial gel was formed. Compared
to the cyclohexane bis-urea compounds the solvent scope of
4 has decreased and the minimal gelation concentrations have
increased.11 This reduction in gelation ability can be explained by
the bulkiness of the t-butyl groups, which will most likely disturb
the packing of the molecules in the stacks. Furthermore, they
will hinder the formation of additional hydrogen bonds between
the carbamates, which would strengthen the aggregates.
Comparison of the gelation behaviour of the enantiomerically
pure compounds (a) and the racemic compounds (b) does reveal
slight differences depending on the solvent, but clear trends
cannot be observed.
The fact that dialkanols 2a and 3b only form hydrogels
within a very narrow concentration range and exhibit long
gelation times makes them inefficient. Furthermore, it seems
that only water can be gelated and aqueous solutions of salts
are not tolerated. Substitution of the hydroxy groups with more
hydrophilic amino groups to increase the solvent compatibility
is expected to improve the gelation ability for water.21 Indeed,
compound 5 was found to be soluble in hot water and upon
cooling, clear gels were formed within one hour both for the
racemic mixture and the enantiomerically pure compound.
Compared to the long gelation times of diol compounds 2 and 3,
this is a major improvement of the gelation ability. Furthermore,
compound 5 was able to gelate water at concentrations of 5
to at least 20 mg ml−1, which is a much broader range than
those observed for the diol compounds. The minimal gelation
concentrations of the diamine compounds are comparable to
those obtained for other hydrogelators.3 The BOC-protected
precursor 4 was found to be completely insoluble in water as
expected from the lack of terminal hydrophilic substituents.
Encouraged by these results, a series of buffers and basic
aqueous solutions was also tested. The tests revealed that
at pH <7, solutions were obtained, but with several basic
aqueous solutions and buffers, gels were formed (Table 2).
Even with 25% ammonia, clear gels were formed at rather low
concentrations. Interestingly, this is one of the very few examples
of the gelation of such strongly basic solutions.10a Remarkably,
in contrast to most LMW gelators,22 the racemic compound was
found to gelate a broader range of aqueous solutions than the
enantiomerically pure compound.
Gelation of water and aqueous solutions
At room temperature, compounds 2–5 were found to be insol-
uble in water and most aqueous solutions. The hydrogelation
properties of compounds 2–5 were investigated as described for
the gelation of organic solvents and the results are depicted in
Table 2.
At low concentrations, the enantiomerically pure compound
2a was found to form solutions in which a gel-like precipitate
was formed after several weeks of standing. At a concentration
of 10 mg ml−1 a weak, highly turbid gel was formed. A further
increase in the concentration resulted in crystallisation of the
compound. Its racemic counterpart, compound 2b, was found
to be soluble in all tests up to concentrations of 15 mg ml−1 and
at higher concentrations, precipitation was observed.
Elongation of the alkyl spacer with one carbon atom resulted
in a different behaviour. The enantiomerically pure compound
3a formed microcrystals, which were unfortunately not suitable
for X-ray crystallography. However, for its racemic counterpart
3b it was observed that at concentrations between 2–10 mg ml−1
a clear, stable gel was formed. The formation of these gels was
very slow; four to eight weeks of standing at room temperature
is necessary. At higher concentrations, crystalline or non-
crystalline precipitates were formed, depending on the cooling
rate. Gelation tests for compound 3 with a series of buffers
of different pH revealed that neither the enantiomerically pure
compound nor the racemic compound was able to form a gel
with these buffer solutions. Instead, microcrystals were formed.
It should be mentioned that the pH of the obtained hydrogels
did not match the original pH of the applied buffers and
preliminary tests showed that the gels possess a pH of ∼11.
To gain a better insight into the pH sensitivity of the minimal
gelation concentrations, a series of tests was performed in which
the pH of the hydrogel of 5b was decreased stepwise by addition
of aqueous HCl (1N) until the gel turned into a solution. The
pH at this transition point was plotted against the concentration
of the hydrogel (Fig. 2).
Table 2 Gelation properties of compounds 2–5 in water and aqueous
solutionsa
Solvents
2a
2b 3a 3b
4a 4b 5a 5b
Water (demi)
10c sd
c
c
c
c
2–10
c
c
c
c
—
—
—
i
i
5
7
Bufferb pH 8.4
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
10 10
Fig. 2 pH dependency of the gel to sol transition of the hydrogel of 5b.
Bufferb pH 8.4 pH 7.8
Bufferb pH 8.4 pH 6.8
Bufferb pH 8.4 pH 6.0
1N NaOH
25% Ammonia
1N NaHCO3
—
—
—
—
—
—
p
sc
s
20
s
s
It can be seen that the pH of the gel to sol transition
ranged from 11.2 to 10.1 in the measured concentration range.
For each point the amount of neutral, monoprotonated and
diprotonated molecules was calculated using the pKa values of
both amino groups. It was assumed that the amino groups acted
independently from each other, yielding pKa(1) = pKa(2) =
pKa. Using a pKa value of 10.6,23 it was calculated that at
c = 12.5 mM, the amount of neutral molecules was dominant,
c
—
—
—
ge
2
i
5
5
10e
a Abbreviations used, see Table 1; c: crystallization; g: gel formation.
b Buffer system: K2HPO4/KH2PO4 (0.1 M). c Crystal formation in time.
d Precipitation above 20 mg ml−1 e Gelation time of several months.
.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9
1 6 3 3

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whereas at higher concentrations the diprotonated species was
the most abundant molecule. Due to the presence of the double
charge, this species is expected to be highly water soluble and not
able to contribute to gel formation. However, at each point the
total concentration of neutral and monoprotonated molecules
corresponds to or exceeds the minimal gelation concentration
(c = 12.5 mM). Therefore, it is proposed that both the neutral
and the monoprotonated molecules participate in the gelation.
For the enantiomerically pure gels, the pH sensitivity could be
different although this was not investigated.
Thus, it can be concluded that also in the hydrogels of 3b and 5b,
hydrogen bond formation between the urea groups contributes
to the assembly of the molecules.
Additionally, spectra were recorded of D2O gels of the diamine
compounds 5a and 5b.25 In both cases absorptions were observed
at 1610 and 1510 cm−1 for the amide I and amide II bands. These
positions are characteristic for hydrogen bonded urea groups in
which the N–H protons are replaced by deuteriums.24
These FT-IR measurements strongly indicate that, despite the
presence of water, the formation of a hydrogel is accompanied
by the formation of intermolecular hydrogen bonds between
the urea groups. The vibration bands in the freeze dried gels
are observed at positions almost identical to the positions
observed in bis-urea organogels (i.e. 3330 cm−1 for the NH
stretch band and 1632 and 1590 cm−1 for the amide I and II
bands),11 suggesting that the aggregates are similar. However,
in view of results reported in the literature3 it is not very
likely that hydrogen bond formation is the primary driving
force for hydrogelation. Most likely, gelation will be driven
by hydrophobic interactions of the methylene units, whereas
urea hydrogen bonding will provide the necessary anisotropy of
the aggregation and the high thermal stability of the gels (vide
infra).26
Infrared spectroscopy
The gelation of apolar organic solvents by cyclohexyl bis-
urea compounds was found to be driven by the formation of
intermolecular hydrogen bonds between the urea groups.11 The
cyclohexyl bis-urea hydrogelators 2–5 possess the same aggre-
gating unit and therefore it can be expected that hydrogelation
by these compounds is also accompanied by the formation
of intermolecular hydrogen bonds. In water, the detection of
hydrogen bonds by FT-IR spectroscopy is strongly hindered.
Therefore, to study hydrogen bond formation in the hydrogel,
spectra were recorded of freeze dried hydrogels or gels of
deuterated water. In the latter case, replacement of the hydrogens
of the urea group by deuteriums causes a shift of the amide I
and amide II bands to lower wavenumbers.24 The results for
compounds 3 and 5 are shown in Table 3.
Morphology of the gels
First, a FT-IR spectrum of a solution of 3b in DMSO was
measured. Absorptions were observed at 1669 and 1558 cm−1
for the amide I and amide II bands, respectively. The position
The morphology of the gels was studied using Transmission
Electron Microscopy (TEM). Micrographs of tetralin gels of 3a
and 3b and a hydrogel of 3b are shown in Fig. 3. The tetraline
gels of the enantiomerically pure 3a (Fig. 3A) and racemic 3b
(Fig. 3C) show profound differences. The enantiomerically pure
compound displays an unusual morphology, consisting of large
platelets together with tiny twisted fibres at the edges of these
platelets. These fibres were typically 25 nm wide and exhibited
a left-handed twist with a pitch of approximately 100–150 nm
(Fig. 3B). The tetraline gel was found to precipitate overnight
and it is possible that this instability is the origin of the observed
large platelets.
=
of the amide I (C O) band is characteristic for a non-hydrogen
bonded urea group24 and is comparable to the amide I band
observed for solutions of non-hydrogen bonded cyclohexane
bis-urea organogelators.11 Thus it can be concluded that 3b does
not form intermolecular hydrogen bonds in DMSO. However,
the involvement of hydrogen bonding is more difficult to deduce
from the position of the amide II (N–H) band, since it is
located in between the values observed for non-hydrogen bonded
(1540–1565 cm−1) and hydrogen bonded (1565–1590 cm−1) urea
groups.11 In this respect, it should be taken into account that
DMSO is able to act as a hydrogen bond acceptor and it can
be expected that hydrogen bonds are formed involving the N–
H protons of the urea groups. Then it is most likely that the
position of the amide II band will be indicative of an urea group
hydrogen bonded to DMSO. This is also observed for lysine
derived hydrogelators.6g
Subsequently, spectra were recorded for the microcrystals
formed by enantiomerically pure 3a during hydrogelation tests.
Compared to the solution of 3b, the vibration bands of amide
I and amide II bands were shifted and, together with the
NH stretch band, observed at positions characteristic for the
presence of hydrogen bonded urea groups.11,24 Thus, in these
microcrystals the molecules are connected via hydrogen bonds
between the urea groups.
The freeze dried racemic hydrogels formed by 3b and 5b also
had vibration bands for the NH stretch and amide I and amide
II at positions characteristic for hydrogen bonded urea groups.
Table 3 Infrared data of compounds 3 and 5
mmax/cm−1
Compound Sample
NH stretch Amide I Amide II
3a
3b
Crystals from H2Oa
Solution in DMSOb
3331
—
1631 1589
1669 1558
1633 1586
1611 1511
1633 1590
1610 1510
Freeze dried hydrogela 3330
5a
5b
Gel in D2Ob
Freeze dried hydrogela 3330
Gel in D2Ob
—
Fig. 3 Electron micrographs of (A) a tetraline gel of 3a (c = 10 mg ml−1
;
—
25 mM), (B) enlarged section of (A) showing twisted fibres, (C) a tetraline
gel of 3b (c = 10 mg ml−1; 25 mM) and (D) the hydrogel of 3b (c =
2 mg ml−1; 5 mM). The bar represents 1 lm.
a KBr. b Measured between CaF plates.
1 6 3 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9

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The racemic tetralin gel of 3b displays a completely different
morphology that consists of elongated, crystalline like, rigid
fibres. The occurrence of tiny twisted fibres was not observed.
The fibres were flat and could be up to 7 lm long and 80–
500 nm wide. It was observed that the flat fibres were composed
of several layers. No intertwining was observed, although the
fibres were found to split occasionally. The formation of twisted
fibres by an enantiomerically pure compound and flat sheet
like fibres by a racemic compound has also been observed for
other gelators.9a It indicates that the racemic compound does
not separate into two enantiomeric chiral phases, but forms
mixed aggregates. This is in agreement with results obtained
for cyclohexane bis-urea derivatives in organic solvents11d and
can be compared with the chiral bilayer effect as observed for
amphiphiles.4a,27 The hydrogel formed by the racemic compound
3b displays a morphology that is somewhat similar to that of
the corresponding tetralin gel (Fig. 3D). As for the tetralin gel
when elongated, flat fibres are observed with a length of up to
11 lm and a width of 40–500 nm. However, these fibres appear
to be less crystalline and rigid and a clear, fine structure can
be observed. The fibres fuse and split regularly to form the gel
network. Analogously to the tetralin gel, the racemic compound
does not separate into two chiral phases.
derivative displayed a somewhat similar morphology both for
the enantiomerically pure compound 4a (Fig. 4A) and the
racemic compound 4b (Fig. 4B). In both cases, the gel consists
of rigid crystalline like fibres, which appear to be multi-layered.
However, a difference can be found in the dimensions of the
fibres. The fibres in the racemic gel exhibited a length of 2–9 lm
and a width of 80–300 nm. In the enantiomerically pure gel,
the fibres appeared to be shorter and narrower, with a length of
1–6 lm and a width of 50–200 nm. Furthermore, the fraction
of long fibres had decreased and the fibres seem to be more
brittle and fragmented. Possibly, this is related to the fact that
an enantiomerically pure sample is used, which compared to the
racemic gel might lead to an enhanced crystallinity. For both
gels, twisting of the fibres was not observed.
The p-xylene gels of the amine compounds 5a (Fig. 4C) and 5b
(Fig. 4D) displayed morphologies very similar to each other. In
both cases elongated, multi-layered sheets were observed, which
did not intertwine. The length of the sheets was approximately
5–11 lm and the width 60–900 nm. Compared to their BOC-
protected counterparts the aspect ratio of the fibres formed by
5a and 5b has clearly increased.
The hydrogels of the deprotected compounds 5a (Fig. 4E) and
5b (Fig. 4F) displayed completely different morphologies, also
compared to the hydrogel of 3b. Instead of flat, sheet-like fibres,
now in both cases elongated, thin, thread-like fibres are observed
and it seems that these fibres are even more flexible than the fibres
in the gel formed by 3b. The fibres in the enantiomerically pure
gel formed by 5a were up to 10 lm long and 7–50 nm wide.
Often a right-handed twisting of the thin fibres was observed.
The thicker fibres are clearly built up from the thinner fibres.
For the racemic gel the fibres appeared to be thicker with a
length of up to 10 lm and a width of 12–300 nm. As observed
in the gel of 5a, the thicker fibres were built up from thin fibres.
Compared to the enantiomerically pure gel, the fibres in the
racemic gel seemed to be somewhat flattened. Occasionally an
irregular right-handed twist was observed. In both gels the fibres
fuse and intertwine regularly to form a dense network.
The morphologies of the enantiomerically pure and racemic
gels of the BOC-protected derivative 4 in p-xylene and of the free
amine derivative 5 in p-xylene and water are illustrated in Fig. 4.
It was observed that the p-xylene gels of the BOC-protected
Thermotropic properties
The thermotropic properties of the hydrogels of 3b, 5b and 5a
have been investigated by the dropping ball method (Fig. 5).
This method is used to determine the temperature at which the
gel has lost its mechanical stability, i.e. has melted, and is not
able to support a steel ball any more.28 At this point the network
structure of the gel is disrupted, although large aggregates can
still be present. The racemic hydrogel of the bis-urea diol 3b
was found to melt at temperatures between 60 and 96 ◦C,
depending on concentration. Such a concentration dependency
is commonly observed for low molecular weight gelators.2
Fig. 4 Electron micrographs of p-xylene gels of (A) 4a (c = 10 mg ml−1
17 mM), (B) 4b (c = 10 mg ml−1; 17 mM), (C) 5a (c = 10 mg ml−1
(F) 5b (c = 10 mg ml−1; 25 mM). The bar represents 1 lm.
;
;
Fig. 5 Thermal behaviour of one year old hydrogels of 3b (-᭜-) and
fresh hydrogels of 5a (-᭹-) and 5b (-᭺-) as deduced by the dropping ball
method.
25 mM), (D) 5b (c = 10 mg ml−1; 25 mM) and hydrogels of (E) 5a and
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9
1 6 3 5

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The melting temperatures for 3b are higher than the melting
temperatures of the racemic hydrogel of the corresponding
diamine 5b. Apparently, the gels formed by diol 3b are thermally
more stable than the gels formed by diamine 5b. This can be
explained by the fact that the dialkanol 3b is less hydrophilic
than the diaminoalkane 5b and thus is less soluble in water. This
will result in a shift of the gel-to-sol transition towards higher
temperatures. This is consistent with the observed lower minimal
gelation concentrations of 3b.
Interestingly, in contrast to most low molecular weight
gelators, the hydrogel of racemic 5b melts almost independently
of concentration. Furthermore, it was observed that the sample
became more turbid upon heating. This suggests a change in the
aggregation state upon increasing the temperature. After melting
of the gel, a turbid sample remained, which turned into a clear
solution at higher temperatures.
and subsequently fibres leading to gel formation. Interactions
that are too strong and lack of anisotropy result in the formation
of a densely packed crystal phase or precipitate. Gelator–solvent
interactions determine the compatibility of the compound with
the solvent and which solvents are gelated, although gelator–
solvent interactions that are too strong will prevent aggregation
and the solution will remain.
The results suggest that compound 2 acts on the border
between the gel phase and the solution phase. The gelator–
solvent interactions are balanced by the hydrophilicity of the
hydroxy group and the hydrophobicity of the alkyl chains and
the cyclohexyl ring. Due to the hydroxy groups, compound 2
is compatible with water and heating results in dissolution.
However due to the hydrophobic alkyl chains and cyclohexyl
ring, the solubility is not infinite and the compounds tend to
aggregate. Furthermore, the hydrogen bonding urea groups are
shielded from the water by these hydrophobic groups. As a
result of the shielding, hydrogen bond formation can provide
anisotropy and together with the hydrophobic interactions of
the alkyl chains the molecules can assemble into stacks.
At this point the enantiomeric purity of the compound
becomes important. Most likely the racemic compound 2b will
form stacks in which both the enantiomers are packed in an
alternating fashion within the same stack (Scheme 2; top left).11d
The resulting disorder prevents the stacks from assembling
together to form large fibres and the compound will stay in
solution (Table 2). The enantiomerically pure compound 2a will
form translational aggregates, which results in more ordered
stacks (Scheme 2; bottom left).11d These stacks can then assemble
into fibres, which in turn form the gel. Apparently, the gelator–
gelator interactions for this compound are not too strong and
crystallisation is not observed.
For compound 3 the behaviour is completely different and it
is observed that compound 3 acts on the border between the
gel phase and the crystalline phase (see Table 1 and Table 2).
As for compound 2 the hexyl spaced derivative 3 is compatible
with water as can be concluded from the dissolution at elevated
temperatures. However, since the alkyl chains are elongated with
one carbon atom, the hydrophobic part of the compound is
enlarged, resulting in weaker gelator–solvent interactions and
stronger gelator–gelator interactions compared to 2. This will
result in an increased aggregation ability, which is supported
by the observation that upon cooling the compound is not
soluble but forms a gel or crystals. Due to this enhanced
aggregation ability, the gelation behaviour as a function of
the stereochemistry changes. For the enantiomerically pure
compound 3a regular translational aggregates will be formed
which can be densely packed into fibres (Scheme 2).11d The
increased gelator–gelator interactions most likely cause the
fibres to be more crystalline in nature, ultimately resulting in
the formation of crystals.
The enantiomerically pure hydrogels formed by the diamine
5a melt at the highest temperatures and thus are thermally
the most stable. At concentrations above 17 mM, the melting
of the hydrogel of the enantiomerically pure compound could
not be observed because for safety reasons, the heating had
to be stopped at 120 ◦C. At these concen◦trations the racemic
∼
compound had already melted at T
70 C. Such differences
=
between the racemic and the enantiomerically pure mixture can
also be found for cyclohexane bis-urea organogelators.29
It was found that all gels showed thermoreversible behaviour,
i.e. after cooling of the melted samples the gel phase was
regained.
Compared to other hydrogelators,3 the hydrogels formed
by the cyclohexane bis-urea compounds described here are
among the most thermally stable hydrogels. This is most likely
due to the presence of strong intermolecular hydrogen bonds
between the urea groups.
Stereochemical aspects of the gelation ability for water
For the gelation of water, striking differences are observed
between the enantiomerically pure and racemic compounds,
especially for dialkanols 2 and 3. Both compounds are able
to gelate water, however for 2 only the enantiomerically pure
compound forms a gel, whereas for 3 only the racemic mixture
forms a gel. For diaminoalkane 5 it is observed that both the
enantiomerically pure and the racemic compound form a gel,
although with higher minimal gelation concentrations and a
much lower thermal stability for the latter together with a slightly
broader scope. The behaviour of 2 and the higher gelation
concentrations of 5b are in accordance with the general gelation
behaviour observed for small molecules.22 However, the gelation
behaviour of 3 and the broader scope of 5b contrasts with this.
These results can be explained by considering the process of
gelation in more detail (Scheme 2).2b,30
However, for the racemic mixture 3b, stacks are formed in
which both the enantiomers are packed in an alternating fashion
within the same stack (Scheme 2). The disorder in these stacks
will prevent the formation of crystalline fibres and subsequently
crystals. However, compared to compound 2 the gelator–gelator
interactions are stronger and instead of a solution a gel is
obtained.
For compound 5 the differences between the racemic and
enantiomeric pure mixture are more subtle. Due to the increased
hydrophilicity of the amino groups, the gelator–solvent interac-
tions for 5 are somewhat stronger compared to 3. This is reflected
in the lower gel-to-sol transition temperature, higher critical
gelation concentrations and broader scope of gelated aqueous
solutions. The expected disorder in stacks of racemic 5b results in
the observed higher critical gelation concentrations and lower
thermal stability compared to 5a. However for some aqueous
solutions, the disorder of the stacks prevents the formation of
highly crystalline fibres, like for compound 3b, resulting in an
enlarged scope of gelated aqueous solutions.
Scheme 2 The gelation process.2b
The gel is a metastable phase between the crystal phase and the
solution phase, favoured by the presence of units that provide
anisotropic self-assembly, and is balanced by gelator–gelator
interactions and gelator–solvent interactions.2b Gelator–gelator
interactions dictate self-assembly of the molecules into stacks
1 6 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9

View Article Online
(3.0 g, 19 mmol) in CH2Cl2 (16 mL) was added a solution of
trans-(1S,2S)-1,2-diaminocyclohexane (1.0 g, 8.8 mmol) and
(iPr)2EtN (3.0 mL) in CH2Cl2 (20 mL). The suspension was
stirred at room temperature for 18 h and subsequently placed
in a cooling cell for 2 h. The obtained precipitate was filtered
off and washed with cold CH2Cl2 and hexane. The white solid
was dried in a vacuum oven yielding 1a (2.23 g, 6.3 mmol,
72%). dH(DMSO-d6) 1.22 (2 H, bp, 2 chexHax), 1.38 (2 H, bp, 2
chexHax), 1.67 (2 H, bd, 3J 7.3, chexH3,4eq), 1.87 (2 H, bd, 3J 12.1,
chexH2,5eq), 3.32 (2 H, m, chexH1,6), 7.05 (4 H, d, 3J 7.7, 4 ×
Conclusions
In conclusion, a new class of efficient hydrogelators was de-
veloped based on design. The compounds were prepared by a
simple modification of the peripheral substituents of the well-
studied cyclohexane bis-urea organogelators with hydrophilic
hydroxy and amino functionalities. For their synthesis an
alternative method was used by applying phenyl carbamates
instead of isocyanates. This resulted in a straightforward and
easily applicable two or three step synthesis of the cyclohexane
bis-urea dialkanols and diamines.
The compounds are capable of gelating organic solvents,
water and basic aqueous solutions. Their minimal gelation
concentrations are comparable to those reported for other
hydrogelators. The more hydrophilic cyclohexane bis-urea di-
aminoalkane compound is less efficient in the gelation of organic
solvents than the cyclohexane bis-urea dialkanols. In contrast,
the gelation ability for water had increased after substitution
of the hydroxy groups with amines as can be expected from the
increased hydrophilicity. Furthermore, diamine bis-urea belongs
to the very few compounds able to gelate highly basic solutions
like 25% aq. ammonia.10a
Remarkably, the enantiomeric purity of the compounds,
together with the balance between the hydrophilicity of the
hydroxy groups and the hydrophobicity of the alkyl spacers,
had a pronounced effect on the hydrogelation by the dialkanol
compounds.
TEM and FT-IR measurements showed that the hydrogels
of 2–5 consisted of a network of fibers, comparable to the
morphologies observed for cyclohexane bis-urea organogels,11
and all urea groups are involved in intermolecular hydrogen
bonding. The latter finding indicates that water molecules do
not interfere, presumably due to shielding of the urea groups
from the water by the hydrophobic alkyl spacers. Most likely,
gelation will be driven by hydrophobic interactions of the
methylene units, whereas urea hydrogen bonding will provide
the necessary anisotropy of the aggregation and is the origin of
the high thermal stability of the gels.
3
3
PhH), 7.17 (2 H, t, J 7.3, 2 × PhH), 7.35 (4 H, t, J 7.7 Hz,
4 × PhH), 7.68 (2 H, d, 3J 7.3, 2 × NH); dC(DMSO-d6) 24.06,
31.35, 53.79, 121.14, 124.34, 128.80, 150.80, 153.62.
Trans-1,2-bis-phenoxycarbonylamino cyclohexane (1b). Com-
pound 1b was synthesised following the same procedure as de-
scribed for 1a, using phenyl chloroformate (15.1 g, 87.6 mmol) in
CH2Cl2 (80 mL), racemic trans-1,2-diaminocyclohexane (5.0 g,
43.8 mmol) and (iPr)2EtN (15.2 mL, 87.6 mmol) in CH2Cl2
(100 mL), yielding 1b as a white solid (11.7 g, 33.0 mmol,
75%). dH(CDCl3) 1.33 (4 H, bp, 4 chexHax), 1.78 (2 H, bp,
chexH3,4eq), 2.16 (2 H, bp, chexH2,5eq), 3.52 (2 H, m, chexH1,6),
5.40 (2 H, bp, 2 × NH), 7.09–7.38 (10 H, m, 10 × PhH);
dC(CDCl3) 24.58, 32.44, 55.60, 121.42, 125.18, 129.14.
Trans-(1S,2S)-1,2-bis[(5-hydroxypentyl)ureido]cyclohexane
(2a). To a solution of 1a (0.50 g, 1.41 mmol) and 5-
aminopentanol (0.33 g, 3.2 mmol) in DMSO (4 ml) was added
Et3N (0.2 mL). The obtained mixture was stirred at 40 ◦C
for 18 h yielding a white suspension. After cooling to room
temperature, water (10 mL) was added and a thick white
precipitate was obtained which was filtered off and washed with
water and ether. The resulting paste was dried in a vacuum
oven, yielding 2a as a white powder (0.30 g, 0.81 mmol, 57%).
Mp 205 ◦C (dec.); [a]D −4.5 (c 1 g/100 ml in DMSO);
20
dH(DMSO-d6) 1.02–1.43 (16 H, m, 2 × CH2(CH2)3CH2 + 4
3
chexHax), 1.56 (2 H, bs, chexH3,4eq), 1.83 (2 H, bd, J 11.7,
che × H2,5eq), 2.92 (4 H, m, 2 × HNCH2), 3.18 (2 H, bs,
chexH1,6), 3.36 (4 H, m, 2 × CH2OH), 4.35 (2 H, t, 3J 4.9, 2 ×
These results confirm the initial considerations in the design of
the cyclohexane bis-urea organogelators,2b,11 i.e. an anisotropic
self-assembling cyclohexane bis-urea unit combined with pe-
ripheral substituents that govern the solvent compatibility.
3
3
OH), 5.67 (2 H, d, J 6.2, 2 × chexNH), 5.85 (2 H, t, J 5.5,
2 × HNCH2); dC(DMSO-d6) 22.96, 24.40, 29.90, 32.29, 33.01,
39.36, 52.97, 60.67, 158.08; m/z (EI) 372.272 (M+ C18H36N4O4
requires 372.274), 372 (9%), 342 (1), 270 (14), 226 (53), 196 (22),
141 (22), 97 (100), 56 (30).
Experimental
Trans-1,2-bis[(5-hydroxypentyl)ureido]cyclohexane (2b). Com-
pound 2b was synthesised following the same procedure as
described for 2a, using 1b (0.50 g, 1.41 mmol), 5-aminopentanol
(0.32 g, 3.1 mmol) in DMSO (4 mL) and Et3N (0.2 mL), yielding
2b as a white powder (0.31 g, 0.83 mmol, 59%). Mp 185–188 ◦C;
dH(DMSO-d6) 1.06–1.43 (16 H, m, 2 × CH2(CH2)3CH2 + 4
General information
Melting points (uncorrected) were determined using a Stuart
Scientific SMP1 melting point apparatus. FT-IR spectra were
recorded on a Nicolet Nexus FT-IR apparatus. 1H NMR
spectra were recorded on a Varian Gemini-200 (200 MHz)
or a Varian VXR-300 (300 MHz) spectrometer operating at
ambient temperature. Chemical shifts are denoted in d-units
(ppm) relative to the residual solvent peaks (CDCl3 = 7.26;
DMSO-d6 = 2.49; MeOH-d4 = 3.31). J values are given in
Hz. 13C NMR spectra were recorded on a Varian Gemini-200
(50.32 MHz) or a Varian VXR-300 (75.48 MHz) spectrometer.
Chemical shifts are denoted in d-units (ppm) relative to the
solvent peaks (CDCl3 = 76.91; DMSO-d6 = 39.5; MeOH-d4 =
49.0) and converted to the TMS scale. The splitting patterns are
designated as follows: s (singlet), bs (broad singlet), d (doublet),
bd (broad doublet), t (triplet), q (quartet), m (multiplet) and bp
(broad peak). Elemental analyses and mass spectrometry were
performed at the analytical department of this laboratory.
Phenyl chloroformate was purchased from Aldrich. Racemic
and enantiomerically pure trans-1,2-cyclohexanediamine, 5-
aminopentanol, 6-aminohexanol and tert-butyl 6-aminohexyl-
carbamate were purchased from Fluka.
3
chexHax), 1.56 (2 H, bs, chexH3,4eq), 1.83 (2 H, bd, J 12.1,
chexH2,5eq), 2.92 (4 H, m, 2 × HNCH2), 3.18 (2 H, bs,
3
chexH1,6), 3.38 (4 H, m, 2 × CH2OH), 4.33 (2 H, t, J 4.9,
2 × OH), 5.67 (2 H, d, 3J 6.6, 2 × chexNH), 5.84 (2 H, t, 3J 5.7,
2 × HNCH2); dC(DMSO-d6) 22.96, 24.40, 29.90, 32.29, 32.99,
39.36, 52.96, 60.67, 158.07; m/z (EI) 372.272 (M+ C18H36N4O4
requires 372.274), 372 (7%), 342 (1), 270 (10), 226 (37), 196 (44),
141 (20), 97 (100), 56 (30).
Trans-(1S,2S)-1,2-bis[(5-hydroxyhexyl)ureido]cyclohexane (3a).
Compound 3a was synthesised following the same procedure as
described for 2a, using 1a (0.50 g, 1.41 mmol), 6-aminohexanol
(0.36 g, 3.1 mmol) in DMSO (4 mL) and Et3N (0.2 mL), yielding
3a as a white powder (0.27 g, 0.68 mmol, 50%). Mp 210 ◦C
(dec.); (found: C 60.42; H 10.25; N 13.93. Calc. for C20H40N4O4:
C 59.97; H 10.07; N 13.99%); mmax(KBr)/cm−1 3301, 1631, 1589;
dH(DMSO-d6) 1.06–1.40 (20 H, m, 2 × CH2(CH2)4CH2 + 4
3
chexHax), 1.56 (2 H, bs, chexH3,4eq), 1.83 (2 H, bd, J 12.1,
chexH2,5eq), 2.92 (4 H, m, 2 × HNCH2), 3.19 (2 H, bs,
3
Trans-(1S,2S)-1,2-bis-phenoxycarbonylamino cyclohexane
(1a). To a cooled (0 ◦C) solution of phenyl chloroformate
chexH1,6), 3.38 (4 H, m, 2 × CH2OH), 4.32 (2 H, t, J 5.1,
2 × OH), 5.67 (2 H, d, 3J 6.2, 2 × chexNH), 5.84 (2 H, t, 3J 5.5,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9
1 6 3 7

View Article Online
2 × HNCH2); dC(DMSO-d6) 24.35, 25.26, 26.31, 29.98, 32.49,
Trans-1,2-bis[(5-aminohexyl)ureido]cyclohexane (5b). Com-
pound 5b was synthesised following the same procedure as
described for 5a, using TFA (8 mL) in CH2Cl2 (50 mL) and
4b (0.4 g, 0.67 mmol), yielding 5b as a white solid (0.23 g,
0.58 mmol, 87%). Mp 207 ◦C (dec.); mmax(KBr)/cm−1 3300, 1633,
1590; dH(MeOH-d4) 1.28–1.49 (20 H, m, 2 × CH2(CH2)4CH2 +
32.96, 39.30, 52.96, 60.64, 158.04.
Trans-1,2-bis[(6-hydroxyhexyl)ureido]cyclohexane (3b). Com-
pound 3b was synthesised following the same procedure as
described for 2a, using 1b (1.00 g, 2.82 mmol), 6-aminohexanol
(0.72 g, 6.2 mmol) in DMSO (6 mL) and Et3N (0.4 mL),
yielding 3b as a white powder (0.58 g, 1.45 mmol, 51%). Mp
186–190 ◦C; mmax(KBr)/cm−1 3300, 1633, 1586; dH(DMSO-d6)
1.06–1.38 (20 H, m, 2 × CH2(CH2)4CH2 + 4 chexHax), 1.56
3
4 chexHax), 1.74 (2 H, bs, chexH3,4eq), 1.97 (2 H, bd, J 12.1,
chexH2,5eq), 2.61 (4 H, m, 2 × CH2NH2), 3.08 (4 H, m, 2 ×
OCHNCH2), 3.32 (2 H, m, chexH1,6); dC(MeOH-d4) 26.05,
27.76, 31.26, 33.90, 34.41, 40.97, 42.52, 55.26; m/z (EI) 398.337
(M+ C20H42N6O2 requires 398.338), 398 (9%), 368 (5), 283 (9),
239 (10), 196 (5), 160 (45), 143 (38), 97 (100), 56 (52).
3
(2 H, bs, chexH3,4eq), 1.83 (2 H, bd, J 11.4, chexH2,5eq), 2.91
(4 H, m, 2 × HNCH2), 3.18 (2 H, bs, chexH1,6), 3.38 (4 H, m, 2 ×
CH2OH), 4.33 (2 H, bs, 2 × OH), 5.68 (2 H, bs, 2 × chexNH),
5.84 (2 H, bs, 2 × HNCH2); dC(DMSO-d6) 24.42, 25.31, 26.36,
30.04, 32.54, 33.02, 39.30, 52.99, 60.67, 158.09; m/z (EI) 400.306
(M+. C20H40N4O4 requires 400.305), 400 (7%), 370 (1), 284 (10),
240 (37), 196 (31), 141 (20), 97 (100), 56 (34).
Gelation experiments
In a typical gelation experiment, a weighed amount of the
compound under investigation and 0.5 mL or 1.0 mL of the
solvent were placed in a closed vial. The vial was heated
using a heating gun or a heating block until the solid had
dissolved, unless the solvent started to reflux prior to dissolution.
The solution was allowed to cool to room temperature and
was subsequently examined. Gelation was considered to have
occurred when a homogeneous substance was obtained that
exhibited no gravitational flow.
Trans-(1S,2S)-1,2-bis[(N-(tert-butoxycarbonyl)-6-aminohexyl)
ureido]cyclohexane (4a). To a solution of 1a (1.0 g, 2.82 mmol)
and tert-butyl 6-aminohexylcarbamate (1.34 g, 6.2 mmol) in
DMSO (12 mL) was added Et3N (0.6 mL). The obtained
mixture was stirred at 40 ◦C for 48 h yielding a white precipitate.
After cooling to room temperature, water (15 mL) was added
yielding a thick white precipitate which was filtered off and
washed with water and ether. The resulting paste was dried in a
vacuum oven, yielding 4a as a white solid (0.99 g, 1.65 mmol,
59%). Mp 204–205 ◦C; (found: C 60.25; H 9.91; N 14.02. Calc.
for C30H58N6O6: C 60.17; H 9.76; N 14.03%); dH(DMSO-d6)
Tests on pH dependent gelation
Gels with a volume of 0.5 mL or 0.25 mL were prepared as
described above. To the gel was added a small amount (2–
5 lL) of aqueous HCl (1N). The gel was melted by heating and
was subsequently cooled to room temperature. The sample was
examined to determine whether a gel or solution had formed.
The sequence of addition of aliquots of acid, melting, cooling
and examination was repeated until a solution was obtained. At
this point, the pH of the sample was measured.
1.06–1.35 (38 H, m, 2 × CH2(CH2)4CH2 + 4 chexHax
+
3
2 × t-Bu), 1.56 (2 H, bs, chexH3,4eq), 1.81 (2 H, bd, J 11.4,
chexH2,5eq), 2.88 (8 H, m, 2 × CH2(CH2)4CH2), 3.19 (2 H,
3
bs, chexH1,6), 5.67 (2 H, d, J 6.2, 2 × chexNH), 5.84 (2 H,
3
3
t, J 5.3, 2 × HNCH2), 6.74 (2 H, t, J 5.1, HNCO2t-Bu);
dC(DMSO-d6) 24.40, 26.13, 28.26, 29.49, 29.94, 33.01, 40.18,
52.97, 77.26, 155.54, 158.06.
Transmission electron microscopy
Trans-1,2-bis[(N-(tert-butoxycarbonyl)-6-aminohexyl)ureido]
cyclohexane (4b). Compound 4b was synthesised following the
same procedure as described for 4a, using 1b (1.0 g, 2.82 mmol),
tert-butyl 6-aminohexylcarbamate (1.34 g, 6.2 mmol) in DMSO
(12 mL) and Et3N (0.6 mL), yielding 4b as a white solid (1.23 g,
2.06 mmol, 73%). Mp 180–182 ◦C; (found: C 60.28; H 9.99;
N 13.94. Calc. for C30H58N6O6: C 60.17; H 9.76; N 14.03%);
dH(DMSO-d6) 1.06–1.36 (38 H, m, 2 × CH2(CH2)4CH2 + 4
chexHax + 2 × t-Bu), 1.56 (2 H, bs, chexH3,4eq), 1.83 (2 H,
Gels were prepared as described above. Collidon and carbon
coated 400 mesh copper grids were prepared following standard
procedures. A piece of gel was carefully placed on a grid
and shadowed with platinum (angle: 40◦, distance: ∼15 cm).
The samples were examined in a JEOL 1200 EX transmission
electron microscope operating at 80 kV. First patches of gel were
searched for, to be sure that the observed structures originate
from the gel. Micrographs were taken from the periphery of the
gel.
3
bd, J 11.7, chexH2,5eq), 2.88 (8 H, m, 2 × CH2(CH2)4CH2),
3
3.19 (2 H, bs, chexH1,6), 5.67 (2 H, d, J 5.5, 2 × chexNH),
3
5.84 (2 H, t, J 5.3, 2 × HNCH2), 6.75 (2 H, s, HNCO2t-Bu);
Dropping ball measurements28
dC(DMSO-d6) 24.38, 26.12, 28.25, 29.48, 29.94, 32.99, 40.18,
52.96, 77.26, 155.53, 158.06.
Gels with a volume of 1.0 mL were prepared as described above.
A stainless steel ball (63 mg; ∅ 2.5 mm) was placed on top
of the gel and the vial was closed. A series of these sa◦mples
was placed in a heating block that was slowly heated (5 C/h)
while observing the positions of the balls with a video camera
and simultaneously monitoring the temperature by means of
a thermocouple placed in the heating block. Unless stated
otherwise, the melting temperature of the gel was taken as the
temperature at which the steel ball reached the bottom of the
flask.
Trans-(1S,2S)-1,2-bis[(6-aminohexyl)ureido]cyclohexane (5a).
To a solution of trifluoroacetic acid (TFA) (8 mL, 0.11 mol)
in CH2Cl2 (50 mL) was added 4a (0.4 g, 0.67 mmol). The
mixture was stirred for 2 h at room temperature, after which
the solvent and excess TFA were evaporated in vacuo. To the
remaining oil was added a small amount of demi water (3 mL)
and subsequently aqueous NaOH (2N, 50 mL) while stirring
the mixture. A gel mixture was obtained which was filtered off
on a sintered glass funnel (P 4) and washed with water. The gel
residue still contained a considerable amount of water, which
was removed by drying in a vacuum oven, yielding 5a as a white
solid (0.21 g, 0.53 mmol, 79%). Mp 193 ◦C (dec.); mmax(D2O-
gel)/cm−1 1611, 1511; dH(MeOH-d4) 1.28–1.47 (20 H, m, 2 ×
CH2(CH2)4CH2 + 4 chexHax), 1.71 (2 H, bs, chexH3,4eq), 1.97
(2 H, bd, 3J 11.4, chexH2,5eq), 2.61 (4 H, m, 2 × CH2NH2), 3.08
(4 H, m, 2 × OCHNCH2), 3.31 (2 H, m, chexH1,6); dC(MeOH-
d4) 26.07, 27.80, 31.26, 33.74, 34.44, 40.99, 42.48, 55.31, 161.18;
m/z (EI) 398.337 (M+ C20H42N6O2 requires 398.338), 398 (20%),
368 (9), 283 (15), 239 (17), 196 (5), 160 (58), 143 (51), 97 (100),
56 (49).
References
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D. DeRossi, K. Kajiwara, Y. Osada and A. Yamauchi, Plenum
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Boca Raton, 1987.
2 (a) P. Terech and R. G. Weiss, Chem. Rev., 1997, 97, 3133–3160;
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1 6 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9

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3 (a) L. A. Estroff and A. D. Hamilton, Chem. Rev., 2004, 104, 1201–
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30 Attempts to support these differences in packing and thus gelation
behaviour with FT-IR data and DSC measurements have been
unsuccessful so far and SAXS measurements could not be performed
due to the small size of the fibres.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 3 1 – 1 6 3 9
1 6 3 9