Synthesis and organogelating ability of bis-urea pseudopeptidic compounds

Article abstract of DOI:10.1016/j.tet.2013.01.007

A large family of amphiphilic pseudopeptidic derivatives in which the aliphatic tails are connected to the pseudopeptidic moiety through urea functionalities have been prepared with excellent yields. The synthetic procedure is simple and very efficient and allows a modular variation of a large number of structural parameters. The self-assembling properties of the resulting compounds has been studied under different conditions and using different media. Very interestingly, many of the compounds obtained have revealed to act as very efficient organogelators at low concentrations. The resulting gels provide some unusual properties. Of particular relevance are the broad scope of organic solvents that can be gelated and the high thermal stability of the resulting gels. Gels that are stable up to temperatures close to 100 °C can be obtained in some instances.

Full text of DOI:10.1016/j.tet.2013.01.007

Tetrahedron 69 (2013) 2302e2308
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and organogelating ability of bis-urea pseudopeptidic
compounds
*
Jenifer Rubio, Vicente Martí-Centelles, M. Isabel Burguete, Santiago V. Luis
ꢀ
ꢀ
ꢀ
Departamento de Química Inorganica y Organica, Universitat Jaume I, Avenida Sos Baynat, s/n, Castellon, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A large family of amphiphilic pseudopeptidic derivatives in which the aliphatic tails are connected to the
pseudopeptidic moiety through urea functionalities have been prepared with excellent yields. The
synthetic procedure is simple and very efficient and allows a modular variation of a large number of
structural parameters. The self-assembling properties of the resulting compounds has been studied
under different conditions and using different media. Very interestingly, many of the compounds ob-
tained have revealed to act as very efficient organogelators at low concentrations. The resulting gels
provide some unusual properties. Of particular relevance are the broad scope of organic solvents that can
be gelated and the high thermal stability of the resulting gels. Gels that are stable up to temperatures
close to 100 ꢀC can be obtained in some instances.
Received 22 November 2012
Accepted 4 January 2013
Available online 11 January 2013
Keywords:
Pseudopeptides
Organogelators
Urea
Thermal stability
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
displaying a good stability for the gels formed in different media and
at relatively high temperatures is still a challenge.55e58
The preparation of chemical structures with high tech applica-
tions have been attracted the interest among chemists. Molecular
gels are one of these new functional materials,1e8 and the design of
compounds that are able to form robust and stable gels is a chal-
lenge for scientist.9e16
In recent years, the gelation ability of urea derivatives has been
deeply investigated.6,59e70 Urea and their derivatives have been
playing a central role in the field of Supramolecular Chemistry. In
this regard, the urea group contains a number of desirable features,
including its rigidity, planarity, polarity, and hydrogen bonding
capacity.59,71 Thus, for instance, different urea derivatives have
proven to be good receptors for the recognition of anions in sol-
ution72e83 or in the gel state.60,84
Technological and industrial applications reported for organo-
gelators17,18 are very broad and those include their use in fields, such
as cosmetics,19e26 development of separation processes,27,28 novel
NMR techniques based on residual dipolar coupling29e32 or con-
trolled drugs release.19,33e35 Other applications are related to the
preparation of intelligent materials being responsive to external
stimuli,36e44 biocompatible33,45e47 or having a structured poros-
ity.17,27 Essential properties of the gels, particularly organogels, are
mainly based on several parameters: on the one hand, the variety of
solvents in which the gelation process can take place and the mini-
mum concentration of compound that are able to form the gel.48e50
On the other hand, an additional parameter to be considered is the
stability of the gels under different external stimuli.51e53 In general,
a broad range of compounds that can form organogels at 1%
weightevolume or even lower concentrations. However, most re-
ported families of organogelator are only appropriate to gelate a lim-
ited number of organic solvents. In the same way, organogels present,
very often, a limited thermal stability, which can preclude their
technical application in different fields such as cosmetics or drug re-
lease.54 So, the synthesisofnewlow molecular weightorganogelators
Moreover, their potential self-assembling based on the hydrogen
bonding capacity of the urea group makes this type of compounds
useful for the design of new materials.9,10,85 Molecular gels formed
by low molecular weight organogelators or hydrogelators are one of
these new functional materials.1e6,86e88 In recent years, the gelation
ability of urea derivatives has been deeply investigated.6,59e69
Recently, we have prepared and studied different amphiphilic
pseudopeptides containing long aliphatic tails bound to the two
nitrogen atoms of a C2 symmetric pseudopeptides.89 This family of
compounds has shown some interesting properties in terms of their
self-assembly in the solid state,90 as well as in the self-assembly with
quantum dots, allowing their solubilisation in water.90 Although, in
this case, strong organogelating properties were not found, the
utility of amphiphilic peptides to build up strong biocompatible
gelator systems has been demonstrated by different groups.45,91e99
In this regard, our research group has investigated how different
C2 symmetric pseudopeptides have interesting properties as orga-
nogelators.100e103 Here, we present the development of a new
family of amphiphilic in which the long aliphatic tails are bound to
the nitrogen amino atoms of a C2 symmetric pseudopeptide through
* Corresponding author. Tel.: þ34 964728239; fax: þ34 964728214; e-mail ad-
dress: luiss@qio.uji.es (S.V. Luis).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.007

J. Rubio et al. / Tetrahedron 69 (2013) 2302e2308
2303
Table 1
a urea linkage. Those compounds not only present interesting self-
Synthesis of bis-urea pseudopeptidic compounds
assembling properties in the solid state, but also provide a new
family of strong organogelators with improved properties.
Product
Aaa
Yielda
1
2
3
4
5
6
7
8
13a
13b
14a
14b
b-14a
b-14b
d-14a
d-14b
n-14b
15a
Phe
Val
Phe
Val
Phe
Val
Phe
Val
Val
Phe
Val
Phe
Phe
Phe
Val
Phe
Val
Phe
Val
Phe
Phe
Val
Phe
Val
Phe
Val
76
80
81
83
71
85
60
88
95
78
77
66
60
40b
84
80
86
84
66
92
84
60
68
70
91
94
2. Results and discussion
2.1. Design and synthesis of the bis-urea pseudopeptidic
compounds
The bis-urea pseudopeptidic compounds were designed to en-
hance the potential for hydrogen bonding and other polar and
non-polar intermolecular interactions, taking advantage of the
properties of the urea group. The general structure of those com-
pounds contains two amino acid moieties connected through
their acid ends by a flexible spacer, two urea groups at both amino
termini with two hydrophobic tails connected to them, rendering
an overall C2 symmetry. This design allows a implementation of the
different structural elements in order to optimize their potential for
establishing intermolecular interactions (H-bond, dipoleedipole,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
15b
d-15a
d-16a
17a
17b
b-17a
b-17b
d-17a
d-17b
n-17a
18a
18b
19a
19b
20a
pe
p
stacking, hydrophobic contacts, etc.).
The synthesis of the proposed enantiomerically pure bis-urea
pseudopeptidic compounds was carried out following a simple
procedure as depicted in Scheme 1. First of all, the corresponding C2
symmetrical bis(amidoamines) were obtained using previously
reported procedures.104 From those starting materials, the bis-urea
compounds were prepared by a reaction with 2 equiv of different
isocyanates (Scheme 1),105 leading to the expected compounds
in good to excellent yields (Table 1). These yields do not seem
dependent on the structural variations of the starting isocyanate or
the bis(amino amide). In this regard, only in a single case the yield
was low (entry 14 in Table 1), but, most likely this can be associated
with its high solubility in most solvents, which seems to make
difficult, the purification process according to the standard pro-
cedure developed.
20b
a
Isolated yields (%) after purification.
The yield was low, as this compound was the most soluble and it was difficult to
b
purify.
a highly hierarchicalised process to provide very well structure
micro and nano-structures.102
In order to study the ability of the bis-urea compounds to
self-assemble into supramolecular nano-structures in the solid
state we performed Scanning Electron Microscopy (SEM) experi-
ments on slowly evaporated samples (ca. 2 mg/mL) onto aluminum
surfaces. The samples were grown from solvents of different po-
larities such as CHCl3, acetonitrile, MeOH or solvent mixtures in
order to study the effect of the environment in the aggregation
behavior. In general, the most observed nano-structures from
bis-urea compounds were fibers (Fig. 1 and Supplementary data).
Most of the derivatives prepared were only slightly soluble in
the solvents assayed. The single exception to this trend was the
behavior of 17a, showing a good solubility in a variety of solvents. In
this case, very different nano-structures (fibers, tapes or even
spheres) were obtained depending on the solvent used for growing
the samples. Evaporation from polar solvents always afforded the
best defined nano-structures (Fig. 2 and Supplementary data).
In all cases, a general trend can be observed as is that upon in-
creasing the polarity of the solvent, an increment of the presence of
fibers is observed. Moreover, these fibers are also more organized in
polar solvents as can be seen in Fig. 3 and Supplementary data.
In order to evaluate the driving forces behind the association
process of bis-urea compounds under different conditions ATR FT-IR
spectra were recorded. Upon association the vibration of the car-
bonyl bond of the urea group moves to lower wavenumbers, which
can be used as an indicator of the strengths of the hydrogen-bond
interactions involving this group. Thus, as can be seen in Fig. 4
those interactions increase when going from diluted solutions to
the solid state. Only for concentrated solutions the sample start to
become opaque.
Scheme 1. General procedure for the synthesis of the bis-urea pseudopeptidic com-
pounds. Prefixes b-, d-, and n- are used to denote the nature of the aliphatic tails (butyl,
dodecyl, 1-naphthyl); when no prefix is present, a phenyl group is present in that
position.
As can be seen in Table 1, it was possible to synthesize a large
variety of gemini amphiphilic pseudopeptides having both ali-
phatic and aromatic components in three key structural elements:
the central spacer, the amino acid side chain and the substituent at
the amino nitrogen atoms.89
2.2. Ultrastructure in the solid state
In general, all compounds prepared show a low solubility, which
can be associated to the strong tendency to be intermolecularly
associated via hydrogen bonding. Fig. 5 shows the expected
hydrogen-bonding pattern expected for those compounds. It is
worth mentioning that the presence of the urea groups plays a key
role in determining the self-assembling properties of those
The ability of the current knowledge of chemistry for the design
and proper understanding of the structureeproperties relation-
ships in low molecular weight compounds clearly favor the de-
velopment of this kind of gelators. The self-assembling process
leading to the formation of the fibrilar network takes place through

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J. Rubio et al. / Tetrahedron 69 (2013) 2302e2308
Fig. 1. SEM micrographs of: (a) b-14a and (b) d-14a grown from CHCl3; (c) b-14a and
(d) 14b grown from acetonitrile; and (e) 14b and (f) d-14b grown from MeOH.
Fig. 3. SEM micrographs of 14b grown from: (a) CHCl3, (b) CHCl3þ5% MeOH, (c)
CHCl3þ10% MeOH, (d) CHCl3þ20% MeOH, (e) MeOHþ10% CHCl3, and (f) MeOH.
Fig. 4. ATR FT-IR spectra during the evaporation of a solution of compound d-15a in
CHCl3.
2.3. Supramolecular gels formation
Studies in solution using different solvents revealed the capacity
of these bis-urea pseudopeptides to act as efficient organogelators.
In order to get a clearer picture of this ability, a systematic study
was carried out in different solvents. The main results of this study
are gathered in Table 2 and some examples of the obtained gels are
shown in Fig. 7.
Several general trends can be concluded from the data in
Table 2. First of all, the tendency to gelation of different solvents
by the bis-urea pseudopeptidic compounds is the following:
ACN>toluene>MeOH>DMF>DMSO>CH2Cl2>CHCl3. Only in the
case of hexane, gelation could not be accomplished with any of
the bis-urea derivatives studied. Secondly, structural changes in the
central spacer show that compounds with aromatic spacers cannot
form gels (entries 7, 8, 9 and 16, 17, 18 in Table 2). Some related
compounds containing functionalized aromatic spacers have been
reported to have organogelating properties,52 but, in this case, the
property seems to be associated to the presence of the specific
functional groups present in the aromatic subunit. However,
Fig. 2. SEM micrographs of 17a grown from: (a) CHCl3, (b) CHCl3þ20% MeOH, (cee)
MeOHþ20% CHCl3, and (f) MeOH.
compounds. Similar compounds without urea groups, prepared in
our research group, are able to form different nano-structures, but
they are not able to form gels.89,90
MMFF calculations are in a good agreement with this proposed
model. This can be seen in Fig. 6 showing the most stable conformer
calculated for an individual molecule of 14b in the gas phase and
the structure obtained though minimization of a set of four inter-
acting molecules. For the sake of simplicity the model was built
from a molecule containing a short chain bonded to the urea group.

J. Rubio et al. / Tetrahedron 69 (2013) 2302e2308
2305
H
N
H
N
O
O
O
H
N
R
R
R
O
O
O
N
H
N
H
N
H
O
O
O
R
R
R
O
O
O
H
N
H
N
H
N
N
H
N
H
N
H
H
N
H
N
H
N
N
H
N
H
N
H
Fig. 5. General aggregation scheme for the aggregation of bis-urea pseudopeptidic compounds. Hydrogen bonds are devoted by dashed lines.
Fig. 6. MMFF molecular models: (a) most stable conformer 14b, (b) proposed aggre-
gation model of 4 molecules of compound 14b.
Fig. 7. Gels obtained using organic solvents and bis-urea pseudopeptidic compounds.
(a) b-17a in CH2Cl2 (entry 14 in Table 2), (b) d-17b in CHCl3 and (c) in toluene (entry 6
in Table 2), (d) b-14a in acetonitrile (entry 11 in Table 2), (e) d-14a in toluene (entry 12
in Table 2) and (f) d-17a in acetonitrile (entry 15 in Table 2).
Table 2
Gelation behavior of bis-urea pseudopeptidic compounds in different organic
solventsa
Compound DMF DMSO CH2Cl2 MeOH ACN
Toluene CHCl3 Hexane
1
2
3
4
5
6
7
8
9
14b
S
S
I
I
I
S
I
I
I
I
I
I
I
I
I
I
2.4. Thermal stability of the gels
b-14b
d-14b
17b
b-17b
d-17b
18b
G (3.5) G (3.9) I
G (5.4) S
S
G (4.3) G (4.2) I
G (3.1) G (4.8) G (4.7) G (3.4) G (3.4) G (4.2) G (3.5) I
S
S
S
S
S
G (3.2) G (4.1) G (4.5)
G (4.4) G (4.4) G (3.9)
I
I
I
Finally, the thermal stability of the gels was measured using
two different techniques: NMR (Fig. 8) and UVevis (Fig. 9). Both
techniques revealed that the gels show a remarkable thermal sta-
bility, maintaining the gel structure up to high temperatures. In
many cases, the gel structure was kept even at temperatures close to
100 ꢀC.
The NMR spectroscopy is a very useful technique for studying
the melting of supramolecular gels, since the molecules in the gel
state are unobservable by NMR due to relaxation produced line
S
I
I
G (3.9) G (4.5) G (3.9)
S
S
S
S
S
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
19b
20b
10 14a
11 b-14a
12 d-14a
13 17a
14 b-17a
15 d-17a
16 18a
G (5.8) S
G (5.2) G (4.9) G (4.9) I
G (4.3) G (6) G (4.3) G (3.9) G (4.6) G (3.7) G (4.1) I
S
S
S
S
S
S
S
S
S
S
I
I
G (4.9) S
G (5.3) S
G (5.3) G (6) G (5.9) G (5.7) G (6.3) G (5.3) G (5.0) I
S
S
S
S
S
S
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
17 19a
18 20a
a
G: gel (Minimum gelator concentration (g Lꢁ1)); S: soluble; I: insoluble.
compounds containing aliphatic spacers of variable lengths are
able to gelate a wide variety of solvents. This trend is similar for
compounds having both short and long aliphatic central spacers
(entries 2 and 5 in Table 2).39,40
The third trend is the ability of compounds with long hydro-
phobic tails to form gels more efficiently than those bearing short
tails (entries 14 and 15 in Table 2). On the contrary, compounds
with aromatic tails are not able to form gels (entries 1, 7, and 10 in
Table 2).
Finally, it can be observed how the amino acid side chain has
a minor influence on the gelifying process. Similar gels in different
solvents are obtained for Val and Phe bis-urea derivatives (entries 3
and 15 in Table 2).
Fig. 8. 1H NMR (500 MHz) spectra of d-14a in DMSO-d6 at different temperatures.

2306
J. Rubio et al. / Tetrahedron 69 (2013) 2302e2308
Fig. 9. A) Absorbance at 600 nm at different temperatures, B) derivative of the ab-
sorbance at 600 nm at different temperatures, for the gel obtained in DMSO with
b-14b.
broadening. Actually, for the solution-state NMR observation, the
molecules in the fibers of the gel behave as a solid matrix. Thus,
when acquiring the 1H NMR spectra in the gel state, the corre-
sponding proton signals are essentially unobservable, as is illus-
trated in Fig. 8 for d-14a in DMSO-d6 (lower trace). As the
temperature of the sample is raised, the supramolecular in-
teractions responsible for the formation of the gel begin to be
broken, and the molecules of the pseudopeptidic bis-urea com-
pounds start to equilibrate between the two possible states, fibers
and solution. In this situation, molecules in solution can be ob-
servable by NMR. Accordingly, the corresponding proton signals
grow when the temperature is raised (see middle traces in Fig. 8).
Only when the fibers responsible of the formation of the gel are
completely destroyed, a well defined and resolved 1H NMR spec-
trum is observable (upper trace in Fig. 8). In the case shown in
Fig. 8, this situation is achieved above 90 ꢀC.
Similar melting/transition studies can be performed by UVevis
spectroscopy. The formation of a gel structure is, in general, ac-
companied by the appearance of some turbidity (absorbance at
600 nm), or at least by some changes in the observed absorption.
This is eliminated when the gel is completely transformed in a clear
solution. Therefore, the absorbance at 600 nm decreases when the
temperature increases (Fig. 9A), which allows estimating the tem-
perature for the solegel transition (Fig. 9B). Similar results are
obtained by DSC analysis.
Fig. 11. Thermal stability of the gel sunflower oil with d-17b (4 g Lꢁ1) measured
by DSC.
elements in order to obtain compounds displaying the desired
properties. The presence of the urea groups plays a key role in
determining the self-assembling properties of those compounds, as
long as similar compounds without urea groups are not able to
form gels. The resulting amphiphilic compounds have a limited
solubility in many solvents, but show interesting properties re-
garding their self-assembling behavior either in the solid state or in
liquid matrices. The results obtained are clearly different from
those obtained from related amphiphilic derivatives obtained from
the same family of bis(amino amide) pseudopeptidic compounds
but lacking the urea groups. Of particular relevance are the prop-
erties of these compounds as strong organogelators for a variety of
organic solvents. Their use as organogelators provide access to
two important properties that cannot be easily achieved in this
field. First, some compounds of this family are able to efficiently
gelate a large variety of solvents with very different properties.
Even most important is the second property associated to this
family of organogelators: once the gel is formed, its thermal sta-
bility is unusually high. Solegel transition temperatures for
many of those gels, as measured by NMR or UVevis techniques, can
reach values close to 100 ꢀC. Those two elements, combined
with the latent biocompatibility of the molecules here developed,
allows considering a high potential for their use in different tech-
nological applications in the areas of cosmetics, pharmaceutical
compounds, etc.
Compound d-17b was able to form gels with sunflower oil (that
contains mainly triglycerides derived from the linoleic acid and
oleic acid). The thermal stability was measured by the inversion of
tube (Fig. 10) and by DSC (Fig. 11), being in both cases greater than
150 ꢀC. The presence of hydrogen-bonding moieties in the chemical
structure of the oil has a direct effect on the selfassembly of the
gelator molecules and plays key role in the formation of high
temperature stable gels.
4. Experimental section
4.1. General
Reagents and solvents were purchased from commercial sup-
pliers (Aldrich, Fluka or Merck) and were used without further
purification. The C2 symmetrical bis(amidoamines) were prepared
as previously described.104,106
4.2. Electron microscopy
Fig. 10. Thermal stability of the gel sunflower oil with d-17b (4 g Lꢁ1).
Scanning Electron Microscopy was performed either in a LEO
440I or in a JEOL 7001F microscope with a digital camera. Samples
were obtained by slow evaporation of a solution of the compounds
(w1e2 mg mLꢁ1) directly onto the sample holder, and were con-
ventionally coated previous to the measurement. Transmission
Electron Microscopy was carried out in a JEOL 2100 microscope at
120 kV. The micrographs were obtained from w1 mg mLꢁ1 solu-
tions onto a holey carbon copper grid. The samples were sonicated
3. Conclusions
A large variety of bis-urea pseudopeptidic compounds can be
easily prepared from previously developed bis(amino amide)
pseudopeptidic structures with C2 symmetry, using different
commercial isocyanates. The process is highly modular and allows
a
simple sequential modification of the different structural

J. Rubio et al. / Tetrahedron 69 (2013) 2302e2308
2307
for 10 min previous to the measurement, one drop added onto the
grid and collected directly without staining.
C34H36N6O4$H2O: C, 68.87; H, 6.27; N, 13.76; found: C, 68.45; H,
6.70; N, 13.53.
4.3. NMR spectroscopy
Acknowledgements
The NMR experiments were carried out on a Varian INOVA 500
spectrometer (500 MHz for 1H and 125 MHz for 13C) or on a Varian
UNITY 300 (300 MHz for 1H and 75 MHz for 13C). Chemical shifts
are reported in parts per milion using solvent residual peak as
reference.
This work was supported by the Spanish Ministry of Science and
Innovation (CTQ2009-14366-C02), GV (Prometeo/2012/020) and
UJI-Bancaixa (P1-1B-2009-59). J.R. and V.M.-C. thank MICINN for
personal financial support (FPU fellowship).
Supplementary data
4.4. Gelation procedure
General experimental and synthetic procedures, 1H and 13C
NMR spectra, and mass spectra for compounds, SEM micrographs
of compounds from chloroform, acetonitrile, and methanol solu-
tions. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.01.007.
The studied compounds were dissolved in a series of organic
solvents in a screw-capped cylindrical glass vial (diameter: 1 cm),
heated to the boiling temperature of the solvent, and left to cool by
standing at room temperature. A gel was considered to have
formed when the soft material was stable upon turning the vial
upside-down.
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4.5. Infrared spectroscopy
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ꢀC minꢁ1 in nitrogen atmosphere.
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