in DMSO-d6 revealed the presence of signals corresponding
to two urea NH groups (see Supporting Information),
indicating that the reaction occurred mainly on the primary
amine of 4-methylamino piperidine. However, the presence
of a small amount of other products resulting from the
reaction of the secondary amino group of the piperidine
moiety cannot be fully discarded. The observed gel dis-
assembly could be tentatively ascribed to the fact that the
basic secondary amino group of the piperidine could also
capture the proton released upon reaction by the primary
amino group, resulting in charged groups that could make
the gel unstable due to electrostatic repulsions.
Scheme 2. Products Obtained after Reaction of Organogel 2
and Diamine c; Rectangles Represent Peptidomimetic Backbone
Bisurea derivatives 3a-e were also prepared by conven-
tional synthesis in refluxing acetonitrile for comparison. For
instance, 4 equiv of the amine was added to a refluxing
acetonitrile solution of compound 2. After a few hours the
suspension was filtered off and exhaustively washed with
acetonitrile to obtain a white solid. The analysis of the
1
compounds by H NMR (DMSO-d6) revealed that they are
indentical to those obtained in the reaction upon a gel for
the cases of 3a, 3b, and 3d. The obtained compounds were
poorly soluble in acetonitrile, and exhaustive heating in a
closed vial was required in order to dissolve them. After a
few minutes at room temperature, strong gels of compounds
3a and 3b were obtained for concentrations in the range of
2 mM. The preparation of gels at a concentration similar to
that employed for compound 2 led to the formation of an
opaque gel with fragments of solid in suspension. In the case
of pyridine-functionalized bisurea 3d, this compound was
not completely soluble even below 1 mM, and the organogel
could not be formed. Thus, in situ gel-to-gel reaction is, in
general, a milder procedure for the preparation of bisurea
gels and, for the case of 3d, the only way to obtain a gel in
acetonitrile.
Scheme 2). Pyridine-functionalized gel 3d was especially
attractive, from a practical point of view, since the free
nitrogen atom could be sensitive to pH and metals. As
expected, reaction of amine d with the organogel 2 gave the
bisurea gel 3d. In these four cases almost quantitative yields
were obtained after few hours as checked by NMR and UV-
vis spectroscopy (measurement of released p-nitrophenolate).
1
Although no starting material was detected by H NMR, a
slight yellow color was observed after dissolution in DMSO-
d6, and in some cases, signals of residual p-nitrophenolate
could be detected. UV-vis quantification was affected by
many experimental errors and has to be taken as approximate.
In most of the cases, yields above 80-90% were calculated.
The most conclusive technique was IR spectroscopy. A
sample of the reaction mixture was spreaded on top of a
NaCl plate and the spectrum was collected. In this case, a
residual band at 1720 cm-1, corresponding to the CdO
vibration of the carbamate in the starting material, could be
observed. However, this band could not be seen when the
gel was isolated from the mixture, exhaustively washed, and
dried (see Supporting Information). Furthermore, the reaction
of compound 2 and propylamine to give 3a was also carried
In the case of the reaction of bifunctional amines c and e
in refluxing acetonitrile, significant differences were found
from the reactions carried out at room temperature in the
gel. Complex mixtures of oligomeric compounds were
obtained after refluxing as revealed by the presence of
multiple and broad signals in their 1H NMR spectra and by
ESI-MS (see, for example, Figure 2 and Supporting Informa-
tion). This constitutes an interesting example of how supra-
molecular organization can modify the outcome of a reaction.
For example, in the case of the reaction of 2 with ethylene-
diamine, the formation of supramolecular aggregates pre-
organizes the system in such a way that cyclization is
favored. Further work is being carried out to better under-
stand this template effect.
1
out in CD3CN and followed by H NMR using TMS as an
internal standard (Figure 1B). It could be seen that after 15
min the reaction was complete since no signals of the
carbamate were observed and signals corresponding to the
release of all of the p-nitrophenolate were quantified.10 These
data also reflect a reinforcement of intermolecular interac-
tions in the newly formed gel since, in difference with the
starting gel, no free gelator molecules in equilibrium with
the gel can be detected upon bisurea formation.
FT-IR studies of both xerogels and solids synthesized
following conventional procedure suggest that, as already
mentioned, the H-bonding interaction is more intense in the
bisurea compounds than in the initial biscarbamates, as
shown by the shift toward lower frequency numbers
experienced by both carbonyl groups (amide and urea)
appearing as a single band centered at 1630 cm-1 in contrast
with the amide CdO in compound 2 that appeared at 1650
cm-1 (see Supporting Information). Remarkably, differences
between the initial gel and the resulting bisurea could be
In the case of 4-methylamino piperidine (e), reaction also
took place in high yield but the gel was progressively
disassembled. Analysis of the reaction products by 1H NMR
(10) The NMR tube was shaken after addition of the amine to avoid
diffusion limitations. It is well-known that diffusion processes are slow in
the gel medium and that the shape of the container also plays an important
role in the strength of the gel. When samples were not shaken, a slow
diffusion of the amine could be detected.
Org. Lett., Vol. 7, No. 22, 2005
4793
Miravet, Juan F.
