Synthesis and characterization of maltose-based amphiphiles as supramolecular hydrogelators

Article abstract of DOI:10.1021/la203447e

Low molecular mass amphiphilic glycolipids have been prepared by linking a maltose polar head and a hydrophobic linear chain either by amidation or copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. The liquid crystalline properties of these amphiphilic materials have been characterized. The influence of the chemical structure of these glycolipids on the gelation properties in water has also been studied. Glycolipids obtained by the click coupling of the two components give rise to stable hydrogels at room temperature. The fibrillar structure of supramolecular hydrogels obtained by the self-assembly of these gelators have been characterized by electron microscopy. Fibers showed some torsion, which could be related with a chiral supramolecular arrangement of amphiphiles, as confirmed by circular dichroism (CD). The sol-gel transition temperature was also determined by differential scanning calorimetry (DSC) and NMR.

Full text of DOI:10.1021/la203447e

ARTICLE
pubs.acs.org/Langmuir
Synthesis and Characterization of Maltose-Based Amphiphiles as
Supramolecular Hydrogelators
María J. Clemente,† Juliette Fitremann,*,‡ Monique Mauzac,‡ Josꢀe L. Serrano,§ and Luis Oriol*,†
†Instituto de Ciencia de Materiales de Aragꢀon (ICMA), Universidad de Zaragoza-CSIC, Dpt. Química Orgꢀanica, Facultad de Ciencias,
Pedro Cerbuna 12, 50009, Zaragoza, Spain
‡Laboratoire des IMRCP, UMR CNRS 5623, B^at. 2r1, Universitꢀe Paul Sabatier, 118 route de Narbonne, F-31062, Toulouse Cedex 9,
France
§Instituto de Nanociencia de Aragꢀon, Universidad de Zaragoza, Dpt. Química Orgꢀanica, Facultad de Ciencias, Pedro Cerbuna 12, 50009,
Zaragoza, Spain
S Supporting Information
b
ABSTRACT: Low molecular mass amphiphilic glycolipids have been pre-
pared by linking a maltose polar head and a hydrophobic linear chain either by
amidation or copper(I)-catalyzed azideꢀalkyne [3 + 2] cycloaddition. The
liquid crystalline properties of these amphiphilic materials have been char-
acterized. The influence of the chemical structure of these glycolipids on the
gelation properties in water has also been studied. Glycolipids obtained by the
click coupling of the two components give rise to stable hydrogels at room
temperature. The fibrillar structure of supramolecular hydrogels obtained by
the self-assembly of these gelators have been characterized by electron
microscopy. Fibers showed some torsion, which could be related with a chiral
supramolecular arrangement of amphiphiles, as confirmed by circular dichroism (CD). The solꢀgel transition temperature was also
determined by differential scanning calorimetry (DSC) and NMR.
’ INTRODUCTION
hydrogelators based on the H-bonding of hydroxyl groups.
Examples of glyco-amphiphiles, conventional single-head amphi-
philes,7 and bolaamphiphiles8 have been described, with interest
focused on the assembled supramolecular structures and their
ability to gel in a mixture of water and alcohol or, in some cases, in
water alone. In the case of conventional single-headed amphi-
philes, mono-9 and disaccharides10 have been used as hydrophilic
polar heads. The cyclic forms of carbohydrates have multiple and
directional hydroxyl groups that provide a strong cooperative
hydrogen bonding network to support the self-assembled fibrous
structure of the gels. The presence of amide groups as linking
units with the hydrophobic tail or the incorporation of aromatic
rings also contributes to the cooperative interactions of glyco-
amphiphiles and consequently to gelation.11 The gelation process
is a consequence of a network resulting from the interpenetration
of nanofibers, which are formed by the bottom-up assembly of
glyco-amphiphiles.12 Amphihilic hydrogels based on carbohy-
drates have been reported, for instance, as drug releasers or
sensors13 and as a means for cell encapsulation.14
A gel can be considered as a viscoelastic solidlike material
composed of an elastic cross-linked network and a solvent, which
is the major component. Macromolecular gels based on polymeric
compounds have been widely studied but interest in supramole-
cular gels has increased in recent years. These types of gels are
formed by the self-aggregation of low molecular weight gelator
molecules, a process that gives rise to a supramolecular structure
that can trap organic or aqueous solvent.1 Self-assembly occurs
through a combination of noncovalent interactions like H-bonding,
πꢀπ stacking, donorꢀacceptor interactions, solvophobic forces,
and van der Waals interactions. This self-assembly allows these
kinds of material to be considered as supramolecular polymers.2
Taking into account the reversibility of these interactions, supra-
molecular gels can be cycled between free-flowing liquids and
nonflowing materials. Furthermore, this reversible behavior can
be triggered by external stimuli such as temperature, pH, or
irradiation.3 Depending on the medium in which the material can
gelate, they have been classified as hydrogels if the solvent is
water4 or organogels in other cases.5 The interest in these soft
materials has also increased in recent years due to their possible
technological applications, mainly as smart materials or biomate-
rials, and they have been explored, for instance, as platforms to
mediate the growth of tissues and as drug delivery systems.6
Carbohydrates provide a rich library of water-soluble, hydro-
philic building blocks, and these can be used in the preparation of
Apart from their ability to self-assemble in solvents, glycolipids
(glyco-amphiphiles) may exhibit liquid crystal (LC) phases due
to the polar asymmetry of these compounds. The head groups
Received: September 2, 2011
Revised:
November 4, 2011
Published: November 07, 2011
r
2011 American Chemical Society
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Figure 1. Chemical structure and nomenclature of the synthesized glycolipids.
Scheme 1. Synthesis of the Functionalized Acetylated Maltose Derivatives
are capable of H-bonding while the alkyl chains self-aggregate into
microsegregated regions. Thermotropic LC phases were first
observed in alkyl glucopyranosides and these compounds are
known to form smectic phases, similar to the lamellar phase formed
in aqueous media, but the number of mesogenic glycolipids having
di- or polysaccharide head groups remains relatively small.15
We report here the synthesis and characterization of new
amphiphilic glycolipids bearing a disaccharide polar head (see
Figure 1) and the study of their liquid crystalline and gel-forming
properties. In a previous study by Fitremann et al., it was
demonstrated that a mixture of isomers of N-palmitoylphenyl-
alanine sucroesters, obtained by direct esterification of sucrose,
can form an “egg-white”-like gel.16 Here, we describe the synth-
esis and properties of similar systems composed of a combination
of maltose as a hydrophilic head and a palmitic fatty chain as a
hydrophobic tail. The polar maltose head and the hydrophobic
chain were connected by amidation or, alternatively, by a copper-
(I)-catalyzed azideꢀalkyne [3 + 2] cycloaddition.17 Further-
more, phenylalanine was incorporated as an alternative in order
to favor the gelification by πꢀπ stacking. The compound Malt-
NH-C16 was described previously18 and this material was
synthesized as a reference in order to assess the influence of
the phenylalanine building block or the triazole ring on the self-
assembly properties. The thermotropic properties of these kinds
of amphiphiles were also studied. The gelation properties either
in water or in mixtures of alcohol and water were also studied.
The supramolecular gel structure was characterized by DSC,
NMR, SEM, TEM, and CD.
between the hydrophilic and the hydrophobic part was ap-
proached using maltose as the starting material. The aim of this
approach was to obtain the product in a reduced number of
steps in a similar way to the previously described sucrose
derivatives.16 The synthesis of maltosylamine was carried out
using ammonium carbonate as an ammonium donor19 or,
alternatively, by the Liskhosherstov method20 using ammo-
nium carbamate instead of carbonate. In both methods an
unstable fluffy product was obtained and the subsequent amide
formation was performed directly without further purification.
Unfortunately, the final pure compound was obtained in very
low yield (5%) by this method (see Supporting Information S1
for experimental details).
In an attempt to increase the yield and facilitate the purifica-
tion of the intermediates, the synthesis of the glycolipids was
accomplished using peracetylated maltose as the starting material,
which was amine-functionalized as shown in Scheme 1 by previ-
ous preparation of glycosyl azides. Maltosylazide 1 was synthe-
sized in a stereoselective manner by treating maltose octa-acetate
with trimethylsilyl azide and tin tetrachloride, as a Lewis acid
catalyst, employing the general procedure described by Paulsen
et al.21 The azide group was reduced to the amine by hydrogena-
tion using a palladium catalyst to yield the acetylated maltosyla-
mine 2 in good yield. This compound can be used in the synthesis
of the target amide derivatives. Alternatively, compound 1 can
react through a 1,3-dipolar cycloaddition, which opens up new
possibilities for the design and preparation of amphiphilic
glycolipids.
Amine derivative 2 can react with palmitic acid or N-palmi-
toylphenylalanine derivatives to give the peracetylated precur-
sors of Malt-NH-C16 and Malt-NH-Phe-C16, as shown in
Scheme 2. In the case of Malt-NH-C16, palmitoyl chloride was
used for the condensation, as described previously,18 and in the
’ RESULTS AND DISCUSSION
Synthesis of Materials. In a first attempt, the synthesis of
glyco-amphiphiles with an amide bond as the connecting group
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Scheme 2. Synthesis of Malt-NH-C16 and Malt-NH-Phe-C16
case of Malt-NH-Phe-C16 dicyclohexylcarbodiimide and hydroxy-
benzotriazole were used for the condensation. Yields in both cases
were around 45%.
Liquid Crystal Properties. The liquid crystal (LC) properties
of carbohydrate amphiphiles have been studied mainly because
this type of compound has similarities with other carbohydrate
related biological systems.15d These compounds have the ability to
self-assemble and undergo microphase segregation due to hydro-
phobic interactions of aliphatic chains and the extensive hydrogen
bonded network formed by the polar carbohydrate heads. The LC
behavior of these compounds and phase transition temperatures
are dependent on the nature of the carbohydrate moiety, the
length of the hydrophobic alkyl chain and the type of linker
between the two parts (e.g., ether, ester or amide bonds). Most of
the glyco-amphiphiles reported to date as liquid crystals are based
on a monosaccharide as the polar head. Different maltose deriva-
tives linked by an ether bond to different alkyl chains have been
found to exhibit a bilayer smectic A phase.23 Maltose derivatives
linked by an amide bond to aliphatic chains have also been studied.
In particular, Malt-NH-C16 was previously reported but the
mesophase was not clearly assigned.18
The thermal properties of the synthesized amphiphilic glyco-
lipids and the peracetylated precursors were studied by thermo-
gravimetric analysis (TGA), polarized light microscopy, and
differential scanning calorimetry (DSC).
The thermogravimetric analysis results are gathered in the
Supporting Information (S4). In peracetylated precursors,
weight loss was observed at temperatures close to 300 °C.
However, thermogravimetric curves for glycolipids display
weight losses at temperatures around 150ꢀ200 °C (in samples
previously dried and immediately analyzed).
In an alternative approach, the linking of hydrophobic chains
derived from palmitic acid can be carried out by a copper(I)-
catalyzed azideꢀalkyne [3 + 2] cycloaddition using compound 1
and propargyl derivatives of palmitic acid. For this purpose, the
propargylamide of palmitic acid (6) and N-palmitoylphenylala-
nine (7) were synthesized. Click reaction22 was carried out in
DMF using CuBr and PMDETA to give the desired product in
around 90% yield (Scheme 3). All of the protected derivatives
were deacetylated at room temperature according to Zempleꢀns
conditions (MeONa and Amberlyst IR120 in anhydrous
MeOH) to give the final product in almost quantitative yield.
All compounds were characterized by 1H, 13C NMR, IR and
mass spectrometry. Bidimensional NMR experiments (COSY,
TOCSY, NOESY, HSQC, and HMBC) were performed in order
to corroborate the chemical structure of the glycolipids. Ele-
mental analysis was performed on peracetylated derivatives OAc-
Malt-NH-C16, OAc-Malt-NH-Phe-C16, OAc-Malt-Tz-C16, and
OAc-Malt-Tz-Phe-C16. In the case of unprotected derivatives
(Malt-NH-C16, Malt-NH-Phe-C16, Malt-Tz-C16, and Malt-Tz-
Phe-C16) elemental analysis was also performed but the water
content led to discrepancies between the results and the calcu-
lated values. The exact masses were determined by mass spectro-
metry, in addition to the other spectroscopic studies, and the
results confirmed the proposed structures of these materials (see
Supporting Information S2 and S3).
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Scheme 3. Synthesis of Malt-Tz-C16 and Malt-Tz-Phe-C16
Table 1. DSC Thermal Cycles in a Nitrogen Atmosphere
(10 °C minꢀ1
)
3
compound
thermal transition (°C) [ΔH] (kJ/mol)a
Malt-NH-C16
Cr 49 [6.2] Cr0 67 [5.0] (cold crystallization 75)
Cr00 144 [2.3] SA
b
SA 62 [3.3] K0 39 [6.9] Cr
Malt-NH-Phe-C16
Cr 24 [3.7] (cold crystallization 80) Cr0
b
127 [7.7] SA
SA 11 [2.2] Cr
Cr 31 [2.0] Cr0 49 [6.2] SA
b
Malt-Tz-C16
SA 25 [9.18] Cr
Cr 45 [3.0] Cr0 142 [4.0] SA
b
Malt-Tz-Phe-C16
Figure 2. Microphotograph of Malt-Tz-C16 taken at 130 °C.
SA 120 [12.5] Cr0 25 [1.6] Cr
a Data corresponding to the second heating and cooling scan. Cr =
crystal, I = isotropic phase, SA = smectic A phase (according to X-ray
data). b The heating cycle was only carried out up to 150 °C to avoid
decomposition, which occurs before isotropization.
The peracetylated precursors were studied by polarized optical
microscopy as a function of temperature and mesomorphic
behavior was not observed, with all compounds melting directly
from a crystalline state to an isotropic liquid (see Supporting
Information S5). However, the final glycolipids exhibited bi-
refringent textures associated with thermotropic liquid crystal-
line behavior. The poorly defined birefringent texture of the
viscous mesophase (see Figure 2) cannot be unambiguously
assigned, but it can be postulated that the mesophase is lamellar
based on previous results on thermotropic glycolipids with a
similar structure. Decomposition of glycolipids was observed by
optical microscopy at temperatures around 170 °C and the
sample became brown around this point, most probably due to
decomposition of the sugar unit.
the second and successive scans were reproducible and the
transition data (both in heating and cooling scans) are gathered
in Table 1. In all cases, broad transition peaks were observed and
traces of water were detected, even after drying under vacuum.
Malt-NH-C16 was previously characterized as a glassy material
with a transition from a glass to a mesophase (the nature of the
mesophase was not described) at around 141 °C.18 On heating,
however, this compound exhibits (once it has been cooled from
150 °C) two endothermic peaks (probably due to crystalline
polymorphism) followed by an exothermic transition that can be
assigned to a cold crystallization. Finally, the compound melts at
around 145 °C into a highly viscous mesophase. On cooling, this
compound crystallizes at around 60 °C. Consequently, the
A DSC study of the glycolipids was performed by heating the
compounds to 150 °C (maximum) in order to minimize the
thermal decomposition of the samples. Under these conditions
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Table 2. Solubility and Gelation Properties of Synthesized
Glycolipids in Different Solvents at 1 wt %, after Heating and
Cooling Down to RTa
Malt-
Malt-NH-
Phe-C16
Malt-
Malt-Tz-
Phe-C16
solvent
hexane
NH-C16
Tz-C16
I
I
I
I
ethyl acetate
tetrahydrofuran
dichloromethane
acetone
I
I
I
I
P
I
I
S
I
I
I
I
I
I
I
I
methanol
P
I
P (Gb)
S
P(Gb)
Gc
water
I
G
Figure 3. Hydrogel of Malt-Tz-C16 (1 wt %).
water/methanol
P
G (3:2)d
not tested
G (3:1)e
dimethyl sulfoxide
S
S
S
S
a I = insoluble, P = precipitate, S = solution, G = gel. b Gels are formed at
in water to form a homogeneous gel, as can be observed in
Figure 3, at a minimum concentration of 1 wt % and in the
absence of other organic solvents. Malt-Tz-Phe-C16 also formed
a stable gel in water at 1% but it was found to be inhomogeneous
as some precipitate was observed within the gel structure once it
had cooled. The addition of methanol as an organic solvent led to
the formation of a homogeneous and stable gel (in a mixture of
water/methanol 3:1). Malt-NH-Phe-C16 can also gelate in a
mixture of water/methanol (3:2) but in this case a larger amount
of methanol was required to achieve complete solubilization
upon heating. In all cases gels are thermoreversible, having a
gelꢀsol transition at around 60ꢀ80 °C, and they are stable at RT
(for additional gel photos see Supporting Information, S7). Malt-
NH-C16 did not form gels even with a 1:1 proportion of water
and methanol. The ability of Malt-Tz-C16 to gel in pure water
instead of alcoholic mixtures led us to focus our attention on this
compound.
higher concentrations (2.5ꢀ5% wt) and upon cooling in a fridge.
e
c See text. d 5 mg in 0.3 mL of water and 0.2 mL of methanol. 3 mg
on 0.3 mL of water and 0.1 mL of methanol.
compound is crystalline up to ca. 145 °C and it finally melts to give
a mesomorphic liquid. The analogue Mal-NH-Phe-C16 shows
similar thermal behavior, but in this case the melting point of the
crystalline solid formed by cold crystallization is around 130 °C.
The thermal behavior of Malt-Tz-Phe-C16 is similar except that
cold crystallization is not observed for this compound and the
melting transition occurs at around 140 °C. However, in the case
of Malt-Tz-C16, the peak corresponding to the melting transition
is depressed and was observed at around 50 °C. Above this
temperature the sample is highly viscous and difficult to character-
ize by optical microscopy. Nevertheless, at temperatures above
approximately 90 °C the sample becomes more fluid and can be
clearly characterized as liquid crystalline according to the optical
observations. In all cases, decomposition was observed in the
mesomorphic state at temperatures above approximately 170 °C
either by optical microscopy or DSC (deviation of baseline).
In an effort to identify the mesomorphic phase, XRD studies
were carried out on the glyco-amphiphile Malt-Tz-C16 as a
representative example. X-ray patterns were recorded at 65 °C
for 4.5 h on samples previously heated to 150 °C in order to
develop the mesophase. Bragg reflexions in the low-angle region
were found that were related to second, third and fifth order. The
lamellar spacing was measured close to 51 Å, which indicates an
interdigitated bilayer Smectic A phase (see Supporting Informa-
tion S6). In the high angle region a diffuse, broad maximum was
found along with several slightly sharper peaks. These peaks were
observed more clearly when the experiment was performed at
150 °C. This fact leads us to suggest that some degradation
occurred during the experiment.
Thermal transitions of gels of Malt-Tz-C16 were studied by
DSC (under a nitrogen atmosphere, 10 °C minꢀ1). In the first
experiment, 5 wt % of solid Malt-Tz-C16 was dispersed in water.
In this case, an endotherm was detected at 66 °C. A thermal peak
was not observed in the cooling scan. On the second heating, a
broad peak was observed at around 65 °C and this could be due
to the gelꢀsol transition. In order to confirm that this peak
corresponds to the solꢀgel transition, a preformed hydrogel of
Malt-Tz-C16 (1 wt %) was directly studied by DSC (5 °C minꢀ1
,
Figure 4a). An endothermic peak was detected at around 65 °C
but a peak was not observed on cooling. However, in the second
heating scan the peak corresponding to the gelꢀsol transition
was again observed, which confirms the reversibility of this
transition. NMR experiments also provide information about
gelꢀsol transitions. On heating progressively a gel sample of
Malt-Tz-C16 at 1 wt % in D2O the spectrum was fully resolved
above 70 °C, the temperature at which a clear solution is obtained
(see Supporting Information S8).
Gel Properties. The solubility and gelation ability of the
amphiphilic glycolipids were examined in different solvents by
dissolving 5 mg of compound in about 0.1ꢀ1 mL of the solvent
(i.e., 0.5ꢀ5 wt %). Glycoamphiphiles are not soluble at room
temperature (RT) in the selected solvents, except DMSO.
However, in some of the selected solvents, the glycolipids
eventually dissolved on heating. The solution was then cooled
down to RT, and either a solution, a precipitate, or a gel was
observed depending on the solvent. The results are summarized
in Table 2 for mixtures with 1 wt % of the sample.
The hydrogel derived from Malt-Tz-Phe-C16 at 1 wt % was
also studied by DSC (5 °C minꢀ1) and two peaks were detected
on heating (Figure 4b, top). This observation could be due to the
presence of a partial precipitate. The first peak could correspond
to a solubilization transition similar to those observed for
surfactants that display a Krafft temperature.24 A second en-
dotherm is measured at higher temperature and this corresponds
to the gelꢀsol transition of the gel. DSC measurements (5 °C/
min) on the gel formed in a water/methanol/water (3:1) mixture
(Figure 4b, bottom) show a peak at around 75 °C corresponding
to the gelꢀsol transition (a small transition can be detected at
It can be seen that only the compounds that contain a triazole
ring give rise to gels in aqueous solution. Malt-Tz-C16 can gelate
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Figure 4. Second DSC thermal cycle in a nitrogen atmosphere (5 °C minꢀ1): (a) Malt-Tz-C16 at 1 wt % water, heating scan (top) and cooling scan
(bottom), (b) Malt-Tz-Phe-C16 at 1 wt % in water, heating scan (top) and at 1 wt % in a mixture of water/methanol 3:1, heating scan (bottom).
πꢀπ interactions. However, these molecules are more hydro-
phobic and the presence of an organic cosolvent is required for
complete solubilization and subsequent gel formation on cool-
ing. Therefore, in the design of these gelators the presence of the
triazole as a linking unit between the hydrophobic and hydro-
philic parts seems to play an important role both for the
formation of the supramolecular network and also for ensuring
an appropriate solubility in water.
Malt-Tz-C16 self-assembled in water to give homogeneous
gels at concentrations above 1 wt % and a study of the lyotropic
Figure 5. Lyotropic phase observed by optical microscopy on a sample
properties of this material was therefore carried out by the
contact method.15d,27 The sample was heated to 120 °C
(mesophase) and then cooled to RT. A small amount of water
was then placed on the slide at the edge of the cover glass and this
completely surrounded the sample. The slide was placed again
for a few seconds on the hot stage at 80 °C and the phase
behavior was immediately investigated by polarizing optical
microscopy. A concentration effect was observed, as can be seen
in Figure 5. A birefringent texture appeared on a gradient of water
from pure liquid to solid glass state and this is due to a lyotropic
phase with a lamellar organization. However, a precipitate finally
appeared over time.
Electron Microscopy. The self-assembled structure of the gels
derived from Malt-Tz-C16, Malt-Tz-Phe-C16, and Malt-NH-
Phe-C16 were studied by electron microscopy (SEM and TEM),
which revealed the typical fibrillar network that characterizes the
supramolecular gels (see Figure 6).
SEM measurements on the xerogel obtained from Malt-Tz-C16
(gel in water) show a fibrillar structure with a diameter of around
80 nm and a length of several micrometers (Figure 6a). Gels
derived from compounds with phenylalanine, that is, Mal-Tz-Phe-
C16 (water or water/methanol) and Malt-NH-Phe-C16 (water/
methanol), also display fibrillar structures by SEM, with estimated
diameters of around 80ꢀ200 nm (see Suporting Information S9).
These fibers can also be measured by TEM (see Experimental
Section), but in this case, a dilute solution of the gel must be used.
In Malt-NH-Phe-C16, the same diameter was found as in SEM
images, that is, around 150 nm (Figure 6f), but in the cases of
Malt-Tz-Phe-C16 and Malt-Tz-C16 the estimated diameters were
smaller: around 15 nm for Mal-Tz-Phe-C16 in water (Figure 6d)
and 40ꢀ80 nm for Mal-Tz-Phe-C16 in water/methanol
(Figure 6e) and 40 nm for Malt-Tz-C16 (Figure 6b). This finding
is consistent with the presence of bundles of fibers of tens of
nanometers that are further interpenetrated to form the physical
network and make the immobilization of the solvent possible.
of Malt-Tz-C16 in water prepared by the contact method: (a) with
polarizers, (b) without polarizers. The concentration increases from left
to right; the solid glycolipid sample is shown on the right side.
around 65 °C, probably due to slight insolubility). DSC mea-
surements (10 °C minꢀ1) on a gel of Malt-NH-Phe-C16
obtained in a mixture of water/methanol (3:2) also show a
single peak at around 80 °C and this corresponds to the solꢀgel
transition. In all cases, subsequent heating scans confirmed the
reversibility of these transitions.
Compounds with phenylalanine (Malt-NH-Phe-C16 and
Malt-Tz-Phe-C16) can gelate in methanol, albeit at a higher
concentration (2.5ꢀ5%), and on cooling the solution in a
freezer. Under other experimental conditions, a swollen trans-
parent precipitate is obtained that is not sufficient to entrap all
the solvent.
It has been reported that two of the driving forces that can
favor gel formation are H-bonding and πꢀπ stacking of aromatic
rings.4 The different behavior of Malt-Tz-C16 and Malt-NH-C16
highlights the effect of the triazole ring. This group can provide
πꢀπ stacking interactions. Hence, an upfield shift in the NMR
signal of the H of the triazole ring is detected by adding water to a
DMSO solution, which indicates the contribution of πꢀπ
stacking to the aggregation of the amphiphiles as it has been
previously reported25 (see 1H NMR experiments in Supporting
Information S9). Moreover, a simultaneous downfield shift of the
1
NH signal in H NMR spectra is also detected, which can be
assigned to self-assembly through hydrogen bonding.25b Further-
more, the triazole ring is a rigid fragment of the amphiphile
structure and can promote the formation of 1D or 2D aggregates
(fibrils and tapes). The dipole moment exhibited by the 1,2,3-
triazole ring increases the hydrophilicity26 and facilitates the
preparation of hydrogels. In the case of Malt-NH-Phe-C16 and
Malt-Tz-Phe-C16, the presence of phenyl groups, located in a
remote position from the axis of the molecule, also can favor
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Figure 6. (a) SEM image of Malt-Tz-C16 (1% wt water) xerogel, (b) TEM image of Malt-Tz-C16 (0.1% wt water), (c) TEM image of a single fiber of
Malt-Tz-C16 (0.1% wt water), (d) TEM image of Malt-Tz-Phe-C16 (0.1% wt water), (e) TEM image of Malt-Tz-Phe-C16 (3 mg in 0.3 mL of water and
0.1 mL of methanol gel, diluted 10 times), and (f) TEM image of Malt-NH-Phe-C16 (5 mg in 0.3 mL of water and 0.2 mL of methanol gel, diluted
10 times).TEM images were dried and negatively stained with uranyl acetate (1 wt % water).
Figure 7. CD spectra of aqueous gel: (a) dashed line, acetonitrile
solution (0.7% wt) and (b) solid line, aqueous gel 1 wt % of Malt-Tz-
C16.
Furthermore, torsion can be detected in the fibrillar structure
studied by TEM. For instance, in Malt-Tz-C16 (Figure 6c) a twisted
helical ribbon was observed in a dried sample of a 0.1% solution of
the material in water, with negative staining by uranyl acetate.
Circular Dichroism Measurements. The twisted fibrillar
structure observed by TEM may indicate a chiral supramolecular
organization in the aqueous gel of Malt-Tz-C16. In order to
confirm this possibility, circular dichroism (CD) measurements
were carried out on both solution and gels and the results are
collected in Figure 7.
The λmax value for a Malt-Tz-C16 aqueous gel at 1 wt % in the
Figure 8. CD (top) and UVꢀvis (bottom) spectra of a solution of
UV absorption spectrum appears at around 232 nm, and this
absorption can be assigned to the triazole group. A Cotton effect
was not observed in the CD spectrum of a solution of the
compound in acetonitrile. However, the hydrogel of this com-
pound (1 wt %), when placed between two quartz discs,
exhibited a negative Cotton effect where the θmin value appeared
to be very slightly displaced from the λmax in the UV spectrum
(236 nm). We confirmed that the contribution of the linear
Malt-Tz-C16 (0.01 wt % in water) taken at different times once the
solution has been previously heated to 80 °C and left to cool to RT.
dichroism (LD) to the true CD spectrum is negligible by comparing
several CD spectra recorded at different angles around the incident
light beam. The Cotton effect for the gel sample supports the
hypothesis that an ordered chiral structure is formed by self-
assembly and gelification in aqueous solution.
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In order to gain an insight into the supramolecular aggregates
formed in water, a dilute solution was studied by this technique
(Figure 8). A solution containing 0.01 wt % of Mal-T-C16 was
first heated to 80 °C and then cooled down to room temperature.
A cloudy solution was obtained due to aggregation. The evolu-
tion of the UVꢀvis and CD spectra was registered at different
times. A displacement in the λmax from 220 to 235 nm in the UV
spectrum was observed. It can also be observed that there is an
evolution of the CD signal corresponding to the aggregates
formed in solution (it should be remarked that in this concentra-
tion, gel formation does not take place). Despite the different
experimental conditions, the final CD spectrum of aggregates
exhibits as main band a negative Cotton effect at a similar
wavelength than the observed in the gel state. This band appears
in the region corresponding to the absorption of the triazole ring.
This result may indicate a similar supramolecular arrangement of
amphiphiles in a chiral fibrillar structure.
After 24 h, CH2Cl2 was added and the solution was washed with
saturated Na2CO3 and twice with water. The organic layer was dried
over MgSO4, filtered, and evaporated under reduced pressure. The
product was purified by flash chromatography using hexane/ethyl
acetate 6:4. A white solid was obtained (1.59 g, 80%). For characteriza-
tion data, see the Supporting Information.
Synthesis of Hepta-O-acetyl-β-maltosyl Amide (2). Azide-
disaccharide-heptaacetate 1 (1.00 g, 1.51 mmol) was dissolved in 10 mL of
anhydrous THF under an argon atmosphere. Palladium hydroxide (20 wt %
Pd on carbon wet, 104 mg, 10 wt %) was added and the reaction mixture
was stirred for 2 days at room temperature under an atmosphere of
hydrogen. The catalyst was removed by filtration and the solvent was
removed under reduced pressure. The disappearance of azide was mon-
itored by the IR signal at 2122 cmꢀ1. The product was used without further
purification. For characterization data, see the Supporting Information.
Synthesis of Palmitoyl Chloride (3). Palmitic acid (295 mg, 1.15
mmol) was dissolved in 25 mL of anhydrous dichloromethane. Oxalyl
chloride (0.30 mL, 2.81 mmol) and N,N-dimethylformamide (0.3 mL)
were added. The reaction mixture was stirred overnight. The solvent was
removed under reduced pressure. The acyl chloride formation was
monitored by appearance of an IR signal at around 1800 cmꢀ1. The
product was used without further purification.
’ CONCLUSIONS
A series of maltose-based amphiphiles have been synthesized
and their liquid crystalline and gel-forming properties have been
determined. The synthetic approach is based on the use of
peracetylated maltose as the starting material. The acetyl group
on the anomeric carbon is replaced by an azide group and this can
finally be reduced to an amino group. Glycolipids were prepared by
amidation of the maltosylamine with palmitic acid derivatives or by
a copper(I)-catalyzed azideꢀalkyne [3 + 2] cycloaddition of the
maltosylazide with a palmitoyl derivative bearing an alkyne group.
All of the synthesized compounds exhibit a mesomorphic fluid
state and three of the four compounds synthesized form gels in
pure water or a mixture of water and alcohol. All compounds
are stable at room temperature. Copper(I)-catalyzed azide
alkyne [3 + 2] cycloaddition seems to have a beneficial effect
in the design and preparation of gelators as a linking strategy for
the hydrophilic maltose head and the hydrophobic tail derived
from palmitic acid.
The study of the resulting self-assembled fibrillar network was
carried out on the maltose/palmitic acid-based molecule with a
linking triazole group. This material was chosen because it forms
a homogeneous hydrogel at a minimum concentration of 1% wt.
The gel was characterized by electron microscopy and fibers of
around 40 nm were observed. Furthermore, the formation of
twisted fibers was supported by the observation of a CD signal.
The solꢀgel transition temperature was determined by DSC and
NMR studies.
Synthesis of Acetylated Maltose Conjugate OAc-Malt-NH-
C16. Amino-disaccharide-heptaacetate 2 was dissolved in 10 mL of
anhydrous N,N-dimethylformamide. Pyridine (130 μL, 1.61 mmol) was
added and the solution was cooled to 0 °C. A solution of palmitoyl
chloride (3) in 5 mL of anhydrous N,N-dimethylformamide was added.
The reaction mixture was stirred for 48 h at room temperature and
poured into 150 mL of water. The aqueous phase was extracted with 3 ꢁ
150 mL of dichloromethane. The combined organic phases were washed
once with 150 mL of saturated sodium bicarbonate solution and 2 ꢁ
150 mL of water. The organic phase was dried with anhydrous MgSO4.
The solution was filtered and the solvent was removed under reduced
pressure. The resulting syrup was purified by flash chromatography with
dichloromethane/ethyl acetate 4:6 as eluent. A white solid was obtained
(0.369 mg, 45%).
1H NMR (400 MHz CDCl3): 0.87 (t, 3H, J = 6.7 Hz) ꢀ(CH2)12ꢀ
CH3, 1.1ꢀ1.38 (m, 24H) CH2ꢀ(CH2)12ꢀCH3, 1.52ꢀ1.62 (m, 2H)
ꢀCH2ꢀCH2ꢀ(CH2)12, 1.99 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 2.06 (s,
3H), 2.09 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H) CH3ꢀCOꢀO, 2.10ꢀ2.20
0
0
0
0
(m, 2H) COꢀCH2ꢀCH2ꢀ, 3.72 (ddd, 1H, J4 ꢀ5 = 9.0 Hz, J5 ‑6 a
=
4.3 Hz, J5 ‑6 b = 2.3 Hz) H50, 3.85 (ddd, 1H, J4ꢀ5 = 9.9 Hz, J5ꢀ6a = 3.8 Hz,
0
0
0
0
0
0
0
J5ꢀ6b = 2.2 Hz) H5, 3.89 (dd, 1H, J3 ‑4 = 9.5 Hz, J4 ‑5 = 9.0 Hz) H4 , 3.97
(dd, 1H, J5ꢀ6b = 2.2 Hz, J6b‑6a = 12.4 Hz) H6b, 4.15 (dd, 1H, J5ꢀ6a
=
0
0
0
0
3.8 Hz, J6a‑6b = 12.4 Hz) H6a, 4.17 (dd, 1H, J5 ‑6 a = 4.3 Hz, J6 a‑6 b = 12.3
Hz) H60a, 4.35 (dd, 1H, J5 ‑6 b = 2.3 Hz, J6 a‑6 b = 12.3 Hz) H60b, 4.68
0
0
0
0
0
0
0
0
0
(dd, 1H, J1 ‑2 = 9.4 Hz, J2 ‑3 = 9.5 Hz) H2 , 4.78 (dd, 1H, J1ꢀ2 = 4.0 Hz,
J2ꢀ3 = 10.5 Hz) H2, 4.99 (dd, 1H, J3ꢀ4 = 9.8 Hz, J4ꢀ5 = 9.9 Hz) H4, 5.21
The systems described in this paper are attractive candidates
to function as a matrix in tissue engineering or in controlled drug
release. The importance of these materials is based on their
potential biocompatibility and degradability.
(dd, 1H, J1 ‑2 = 9.4 Hz, J1 ‑NH = 9.4 Hz) H10, 5.26ꢀ5.33 (m, 3H) H1, H3,
0
0
0
H30, 5.97 (d, 1H, J1 ‑NH = 9.4 Hz) mal-NH-CO.
0
13C NMR (100 MHz, CDCl3): 14.1 ꢀ(CH2)12ꢀCH3, 20.6, 20.6, 20.7,
20.8 (CH3ꢀCOꢀO)7, 22.7, 25.2, 29.0, 29.3, 29.3, 29.4, 29.6, 31.9, 36.7
ꢀCOꢀCH2ꢀ(CH2)13ꢀCH3, 61.4 C6, 62.8 C60, 67.9 C4, 68.5 C5, 69.3
C3, 70.0 C2, 71.4 C20, 72.7 C40, 73.9 C50, 75.0 C30, 77.7 C10, 95.6 C1,
169.5 CH3ꢀCOꢀOꢀC4, 169.6, 169.8, 170.4 CH3ꢀCOꢀOꢀC2/C6/
C60, 170.5, 170.7 CH3ꢀCOꢀOꢀC3/C30, 171.1 CH3ꢀCOꢀOꢀC20,
173.2 NHꢀCOꢀCH2.
’ EXPERIMENTAL SECTION
Characterization data (elemental analysis, 1H and 13C NMR, FTIR,
and MS) for the intermediate compounds 1ꢀ7 are collected in the
Supporting Information. Only data corresponding to the peracetylated
and final amphiphilic glycolipids are included in this section.
Synthesis of Hepta-O-acetyl-β-maltosyl Azide (1). Tri-
methylsilyl azide (543 μL, 4.13 mmol) and tin tetrachloride (173 μL,
1.48 mmol) were added, at room temperature and under argon, to a
solution of β-D-maltose octaacetate (2.00 g, 2.95 mmol) in dry CH2Cl2
(6 mL, 0.5 M). The reaction mixture was stirred at room temperature
and the reaction was monitored by TLC (6:4 hexane/ethyl acetate).
MALDI-TOF MS (DCTB+NaTFA): 896.4 [M + Na]+.
Anal. Calcd for C42H67NO18: C, 57.72; H, 7.73; N, 1.60. Found: C,
57.30; H, 7.57; N, 1.60.
IR (KBr, cmꢀ1): 3322 (broad), 2925, 2853, 1747, 1672, 1538, 1371,
1236, 1039, 900, 603.
SynthesisofN-PalmitoylSuccinimide (4). Palmiticacid(5.13g,
20 mmol) was dissolved in 30 mL of THF, N-hydroxysuccinimide
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(3.24 g, 28 mmol) was dissolved in 45 mL of THF, and dicyclo-
hexylcarbodiimide (DCC) (6.60 g, 32 mmol) was dissolved in 35 mL
of THF. These solutions were mixed and stirred for 96 h at room
IR (KBr, cmꢀ1): 3332, 2918, 2849, 1745, 1689, 1649, 1533, 1371,
1226, 1040, 938, 611.
Synthesis of Maltose Conjugates Malt-NH-C16 and Malt-
NH-Phe-C16. The protected peracetylated glycolipids OAc-Malt-NH-
C16 and OAc-Malt-NH-Phe-C16 (149.7 mg, 0.146 mmol) were dis-
solved in 7.5 mL of anhydrous methanol and sodium methoxide (55.3
mg, 1.023 mmol) was added. The solution was stirred at room
temperature until the reaction was complete (TLC, hexane/ethyl acetate
1:1). Amberlyst IR 120 (H+ form) was added to exchange sodium ions.
The resin was filtered off and the solvent was evaporated in vacuo to give
a white solid (70ꢀ85%).
1
temperature. The reaction was monitored by H NMR. The reaction
mixture was filtered and the solvent was distilled off. The product was
recrystallized from iPrOH to give a white powder (5.55 g, 78%). For
characterization data, see the Supporting Information.
Synthesis of N-Palmitoylphenylalanine (5). L-Phenylalanine
(1.26 g, 7.63 mmol) and diisopropylethylamine (2.50 mL, 15.26 mmol)
were dissolved in 100 mL of water and 50 mL of THF. A solution of N-
palmitoylsuccinimide (2.70 g, 7.63 mmol) in 115 mL of THF was added.
The mixture was stirred at room temperature for 6 h. The reaction was
Malt-NH-C16. 1H NMR (400 MHz, MeOD, 55 °C): 0.90 (t, 3H, J =
6.7 Hz) ꢀ(CH2)12ꢀCH3, 1.20ꢀ1.41 (m, 24H) CH2ꢀ(CH2)12ꢀCH3,
1.56ꢀ1.67 (m, 2H) CH2ꢀCH2ꢀ(CH2)12ꢀ, 2.23(m, 2H) ꢀCOꢀCH2ꢀ
CH2ꢀ, 3.20ꢀ3.88 (m, 12H) H2, H3, H4, H5, H6a, H6b, H20, H30, H40,
1
monitored by H NMR. A solution of HCl (37%) was added to give
pH = 4. The solvent was partially removed, and the resulting aqueous
phase was extracted with dichloromethane (3 ꢁ 100 mL). The organic
layer was dried with anhydrous Na2SO4 and finally the solvent was
evaporated. A white solid was obtained and recrystallized from petro-
leum ether/dichloromethane (95/5) (2.27 g, 78%). For characterization
data, see the Supporting Information.
H50,H60a, H60b, 4.89 (d, 1H, J1 ‑2 = 9.2 Hz) H10, 5.16 (d, 1H, J1ꢀ2
=
0
0
3.7 Hz) H1.
13C NMR (100 MHz, DMSO):14.5 ꢀ(CH2)12ꢀCH3, 25.4 ꢀCH2ꢀ
CH2ꢀ(CH2)12ꢀ, 22.5, 29.1 29.2, 29.3, 29.4, 29.5, 29.5, 31.7, CH2ꢀ
(CH2)12ꢀCH3, 35.9 ꢀCOꢀCH2ꢀCH2ꢀ, 60.9, 61.2, 70.4, 72.4, 73.0,
73.7, 73.9, 77.2, 77.7, 79.6, C2, C3, C4, C5, C6, C20, C30, C40,C50, C60,
80.1 C10, 101.4 C1, 173.1 NHꢀCOꢀCH2.
Synthesis of Acetylated Maltose Conjugate OAc-Malt-NH-
Phe-C16. Amino-disaccharide-heptaacetate 2 (700 mg, 1.10 mmol) was
dissolved in 10 mL of anhydrous THF, N-palmitoylphenylalanine 5 (680
mg, 1.68 mmol) and hydroxybenzotriazole (255 mg, 1.89 mmol) were
added, and the solution was cooled to 0 °C. A solution of dicyclohexyl-
carbodiimide (330 mg, 1.60 mmol) in 10 mL of anhydrous THF was
added. The reaction mixture was stirred for 2 days at room temperature.
The reaction was monitored by TLC using a mixture of hexane/ethyl
acetate 1:1 as eluent. The mixture was filtered, and the solvent was
removed under reduced pressure. Then 150mLofethylacetate wasadded
and the organic phase was washed three times with 1 M KHSO4 solution
and three times with 1 M NaHCO3 solution. The organic layer was dried
over anhydrous MgSO4. The solution was filtered, and the solvent was
removed under reduced pressure. Theresulting white solidwaspurifiedby
flash chromatography with a mixture of hexane/ethyl acetate 1:1 and
recrystallized from ethanol. A white solid was obtained (720 mg, 50%).
1H NMR (500 MHz, CDCl3): 0.87 (t, 3H, J = 7.0 Hz) ꢀ(CH2)12ꢀ
CH3, 1.25ꢀ1.40 (m, 24H) ꢀCH2ꢀ(CH2)12ꢀCH3, 1.46ꢀ1.60 (m,
2H) ꢀCH2ꢀ(CH2)12ꢀCH3, 1.93 (s, 3H), 1.99 (s, 6H), 2.02 (s, 3H),
2.05 (s, 3H), 2.10 (s, 3H), 2.15 (s, 3H), CH3ꢀCOꢀOꢀ, 2.10ꢀ2.20 (m,
2H) COꢀCH2ꢀCH2, 2.97ꢀ3.15 (m, 2H) CHꢀCH2-ar, 3.75ꢀ3.85
(m, 1H) H50, 3.91ꢀ3.96 (m, 2H) H40, H5, 4.03 (dd, 1H, J5ꢀ6b = 2.0 Hz,
J6a‑6b = 12.4 Hz) H6b, 4.20ꢀ4.26 (m, 2H) H6a, H60a, 4.47 (dd, 1H,
Micro-TOF MS: 580.3698 [M + H]+ calcd 580.3691; 602.3521[M +
Na]+ calcd 602.3511.
IR (KBr, cmꢀ1): 3312 (broad), 2914, 2850, 1670, 1548, 1472, 1151,
1083, 1033, 715.
Malt-NH-Phe-C16. 1H NMR (400 MHz, MeOD, 55 °C): 0.89 (t, 3H,
J = 6.5 Hz) ꢀ(CH2)12ꢀCH3, 1.20ꢀ1.29 (m, 24 H) ꢀCH2ꢀ(CH2)12ꢀ
CH3, 1.42ꢀ1.49 (m, 2H) ꢀCH2ꢀCH2ꢀ(CH2)12ꢀ, 2.14 (t, 2H, J =
7.3 Hz) ꢀCOꢀCH2ꢀCH2ꢀ, 2.89 (dd, 1H, JCHꢀCH2a = 9.4 Hz,
JCH2a‑CH2b = 14.0 Hz) ꢀCHꢀ(CH2)b-arom, 3.18 (dd, 1H, JCHꢀCH2b
=
4.9 Hz, JCH2a‑CH2b = 14.0 Hz) ꢀCHꢀ(CH2)a-arom, 3.27ꢀ3.88 (m, 11H)
H30, H40, H50,H60a, H60b, H2, H3, H4, H5, H6a, H6b, 3.37 (dd, 1H,
JH1 ‑H2 = 9.1 Hz, JH2 ‑H3 = 9.2 Hz) H20, 4.67 (dd, 1H, JCHꢀCH2b
=
=
0
0
0
0
0
0
4.9 Hz JCHꢀCH2a = 9.4 Hz) ꢀCHꢀCH2-arom, 4.92 (d, 1H, JH1 ‑H2
9.1 Hz) H10, 5.18 (d, 1H, JH1ꢀH2 = 3.5 Hz) H1, 7.17ꢀ7.26 (m, 5H)
CH arom.
13C NMR (100 MHz, MeOD, 55 °C): 14.3 ꢀ(CH2)12ꢀCH3, 26.7
ꢀCH2ꢀCH2ꢀ(CH2)12ꢀ, 23.6, 30.3, 30.4, 30.6, 32.9 ꢀCH2ꢀ(CH2)12ꢀ
CH3, 36.9 ꢀCOꢀCH2ꢀCH2ꢀ, 38.8 ꢀCHꢀCH2-arom, 55.7 ꢀCHꢀ
CH2-arom, 62.2, 62.8, 71.7, 74.2, 74.8, 75.2, 78.45, 78.7, 80.9 C2, C3, C4,
C5, C6, C30, C40, C50, C60, 73.7 C20, 81.3 C10, 102.8 C1, 127.7, 129.3,
130.4 CH arom, 138.3 Carom, 174.63 malt-NHꢀCOꢀCH, 176.1
CHꢀNHꢀCOꢀCH2.
J5ꢀ6 b = 2.2 Hz, J6 a‑6 b = 12.3 Hz) H60b, 4.57 (m, 1H) NHꢀCHꢀ
0
0
0
0
0
0
0
0
CH2ꢀ, 4.67 (dd, 1H, J1 ‑2 = 9.5 Hz, J2 ‑3 = 9.5 Hz) H2 , 4.84 (dd, 1H,
Micro-TOF MS: 727.4400 [M + H]+ calcd 727.4375; 749.4234 [M +
Na]+, calcd 749.4194.
J
1ꢀ2 = 4.0 Hz, J2ꢀ3 = 10.5 Hz) H2, 5.06 (dd, 1H, J3ꢀ4 = 10.0 Hz, J4ꢀ5 =
10.0 Hz) H4, 5.20 (dd, 1H, J1 ‑2 = 9.5 Hz, J1 ‑NH = 9.1 Hz) H10, 5.33 (dd,
0
0
0
IR(KBr, cmꢀ1): 3323 (broad), 2919, 2850, 1645, 1540, 1147, 1081,
1034, 698.
1H, J2 ‑3 = 9.5 Hz, J3 ‑4 = 9.2 Hz,) H30, 5.35(dd, 1H, J3ꢀ4 = 10.0 Hz,
0
0
0
0
J
2ꢀ3 =10.5Hz)H3, 5.37(d, 1H,J1ꢀ2 =4.0Hz) H1, 5.77 (d, 1H, JNHꢀCH
=
Synthesis of N-Propargyl Palmitoylamide (6) and N-Pro-
pargyl (N0-palmitoylphenylalanine) Amide (7). Palmitic acid or
N-Palmitoyl phenylalanine (5) (1.0 g, 2.48 mmol) and hydroxybenzo-
triazole were dissolved in 20 mL of anhydrous tetrahydrofuran. Propargy-
lamine (0.16 mL, 2.50 mmol) was added. The solution was cooled to 0 °C.
A solution of dicyclohexylcarbodiimide (511 mg mg, 2.48 mmol) in 15 mL
of anhydrous THF was added. The reaction mixture was stirred for 2 days
at room temperature. The reaction was monitored by TLC with hexane/
ethyl acetate 7:3 as eluent. The mixture was filtered and the solvent was
removed under reduced pressure. 250 mL of dichoromethane were added
and the organic phase was washed three times with 1 M KHSO4 solution,
and three times with 1 M NaHCO3 solution. The organic layer was dried
over anhydrous MgSO4. The solution was filtered and the solvent was
removed under reduced pressure. The resulting white solid was purified by
recrystallization from ethanol. A white solid was obtained (yield around
75%). For characterization data see Supporting Information.
0
7.6 Hz) CHꢀNHꢀCO, 6.64 (dd, 1H, J H1 ‑NH = 9.1 Hz) malt-NHꢀCO,
7.16ꢀ7.11 (m, 2H) ar-CHꢀCꢀNH, 7.29ꢀ7.21 (m, 3H) ar-CHdCHꢀ
CHdar.
13C NMR (125 MHz, CDCl3): 14.1 (CH2)13ꢀCH3, 20.5, 20.6, 20.7,
20.9, (CH3ꢀCOꢀO)7, 22.7, 24.9, 25.4, 25.6, 29.1, 29.3, 29.3, 29.4, 29.6,
29.7, 31.9, 33.9 ꢀCH2ꢀ(CH2)12ꢀCH3, 36.4 COꢀCH2ꢀCH2ꢀ, 37.1
CHꢀCH2ꢀarom, 53.9 COꢀCHꢀCH2, 61.4 C6, 62.7 C60, 67.9 C4,
68.6 C5, 69.3 C3, 70.0 C2, 71.2 C20, 72.6 C40, 73.9 C50, 74.8 C30, 77.8
C10, 95.6 C1, 127.1, 128.7, 128.8, 129.1, 129.4 CHarom, 135.9 Carom,
169.5 CH3ꢀCOꢀOꢀC4, 169.7, 169.8 CH3ꢀCOꢀOꢀC3/CH3ꢀ
COꢀOꢀC30, 170.4, 170.5, 170.6 CH3ꢀCOꢀOꢀC2/CH3ꢀCOꢀ
OꢀC6/CH3ꢀCOꢀOꢀC60, 170.9 CH3ꢀCOꢀOꢀC20, 171.7 mal-
NHꢀCOꢀCH, 173.3 NH-CO-CH2ꢀ.
MALDI-TOF MS (DCTB+NaTFA): 1043.6 [M + Na]+.
Anal. Calcd for C51H76N2O19: C, 59.99; H, 7.50; N, 2.74. Found: C,
59.60, H, 7.51, N, 2.99.
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Synthesis of Acetylated Maltose Conjugates OAc-Malt-Tz-
C16 and OAc-Malt-Tz-Phe-C16. Propargyl derivatives 6 or 7 (266
mg, 0.91 mmol), azide 1 (602 mg, 0.91 mmol), copper(I) bromide (27.7
mg, 0.19 mol) and N-pentamethyldiethylenetriamine (PMDETA) (38
μL, 0.18 mmol) were dissolved in anhydrous dimethylformamide
(6 mL) under an argon atmosphere. The mixture was stirred at room
temperature for 2 days. The reaction was monitored by TLC with
hexane/ethyl acetate 1:1 as eluent. The catalyst was removed by
filtration and the solvent was removed under reduced pressure. The
reaction was poured into 150 mL of water. The aqueous phase was
extracted three times, each with 150 mL of dichloromethane/ethyl
acetate 1:1. The organic phase was dried with anhydrous MgSO4. The
solution was filtered and the solvent was removed under reduced
pressure. The resulting white solid was purified by flash chromatography
using initially dichloromethane/ethyl acetate 1:1 and then increasing the
polarity. A white solid was obtained (756 mg, 87%).
36.5 COꢀCH2ꢀCH2, 38.2 CHꢀCH2ꢀPhe, 54.3 ꢀCOꢀCHꢀCH2,
61.5 C6, 62.5 C60, 68.0 C4, 68.8 C5, 69.3 C3, 70.0 C2, 70.9 C20, 72.5 C40,
75.2 C30, 75.5 C50, 85.0 C10, 96.0 C1, 120.8 NꢀCHdCꢀN triazole,
127.0, 128.9, 129.2 CHarom, 136.5 Carom, 144.9 CHdCꢀN triazole,
169.1 CH3ꢀCOꢀOꢀC20, 169.3 CH3ꢀCOꢀOꢀC4, 169.8 CH3ꢀ
COꢀOꢀC3, 169.9 CH3ꢀCOꢀOꢀC30, 170.4 CH3ꢀCOꢀOꢀC2,
170.5, 170.3 CH3ꢀCOꢀOꢀC6/C60, 171.0 NHꢀCOꢀCHꢀ, 173.2
NHꢀCOꢀCH2ꢀ.
MALDI-TOF MS (DCTB): 1124.4 [M + Na]+.
Anal. Calcd for C54H79N5O19: C, 58.84; H, 7.22; N, 6.35. Found: C,
58.24; H, 7.12; N, 6.28.
IR (KBr, cmꢀ1): 3306, 2923, 2852, 1753, 1640, 1546, 1370, 1234,
1037.
Synthesis of Maltose Conjugates Malt-Tz-C16 and Malt-Tz-
Phe-C16. The protected triazole-disaccharide-octaateate derivatives
(OAc-Malt-Tz-C16 and OAc-Malt-Tz-Phe-C16) (149.7 mg, 0.146
mmol) were dissolved in 7.5 mL of anhydrous methanol. Sodium
methoxide (55.3 mg, 1.023 mmol) was added. The solution was stirred
at room temperature until the reaction was complete (TLC, hexane/
ethyl acetate 1:1). Amberlyst IR 120 (H+ form) was added to exchange
sodium ions, the resin was filtered off, and the solvent was evaporated in
vacuo. A white solid was obtained (85ꢀ90%).
OAc-Malt-Tz-C16. 1H NMR (400 MHz, CDCl3): 0.87 (t, 3H, J = 6.2
Hz) ꢀ(CH2)12ꢀCH3, 1.16ꢀ1.35 (m, 24H) ꢀ(CH2)12ꢀ, 1.55ꢀ1.66
(m, 2H) ꢀCH2ꢀ(CH2)12, 1.84 (s, 3H) CH3ꢀCOꢀOꢀC20, 2.00 (s,
3H), 2.02 (s, 6H), 2.06 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H),
CH3ꢀCOꢀO, 2.17 (t, 2H, J = 7.7 Hz) COꢀCH2ꢀCH2, 3.96ꢀ3.98
(m, 2H) H5/H50, 4.05 (dd, 1H, J6b‑5 = 1.5 Hz, J6a‑6b = 1.6 Hz) H6b, 4.13
(dd, 1H, J3 ‑4 = 9.3 Hz, J4 ‑5 = 9.3 Hz) H40, 4.23ꢀ4.27 (m, 2H) H6a/
Malt-Tz-C16. 1H NMR (400 MHz, MeOD, 55 °C): 0.90 (t, 3H, J =
6.9 Hz) ꢀ(CH2)12ꢀCH3, 1.20ꢀ1.36 (m, 24H), ꢀ(CH2)12ꢀCH3,
1.56ꢀ1.60 (m, 2H) CH2ꢀCH2ꢀ(CH2)12, 2.21 (t, 2H, J = 7.4 Hz)
COꢀCH2ꢀCH2, 3.28 (dd, 1H, J3ꢀ4 = 9.6 Hz, J4ꢀ5 = 9.5 Hz) H4, 3.47
(dd, 1H, J1ꢀ2 = 3.8 Hz, J2ꢀ3 = 9.7 Hz) H2, 3.64 (dd, 1H, J2ꢀ3 = 9.7 Hz,
J3ꢀ4 = 9.6 Hz) H3, 3.65ꢀ3.90 (m, 8H) H5, H6a, H6b, H30, H40, H50,
0
0
0
0
H60a, 4.44ꢀ4.54 (m, 3H) C = CꢀCH2ꢀNH, H60b, 4.87 (dd, 1H, J1ꢀ2
=
3.9 Hz, J2ꢀ3 = 10.7 Hz) H2, 5.07 (dd, 1H, J3ꢀ4 = 10.0 Hz, J4ꢀ5 = 9.8 Hz)
0
0
0
0
0
H4, 5.31 (dd, 1H, J1 ‑2 = 9.1 Hz, J2 ‑3 = 8.8 Hz) H2 , 5.37 (dd, 1H, J2ꢀ3
=
0
0
0
0
10.7 Hz, J3ꢀ4 = 10.0 Hz) H3, 5.43 (dd, 1H, J2 ‑3 = 8.8 Hz, J3 ‑4 = 9.3 Hz)
H30, 5.44 (d, 1H, J1ꢀ2 = 3.9 Hz) H1, 5.84 (d, 1H, J1 ‑2 = 9.1 Hz) H10,
6.06 (t, 1H, J = 4.7 Hz) ꢀCH2ꢀNHꢀCO, 7.69 (s, 1H) NꢀCH =
CꢀCH2 triazole.
0
0
0
0
H60a, H60b, 3.93 (dd, 1H, J1 ‑2 = 9.1 Hz, J2 ‑3 = 9.0 Hz) H20, 4.34 (s,
0
0
0
0
2H) CꢀCH2ꢀNH, 5.13 (d, 1H, J1ꢀ2 = 3.8 Hz) H1, 5.50 (d, 1H, J1 ‑2
=
13C NMR (100 MHz, CDCl3): 14.1 ꢀ(CH2)12ꢀCH3, 20.2, 20.6,
20.7, 20.8, 20.8 (CH3ꢀCOꢀO)7, 25.6 CH2ꢀCH2ꢀ(CH2)12ꢀ, 22.7,
29.3, 29.4, 29.4, 29.5, 29.6, 29.7, 29.7, 31.9, 35.6, ꢀ(CH2)12ꢀ, COꢀ
CH2ꢀCH2, 34.8 CꢀCH2ꢀNH, 61.5 C6, 62.5 C60, 67.9 C4, 68.8 C5,
69.2 C3, 70.0 C20, 70.9 C2, 72.4 C40, 75.1 C30, 75.4 C50, 85.3 C10, 95.9
C1, 120.8 NꢀCHdCꢀN triazole, 145.3 CH = CꢀN triazole, 169.1,
169.4, 169.9 CH3ꢀCOꢀOꢀC2/C6/C60, 169.9, 170.3 CH3ꢀCOꢀOꢀ
C3/30, 170.5 CH3ꢀCOꢀOꢀC4, 170.6 CH3ꢀCOꢀOꢀC20, 173.2
NHꢀCOꢀCH2.
9.1 Hz) H10, 7.95 (s, 1H) NꢀCHꢀC-triazole.
13C NMR (100 MHz, MeOD, 55 °C):13.0 ꢀ(CH2)12ꢀCH3, 22.3,
25.4, 28.9, 29.2, 31.6 ꢀCH2ꢀ(CH2)12ꢀ, 34.1 CꢀCH2ꢀNHꢀ, 35.5
COꢀCH2ꢀCH2, 60.4, 61.3, 73.7, 76.8, 78.2, C6, C30,C40, C50,C60, 70.1
C4, 72.2 C20, 72.8 C2, 73.5 C3, 78.9 C5, 88.0 C10, 101.5 C1, 120.0
NꢀCHdC triazole, 145.0 CHdCꢀCH2 triazole, 174.9 NHꢀCOꢀCH2.
MicroTOF MS: 683.383 [M+ Na]+, calcd: 683.384.
IR (KBr, cmꢀ1): 3313 (broad), 2917, 2849, 1643, 1543, 1464, 1429,
1241, 1050, 719.
MALDI-TOF MS (DCTB+NaTFA): 977.5 [M + Na]+.
Anal. Calcd for C45H70N4O18: C, 56.59; H, 7.39; N, 5.87. Found: C,
56.25; H, 7.28; N, 5.80.
Malt-Tz-Phe-C16. 1H NMR (400 MHz, MeOD, 55 °C): 0.86 (t, 3H,
J = 6.8 Hz) ꢀ(CH2)12ꢀCH3, 1.10ꢀ1.32 (m, 24H), CH2ꢀCH2ꢀ
(CH2)12, 1.38ꢀ1.48 (m, 2H) CH2ꢀCH2ꢀ(CH2)12‑, 2.15 (t, 2H,
J = 7.5 Hz) COꢀCH2ꢀCH2, 2.89 (dd, 1H, JCHꢀCH2a = 8.9 Hz,
IR (KBr, cmꢀ1): 3303, 2925, 2854, 1754, 1645, 1552, 1369, 1233,
1036.
JCH2a‑CH2b = 13.9 Hz) CHꢀ(CH2)a-Phe, 3.11 (dd, 1H, JCHꢀCH2b
6.4 Hz, JCH2a‑CH2b = 13.9 Hz) CHꢀ(CH2)b-Phe, 3.34 (dd, 1H, J3ꢀ4
=
=
OAc-Malt-Tz-Phe-C16. 1H NMR (400 MHz, CDCl3): 0.87 (t, 3H, J =
6.8 Hz) ꢀ(CH2)12ꢀCH3, 1.14ꢀ1.40 (m, 24H) -(CH2)12ꢀ, 1.47ꢀ1.58
(m, 2H) ꢀCH2ꢀ(CH2)12ꢀ, 1.83 (s, 3H) CH3ꢀCOꢀOꢀC20, 2.01 (s,
3H), 2.03 (s, 6H), 2.07 (s, 3H), 2.10 (s, 3H), 2.12 (s, 3H),
CH3ꢀCOꢀO, 2.10ꢀ2.17 (m, 2H) COꢀCH2ꢀCH2, 2.98ꢀ3.10 (m,
2H) ꢀCHꢀCH2ꢀPhe, 3.94ꢀ4.01 (m, 2H) H5/H50, 4.07 (dd, 1H,
8.8 Hz, J4ꢀ5 = 9.0 Hz) H4, 3.52 (dd, 1H, J1ꢀ2 = 3.8 Hz, J2ꢀ3 = 9.6 Hz)
H2, 3.67 (dd, 1H, J2ꢀ3 = 9.6 Hz, J3ꢀ4 = 8.8 Hz) H3, 3.70ꢀ3.93 (m,
9H) H5, H6a, H6b, H20, H30,H40,H50,H60a, H60b, 4.42 (s, 2H)
CꢀCH2ꢀNH, 4.61 (dd, 1H, JCHꢀCH2a = 8.9 Hz, JCHꢀCH2b = 6.4
Hz) COꢀCHꢀNH, 5.29 (d, 1H, J1ꢀ2 = 3.8 Hz) H1, 5.59 (d, 1H,
0
J1 ‑2 = 8.8 Hz) H10, 7.16ꢀ7.29 (m, 5H) Harom, 7.88 (s, 1H)
0
0
0
0
J5ꢀ6b = 1.8 Hz, J6a‑6b = 12.4 Hz) H6b, 4.16 (dd, 1H, J3 ‑4 = 9.4 Hz, J4 ‑5
=
0
9.4 Hz) H40, 4.23ꢀ4.28 (m, 2H) H6a/H60a, 4.42 (d, 2H, J = 5.8 Hz)
NꢀCHdC-triazole.
CꢀCH2ꢀNH, 4.51 (dd, 1H, J5 ‑6 b = 2.2 Hz, J6 a‑6 b = 12.4 Hz) H60b,
4.60ꢀ4.66 (m, 1H) ꢀCOꢀCHꢀNHꢀ, 4.88 (dd, 1H, J1ꢀ2 = 3.9 Hz,
J2ꢀ3 = 10.5 Hz) H2, 5.07 (dd, 1H, J3ꢀ4 = 9.7 Hz, J4ꢀ5 = 10.0 Hz) H4,
13C NMR (100 MHz, MeOD, 55 °C): 13.0 ꢀ(CH2)12ꢀCH3, 25.3
CH2ꢀCH2ꢀ(CH2)12ꢀ, 22.1, 28.5 28.7, 28.8, 28.9, 31.4 ꢀ(CH2)12ꢀ,
34.4 CꢀCH2ꢀNHꢀ, 35.6 COꢀCH2ꢀCH2, 37.5 CHꢀCH2-arom,
54.7 COꢀCHꢀNHꢀ, 60.6, 61.3, 73.3, 76.8, 78.2, 78.3 C5, C6, C30,
C40, C50, C60, 70.2 C4, 72.3 C20, 72.6 C2, 73.7 C3, 87.9 C10, 101.1 C1,
122.4 NꢀCHdC triazole, 126.5 Carom, 128.2, 128.9, 136.9 CHarom,
0
0
0
0
5.32 (dd, 1H, J1 ‑2 = 9.4 Hz, J2 ‑3 = 9.2 Hz) H20, 5.38 (dd, 1H, J2ꢀ3
=
0
0
0
0
0
0
0
0
10.5 Hz, J3ꢀ4 = 9.7 Hz) H3, 5.45 (dd, 1H, J2 ‑3 = 9.2 Hz, J3 ‑4 = 9.4 Hz)
H30, 5.46 (d, 1H, J1ꢀ2 = 3.9 Hz) H1, 5.83 (d, 1H, J1 ‑2 = 9.4 Hz) H10,
6.04 (d, 1H, J = 7.6 Hz) CHꢀNHꢀCO, 6.36 (t, 1H, J = 5.7 Hz)
CH2ꢀNHꢀCO, 7.12ꢀ7.13 (m, 2H) Harom, 7.27ꢀ7.22 (m, 3H)
Harom, 7.54 (s, 1H) NꢀCHdC.
0
0
144.8 CH
=
CꢀCH2 triazole, 175.6 NHꢀCOꢀCH, 175.2
NHꢀCOꢀCH2ꢀ.
Micro-TOF MS: 808.4666 [M + H]+ calcd: 808.4702; 830.4495 [M +
13C NMR (100 MHz, CDCl3): 14.1 ꢀ(CH2)12ꢀCH3, 20.5, 20.6,
20.7, 20.8, (CH3ꢀCOꢀO)7, 22.7 ꢀ(CH2)12ꢀ, 25.5 ꢀCH2ꢀ(CH2)12,
29.2, 29.3, 29.3, 29.4, 29.6, 29.7, 32.0 ꢀ(CH2)12ꢀ, 34.9 CꢀCH2ꢀNH,
Na]+, calcd: 830.4521.
IR (KBr, cmꢀ1): 3297 (broad), 2919, 2850, 1638, 1543, 1456, 1377,
1036, 699.
15245
dx.doi.org/10.1021/la203447e |Langmuir 2011, 27, 15236–15247

Langmuir
ARTICLE
1
Characterization Techniques. H and 13C NMR spectra were
recorded on a BRUKER AV-400 spectrometer. IR spectra were mea-
sured on Thermo NICOLET Avatar 360 FT-IR spectrophotometer
using KBr pellets. Mass analysis was performed using a MALDI+/TOF
Br€uker Microflex system with a different matrix depending on the
compound (DCTB or DHB) and MicroTOF Br€uker equipment for
exact mass measurements. Elemental analysis was performed using a
Perkin-Elmer CHN2400 microanalyzer.
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was obtained. The solution was cooled to room temperature, and if the
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of a gel was registered.
’ ASSOCIATED CONTENT
S
Supporting Information. Synthesis of Malt-NH-Phe-
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C16 using maltose as starting material; characterization data of
compounds 1ꢀ7; NMR spectra, EM, and FTIR of OAc-Malt-Tz-
C16 and Malt-Tz-C16; thermogravimetric analysis; DSC thermal
cycles of peracetylated compounds; models of the Malt-Tz-C16
molecules on the lamellar phase; Malt-Tz-Phe-C16 and Malt-NH-
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Malt-Tz-C16 gel; 1H NMR spectra of Malt-Tz-C16 in DMSO-d6
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and Malt-NH-Phe-C16. This material is available free of charge via
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: loriol@unizar.es (L.O.); fitremann@chimie.ups-tlse.fr
(J.F.).
’ ACKNOWLEDGMENT
Financial support from the Spanish MICINN project
MAT2009-06522-C02-01, CSD2006-00012, FEDER funding,
Gobierno de Aragꢀon and Early Stage Research Nanotool project,
Marie Curie Actions program are gratefully acknowledged. The
authors acknowledge Dr. Pilar Romero her fruitful comments and
suggestions about NMR measurements.
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