A family of hydrogels based on ureido-linked aminopolyol-derived amphiphiles and bolaamphiphiles: Synthesis, gelation under thermal and sonochemical stimuli, and mesomorphic characterization

Article abstract of DOI:10.1002/chem.200701897

This article describes the systematic preparation of a novel family of carbohydrate amphiphiles and bolaamphiphiles in which hydrophilic and hydrophobic units are connected via a ureido or bis(ureido) moiety. The sugar core is derived from aminopolyols such as D-glucamine (1), N-methyl-D-glucamine (2), or the sugar-like species tris(hydroxymethyl)aminomethane (3). The O-unprotected derivatives behave as self-organizing nonionic surfactants with good water gelation ability, which can be induced under thermal or ultra-sound-driven stimuli. In addition, some derivatives of 1 and 2, and rarely 3 also formed lyotropic liquid crystals with lamellar or hexagonal structures that exhibit low-temperature transitions.

Full text of DOI:10.1002/chem.200701897

DOI: 10.1002/chem.200701897
A Family of Hydrogels Based on Ureido-Linked Aminopolyol-Derived
Amphiphiles and Bolaamphiphiles: Synthesis, Gelation under Thermal and
Sonochemical Stimuli, and Mesomorphic Characterization
Martín valos,[a] Reyes Babiano,[a] Pedro Cintas,*[a] Antonio Gómez-Carretero,[a]
JosØ L. JimØnez,[a] Marina Lozano,[b] Angel L. Ortiz,[c] Juan C. Palacios,[a] and
Aurora Pinazo[b]
Abstract: This article describes the sys-
tematic preparation of a novel family
of carbohydrate amphiphiles and bo-
laamphiphiles in which hydrophilic and
hydrophobic units are connected via a
mine (2), or the sugar-like species
tris(hydroxymethyl)aminomethane (3).
The O-unprotected derivatives behave
as self-organizing nonionic surfactants
with good water gelation ability, which
can be induced under thermal or ultra-
sound-driven stimuli. In addition, some
derivatives of 1 and 2, and rarely 3 also
formed lyotropic liquid crystals with la-
mellar or hexagonal structures that ex-
hibit low-temperature transitions.
Keywords: amino sugars · amphi-
philes · gels · liquid crystals · self-
assembly
ureido or bis(ureido) moiety. The sugar
A
core is derived from aminopolyols such
as D-glucamine (1), N-methyl-d-gluca-
Introduction
forces that lead ultimately to stacking options and alignment
preferences.
Molecular aggregation and self-assembly leading to supra-
molecular structures such as plaques, fibers, as well as lamel-
lar or columnar arrangements represent dominant research
topics in modern chemistry. Prominent architectures in soft
matter are exemplified by both gels[1] and liquid-crystalline
phases,[2] which can be tailored for multiple and varied ap-
plications. Their design, however, and the search for specific
properties are still far from being a mature discipline. Struc-
tural elements such as complementary shape and directional
intermolecular interactions are often viewed as the driving
With these premises in mind and in view of our previous
experience of the preparation and transformation of carbo-
hydrate-based ureas,[3] we recently embarked on the synthe-
sis and characterization of amphiphilic and bolaamphiphil-
ic[4] structures that combine a polar carbohydrate moiety
and a long-chain fragment through one or more urea linkag-
es. Protection of the sugar hydroxy groups, for instance, by
O-acylation, increases the lipophilicity, whereas incorpora-
tion of another carbohydrate fragment in the place of a hy-
drocarbon chain increases the hydrophilic character. The di-
versity of such glycoconjugates is summarized in Figure 1.
Conceptually, one or more of the above structural ele-
ments has already been explored in the construction of dif-
ferent supramolecular structures by the self-assembly of
low-molecular-weight compounds. Thus, amphiphiles con-
taining sugars as well as cyclic and acyclic polyols as polar
heads often exhibit liquid-crystalline phases.[5] Our choice of
introducing a ureido group to connect polar and nonpolar
moieties follows a well-established rationale. It was demon-
strated more than five decades ago that urea-type hydrogen
bonds are capable of stabilizing gelator assemblies.[6] For
ureas, the energies of hydrogen-bonding interactions are cal-
culated to be 37.3 kJmolÀ1 for the ribbon structure and
44.8 kJmolÀ1 for a chain arrangement, although London dis-
persion forces also contribute to the stability of intermolecu-
[a] Dr. M. valos, Dr. R. Babiano, Dr. P. Cintas,
Dipl. A. Gómez-Carretero, Dr. J. L. JimØnez, Dr. J. C. Palacios
Dpto. de Química Orgµnica e Inorgµnica
Facultad de Ciencias-UEX, 06071 Badajoz (Spain)
Fax : (+34)924-271-149
E-mail: pecintas@unex.es
[b] Dipl. M. Lozano, Dr. A. Pinazo
Dpto. de Tecnología de Tensioactivos, IIQAB-CSIC
C/Jordi Girona 18–26, 08034 Barcelona, Catalonia (Spain)
[c] Dr. A. L. Ortiz
Dpto. de Ingeniería Mecµnica, EnergØtica
y de los Materiales, Escuela de Ingenierías Industriales-UEX
06071 Badajoz (Spain)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
acetyl groups acting as CO2-philic arms) and subsequently
forming fibrillar foams.[11] This study, however, focuses on
more amphiphilic substances, paying attention to unprotect-
ed derivatives at the sugar moiety and assessing the propen-
sity for self-organization and aggregation in the search for
more biodegradable materials. Such results are comprehen-
sively shown in this article and complement current studies
by other groups. It is gratifying to see how sugar aminoaldi-
tols, which have long been confined to the rich history of
carbohydrate chemistry,[12] could now enjoy a further renais-
sance as precursors of novel synthetic and bioactive materi-
als.
Figure 1. Schematic and simplified representation of amphiphiles and bo-
laamphiphiles that combine protected and unprotected carbohydrate and
long-chain hydrocarbons through a ureido spacer.
lar interactions, especially in longer-chain ureas.[7] Moreover,
the self-association of ureas involving two hydrogen bonds
is much stronger than that of amides or urethanes and the
resulting assemblies are often insoluble materials. Therefore,
it is not surprising that ureido linkages have largely been ex-
ploited as molecular constituents of low-molecular-mass or-
ganogels (LMOGs), oligomers, and foldamers.[7a,8,9] In addi-
tion, the urea moiety represents an attractive isosteric re-
placement of the peptide linkage and there have been nu-
merous studies on oligoureas and ureidopeptoids that are
capable of generating stable hydrogen-bonded structures
that mimic the secondary structural motifs present in pro-
teins.[10] Such peptidomimetics show promising perspectives
for drug discovery and biomedical therapies because of their
resistance to protease degradation.
Results and Discussion
Synthesis of isocyanates and monoureas: A straightforward
route to unprotected urea-based amphiphiles involves the
condensation of aminopolyols with long-chain isocyanates.
To this end, a preliminary screening of different heterocu-
mulenes featuring flexible and rigid structures, as well as
variable degrees of hydrophobicity, was carried out. Thus,
monoureas have been generated from octyl isocyanate (4),
dodecyl isocyanate (5), and 4-(octyloxy)phenyl isocyanate
(6). Bifunctional derivatives suitable for the construction of
In contrast, urea–carbohydrate hybrids have received min-
imal attention[3] and, in this context, and as mentioned
above (Figure 1), we wanted to move from the conventional
the corresponding bis
include decane-1,10-diyl diisocyanate (7), 1,4-phenylene di-
isocyanate (8), and 4,4’-methylenediphenylene isocyanate
A
AHCTREUNG
synthesis of sugar–iso
A
(9). Note that neither compound 6 nor 7 were commercially
available, although both could be satisfactorily prepared in
yields in excess of 80% from 4-(octyloxy)aniline and 1,10-
diaminodecane, respectively.
tionalized by discrete alkyl and aryl groups to structures re-
sembling glycolipids, susceptible to self-organization and
with a diverse range of specific properties (amphiphilic, bo-
laamphiphilic, mesogenic, nonionic surfactant, etc.). To this
end, two readily available sugar aminopolyols, d-glucamine
(1) and N-methyl-d-glucamine (2), were chosen as polar
structural elements that can be further linked through a
ureido group at a nonanomeric position. This latter aspect is
particularly noteworthy as, unlike the corresponding glyco-
sylamines, these aminopolyols are expected to exhibit resist-
ance to hydrolytic cleavage or degradation. In the search for
more simplified models, a non-carbohydrate aminopolyol,
tris(hydroxymethyl)aminomethane (TRIS, 3), was also en-
visaged as a polar scaffold.
The synthesis of isocyanates is invariably challenging be-
cause it rests largely upon the use of phosgene and its deriv-
atives,[13] although more environmentally benign and less
hazardous processes have also emerged.[14] Isocyanates 6
and 7 were obtained as oils by using either a commercially
and safer solution of phosgene in toluene or, better yet, with
solid triphosgene,[15] which provides cleaner reactions. In ad-
dition, the range of isocyanates was expanded to 2,3,4,5,6-
penta-O-acetyl-1-deoxy-1-isocyanato-d-glucitol (10), a val-
uable chiral precursor that can be employed in the construc-
tion of O-protected derivatives and bolaform ureas (see
below). Compound 10 has recently been prepared in our
laboratories from penta-O-acetylated d-glucamine hydro-
bromide by using both COCl2 in toluene solution and tri-
phosgene[3,16]
While this manuscript was in preparation, Hamilton and
co-workers reported the use of per-O-acetylated d-gluca-
mine in the preparation of a series of non-fluorous hydro-
gen-bonding bis
A
virtue of the interactions between this substance and the
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P. Cintas et al.
The reactions of aminopolyols 1–3 with isocyanates 4–6
gave rise to a series of asymmetrically substituted monour-
eas (11–19) with different structural variations of the head-
and tail-group moieties (Scheme 1).
duction of a lateral methyl substituent at the nitrogen atom
hinders the attack on the carbon atom of the isocyanate.
Therefore, in aqueous dioxane, hydrolysis of the isocyanate
competes with the attack of the amino group, thereby de-
creasing the isolated yields.
Peracetylated sugars exhibit enhanced lipophilicity and
extraordinary solubility in numerous organic solvents. Such
derivatives were prepared by direct condensation of sugar
isocyanate 10 with the corresponding amines leading to
ureas 20–22 (Scheme 2). This procedure thus complements
the conventional acylation of the unprotected derivatives
avoiding the use of the more expensive and irritant isocya-
nates.
These condensations can easily be carried out in dioxane/
water under vigorous agitation. Under these experimental
conditions, monoureas 11–19 precipitated quickly and the
free hydroxy groups remained unaffected as the electrophil-
ic isocyanato group targets selectively the nitrogen atom of
the aminopolyol. Alternatively, such monoureas can be gen-
erated by adding the isocyanate to a pyridine solution of the
aminopolyol and subsequently pouring the reaction mixture
into ice/water. This strategy was especially convenient for
N-methyl-d-glucamine-based ureas (e.g., 14–16) as the intro-
Scheme 1. Synthesis of O-unprotected aminopolyol-based ureido derivatives
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Hydrogels Based on Ureido-Linked Amphiphiles
FULL PAPER
Scheme 2. Formation of per-O-acetylated monoureas from isocyanate 10.
The secondary aminopolyol 2 cannot be converted into its
isocyanate and, moreover, our attempts to transform 3 into
the corresponding isocyanate were also unsuccessful. Ac-
cordingly, per-O-acetylated monoureas 23–28 were obtained
by acetylation of 14–19 in pyridine at 08C affording oily or
solid products that were further purified by chromatograph-
ic methods.
By following the above methodology for monoureas,
chiral bolaforms with d-gluco configurations could be gener-
ated by condensation of d-glucamine isocyanate 10 with the
corresponding diamines, which again avoids the use of diiso-
cyanates (Scheme 4).
These transformations occurred readily in CH2Cl2 solu-
tions at room temperature and were essentially complete
within 10–15 min. Per-O-acetylated N-methyldiureas arising
from 2 (compounds 41–43) as well as those derived from
aminopolyol 3 (compounds 44–46) were prepared by acety-
lation (acetic anhydride, pyridine) of the corresponding un-
protected derivatives.
Formation of bis(ureas): As mentioned previously, carbohy-
A
drate and carbohydrate-like bolaamphiphiles can also be ob-
tained by the reaction of aminopolyols 1–3 with diisocya-
nates 7–9 in dioxane/water leading to insoluble products
(Scheme 3). The alternative protocol in pyridine solution
took place with the formation of unwanted side-products
and was ruled out. Three series of structurally analogous bo-
laamphiphiles (29–31, 32–34, and 35–37), which combine
flexible and rigid, aliphatic and aromatic spacers, were thus
readily available.
Structural characterization of ureas: Spectroscopic elucida-
tion, combustion analyses, and/or mass spectral data fully
agree with the proposed structures for the above ureido de-
rivatives. Among the diagnostic signals, isocyanates 6 and 7
show a strong IR absorption at about 2270 cmÀ1 and a 13C
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P. Cintas et al.
Scheme 3. Formation of bolaamphiphilic structures 29–37.
NMR
resonance
at
d
ꢀ122 ppm, which are typical of
the isocyanato group. All of the
ureas synthesized also exhibit
characteristic IR absorptions at
about 1650 and 1580 cmÀ1
(amide I and II bands) for the
ureido moiety.[17]
The symmetrical derivatives
29–46 possess a C2-symmetry
axis and thus display simplified
1H and 13C NMR spectra that
facilitate their interpretation.
The diastereotopic protons of
À
the N CH2 group of the bis-
(ureas) derived from 1 and 2 lie
in the range d=3.4–3.2 and
3.2–3.0 ppm, respectively. In
stark contrast, the protons of
À
the N CH2 group of the poly-
methylene side-chain appear as
one signal at dꢀ3.0 ppm. The
urea carbonyl groups resonate
at dꢀ156–159 ppm. The skele-
tons derived from structures 1
Scheme 4. Preparation of O-protected bis(ureas) 38–40.
A
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Hydrogels Based on Ureido-Linked Amphiphiles
FULL PAPER
Table 1. Gelation properties of O-unprotected ureas in different solvents
and 2 show a signal from the carbon atom linked to the ni-
trogen at dꢀ40 and ꢀ49 ppm, respectively, whereas the sig-
nals of the remaining carbon atoms are shifted downfield, in
the range d=72–68 ppm, in agreement with the expected
values for acyclic polyhydroxyalkyl chains.[3,18]
In addition, it should also be mentioned that the relatively
low optical rotations measured for the chiral derivatives are
consistent with the presence of acyclic sugar moieties.[3]
at a concentration of 1 wt% unless otherwise specified.[a]
Compound
H2O
EtOH
MeOH
CHCl3
Benzene
DMSO
11
12
13
14
15
16
17
18
19
29
30
31
32
33
34
35
36
37
G[b]
G
G
S
P
P
P
S
S
S
S
P
S
I
P
P
P
I
I
I
P
P
P
S
S
S
S
P
S
I
P
P
P
P
I
I
I
I
P
P
G[c]
I
P
P
I
I
I
I
I
P
I
I
I
I
I
P
P
G[c]
S
P
P
I
I
I
I
I
I
I
I
I
S
S
S
S
S
S
S
S
G[b]
S
G
I
I
G
G[e]
P
P
S
P
P
Gelation properties: Having established simple and reliable
methodologies for the construction of amphiphiles and bo-
laamphiphiles with multiple hydroxy and peracetyl groups,
we were interested in studying the gelation ability of such
low-molecular-mass molecules. A gelator, usually at a low
concentration, self-assembles to form a three-dimensional
network in which the solvent molecules are immobilized. At
first glance, one could anticipate that an amphiphilic struc-
ture having an appropriate head group with long and/or hy-
drophobic chains is sufficient for the formation of detergen-
cy or soft solid-like materials. But, as noted by Terech and
Weiss in their seminal review on the subject,[1b] it is not usu-
ally possible to predict in advance if a molecule will form a
gel in a given solvent as this property depends on a subtle
balance of different noncovalent intermolecular interactions.
A recent study has shown that dendritic amphiphiles exhibit
an unusual decrease in the critical micelle concentration
(cmc) as the chain length increases; the longer homologues
did not form micelles.[19,20]
S
G[d]
S
S
S
S
S
S
S
S
I
I
P
S
P
P
I
I
[a] G: Formation of stable gel; S: soluble after cooling; I: insoluble or
partially soluble at the boiling point of the solvent; P: precipitates upon
cooling. [b] Stable gel formed after sonication at room temperature.
[c] Precipitates at 1 wt%, gel forms at 2 wt% and at 1 wt% with ultra-
sound at room temperature. [d] Soluble at 1 wt%, gelation at 3 wt%.
[e] Soluble at 1 wt% on heating, gel forms at 2 wt% and at 1 wt% with
ultrasound at room temperature.
the ureido moiety causes a dramatic change in the gelation
ability, presumably by decreasing the number of hydrogen-
bond-forming units. Compounds 14 and 16 are soluble on
heating, although gelation at 1 wt% could only be observed
for the longer dodecyl derivative 15. For the tris(hydroxy-
methyl)aminomethane series, only 17 behaves as a hydroge-
lator under these experimental conditions, whereas 18 and
19 with longer chains and a smaller head group are insolu-
ble. A similar trend was observed for bolaamphiphilic bis-
We first observed the enhanced hygroscopicity of bis-
A
a wide range of organic solvents (from methanol and etha-
nol to dichloromethane, benzene, and n-hexane), and at-
tempts to purify them by recrystallization from water result-
ed in foaming and gel formation. This suggests that unpro-
tected mono- and bis(ureas) might immobilize water mole-
U
cules. Supramolecular hydrogels consist of water-soluble
cross-linked polymers that can modify their degree of swel-
ling, among other properties, in response to external stimuli
such as changes in temperature, pH, or ionic strength. They
are attractive materials that have found application as matri-
ces for artificial enzymes, tissue engineering, biomineraliza-
tion, or biocompatible scaffolds for wound healing.[21]
The gelation properties of the ureido amphiphiles and bo-
laamphiphiles were evaluated in various solvents, with the
emphasis on water, by the inverted tube method. Mixtures
of ureas at 1 wt% in a given solvent were heated (oil bath)
until complete dissolution, if possible. The solutions were
cooled to room temperature and gelation was observed visu-
ally. Positive results were considered to have been obtained
when gels exhibited no gravitational flow over a period of
several hours, even days. The process can be repeated,
thereby demonstrating the thermoreversibility of the sol–gel
transformation (Table 1).
C
In general, amphiphilic ureas are good hydrogelators, as
evidenced in the cases of d-glucamine derivatives with long
alkyl or oxyalkyl chains, even in the presence of an aromatic
bridge. However, the presence of a methyl substituent on
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P. Cintas et al.
to organogels at 2 wt% and, remarkably, at 1 wt% when
such mixtures were sonicated at room temperature.
Molecular aggregation under ultrasound is still poorly un-
derstood. Further experiments suggest that multiple hydro-
gen-bonding interactions cause the precipitation of the com-
pounds when the system is cooled without perturbation,
whereas ultrasonic waves could partially disrupt hydrogen-
bonding, which would facilitate the formation of the gel net-
work.[23b,24,25] This conjecture also implies that ultrasonic ef-
fects can be restricted to supramolecular aggregates having
weak intermolecular interactions.
SEM images of the as-prepared hydrogels (see the Sup-
porting Information) reveal different micron-sized architec-
tures, and although a molecular pattern cannot be inferred
from such images, it is logical to assume that networking in
aqueous solution is mainly due to hydrogen bonding and hy-
drophobic interactions, whereas p-stacking could be equally
relevant with aromatic derivatives.
Figure 2. Typical textures observed for binary water/amphiphile systems
under polarized light: lamellar (e.g., 15, left) and hexagonal (e.g., 13,
right).
curvature to produce globular aggregates arranged in cubic
lattices. These effects are also observed on increasing the
hydrophilic parts, which leads to columnar and cubic struc-
tures with the hydrophobic chains on the inner sides. As ex-
pected, the driving force for the formation of the liquid-crys-
tal phase is the generation of intermolecular hydrogen-
bonding between hydroxy groups and the segregation of hy-
drophobic chains and sugar head groups.[30]
The self-organization of the corresponding per-O-acetyl
mono- and bis(ureas) will be reported elsewhere, however,
G
preliminary screenings reveal that most are insoluble in
water, although 26 and 27 derived from 3 are soluble. They
dissolve in benzene or toluene solutions, with the exception
of 38, 39, 45, and 46, which precipitate upon cooling. Both
protected and unprotected ureas are highly soluble in
DMSO, gelation being observed in the case of 29 at a rather
modest concentration of 3 wt%.
Table 2 summarizes the type of phase formed for each
compound and the temperature at which it is formed. Ureas
derived from aminopolyol 3 showed in general little or no
Table 2. Liquid-crystal phases observed for O-unprotected ureido amphi-
philes.
Mesomorphic behavior: Conventional surfactants aggregate
in solution to form micelles because of the hydrophobic
effect.[26] At high concentrations, micelles become ordered,
forming lyotropic liquid crystals. Such mesophases are in-
duced by the presence of a solvent and are characteristic of
small molecules having hydrophilic and lipophilic termini.[27]
This behavior has been previously studied in a series of
linear nonionic urea surfactants derived from decyl and do-
decyl ureas, the intermolecular hydrogen-bonding by the
urea moiety being the dominant factor in determining the
solid-state thermal behavior and crystal solubility boun-
dary.[28] In this study, the surfactant properties of the amphi-
philic molecules could be further assessed by means of sur-
face-pressure–molecular-area isotherms and estimations of
the critical micelle concentrations, as shown in the Support-
ing Information.
Compound
Parent sugar
Mesophase
Temperature [8C]
[a]
11
14
12
15
13
16
29
30
32
33
35
36
37
1
2
1
2
1
2
1
2
1
2
1
2
3
–
–
29
120
31
120
60
160
60
–
37
–
25
37
lamellar
hexagonal
lamellar
hexagonal
hexagonal
hexagonal
hexagonal
[a]
–
lamellar
[a]
–
lamellar[b]
lamellar[c]
[a] No liquid-crystal formation was observed. [b] Observation at 258C in
the absence of water. [c] No mesophase was detected with other ureas
derived from TRIS (3), such as 17, 18, and 34.
Visual observation of the samples between crossed-polar-
izing filters revealed the formation of just two types of
activity. The rest of the compounds are grouped, for compa-
rative purposes, in pairs according to the fatty chain length,
with the second compound in each pair having a methyl
group that is missing in the first compound. Thus, as a gener-
al trend, surfactants lacking the methyl substituent need a
higher temperature than those of methylated derivatives for
the liquid-crystal phase to occur.
liquid-crystalline
(Figure 2).
textures, lamellar and hexagonal
The mesomorphic behavior of amphiphilic molecules con-
taining polyhydroxy moieties and alkyl chains has also been
studied in detail.[29] Although general rules cannot always be
established, liquid-crystalline phases emerge from a balance
of the volume fraction of the two incompatible philic parts
and the molecular shape.[5g] Single-chain compounds usually
form smectic phases, whereas the presence of two lipophilic
parts leads to cylindrical aggregates that result in hexagonal
columnar phases. Additional chains increase the interface
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Hydrogels Based on Ureido-Linked Amphiphiles
FULL PAPER
General procedures for the preparation of ureas—Method A: A solution
of the isocyanate (4.0 mmol for monoisocyanates or 2.0 mmol for diiso-
cyanates) in dioxane (0.6 mL/mmol) was added to a solution of d-gluca-
mine (1), N-methyl-d-glucamine (2), or TRIS (3) (4.1 mmol) in water
(2 mL), and the mixture was stirred at room temperature for 2 h. The re-
sulting solid was filtered, washed successively with cold water, ethanol,
and diethyl ether, and dried under vacuum.
Conclusion
We have described a convenient and reliable protocol for
the synthesis of unprotected and peracetylated amphiphilic
and bolaamphiphilic ureido sugars derived from aminopo-
lyols. The O-unprotected derivatives act as highly efficient
hydrogelators, with ultrasound stimulating gelation in most
cases at room temperature and at a low critical concentra-
tion of 1 wt%. The gelation capability can chiefly be ascri-
bed to hydrogen-bonding between the urea groups and van
der Waals interactions between the long alkyl chains. Fur-
thermore, it has been shown that some amphipathic struc-
tures bearing d-glucamine or N-methyl-d-glucamine unpro-
tected chains can also form lyotropic liquid-crystalline
phases. These findings consistently point to facile strategies
en route to novel carbohydrate-based materials. In addition,
owing to both the chelating and coordinating properties of
the urea linkage, these compounds have good prospects in
catalysis and organocatalysis, which are currently being ex-
plored.
Method B: The isocyanate (4.0 mmol for isocyanates or 2.0 mmol for dii-
socyanates) was added to a solution of d-glucamine (1), N-methyl-d-gluc-
amine (2), or TRIS (3) (4.1 mmol) in pyridine (15 mL), and the mixture
was vigorously stirred for 15 min. Then, it was poured into ice/water
(120 mL) and the mixture was kept at 08C for 24 h. In most cases a solid
appeared, which was filtered, washed with cold water, ethanol, and dieth-
yl ether, and dried. In the absence of a precipitate, the solution was
evaporated to dryness and the residue washed and dried as above.
N-(1-Deoxy-d-glucitol-1-yl)-N’-octylurea (11): Prepared from d-gluca-
mine and octyl isocyanate (4) in a yield of 58% (Method A) and recrys-
tallized from MeOH; m.p. 159–1608C; [a]D =À1.2, [a]578 =À1.0, [a]546
=
À1.6, [a]436 =À2.48 (c=1.0 in pyridine); 1H NMR (400 MHz,
[D6]DMSO): d=6.00 (t, JNH-CH2 =5.6 Hz, 1H; NH-CH2), 5.77 (t, JNH,H1
=
J
NH,H1’ =5.4 Hz, 1H; NH-H1,1’), 4.80 (d, J2-OH =3.6 Hz, 1H; 2-OH), 4.44
(d, J5-OH =6.4 Hz, 1H; 5-OH), 4.36 (d, J4-OH =5.2 Hz, 1H; 4-OH), 4.32 (t,
J6,OH ꢀJ6’,OH =5.4 Hz, 1H; 6-OH), 4.28 (d, J3-OH =6.4 Hz, 1H; 3-OH), 3.58
(m, 1H; 2-H), 3.54 (m, 2H; 3-H, 6-H), 3.46 (m, 1H; 5-H), 3.36 (m, 2H;
4-H, 6’-H), 3.20 (ddd, J1,1’ =13.2, J1,2 =4.0, JNH,1 =5.4 Hz, 1H; 1-H), 2.95
(m, 3H; 1-H’, CH2-NH), 1.32 (q, 2H; CH2-CH2-NH), 1.24 (m, 10H;
CH2), 0.85 ppm (t, 3H; CH3); 13C NMR (100 MHz, [D6]DMSO): d=
158.6 (C=O, urea), 72.7 (C-5), 72.1 (C-2), 71.5 (C-3), 69.6 (C-4), 63.4 (C-
6), 42.5 (C-1), 39.8 (C-1’), 31.3 (C-6’), 30.1 (C-2’), 28.8 (C-4’, C-5’), 26.5
(C-3’), 22.2 (C-7’), 14.0 ppm (C-8’); IR (KBr): n˜ =3356, 3317 (OH, NH),
2923 (CH3), 2844 (CH2), 1610 (C=O, urea), 1580 (NH, urea), 1083 cmÀ1
Experimental Section
General methods: See the Supporting Information for a detailed descrip-
tion of the methods employed in product purification, structural charac-
terization, and the assessment of surfactant properties.
À
(C O); elemental analysis calcd (%) for C15H32N2O6: C 53.55, H 9.59, N
8.33; found: C 53.43, H 9.40, N 8.23.
General procedures for the preparation of isocyanates—Method A: The
amine derivative (1.0 mmol) was added to a cooled solution of pyridine
(0.32 mL) in anhydrous CH2Cl2 (10 mL) and the reaction mixture was
vigorously stirred at 08C for 30 min. Then, a solution of phosgene in tolu-
ene (1.93m, 1.1 mL/amino group, 2.0 mmol/amino group) was added
dropwise and the resulting mixture was stirred at that temperature for a
further 2 h. This solution was subsequently washed with 0.5n HCl (2”
5mL), brine (1”5mL), and distilled water, dried over anhydrous MgSO4,
and evaporated to dryness.
N-(1-Deoxy-d-glucitol-1-yl)-N’-dodecylurea (12): Prepared from d-gluca-
mine and dodecyl isocyanate (5) in a yield of 77% (Method A) and re-
crystallized from MeOH; m.p. 154–1558C; [a]D =À2.0, [a]578 =À1.2,
[a]546 =À2.2, [a]436 =À3.28 (c=1.0 in pyridine); 1H NMR (400 MHz,
[D6]DMSO): d=6.00 (t, JNH-CH2 =5.6 Hz, 1H; NH-CH2), 5.78 (t, JNH,H1
=
J
NH,H1’ =5.2 Hz, 1H; NH-H1,1’), 4.80 (d, J2-OH =4.8 Hz, 1H; 2-OH), 4.44
(d, J5-OH =5.2 Hz, 1H; 5-OH), 4.37 (d, J4-OH =5.6 Hz, 1H; 4-OH), 4.33 (t,
6,OH =J6’,OH =5.6 Hz, 1H; 6-OH), 4.28 (d, J3-OH =6.0 Hz, 1H; 3-OH), 3.58
J
(m, 1H; 2-H) 3.55 (m, 2H; 3-H, 6-H), 3.47 (m, 1H; 5-H), 3.38 (m, 2H; 4-
H, 6’-H), 3.21 (ddd, J1,1’ =13.2, J1,2 =4.0, JNH,1 =5.2 Hz, 1H; 1-H), 2.95 (m,
3H; 1’-H, CH2-NH), 1.33 (q, 2H; CH2-CH2-NH), 1.24 (m, 18H; CH2),
0.85 ppm (t, 3H; CH3); 13C NMR (100 MHz, [D6]DMSO): d=158.7 (C=
O, urea), 72.7 (C-5), 72.1 (C-2), 71.5 (C-3), 69.6 (C-4), 63.4 (C-6), 42.5
(C-1), 39.8 (C-1’), 31.4 (C-10’), 30.1, 29.1, 28.9, 28.8 (C-2’, C-4’, C-5’, C-6’,
C-7’, C-8’, C-9’), 26.5 (C-3’), 22.2 (C-11’), 14.0 ppm (C-12’); IR (KBr): n˜ =
3353 (NH, OH), 2919 (CH3), 2848 (CH2), 1613 (C=O, urea), 1581 (NH,
Method B: Triphosgene (1.35 g, 4.6 mmol) was added to a mixture of the
amine (4.6 mmol) in CH2Cl2 (50 mL) and
a saturated solution of
NaHCO3 (30 mL). The resulting mixture was stirred vigorously at 08C
for 30 min. The organic layer was separated and washed with brine and
distilled water, dried (MgSO4), and evaporated to dryness.
4-(Octyloxy)phenyl isocyanate (6): This derivative was obtained from 4-
(octyloxy)aniline in yields of 83 (Method A) and 84% (Method B) after
purification of the resulting oil by column chromatography (EtOAc/
urea), 1084 cmÀ1 (C O); elemental analysis calcd (%) for C19H40N2O6: C
À
1
58.14, H 10.27, N 7.14; found: C 58.42, H 10.04, N 7.44.
hexane, 1:10); H NMR (400 MHz, CDCl3): d=7.02 (d, Jo,m =9.0 Hz, 2H;
2-H, 6-H, Ar), 6.84 (d, Jo,m =9.0 Hz, 2H; 3-H, 5-H, Ar), 3.94 (t, 2H; CH2-
O), 1.80 (m, 2H; CH2-CH2-O), 1.46 (m, 2H; -CH2-(CH2)2-O-), 1.36 (m,
8H; CH2), 0.92 ppm (t, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
157.0 (C-4, Ar), 125.7 (C-1, Ar), 125.6 (C-2, C-6, Ar), 124.1 (NCO), 115.4
(C-3, C-5, Ar), 68.4 (C-1), 31.8 (C-2), 29.4, 29.3 (C-4, C-5, C-6), 26.1 (C-
N-(1-Deoxy-d-glucitol-1-yl)-N’-(4-octyloxyphenyl)urea (13): Prepared
from d-glucamine and 4-(octyloxy)phenyl isocyanate (6) in a yield of
79% (Method A) and recrystallized from EtOH; m.p. 163–1648C; [a]D =
À9.6, [a]578 =À10.6, [a]546 =À11.0, [a]436 =À20.0 (c=1.0 in pyridine);
1H NMR (400 MHz, [D6]DMSO): d=8.41 (s, 1H; NH), 7.31 (d, Jo,m
=
3), 22.7 (C-7), 14.1 ppm (C-8); IR (Nujol): n˜ =2928 (CH3), 2856 (CH2),
8.8 Hz, 2H; 3-H, 5-H, Ar), 6.78 (d, Jo,m =8.8 Hz, 2H; 2-H, 6-H, Ar), 6.02
(t, JNH,H1 =JNH,H1’ =5.2 Hz, 1H; NH-H1,1’) 4.82 (d, J2-OH =4.4 Hz, 1H; 2-
OH), 4.48 (d, J5-OH =6.0 Hz, 1H; 5-OH), 4.41 (d, J4-OH =5.6 Hz, 1H; 4-
OH), 4.37 (t, J6,OH =J6’,OH =5.6 Hz, 1H; 6-OH), 4.32 (d, J3-OH =6.4 Hz,
1H; 3-OH), 3.86 (t, 2H; CH2-O), 3.60 (m, 3H; 2-H, 3-H, 6-H), 3.49
(dddd, 1H; 5-H), 3.41 (m, 2H; 4-H, 6-H’), 3.31 (ddd, J1,1’ =13.2, J1,2 =4.0,
À1
À
À
2272 (NCO), 1523, 1458, 829 (Ar), 1245 (C O), 1106, 1028 cm (C O);
HRMS (CI): m/z calcd for C15H22NO2: 248.1650; found: 248.1648.
Decamethylene diisocyanate (7): Obtained as above in yields of 80.5
(Method A) and 75% (Method B) on purification of the resulting oil by
column chromatography (EtOAc/hexane, 1:10); 1H NMR (400 MHz,
CDCl3): d=3.30 (t, 4H; CH2-NCO), 1.38 (m, 4H; CH2-CH2-NCO), 1.32
(m, 4H; CH2-(CH2)2-NCO), 1.31 ppm (m, 8H; CH2); 13C NMR
(100 MHz, CDCl3): d=122.0 (NCO), 43.0 (2C; C-1, C-10), 31.3 (2C; C-2,
C-9), 29.3, 28.9 (4C; C-4, C-5, C-6, C-7), 26.5 ppm (2C; C-3, C-8); IR
(Nujol): n˜ =2930, 2856 (CH2), 2273 (NCO), 1468 cmÀ1 (CH2); LR-MS
(CI): m/z (%): 227 (20) [M+3H]+, 199 (100), 182 (45), 173 (29), 84 (35).
J
NH,1 =5.2 Hz, 1H; 1-H), 2.98 (dd, J1,1’ =13.2, J1’,2 =7.2 Hz, 1H; 1’-H) 1.66
(q, 2H; CH2-CH2-O), 1.37 (q, 2H; -CH2-(CH2)2-O-), 1.26 (m, 8H; CH2),
0.85 ppm (t, 3H; CH3); 13C NMR (100 MHz, [D6]DMSO): d=155.8 (C=
O, urea), 153.4 (C-4, Ar), 133.7 (C-1, Ar), 119.3 (C-2, C-6, Ar), 114.5 (C-
À
3, C-5, Ar) 72.2 (C-5), 72.0 (C-2), 71.5 (C-3), 70.0 (C-4), 67.6 (C O), 63.5
(C-6), 42.3 (C-1), 31.4 (C-3’), 28.9, 28.8 (C-4’, C-5’, C-7’), 25.7 (C-6’), 22.2
Chem. Eur. J. 2008, 14, 5656 – 5669
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5663

P. Cintas et al.
(C-2’), 14.0 ppm (C-1’); IR (KBr): n˜ =3512 (OH), 3349 (NH), 2922
recrystallized from EtOAc; m.p. 145–1468C; 1H NMR (400 MHz,
[D6]DMSO): d=6.45 (t, JNH-CH2 =5.6 Hz, 1H; NH-CH2), 5.71 (s, 1H;
NH-C), 5.09 (t, JOH-H =5.6 Hz, 3H; OH), 3.40 (d, JOH-H =5.6 Hz, 6H;
CH2-OH), 2.93 (q, 2H; CH2-NH), 1.33 (q, 2H; CH2-CH2-NH), 1.24 (m,
10H; CH2), 0.86 ppm (t, 3H; CH3); 13C NMR (100 MHz, [D6]DMSO):
d=159.1 (C=O, urea), 61.4 (3C; CH2OH), 60.6 (C-NH), 39.7 (C-1’), 31.3
(C-6’), 29.9 (C-2’), 28.8 (C-4’, C-5’), 26.5 (C-3’), 22.2 (C-7’), 14.0 ppm (C-
8’) ppm; IR (KBr): n˜ =3368, 3240 (OH, NH), 2921 (CH3), 2855 (CH2),
(CH3), 2854 (CH2), 1649 (C=O, urea), 1603 (aryl), 1579 (NH, urea), 1512
À1
À
À
(Ar), 1248 (C O, Ar), 1090 cm (C O); elemental analysis calcd (%)
for C21H36N2O7: C 58.86, H 8.47, N 6.54; found: C 59.14, H 8.22, N 6.17.
N-(1-Deoxy-d-glucitol-1-yl)-N-methyl-N’-octylurea (14): Prepared from
N-methyl-d-glucamine and octyl isocyanate (4) in yields of 14 (Method
A) and 91% (Method B), and recrystallized from EtOAc; m.p. 116–
1178C; [a]D =+9.6, [a]578 =+10.2, [a]546 =+12.0, [a]436 =+20.6 (c=1.0 in
pyridine); 1H NMR (400 MHz, [D6]DMSO): d=6.20 (t, JNH-CH2 =5.2 Hz,
1H; NH-CH2), 4.96 (d, J2-OH =4.8 Hz, 1H; 2-OH), 4.48 (d, J5-OH =5.2 Hz,
1H; 5-OH), 4.43 (m, 2H; 3-OH, 4-OH), 4.33 (t, J6,OH ꢀJ6’,OH =5.6 Hz,
1H; 6-OH), 3.71 (dddd, J2-OH =4.8, J1,2 =4.0, J1’,2 =8.0, J2,3 =3.6 Hz, 1H;
2-H), 3.55 (ddd, J6-OH =5.6, J5,6 =2.8, J6,6’ =11.2 Hz, 1H; 6-H), 3.49 (m,
2H; 3-H, 5-H), 3.42 (ddd, J3,4 =2.0, J4-OH =5.0, J4,5 =8.0 Hz, 1H; 4-H),
1654 (C=O, urea), 1564 (NH, urea), 1048 cmÀ1 (C O); elemental analysis
À
calcd (%) for C13H28N2O4: C 56.50, H 10.21, N 10.14; found: C 56.70, H
10.23, N 10.07.
N-[Tris(hydroxymethyl)methyl]-N’-dodecylurea (18): Prepared from
3
and dodecyl isocyanate (5) in yields of 25 (Method A) and 42% (Method
1
B), and recrystallized from EtOAc; m.p. 148-1498C; H NMR (400 MHz,
[D6]DMSO): d=6.44 (t, JNH-CH2 =6.0 Hz, 1H; NH-CH2), 5.71 (s, 1H;
NH-C), 5.09 (t, JOH-H =5.6 Hz, 3H; OH), 3.40 (d, JOH-H =5.6 Hz, 6H;
CH2-OH), 2.93 (q, 2H; CH2-NH), 1.32 (q, 2H; CH2-CH2-NH), 1.24 (m,
18H; CH2), 0.85 ppm (t, 3H; CH3); 13C NMR (100 MHz, [D6]DMSO):
d=159.1 (C=O, urea), 61.4 (3C; CH2OH), 60.5 (C-NH), 40.1 (C-1’), 31.4
(C-10’), 29.8, 29.1, 28.9, 28.8 (C-2’, C-4’, C-5’, C-6’, C-7’, C-8’, C-9’), 26.5
(C-3’), 22.2 (C-11’), 14.0 ppm (C-12’); IR (KBr): n˜ =3372, 3240 (OH,
NH), 2917 (CH3), 2850 (CH2), 1654 (C=O, urea), 1565 (NH, urea),
3.35 (ddd, J6-OH =5.6, J5,6’ =6.0, J6,6’ =11.2 Hz, 1H; 6-H’), 3.27 (dd, J1,1’
=
14.8, J1,2 =4.8 Hz, 1H; 1-H), 3.12 (dd, J1,1’ =14.8, J1’,2 =8.0 Hz, 1H; 1’-H),
2.97 (q, 2H; CH2-NH), 2.80 (s, 3H; CH3-N) 1.37 (q, 2H; CH2-CH2-NH),
1.24 (m, 10H; CH2), 0.85 ppm (t, 3H; CH3) ppm; 13C NMR (100 MHz,
[D6]DMSO): d=158.7 (C=O, urea), 72.4 (C-5), 72.1 (C-3), 71.4 (C-4),
69.1 (C-2), 63.3 (C-6), 51.6 (C-1), 40.1 (C-1’), 35.3 (CH3-N), 31.3 (C-6’),
30.0 (C-2’), 28.8 (C-4’, C-5’), 26.5 (C-3’), 22.2 (C-7’), 14.0 ppm (C-8’); IR
(KBr): n˜ =3432 (OH), 3375 (NH), 2926 (CH3), 2852 (CH2), 1632 (C=O,
À
1120 cmÀ1 (C O); elemental analysis calcd (%) for C17H36N2O4: C 61.41,
urea), 1583 (NH, urea), 1096 cmÀ1 (C O); elemental analysis calcd (%)
À
H 10.91, N 8.43; found: C 61.75, H 11.06, N 8.28.
for C16H34N2O6: C 54.84, H 9.78, N 7.99; found: C 54.79, H 9.57, N 7.84.
N-[Tris(hydroxymethyl)methyl]-N’-(4-octyloxyphenyl)urea (19): Prepared
from 3 and 4-(octyloxy)phenyl isocyanate (6) in yields of 54 (Method A)
and 53% (Method B), and recrystallized from EtOAc; m.p. 150-1518C;
N-(1-Deoxy-d-glucitol-1-yl)-N-methyl-N’-dodecylurea (15): Prepared
from N-methyl-d-glucamine and dodecyl isocyanate (5) in yields of 74
(Method A) and 82% (Method B), and recrystallized from EtOAc; m.p.
120–1218C; [a]D =+7.8, [a]578 =+8.8, [a]546 =+10.4, [a]436 =+17.6 (c=
1H NMR (400 MHz, [D6]DMSO): d=8.71 (s, 1H; NH-Ar), 7.22 (d, Jo,m
=
1.0 in pyridine); 1H NMR (400 MHz, [D6]DMSO): d=6.20 (t, JNH-CH2
5.4 Hz, 1H; NH-CH2), 4.96 (d, J2-OH =4.8 Hz, 1H; 2-OH), 4.49 (d, J5-OH
=
8.8 Hz, 2H; 2-H, 6-H, aryl), 6.78 (d, Jo,m =8.8 Hz, 2H; 3-H, 5-H, aryl),
5.91 (s, 1H; NH-C), 4.92 (t, JOH-H =5.6 Hz, 3H; OH), 3.86 (t, 2H; CH2-
O), 3.52 (d, JOH-H =5.6 Hz, 6H; CH2-OH), 1.66 (q, 2H; CH2-CH2-O),
1.37 (q, 2H; CH2-(CH2)2-O-), 1.27 (m, 8H; CH2), 0.86 ppm (t, 3H; CH3);
13C NMR (100 MHz, [D6]DMSO): d=156.2 (C=O, urea), 153.4 (C-4, Ar),
133.4 (C-1, Ar), 119.5 (C-2, C-6, Ar), 114.5 (C-3, C-5, Ar), 67.6 (C-1’),
61.1 (3C; CH2-OH), 60.7 (C-NH), 31.3 (C-3’), 28.8, 28.7 (C-4’, C-5’, C-7’),
25.6 (C-6’), 22.1 (C-2’), 14.0 ppm (C-8’); IR (KBr): n˜ =3368, 3226 (OH,
=
5.2 Hz, 1H; 5-OH), 4.43 (m, 2H; 3-OH, 4-OH), (t, J6,OH ꢀJ6’,OH =5.6 Hz,
1H; 6-OH), 3.71 (dddd, J2-OH =4.8, J1,2 =4.0, J1’,2 =8.0, J2,3 =3.6 Hz, 1H;
2-H), 3.55 (ddd, J6-OH =5.6, J5,6 =2.8, J6,6’ =11.2 Hz, 1H; 6-H), 3.49 (m,
2H; 3-H, 5-H), 3.42 (m, 1H; 4-H), 3.35 (ddd, J6-OH =5.6, J5,6’ =6.0, J6,6’
11.2 Hz, 1H; 6’-H), 3.29 (dd, J1,1’ =14.8, J1,2 =4.8 Hz, 1H; 1-H), 3.13 (dd,
1,1’ =14.8, J1’,2 =8.0 Hz, 1H; 1’-H), 2.97 (q, 2H; CH2-NH), 2.80 (s, 3H;
=
J
NH), 2937 (CH3), 2867 (CH2), 1675 (C=O, urea), 1606 (Ar), 1560 (NH,
CH3-N) 1.37 (q, 2H; CH2-CH2-NH), 1.24 (m, 18H; CH2), 0.85 ppm (t,
3H; CH3); 13C NMR (100 MHz, [D6]DMSO): d=158.7 (C=O, urea), 72.4
(C-5), 72.1 (C-2), 71.4 (C-3), 69.1 (C-4), 63.3 (C-6), 51.6 (C-1), 40.1 (C-
1’), 35.3 (CH3-N), 31.4 (C-10’), 30.0, 29.1, 28.9, 28.8 (C-2’, C-4’, C-5’, C-6’,
C-7’, C-8’, C-9’), 26.5 (C-3’), 22.1 (C-11’), 14.0 ppm (C-12’); IR (KBr): n˜ =
3431 (OH), 3372 (NH), 2920 (CH3), 2851 (CH2), 1630 (C=O, urea), 1583
À1
À
À
urea), 1511 (Ar), 1232, (Ar O), 1125, 1021 cm (C O); elemental analy-
sis calcd (%) for C19H32N2O5: C 61.93, H 8.75, N 7.60; found: C 62.28, H
8.77, N 7.84.
General preparation of per-O-acetylated ureas derived from d-gluc-
A
(NH, urea), 1101 cmÀ1 (C O); elemental analysis calcd (%) for
À
rivatives and 1.5 mmol for diamines) was added to a solution of isocya-
nate 10 (1.25 g, 3.0 mmol) in CH2Cl2 (15 mL). The reaction mixture was
vigorously stirred at room temperature for 15 min and then evaporated
to dryness.
C20H42N2O6: C 59.08, H 10.41, N 6.89; found: C 59.38, H 10.12, N 6.65.
N-(1-Deoxy-d-glucitol-1-yl)-N-methyl-N’-(4-octyloxyphenyl)urea
(16):
Prepared from N-methyl-d-glucamine and 4-(octyloxy)phenyl isocyanate
(6) in a yield of 66% (Method A), and recrystallized from EtOAc; m.p.
121–1228C; [a]D =+7.8, [a]578 =+8.4, [a]546 =+9.8, [a]436 =+22.6 (c=1.0
N-(2,3,4,5,6-Penta-O-acetyl-1-deoxy-d-glucitol-1-yl)-N’-octylurea
(20):
This substance was synthesized from 10 and octylamine in a yield of 85%
as a homogeneous oil that was further purified by preparative chroma-
1
in pyridine); H NMR (400 MHz, [D6]DMSO): d=8.28 (s, 1H; NH), 7.26
(d, Jo,m =8.8 Hz, 2H; 2-H, 6-H, aryl), 6.79 (d, Jo,m =8.8 Hz, 2H; 3-H, 5-H,
aryl), 5.17 (d, J2-OH =4.0 Hz, 1H; 2-OH), 4.54 (m, 2H; 3-OH, 4-OH), 4.50
(d, J5-OH =4.8 Hz, 1H; 5-OH), 4.37 (t, J6,OH ꢀJ6’,OH =5.6 Hz, 1H; 6-OH),
tography (EtOAc/hexane, 3:1); [a]D =+10.5, [a]578 =+12.6, [a]546
=
+13.8, [a]436 =+25.0, [a]365 =+40.5 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.48 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 1H; 4-H), 5.35 (t,
3.87 (t, 2H; CH2-O), 3.82 (dddd, J2-OH =4.0, J1,2 =4.0, J1’,2 =8.0, J2,3
=
J
2,3 =J3,4 =4.8 Hz, 1H; 3-H), 5.04 (m, 2H; 2-H, 5-H), 4.65 (brs, 2H; NH-
CH2, NH-H-1,1’), 4.27 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 1H; 6-H), 4.13 (dd,
5,6’ =5.6, J6,6’ =12.4 Hz, 1H; 6’-H), 3.50 (dd, J1,1’ =14.8, J1,2 =5.4 Hz, 1H;
3.6 Hz, 1H; 2-H), 3.63 (ddd, J6-OH =5.6, J5,6 =2.8, J6,6’ =11.2 Hz, 1H; 6-H),
3.57 (m, 2H; 3-H, 5-H), 3.51 (m, 1H; 4-H), 3.44 (ddd, J6-OH =5.6, J5,6’
=
J
6.0, J6,6’ =11.2 Hz, 1H; 6’-H), 3.41 (dd, J1,1’ =14.8, J1,2 =4.8 Hz, 1H; 1-H),
3.28 (dd, J1,1’ =14.8, J1’,2 =8.0 Hz, 1H; 1’-H), 2.93 (s, 3H; CH3-N), 1.67 (q,
2H; CH2-CH2-O), 1.38 (q, 2H; -CH2-(CH2)2-O-), 1.27 (m, 8H; CH2),
0.86 ppm (t, 3H; CH3); 13C NMR (100 MHz, [D6]DMSO): d=156.3 (C=
O, urea), 153.8 (C-4, Ar), 133.6 (C-1, Ar), 121.2 (C-2, C-6, Ar), 114.2 (C-
3, C-5, Ar), 72.1 (C-5), 71.9 (C-2), 71.4 (C-3), 69.4 (C-4), 67.5 (C-1’), 63.3
(C-6), 51.8 (C-1), 35.5 (CH3-N), 31.3 (C-3’), 28.8, 28.7 (C-4’, C-5’, C-7’),
25.6 (C-6’), 22.1 (C-2’), 14.0 ppm (C-8’); IR (KBr): n˜ =3399 (NH, OH),
1-H), 3.23 (dd, J1,1’ =14.8, J1’,2 =5.2 Hz, 1H; 1’-H), 3.15 (t, 2H; CH2-NH),
2.13, 2.11, 2.10, 2.08, 2.05 (s, 15H; OAc), 1.49 (q, 2H; CH2-CH2-NH),
1.29 (m, 10H; CH2), 0.88 ppm (t, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=170.3, 170.0, 169.6, 169.5 (5C; acetates), 157.6 (C=O, urea),
70.7 (C-2), 68.9 (C-4), 68.5 (C-3), 68.4 (C-5), 61.1 (C-6), 40.4 (C-1’), 40.1
(C-1), 31.5 (C-6’), 29.7 (C-2’), 28.9 (C-4’, C-5’), 26.5 (C-3’), 22.3 (C-7’),
20.5, 20.4, 20.2 (5C; acetates), 13.7 ppm (C-8’); IR (Nujol): n˜ =3374
(NH), 2928 (CH3), 2856 (CH2), 1748 (C=O, acetate), 1641 (C=O, urea),
À1
À
À
À
2920 (CH3), 2852 (CH2), 1620 (C=O, urea), 1548 (NH, urea), 1515, 1413
1569 (NH, urea), 1219 (C O C, ester), 1049 cm (C O); HRMS (CI):
À1
À
À
(Ar), 1249 (C O, Ar), 1079 cm (C O); elemental analysis calcd (%)
for C22H38N2O7: C 59.71, H 8.65, N 6.33; found: C 59.81, H 8.74, N 6.40.
m/z calcd for C25H43N2O11: 547.2867; found: 547.2857.
N-(2,3,4,5,6-Penta-O-acetyl-1-deoxy-d-glucitol-1-yl)-N’-dodecylurea (21):
Prepared from 10 and dodecylamine in a yield of 80% as a homogeneous
oil, which was further purified by preparative chromatography (EtOAc/
N-[Tris(hydroxymethyl)methyl]-N’-octylurea (17): Prepared from 3 and
octyl isocyanate (4) in yield of 67 (Method A) and 59% (Method B), and
5664
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 5656 – 5669

Hydrogels Based on Ureido-Linked Amphiphiles
FULL PAPER
hexane, 3:1); [a]D =+10.3, [a]578 =+10.3, [a]546 =+12.3, [a]436 =+21.3,
[a]365 =+33.2 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=5.49
(dd, J3,4 =4.8, J4,5 =6.4 Hz, 1H; 4-H), 5.36 (t, J2,3 =J3,4 =4.8 Hz, 1H; 3-H),
5.05 (m, 2H; 2-H, 5-H), 4.72 (brs, 2H; NH-CH2, NH-H-1,1’), 4.28 (dd,
N-(2,3,4,5,6-Penta-O-acetyl-1-deoxy-d-glucitol-1-yl)-N-methyl-N’-dodec-
A
rified by preparative chromatography (EtOAc/hexane, 3:1); [a]D =+5.0,
[a]578 =+5.8, [a]546 =+6.6, [a]436 =+13.0 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=5.45 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 1H; 4-H), 5.32
J
5,6 =3.6, J6,6’ =12.4 Hz, 1H; 6-H), 4.13 (dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 1H;
6’-H), 3.50 (dd, J1,1’ =14.8, J1,2 =4.6 Hz, 1H; 1-H), 3.23 (dd, J1,1’ =14.8,
1’,2 =5.4 Hz, 1H; 1’-H), 3.15 (t, 2H; CH2-NH), 2.13, 2.11, 2.10, 2.09, 2.05
(dd, J2,3 =6.4, J3,4 =4.8 Hz, 1H; 3-H), 5.20 (ddd, J1,2 =7.6, J1’,2 =4.4, J2,3
=
6.4 Hz, 1H; 2-H), 5.03 (ddd, J4,5 =6,4, J5,6 =3.2, J5,6’ =5.8 Hz, 1H; 5-H),
4.69 (brs, 1H; NH), 4.30 (dd, J5,6 =3.2, J6,6’ =12.4 Hz, 1H; 6-H), 4.12 (dd,
J
(s, 15H; OAc), 1.48 (q, 2H; CH2-CH2-NH), 1.26 (m, 18H; CH2),
0.88 ppm (t, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=170.7, 170.6,
170.3, 169.9 (5C; acetates), 157.9 (C=O, urea), 71.1 (C-2), 69.3 (C-4), 68.9
(C-3), 68.8 (C-5), 61.5 (C-6), 40.8 (C-1’), 40.4 (C-1), 31.9 (C-10’), 29.7,
29.6, 29.4 (C-2’, C-4’, C-5’, C-6’, C-7’, C-8’, C-9’), 26.9 (C-3’), 22.7 (C-11’),
20.9, 20.8, 20.7, 20.6 (5C; acetates), 14.1 ppm (C-12’); IR (Nujol): n˜ =
3376 (NH), 2926 (CH3), 2854 (CH2), 1752 (C=O, acetate), 1639 (C=O,
J
5,6’ =5.8, J6,6’ =12.4 Hz, 1H; 6’-H), 3.61 (dd, J1,1’ =14.6, J1,2 =7.6 Hz, 1H;
1-H), 3.36 (dd, J1,1’ =14.6, J1’,2 =4.4 Hz, 1H; 1’-H), 3.19 (dt, 2H; CH2-
NH), 2.86 (s, 3H; CH3-N), 2.13, 2.09, 2.08, 2.07, 2.05 (s, 15H; OAc), 1.49
(q, 2H; CH2-CH2-NH), 1.28 (m, 10H; CH2), 0.88 ppm (t, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=170.4, 170.2, 169.8, 169.7 (5C; acetates),
158.0 (C=O, urea), 69.8 (C-2), 69.2 (C-4), 68.9 (C-3), 68.7 (C-5), 61.3 (C-
6), 48.6 (C-1), 41.0 (C-1’), 35.2 (CH3-N), 31.8 (C-10’), 30.1, 29.5, 29.3, 29.2
(C-2’, C-4’, C-5’, C-6’, C-7’, C-8’, C-9’), 26.8 (C-3’), 22.6 (C-11’), 20.7, 20.6,
20.5, 20.4 (5C; acetates), 14.1 ppm (C-12’); IR (Nujol): n˜ =3375 (NH),
À1
À1
À
À
À
urea), 1571 (NH, urea), 1221 (C O C, ester), 1050 cm (C O) cm
;
HRMS (CI): m/z calcd for C29H51N2O11: 603.3493; found: 603.3513.
N-(2,3,4,5,6-Penta-O-acetyl-1-deoxy-d-glucitol-1-yl)-N’-(4-octyloxyphen-
yl)urea (22): Prepared from 10 and 4-octyloxyaniline in a yield of 95% as
a solid that was purified by preparative chromatography (EtOAc/hexane,
2927 (CH3), 2854 (CH2), 1748 (C=O, acetate), 1642 (C=O, urea), 1537
ACHTREUNG
À1
À
À
À
(NH, urea), 1220 (C O C, ester), 1050 cm (C O); HRMS (CI): m/z
calcd for C30H53N2O11: 617.3649; found: 617.3611.
3:1); m.p. 113–1148C; [a]D =+9.1, [a]578 =+10.5, [a]546 =+12.5, [a]436
+20.4 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.20 (d, Jo,m
=
=
N-(2,3,4,5,6-Penta-O-acetyl-1-deoxy-d-glucitol-1-yl)-N-methyl-N’-(4-oct-
A
8.8 Hz, 2H; 2-H, 6-H, Ar), 6.83 (d, Jo,m =8.8 Hz, 2H; 3-H, 5-H, Ar), 6.74
solid was purified by preparative chromatography (EtOAc/hexane, 3:1);
(s, 1H; NH-Ar), 5.51 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 1H; 4-H), 5.37 (t, J2,3
3,4 =4.8 Hz, 1H; 3-H), 5.11 (m, 2H; 2-H, 5-H), 5.05 (t, JNH-H1 =JNH-H1’
=
=
m.p. 109–1108C; [a]D =+5.8, [a]578 =+7.2, [a]546 =+8.2, [a]436 =+13.8
J
1
(c=1.0 in CHCl3); H NMR (400 MHz, CDCl3): d=7.30 (d, Jo,m =9.2 Hz,
6.0 Hz, 1H; NH-H1,1’), 4.27 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 1H; 6-H), 4.10
(dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 1H; 6’-H), 3.91 (t, 2H; CH2-O-) 3.50 (ddd,
2H; 2-H, 6-H, Ar), 6.82 (d, Jo,m =9.2 Hz, 2H; 3-H, 5-H, Ar), 6.73 (s, 1H;
NH-Ar), 5.48 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 1H; 4-H), 5.37 (dd, J2,3 =6.4,
J
J
NH-H1 =6.0, J1,1’ =14.8, J1,2 =4.6 Hz, 1H; 1-H), 3.23 (ddd, JNH-H1’ =6.0,
1,1’ =14.8, J1’,2 =5.4 Hz, 1H; 1’-H), 2.12, 2.07, 2.06, 2.02 (s, 15H; OAc),
J
3,4 =4.8 Hz, 1H; 3-H), 5.25 (ddd, J1,2 =7.6, J1’,2 =4.4, J2,3 =6.4 Hz, 1H; 2-
H), 5.04 (ddd, J4,5 =6,4, J5,6 =3.2, J5,6’ =5.8 Hz, 1H; 5-H), 4.31 (dd, J5,6
=
1.76 (q, 2H; -CH2-CH2-O-), 1.44 (q, 2H; CH2-(CH2)2-O-), 1.31 (m, 8H;
CH2), 0.89 ppm (t, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=170.7,
170.4, 170.2, 169.9, 169.8 (5C; acetates), 156.5 (C=O, urea), 156.2 (C-4,
Ar), 130.6 (C-1, Ar), 124.5 (C-2, C-6, Ar), 115.1 (C-3, C-5, Ar), 70.9 (C-
2), 69.0 (C-4), 68.8 (C-3), 68.7 (C-5), 68.3 (C-1’), 61.4 (C-6), 40.1 (C-1),
31.8 (C-6’), 29.3, 29.2 (C-5’, C-4’, C-2’), 26.0 (C-3’), 22.6 (C-7’), 20.8, 20.7,
20.5 (5C; acetates), 14.0 ppm (C-8’); IR (KBr): n˜ =3414, 3375 (NH),
3.2, J6,6’ =12.4 Hz, 1H; 6-H), 4.12 (dd, J5,6’ =5.8, J6,6’ =12.4 Hz, 1H; 6’-H),
3.91 (t, 2H; CH2-O-), 3.70 (dd, J1,1’ =14.6, J1,2 =7.6 Hz, 1H; 1-H), 3.43
(dd, J1,1’ =14.6, J1’,2 =4.4 Hz, 1H; 1’-H), 3.00 (s, 3H; CH3-N), 2.13, 2.11,
2.10, 2.05, 2.03 (s, 15H; OAc), 1.75 (q, 2H; CH2-CH2-O-), 1.44 (q, 2H;
CH2-(CH2)2-O-), 1.32 (m, 8H; CH2), 0.89 ppm (t, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=170.6, 170.5, 170.1, 169.9, 169.8 (5C; acetates),
155.3 (C=O, urea and C-4, Ar), 132.0 (C-1, Ar), 122.0 (C-2, C-6, Ar),
114.7 (C-3, C-5, Ar), 70.1 (C-2), 69.3 (C-4), 68.9 (C-3), 68.8 (C-5), 68.3
(C-1’), 61.4 (C-6), 49.0 (C-1), 35.9 (CH3-N), 31.8 (C-6’), 29.3, 29.2 (C-5’,
C-4’, C-2’), 26.0 (C-3’), 22.6 (C-7’), 20.8, 20.7, 20.5 (5C; acetates),
14.1 ppm (C-8’); IR (KBr): n˜ =3408 (NH), 2924 (CH3), 2860 (CH2), 1748,
2926 (CH3), 2860 (CH2), 1745, 1742, (C=O, acetate), 1681 (C=O, urea),
À1
À
À
À
1543 (NH, urea), 1505 (Ar), 1222 (C O C, ester), 1027 cm (C O); ele-
mental analysis calcd (%) for C31H46N2O12: C 58.29, H 7.26, N 4.39;
found: C 58.10, H 7.15, N 4.22.
General preparation of per-O-acetylated ureas derived from N-methyl-d-
glucamine: Acetic anhydride (35 mL) was slowly added to a solution of
the corresponding unprotected urea (4.0 mmol) in pyridine (15 mL). The
reaction mixture was stirred at 08C for 24 h and then it was poured into
ice/water (200 mL). The solution was subsequently extracted with CH2Cl2
(3”100 mL) and washed successively with 2n HCl (3”100 mL), a satu-
rated solution of NaHCO3 (2x100 mL), and distilled water (2”100 mL),
dried (MgSO4), and evaporated to dryness.
1729, (C=O, acetate), 1657 (C=O, urea), 1541 (NH, urea), 1512 (Ar),
À1
À
À
À
1243 (C O C, ester), 1049 cm (C O); elemental analysis calcd (%) for
C32H48N2O12: C 58.88, H 7.41, N 4.29; found: C 58.56, H 7.51, N 4.37.
N-[Tris(acetoxymethyl)methyl]-N’-octylurea (26): By following the above
protocol for the acetylation of ureas derived from N-methyl-d-glucamine,
the title compound was obtained from 17 in a yield of 76% yield as a
solid that was further purified by preparative chromatography (EtOAc/
1
hexane, 1:1); m.p. 121–1228C; H NMR (400 MHz, CDCl3): d=4.62 (brs,
N-(2,3,4,5,6-Penta-O-acetyl-1-deoxy-d-glucitol-1-yl)-N-methyl-N’-octyl-
2H; NH-C, NH-CH2), 4.43 (s, 6H; CH2-OAc), 2.93 (t, 2H; CH2-NH),
2.08 (s, 9H; OAc), 1.46 (q, 2H; CH2-CH2-NH), 1.28 (m, 10H; CH2),
0.88 ppm (t, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=170.3 (3C; ace-
tates), 156.9 (C=O, urea), 63.5 (3C; CH2OAc), 57.4 (C-NH), 40.6 (C-1’),
31.8 (C-6’), 30.0 (C-2’), 29.2 (C-4’, C-5’), 26.8 (C-3’), 22.6 (C-7’), 20.8 (3C;
ACHTREUNG
chromatography (EtOAc/hexane, 3:1); [a]D =+5.3, [a]578 =+5.8, [a]546
=
+6.5, [a]436 =+11.3 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
5.45 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 1H; 4-H), 5.32 (dd, J2,3 =6.4, J3,4 =4.8 Hz,
1H; 3-H), 5.20 (ddd, J1,2 =7.6, J1’,2 =4.4, J2,3 =6.4 Hz, 1H; 2-H), 5.03 (ddd,
acetates), 14.0 ppm (C-8’); IR(KBr): n˜ =3360, 3309 (NH), 2924 (CH3),
A
2854 (CH2), 1754, 1733 (C=O, acetates), 1627 (C=O, urea), 1571 (NH,
À1
À
À
À
urea), 1233 (C O C), 1043 cm (C O); elemental analysis calcd (%)
for C19H34N2O7: C 56.70, H 8.51, N 6.96; found: C 56.75, H 8.48, N 6.95.
J
J
4,5 =6,4, J5,6 =3.2, J5,6’ =5.8 Hz, 1H; 5-H), 4.70 (brs, 1H; NH), 4.30 (dd,
5,6 =3.2, J6,6’ =12.4 Hz, 1H; 6-H), 4.12 (dd, J5,6’ =5.8, J6,6’ =12.4 Hz, 1H;
6’-H), 3.61 (dd, J1,1’ =14.6, J1,2 =7.6 Hz, 1H; 1-H), 3.36 (dd, J1,1’ =14.6,
1’,2 =4.4 Hz, 1H; 1’-H), 3.15 (m, 2H; CH2-NH), 2.87 (s, 3H; CH3-N),
N-[Tris(acetoxymethyl)methyl]-N’-dodecylurea (27): Prepared by acety-
lation of 18 in a yield of 69% as a solid that was purified by preparative
chromatography (EtOAc/hexane, 1:1); m.p. 127–1288C; 1H NMR
(400 MHz, CDCl3): d=4.81 (brs, 1H; NH-CH2), 4.44 (s, 6H; CH2-OAc),
4.34 (brs, 1H; NH-C), 3.09 (t, 2H; CH2-NH), 2.09 (s, 9H; OAc), 1.47 (q,
2H; CH2-CH2-NH), 1.28 (m, 18H; CH2), 0.88 ppm (t, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=170.6 (3C; acetates), 157.0 (C=O, urea),
63.3 (3C; CH2OAc), 57.1 (C-NH), 40.4 (C-1’), 31.8 (C-10’), 30.0, 29.5,
29.3 (C-2’, C-4’, C-5’, C-6’, C-7’, C-8’, C-9’), 26.8 (C-3’), 22.6 (C-11’), 20.8
J
2.14, 2.09, 2.08, 2.07, 2.05 (s, 15H; OAc), 1.48 (q, 2H; CH2-CH2-NH),
1.27 (m, 10H; CH2), 0.88 ppm (t, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=170.5, 170.3, 169.9, 169.8 (5C; acetates), 158.0 (C=O, urea),
69.9 (C-2), 69.2 (C-4), 68.9 (C-3), 68.8 (C-5), 61.4 (C-6), 48.7 (C-1), 41.0
(C-1’), 35.3 (CH3-N), 31.8 (C-6’), 30.2 (C-2’), 29.3, 29.2 (C-4’, C-5’), 26.9
(C-3’), 22.6 (C-7’), 20.8, 20.7, 20.6, 20.5 (5C; acetates), 14.0 ppm (C-8’);
IR (Nujol): n˜ =3370 (NH), 2927 (CH3), 2855 (CH2), 1748 (C=O, acetate),
À1
À
À
À
1642 (C=O, urea), 1536 (NH, urea), 1220 (C O C, ester), 1049 cm (C
O); HRMS (CI): m/z calcd for C26H45N2O11: 561.3023; found: 561.3028.
(3C; acetates), 14.0 ppm (C-12’); IR
A
2852 (CH2), 1754, 1733 (C=O, acetates), 1627 (C=O, urea), 1572 (NH,
Chem. Eur. J. 2008, 14, 5656 – 5669
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5665

P. Cintas et al.
À1
À
À
À
urea), 1233 (C O C), 1042 cm (C O); elemental analysis calcd (%)
for C23H42N2O7: C 60.24, H 9.23, N 6.11; found: C 60.21, H 9.42, N 6.10.
J
NH,H1’ =5.2 Hz, 2H; NH-H1,1’), 4.83 (d, J2-OH =2.8 Hz, 2H; 2-OH), 4.49
(d, J5-OH =6.0 Hz, 2H; 5-OH), 4.10 (d, J4-OH =5.6 Hz, 2H; 4-OH), 4.37 (t,
6,OH =J6’,OH =5.6 Hz, 2H; 6-OH), 4.32 (d, J3-OH =5.6 Hz, 2H; 3-OH), 3.55
(m, 6H; 2-H, 3-H, 6-H), 3.47 (m, 2H; 5-H), 3.32 (m, 4H; 4-H, 6’-H), 3.29
(ddd, J1,1’ =13.2, J1,2 =4.0, JNH,H1 =5.2 Hz, 2H; 1-H), 2.98 ppm (ddd, J1,1’
13.2, 1’,2 =7.2,
NH,H1’ =5.2 Hz, 2H; 1’-H); 13C NMR (100 MHz,
J
N-[Tris(acetoxymethyl)methyl]-N’-(4-octyloxyphenyl)urea (28): Prepared
by acetylation of 19 in a yield of 77% as a solid that was further purified
by preparative chromatography (EtOAc/hexane, 1:1); m.p. 125-1268C;
1H NMR (400 MHz, CDCl3): d=7.14 (d, Jo,m =8.8 Hz, 2H; 2-H, 6-H, Ar),
6.94 (brs, 1H; NH-Ar), 6.84 (d, Jo,m =8.8 Hz, 2H; 3-H, 5-H, Ar), 5.32
(brs, 1H; NH-C), 4.42 (s, 6H; CH2-OAc), 3.90 (t, 2H; CH2-O), 2.04 (s,
9H; OAc), 1.76 (q, 2H; CH2-CH2-O), 1.42 (q, 2H; CH2-(CH2)2-O-), 1.31
(m, 8H; CH2), 0.89 ppm (t, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
170.4 (3C; acetates), 156.4 (C=O, urea), 155.6 (C-4, Ar), 130.3 (C-1, Ar),
124.0 (C-2, C-6, Ar), 115.0 (C-3, C-5, Ar), 68.2 (C-1’), 63.0 (CH2-OAc),
57.0 (C-NH), 31.7 (C-6’), 29.2, 29.1 (C-5’, C-4’, C-2’), 25.9 (C-3’), 22.5 (C-
7’), 20.6 (3C; acetates), 14.0 ppm (C-8’); IR (KBr): n˜ =3334, 3274 (NH),
=
J
J
[D6]DMSO): d=155.7 (2C; urea), 134.4 (4C; C-1, C-4, Ar), 121.8 (8C;
Ar), 72.1 (2C; C-5), 71.8 (2C; C-2), 71.5 (2C; C-3), 69.9 (2C; C-4), 63.4
(2C; C-6), 42.2 ppm (2C; C-1); IR (KBr): n˜ =3519 (OH), 3354 (NH),
2920 (CH2), 1649, 1625 (C=O, urea), 1577 (NH, urea), 1404 (Ar),
1079 cmÀ1 (C O); elemental analysis calcd (%) for C20H34N4O12: C 45.97,
À
H 6.56, N 10.72; found: C 46.17, H 6.48, N 11.01.
N,N’-(1,4-Phenylene)bis[N’’-(1-deoxy-d-glucitol-1-yl)-N’’-methylurea]
A
(33): Prepared from N-methyl-d-glucamine and diisocyanate 8 in a yield
of 80% (Method A) and recrystallized from MeOH; m.p. 170–1718C;
[a]D =+19.4, [a]578 =+21.0, [a]546 =+25.2, [a]436 =+51.8 (c=1.0 in pyri-
dine); 1H NMR (400 MHz, [D6]DMSO): d=8.34 (s, 2H; NH), 7.23 (s,
4H; Ar), 5.25 (d, J2-OH =3.2 Hz, 2H; 2-OH), 4.80 (m, 4H; 3-OH, 4-OH),
4.52 (d, J5-OH =5.2 Hz, 2H; 5-OH), 4.39 (t, J6-OH =J6’-OH =5.6 Hz, 2H; 6-
OH), 3.80 (dddd, J2-OH =3.2, J1,2 =4.0, J1’,2 =8.0, J2,3 =3.6 Hz, 2H; 2-H),
3.61 (ddd, J6-OH =5.6, J5,6 =2.8, J6,6’ =11.2 Hz, 2H; 6-H), 3.57 (m, 4H; 3-
H, 5-H), 3.49 (m, 2H; 4-H), 3.42 (ddd, J6’,OH =5.6, J5,6’ =6.0, J6,6’ =11.2 Hz,
2921 (CH3), 2853 (CH2), 1754, 1737 (C=O, acetates), 1643 (C=O, urea),
À1
À
À
À
1564 (NH, urea), 1513, 1478 (Ar), 1219 (C O C), 1049 cm (C O); ele-
mental analysis calcd (%) for C25H38N2O8: C 60.71, H 7.74, N 5.66;
found: C 60.57, H 7.54, N 5.66.
N,N’-Decamethylenebis[N’’-(1-deoxy-d-glucitol-1-yl)urea] (29): Prepared
E
from d-glucamine and diisocyanate 7 in a yield of 80% (Method A) and
recrystallized from water; m.p. 160–1618C; [a]D =+5.6, [a]578 =+6.4,
[a]546 =+7.8, [a]436 =+15.2, [a]365 =+25.2 (c=1.0 in pyridine); 1H NMR
(400 MHz, [D6]DMSO): d=6.02 (brs, 2H; NH-CH2), 5.79 (brs, 2H; NH-
H1,1’), 4.82 (brs, 2H; 2-OH), 4.47 (brs, 2H; 5-OH), 4.39 (brs, 2H; 4-
OH), 4.36 (brs, 2H; 6-OH), 4.31 (brs, 2H; 3-OH), 3.53 (brs, 6H; 2-H, 3-
H, 6-H), 3.46 (brs, 2H; 5-H), 3.40 (brs, 4H; 4-H, 6’-H), 3.19 (brs, 2H; 1-
H), 2.93 (brs, 6H; 1’-H, CH2-NH), 1.32 (brs, 4H; CH2-CH2-NH),
1.23 ppm (brs, 12H; CH2); 13C NMR (100 MHz, [D6]DMSO): d=158.7
(2C; urea), 72.7 (2C; C-5), 72.1 (2C; C-3), 71.6 (2C; C-4), 69.6 (2C; C-
2), 63.5 (2C; C-6), 42.5 (2C; C-1), 40.0 (2C; C-1’, C-10’), 30.1 (2C; C-5’,
C-6’), 29.2, 29.0 (4C; C-2’, C-4’ C-7’, C-9’), 26.5 ppm (2C; C-3’, C-8’); IR
(KBr): n˜ =3254 (NH, OH), 2924, 2849 (CH2), 1617 (C=O, urea), 1582
2H; 6’-H), 3.37 (dd, J1,1’ =14.8, J1,2 =4.8 Hz, 2H; 1-H), 3.13 (dd, J1,1’
14.8,
=
J
1’,2 =8.0 Hz, 2H; 1’-H), 2.92 ppm (s, 6H; CH3-N); 13C NMR
(100 MHz, [D6]DMSO): d=156.3 (2C; urea), 134.8 (2C; C-1, C-4, Ar),
119.9 (4C; Ar) 72.1 (2C; C-5), 71.9 (2C; C-2), 71.5 (2C; C-3), 69.4 (2C;
C-4), 63.3 (2C; C-6), 51.9 (2C; C-1), 36.5 ppm (2C; CH3-N); IR (KBr):
n˜ =3360 (NH, OH), 2928 (CH2), 1636 (C=O, urea), 1548 (NH, urea),
1515, 1404 (Ar), 1088 cmÀ1 (C O); elemental analysis calcd (%) for
À
C22H39N4O12: C 47.99, H 6.96, N 10.18; found: C 47.74, H 6.84, N 10.25.
N,N’-(1,4-Phenylene)bis
pared from aminopolyol 3 and diisocyanate 8 in a yield of 98% (Method
A) and recrystallized from MeOH; m.p. 201–2028C; H NMR (400 MHz,
A
N
(NH, urea), 1085 cmÀ1 (C O); elemental analysis calcd (%) for
C24H50N4O12: C 49.13, H 8.59, N 9.55; found: C 48.82, H 8.85, N 9.42.
1
À
[D6]DMSO): d=8.73 (s, 2H; NH-Ar), 7.19 (s, 4H; Ar) 5.91 (s, 2H; NH-
C), 4.91 (t, JOH-H =5.6 Hz, 6H; OH), 3.40 ppm (d, JOH-H =5.6 Hz, 12H;
CH2-OH); 13C NMR (100 MHz, [D6]DMSO): d=156.1 (2C; urea), 134.3
(2C; C-1, C-4, Ar), 118.5 (4C; Ar), 61.4 (6C; CH2OH), 60.5 ppm (2C;
C-NH); IR (KBr): n˜ =3324 (OH, NH), 2942 (CH2), 1620 (C=O, urea),
N,N’-Decamethylenebis[N’’-(1-deoxy-d-glucitol-1-yl)-N’’-methylurea]
A
(30): Prepared from N-methyl-d-glucamine and diisocyanate 7 in yields
of 98 (Method A) and 85% (Method B), and recrystallized from EtOH;
m.p. 110–1118C; [a]D =+5.6, [a]578 =+6.4, [a]546 =+7.8, [a]436 =+15.2,
[a]365 =+25.2 (c=1.0 in pyridine); 1H NMR (400 MHz, [D6]DMSO): d=
6.20 (t, 2H; NH), 4.97 (brs, 2H; 2-OH), 4.51 (brs, 2H; 5-OH), 4.46 (brs,
4H; 3-OH, 4-OH), 4.38 (brs, 2H; 6-OH), 3.70 (m, 2H; 2-H), 3.55 (m,
2H; 6-H), 3.52 (m, 4H; 3-H, 5-H), 3.45 (m, 2H; 4-H), 3.36 (dd, J5,6’ =6.0,
1560 (NH, urea), 1514, 1403 (Ar), 1135 cmÀ1 (C O); elemental analysis
calcd (%) for C16H26N4O8: C 47.76, H 6.51, N 13.92; found: C 47.36, H
6.25, N 13.52.
À
4,4’-Methylene-N,N’-di(1,4-phenylene)bis
[N’’-(1-deoxy-d-glucitol-1-yl)-
J
6,6’ =11.2 Hz, 2H; 6’-H), 3.30 (dd, J1,1’ =14.8, J1,2 =4.8 Hz, 2H; 1-H), 3.12
AHCTREUNG
(dd, J1,1’ =14.8, J1’,2 =8.0 Hz, 2H; 1’-H), 2.96 (q, 4H; CH2-NH) 2.80 (s,
6H; CH3-N), 1.37 (q, 4H; CH2-CH2-NH), 1.23 ppm (m, 12H; CH2);
13C NMR (100 MHz, [D6]DMSO): d=158.9 (2C; urea), 72.5 (2C; C-5),
72.1 (2C; C-3), 71.5 (2C; C-4), 69.2 (2C; C-2), 63.4 (2C; C-6), 51.7 (2C;
C-1), 40.5 (2C; C-1’, C-10’), 35.4 (2C; CH3-N), 30.0 (2C; C-5’, C-6’), 29.2,
29.0 (4C; C-2’, C-4’, C-7’, C-9’), 26.6 ppm (2C; C-3’, C-8’); IR (KBr): n˜ =
3450 (OH), 3371 (NH), 2924 (CH3), 2852 (CH2), 1617 (C=O, urea), 1584
74% (Method A) and recrystallized from water; m.p. 212–2138C; [a]D =
+51.6, [a]578 =+54.2, [a]546 =+62.8, [a]436 =+107.2, [a]365 =+169.0 (c=
1.0 in pyridine); 1H NMR (400 MHz, [D6]DMSO): d=8.54 (s, 2H; NH-
Ar), 7.27 (d, Jo,m =8.6 Hz, 4H; 3-H, 5-H, Ar), 7.03 (d, Jo,m =8.6 Hz, 4H;
2-H, 6-H, Ar), 6.09 (t, JNH,H1 =JNH,H1’ =5.2 Hz, 2H; NH-H1,1’), 4.83 (d, J2-
OH =4.0 Hz, 2H; 2-OH), 4.49 (d, J5-OH =5.6 Hz, 2H; 5-OH), 4.42 (d, J4-
OH =5.6 Hz, 2H; 4-OH), 4.37 (t, J6,OH ꢀJ6’,OH =5.6 Hz, 2H; 6-OH), 4.32
(d, J3-OH =6.4 Hz, 2H; 3-OH), 3.74 (s, 2H; CH2 bridge) 3.60 (m, 6H; 2-H,
(NH, urea), 1096 cmÀ1 (C O); elemental analysis calcd (%) for
À
C26H54N4O12: C 50.80, H 8.85, N 9.11; found: C 50.49, H 8.46, N 9.42.
3-H, 6-H), 3.49 (m, 2H; 5-H), 3.42 (m, 4H; 4-H, 6’-H), 3.31 (ddd, J1,1’
13.2, J1,2 =4.0, JNH,1 =5.2 Hz, 2H; 1-H), 2.98 ppm (ddd, J1,1’ =13.2, J1’,2
=
=
N,N’-Decamethylenebis
N
N
7.2, JNH, 1’ =5.2 Hz 2H; 1’-H); 13C NMR (100 MHz, [D6]DMSO): d=155.6
(2C; urea), 138.5 (2C; C-1, Ar), 134.3 (2C; C-4, Ar), 128.8 (4C; C-2, C-
6, Ar), 117.8 (4C; C-3, C-5, Ar) 72.1 (2C; C-5), 71.9 (2C; C-2), 71.5 (2C;
C-3), 67.0 (2C; C-4), 63.5 (2C; C-6), 42.2 (2C; C-1), 39.8 ppm (CH2
bridge); IR (KBr): n˜ =3402 (OH), 3341 (NH), 2931 (CH2), 1674, 1631
pared from aminopolyol 3 and diisocyanate 7 in yields of 61 (Method A)
and 60% (Method B), and recrystallized from EtOH; m.p. 155–1568C;
1H NMR (400 MHz, [D6]DMSO): d=6.45 (t, 2H; NH), 5.70 (s, 2H; NH-
C), 5.08 (t, JOH-H =3.2 Hz, 6H; OH), 3.40 (d, JOH-H =3.2 Hz, 12H; CH2-
OH), 2.93 (q, 4H; CH2-NH), 1.33 (q, 4H; CH2-CH2-NH), 1.24 ppm (m,
12H; CH2); 13C NMR (100 MHz, [D6]DMSO): d=159.1 (2C; urea), 61.4
(6C; CH2-OH), 60.7 (2C; C-NH), 39.9 (2C; C-1’, C-10’), 29.8 (2C; C-5’,
C-6’), 29.1, 28.8 (4C; C-2’, C-4’, C-7’, C-9’), 26.5 ppm (2C; C-3’, C-8’); IR
(KBr): n˜ =3349 (OH, NH), 2926, 2853 (CH2), 1615 (C=O, urea), 1566
(C=O, urea), 1594 (NH, urea), 1556 (Ar), 1086 cmÀ1 (C O); elemental
À
analysis calcd (%) for C27H40N4O12: C 52.93, H 6.58, N 9.15; found: C
52.89, H 6.60, N 8.95.
4,4’-Methylene-N,N’-di(1,4-phenylene)bis[N’’-(1-deoxy-d-glucitol-1-yl)-
R
(NH, urea), 1024 cmÀ1 (C O); elemental analysis calcd (%) for
À
N’’-methylurea] (36): Prepared from N-methyl-d-glucamine and diisocya-
nate 9 in a yield of 80% (Method A) and recrystallized from EtOH; m.p.
149–1508C; [a]D =+13.6, [a]578 =+15.0, [a]546 =+16.4, [a]436 =+32.6 (c=
1.0 in pyridine); 1H NMR (400 MHz, [D6]DMSO): d=8.42 (s, 2H; NH),
7.28 (d, Jo,m =8.0 Hz, 4H; 3-H, 5-H, Ar), 7.04 (d, Jo,m =8.0 Hz, 4H; 2-H,
6-H, Ar), 5.22 (d, J2-OH =4.0 Hz, 2H; 2-OH), 4.55 (m, 4H; 3-OH, 4-OH),
C20H42N4O8: C 51.49, H 9.07, N 12.01; found: C 51.93, H 9.09, N 11.96.
N,N’-(1,4-Phenylene)bis[N’’-(1-deoxy-d-glucitol-1-yl)urea] (32): Prepared
R
from d-glucamine and diisocyanate 8 in a yield of 82% (Method A) and
recrystallized from water; m.p. 210–2118C; 1H NMR (400 MHz,
[D6]DMSO): d=8.42 (s, 2H; NH-Ar), 7.20 (s, 4H; Ar), 6.03 (t, JNH,H1
=
5666
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 5656 – 5669

Hydrogels Based on Ureido-Linked Amphiphiles
FULL PAPER
4.51 (d, J5-OH =5.2 Hz, 2H; 5-OH), 4.38 (t, J6-OH =5.6 Hz, 2H; 6-OH),
3.81 (dddd, J2-OH =4.0, J1,2 =4.0, J1’,2 =8.0, J2,3 =3.6 Hz, 2H; 2-H), 3.77 (s,
2H; CH2 bridge), 3.62 (ddd, J6-OH =5.6, J5,6 =2.8, J6,6’ =11.2 Hz, 2H; 6-H),
3.58 (m, 4H; 3-H, 5-H), 3.50 (m, 2H; 4-H), 3.43 (dd, J6’,OH =5.6, J5,6’ =6.0,
ysis calcd (%) for C40H54N4O22: C 50.95, H 5.77, N 5.94; found: C 50.56,
H 5.93, N 5.71.
4,4’-Methylene-N,N’-di(1,4-phenylene)bis[N’’-(2,3,4,5,6-penta-O-acetyl-1-
A
deoxy-D-glucitol-1-yl)urea] (40): Prepared from isocyanate 10 and 4,4’-
methylenedianiline in a yield of 88% as a solid that was purified by prep-
arative chromatography (EtOAc/Et2O, 5:1); m.p. 106–1078C; [a]D =
+19.0, [a]578 =+20.2, [a]546 =+24.0, [a]436 =+40.4 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.18 (d, Jo,m =8.2 Hz, 4H; 3-H, 5-H, Ar),
7.03 (d, Jo,m =8.2 Hz, 4H; 2-H, 6-H, Ar), 6.91 (s, 2H; NH-Ar), 5.51 (dd,
J
6,6’ =11.2 Hz, 2H; 6’-H), 3.40 (dd, J1,1’ =14.8, J1,2 =4.8 Hz, 2H; 1-H), 3.30
(dd, 1,1’ =14.8, 1’,2 =8.0 Hz, 2H; 1’-H), 2.92 ppm (s, 6H; CH3-N);
J
J
13C NMR (100 MHz, [D6]DMSO): d=156.2 (2C; urea), 138.6 (2C; C-1,
Ar), 134.9 (2C; C-4, Ar), 128.6 (4C; C-2, C-6, Ar), 119.9 (4C; C-3, C-5,
Ar) 72.1 (2C; C-5), 71.9 (2C; C-2), 71.5 (2C; C-3), 69.4 (2C; C-4), 63.4
(2C; C-6), 51.9 (2C; C-1), 39.8 (CH2 bridge), 35.5 ppm (2C; CH3-N); IR
(KBr): n˜ =3304 (NH, OH), 2907 (CH2), 1656 (C=O, urea), 1594 (aryl),
J
3,4 =4.8, J4,5 =6.4 Hz, 2H; 4-H), 5.38 (t, J2,3 =J3,4 =4.8 Hz, 2H; 3-H), 5.28
(t, JNH-H1 =JNH-H1’ =6.0 Hz, 2H; NH-H-1,1’), 5.13 (ddd, J1,2 =4.6, J1’,2 =5.2,
2,3 =4.8 Hz, 2H; 2-H), 5.05 (ddd, J4,5 =6.4, J5,6 =3.6, J5,6’ =5.6 Hz, 2H; 5-
1536 (NH, urea), 1411 (Ar), 1078 cmÀ1 (C O); HRMS (FAB): m/z calcd
À
J
for C29H44N4O12Na: 663.2853; found: 663.2882; elemental analysis calcd
(%) for C29H44N4O12: C 54.37, H 6.92, N 8.74; found: C 54.30, H 6.49, N
9.05.
H), 4.28 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 2H; 6-H), 4.12 (dd, J5,6’ =5.6, J6,6’
12.4 Hz, 2H; 6’-H), 3.82 (s, 2H; CH2 bridge), 3.55 (ddd, JNH-H1 =6.0, J1,1’
14.8, J1,2 =4.6 Hz, 2H; 1-H), 3.35 (ddd, JNH-H1’ =6.0, J1,1’ =14.8, J1’,2
=
=
=
4,4’-Methylene-N,N’-di(1,4-phenylene)bis
A
[tris(hydroxymethyl)-
5.2 Hz, 2H; 1’-H), 2.12, 2.08, 2.07, 2.05, 2.01 ppm (s, 30H; OAc);
13C NMR (100 MHz, CDCl3): d=170.8, 170.2, 169.9 (10C; acetates),
156.0 (2C; C=O, urea), 136.7 (2C; C-1, Ar), 136.5 (2C; C-4, Ar), 129.3
(4C; C-2, C-6, Ar), 120.7 (4C; C-3, C-5, Ar), 70.9 (2C; C-2), 69.2 (2C;
C-4), 69.0 (2C; C-3), 68.8 (2C; C-5), 61.5 (2C; C-6), 40.0 (3C; C-1, CH2
bridge), 20.8, 20.7, 20.6, 20.5 ppm (10C; acetates); IR (KBr): n˜ =3386
ACHTREUNG
yield of 92% (Method A) and recrystallized from EtOH; m.p. 196–
1978C; 1H NMR (400 MHz, [D6]DMSO): d=8.82 (s, 2H; NH-Ar), 7.19
(d, Jo,m =8.0 Hz, 4H; 3-H, 5-H, Ar), 7.02 (d, Jo,m =8.0 Hz, 4H; 2-H, 6-H,
Ar), 5.95 (s, 2H; NH-C), 4.89 (t, JOH-H =5.6 Hz, 6H; OH), 3.75 (s, 2H;
CH2 bridge), 3.53 ppm (d,
J
OH-H =5.6 Hz, 12H; CH2-OH); 13C NMR
(NH), 2960 (CH2), 1750 (C=O, acetate), 1655 (C=O, urea), 1600 (Ar),
À1
À
À
À
(100 MHz, [D6]DMSO): d=155.9 (2C; urea), 138.2 (2C; C-1, Ar), 134.4
(2C; C-4, Ar), 128.8 (4C; C-2, C-6, Ar), 117.9 (4C; C-3, C-5, Ar), 61.0
(6C; CH2OH), 60.7 (2C; C-NH), 39.8 ppm (CH2 bridge); IR (KBr): n˜ =
3325 (OH, NH), 2932 (CH2), 1620 (C=O, urea), 1546 (NH, urea), 1510,
1548 (NH, urea), 1512 (Ar), 1219 (C O C, ester), 1045 cm (C O);
HRMS (FAB): m/z calcd for C47H60N4O22Na: 1055.3597; found:
1055.3620.
N,N’-Decamethylenebis[N’’-(2,3,4,5,6-penta-O-acetyl-1-deoxy-d-glucitol-
R
1411 (Ar), 1134 cmÀ1 (C O); elemental analysis calcd (%) for
À
1-yl)-N’’-methylurea] (41): Prepared by acetylation of the unprotected
derivative 30 in a yield of 41%. Further purification by preparative chro-
matography (EtOAc/MeOH, 1:1) gave the pure material; m.p. 68–698C;
[a]D =+7.6, [a]578 =+7.6, [a]546 =+9.0, [a]436 =+16.6 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=5.45 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 2H; 4-
C23H32N4O8: C 56.09, H 6.55, N 11.38; found: C 56.44, H 6.19, N 11.22.
N,N’-Decamethylenebis[N’’-(2,3,4,5,6-penta-O-acetyl-1-deoxy-d-glucitol-
R
1-yl)urea] (38): By following the general acetylation procedure, the title
substance was obtained from isocyanate 10 and 1,10-diaminodecane in a
yield of 87%, which was further purified by preparative chromatography
H), 5.32 (dd, J2,3 =6.4, J3,4 =4.8 Hz, 2H; 3-H), 5.20 (ddd, J1,2 =7.6, J1’,2
=
(EtOAc/hexane, 5:1); m.p. 71–728C; [a]D =+15.8, [a]578 =+17.4, [a]546
=
4.4, J2,3 =6.4 Hz, 2H; 2-H), 5.03 (ddd, J4,5 =6,4, J5,6 =3.2, J5,6’ =5.8 Hz,
2H; 5-H), 4.70 (brs, 2H; NH), 4.30 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 2H; 6-
1
+19.8, [a]436 =+34.4 (c=1.0 in CHCl3); H NMR (400 MHz, CDCl3): d=
5.49 (dd, J3,4 =4.8, J4,5 =6.4 Hz, 2H; 4-H), 5.35 (t, J2,3 =J3,4 =4.8 Hz, 2H;
3-H), 5.06 (m, 4H; 2-H, 5-H), 4.98 (t, JNH-CH2 =6.4 Hz, 2H; NH-CH2),
4.80 (t, JNH-H1 =JNH-H1’ =6.0 Hz, 2H; NH-H-1,1’), 4.28 (dd, J5,6 =3.6, J6,6’
12.4 Hz, 2H; 6-H), 4.13 (dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 2H; 6’-H), 3.48
(ddd, JNH-H1 =6.0, J1,1’ =14.8, J1,2 =5.4 Hz, 2H; 1-H), 3.24 (ddd, JNH-H1’
6.0, J1,1’ =14.8, J1’,2 =5.2 Hz, 2H; 1’-H), 3.14 (brs, 4H; CH2-NH), 2.13,
2.10, 2.08, 2.05 (s, 30H; OAc), 1.48 (q, 4H; CH2-CH2-NH), 1.28 ppm (m,
12H; CH2); 13C NMR (100 MHz, CDCl3): d=170.6, 170.5, 170.3, 169.9,
(10C; acetates), 157.8 (2C; urea), 71.1 (2C; C-2), 69.2 (2C; C-4), 68.8
(2C; C-3), 68.7 (2C; C-5), 61.5 (2C; C-6), 40.5 (2C; C-1’, C-10’), 40.3
(2C; C-1), 29.9, 29.1, 28.9 (6C; C-2’, C-4’, C-5’, C-6’, C-7’, C-9’), 26.6 (C-
3’, C-8’), 20.9, 20.7, 20.5 ppm (10C; acetates); IR (KBr): n˜ =3350 (NH),
H), 4.12 (dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 2H; 6’-H), 3.60 (dd, J1,1’ =14.8, J1,2
=
5.4 Hz, 2H; 1-H), 3.36 (dd, J1,1’ =14.8, J1’,2 =5.2 Hz, 2H; 1’-H), 3.19 (t,
4H; CH2-NH), 2.86 (s, 6H; CH3-N), 2.13, 2.09, 2.08, 2.05 (s, 30H; OAc),
1.49 (q, 4H; CH2-CH2-NH), 1.27 ppm (m, 12H; CH2); 13C NMR
(100 MHz, CDCl3): d=170.6, 170.3, 170.0, 169.9, (10C; acetates), 158.1
(2C; C=O, urea), 70.0 (2C; C-2), 69.3 (2C; C-4), 69.0 (2C; C-3), 68.9
(2C; C-5), 61.5 (2C; C-6), 48.8 (2C; C-1), 41.1 (2C; C-1’, C-10’), 35.6
(2C; CH3-N), 30.3 (2C; C-2’, C-9’), 29.5, 29.4 (4C; C-4’, C-5’, C-6’, C-7’),
26.9 (2C; C-3’, C-8’), 20.9, 20.8, 20.7, 20.6 ppm (10C; acetates); IR
=
=
(KBr): n˜ =3435 (NH), 2937 (CH3), 2855 (CH2), 1752 (C=O, acetate),
À1
À
À
À
1642 (C=O, urea), 1540 (NH, urea), 1218 (C O C, ester), 1049 cm (C
O); HRMS (FAB): m/z calcd for C46H74N4O22Na: 1057.4692; found:
1057.4730.
2931 (CH2), 1752 (C=O, acetate), 1660 (C=O, urea), 1561 (NH, urea),
À1
À
À
À
1222 (C O C, ester), 1050 cm (C O); HRMS (FAB): m/z calcd for
N,N’-(1,4-Phenylene)bis[N’’-(2,3,4,5,6-penta-O-acetyl-1-deoxy-d-glucitol-
R
C44H70N4O22Na: 1029.4379; found: 1029.4398.
1-yl)-N’’-methylurea] (42): Prepared by acetylation of urea 33 in a yield
of 60% as a solid that was further purified by preparative chromatogra-
phy (EtOAc/hexane, 8:1); m.p. 116–1178C; [a]D =+9.2, [a]578 =+7.9,
[a]546 =+10.8, [a]436 =+18.8 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.35 (s, 4H; Ar), 6.83 (brs, 2H; NH-Ar), 5.48 (dd, J3,4 =4.8,
N,N’-(1,4-Phenylene)bis[N’’-(2,3,4,5,6-penta-O-acetyl-1-deoxy-d-glucitol-
E
1-yl)urea] (39): Prepared from isocyanate 10 and 1,4-phenylenediamine
in a yield of 93% as a solid that was further purified by preparative chro-
matography (EtOAc/Et2O, 5:1); m.p. 106–1078C; [a]D =+17.5, [a]578 =+
17.5, [a]546 =+21.1 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.30 (s, 4H; Ar), 7.04 (s, 2H; NH-Ar), 5.64 (brs, 2H; NH-H1,1’), 5.52
(dd, J3,4 =4.8, J4,5 =6.4 Hz, 2H; 4-H), 5.38 (t, J2,3 =J3,4 =4.8 Hz, 2H; 3-H),
5.17 (ddd, J1,2 =4.6, J1’,2 =5.2, J2,3 =4.8 Hz, 2H; 2-H), 5.07 (ddd, J4,5 =6.4,
J
J
J
4,5 =6.4 Hz, 2H; 4-H), 5.36 (t, J2,3 =J3,4 =4.8 Hz, 2H; 3-H), 5.25 (ddd,
1,2 =4.6, J1’,2 =5.2, J2,3 =4.8 Hz, 2H; 2-H), 5.04 (ddd, J4,5 =6.4, J5,6 =3.6,
5,6’ =5.6 Hz, 2H; 5-H), 4.31 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 2H; 6-H), 4.13
(dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 2H; 6’-H), 3.71 (ddd, JNH-H1 =6.0, J1,1’ =14.8,
J1,2 =4.6 Hz, 2H; 1-H), 3.43 (ddd, JNH-H1’ =6.0, J1,1’ =14.8, J1’,2 =5.2 Hz,
J
5,6 =3.6, J5,6’ =5.6 Hz, 2H; 5-H), 4.29 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 2H; 6-
H), 4.12 (dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 2H; 6’-H), 3.47 (ddd, JNH-H1 =6.0,
1,1’ =14.8, J1,2 =4.6 Hz, 2H; 1-H), 3.36 (ddd, JNH-H1’ =6.0, J1,1’ =14.8, J1’,2
2H; 1’-H), 3.01 (s, 6H; CH3-N), 2.14, 2.11, 2.10, 2.06, 2.03 ppm (s, 30H;
OAc); 13C NMR (100 MHz, CDCl3): d=170.5, 170.3, 169.9, 169.8, 169.7
(10C; acetates), 155.5 (2C; C=O, urea), 134.4 (2C; C-1, C-4, Ar), 120.5
(4C; Ar), 69.9 (2C; C-2), 69.0 (2C; C-4), 68.8 (2C; C-3), 68.6 (2C; C-5),
61.2 (2C; C-6), 48.8 (2C; C-1), 35.6 (2C; CH3-N), 20.6, 20.5, 20.4 ppm
(10C; acetates); IR (KBr): n˜ =3402 (NH), 2964 (CH2), 1748 (C=O, ace-
J
=
5.2 Hz, 2H; 1’-H), 2.13, 2.09, 2.05, 2.02 ppm (s, 30H; OAc); 13C NMR
(100 MHz, CDCl3): d=170.7, 170.5, 170.2, 169.9 (5C; C=O, acetates),
156.5 (2C; urea), 134.4 (2C; C-1, C-4, Ar), 122.1 (4C; Ar), 70.9 (2C; C-
2), 69.2 (2C; C-4), 69.0 (2C; C-3), 68.7 (2C; C-5), 61.4 (2C; C-6), 39.33
(2C; C-1), 20.8, 20.7, 20.5 ppm (10C; acetates); IR (KBr): n˜ =3380 (NH),
À
À
tate), 1656 (C=O, urea), 1545 (NH, urea), 1517, 1408 (Ar), 1219 (C O
C, ester), 1044 cmÀ1 (C O); elemental analysis calcd (%) for
À
2970 (CH2), 1750 (C=O, acetate), 1660 (C=O, urea), 1564 (NH, urea),
À1
À
À
À
1515, 1435 (Ar), 1220 (C O C, ester), 1030 cm (C O); elemental anal-
C42H58N4O22: C 51.96, H 6.02, N 5.77; found: C 51.46, H 6.14, N 5.49.
Chem. Eur. J. 2008, 14, 5656 – 5669
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5667

P. Cintas et al.
4,4’-Methylene-N,N’-di(1,4-phenylene)bis
A
cal data (IR and NMR spectra, and combustion analyses). The present
research was also conducted under the auspices of the EU COST Action
D32/WG06.
deoxy-d-glucitol-1-yl)-N’’-methylurea] (43): Prepared by acetylation of
compound 36 in a yield of 51%. The resulting solid was further purified
by preparative chromatography (EtOAc/hexane, 8:1); m.p. 111–1128C;
[a]D =+7.4, [a]578 =+7.0, [a]546 =+8.8, [a]436 =+17.2 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.33 (d, Jo,m =8.2 Hz, 4H; 3-H, 5-H, Ar),
7.07 (d, Jo,m =8.2 Hz, 4H; 2-H, 6-H, Ar), 6.81 (s, 2H; NH-Ar), 5.47 (dd,
[1] a) Low Molecular Mass Gelators. Design, Self-Assembly, Function
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J
3,4 =4.8, J4,5 =6.4 Hz, 2H; 4-H), 5.36 (t, J2,3 =J3,4 =4.8 Hz, 2H; 3-H), 5.25
(ddd, J1,2 =4.6, J1’,2 =5.2, J2,3 =4.8 Hz, 2H; 2-H), 5.03 (ddd, J4,5 =6.4, J5,6
3.6, J5,6’ =5.6 Hz, 2H; 5-H), 4.30 (dd, J5,6 =3.6, J6,6’ =12.4 Hz, 2H; 6-H),
4.12 (dd, J5,6’ =5.6, J6,6’ =12.4 Hz, 2H; 6’-H), 3.87 (s, 2H; CH2 bridge),
=
3.71 (dd, J1,1’ =14.8, J1,2 =4.6 Hz, 2H; 1-H), 3.42 (dd, J1,1’ =14.8, J1’,2
=
5.2 Hz, 2H; 1’-H), 3.00 (s, 6H; CH3-N), 2.14, 2.10, 2.05, 2.03 ppm (s,
30H; OAc); 13C NMR (100 MHz, CDCl3): d=170.6, 170.1, 170.0, 169.9
(10C; acetates), 155.6 (2C; C=O, urea), 137.1 (2C; C-1, Ar), 136.1 (2C;
C-4, Ar), 129.2 (4C; C-2, C-6, Ar), 120.1 (4C; C-3, C-5, Ar), 70.1 (2C;
C-2), 69.3 (2C; C-4), 68.9 (2C; C-3), 68.8 (2C; C-5), 61.4 (2C; C-6), 49.0
(2C; C-1), 40.6 (CH2 bridge), 20.9, 20.8, 20.7, 20.6, 20.5 ppm (10C; ace-
tates); IR (KBr): n˜ =3414 (NH), 2932 (CH3), 1749 (C=O, acetate), 1665
À
À
(C=O, urea), 1595 (NH, urea), 1518 (Ar), 1219 (C O C, ester),
[2] Handbook of Liquid Crystals (Eds.: D. Demus, J. W. Goodby, G. W.
Gray, H. W. Spiess, V. Vill), Wiley-VCH, Weinheim, Vols. 1–4, 1998.
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M. E. Light, J. C. Palacios, E. M. S. PØrez, Eur. J. Org. Chem. 2006,
657–671, and references therein.
1045 cmÀ1 (C O); HRMS (FAB): m/z calcd for C49H64N4O22Na:
À
1083.3910; found: 1083.3904.
N,N’-Decamethylenebis
A
N
pared by acetylation of the unprotected derivative 31 in a yield of 74%
yield as a solid that was recrystallized from ethyl acetate; m.p. 131–
1328C; 1H NMR (400 MHz, [D6]DMSO): d=5.98 (brs, 2H; NH-CH2),
5.73 (s, 2H; NH-C), 4.25 (s, 12H; CH2-OAc), 2.93 (q, 4H; CH2-NH),
2.01 (s, 18H; OAc), 1.33 (q, 4H; CH2-CH2-NH), 1.23 ppm (m, 12H;
CH2); 13C NMR (100 MHz, [D6]DMSO): d=170.2, (6C; acetates), 157.2
(2C; C=O, urea), 62.9 (6C; CH2-OAc), 55.9 (2C; C-NH), 39.0 (2C; C-1’,
C-10’), 29.9 (2C; C-5’, C-6’), 29.1 (2C; C-4’, C-7’), 28.9 (2C; C-2’, C-9’),
26.5 (2C; C-3’, C-8’), 20.7 ppm (6C; acetates); IR (KBr): n˜ =3355 (NH),
[4] For an excellent review of bolaamphiphilic structures, see: J.-H.
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2926, 2855 (CH2), 1753 (C=O, acetate), 1628 (C=O, urea), 1572 (NH,
urea), 1233 (C O C), 1044 cm (C O); HRMS (FAB): m/z calcd for
C32H54N4O14Na: 741.3534; found: 741.3572.
À1
À
À
À
N,N’-(1,4-Phenylene)bis
A
N
pared by acetylation of urea 34 in a yield of 46% as a solid that was re-
crystallized from MeOH; m.p. 125–1268C; 1H NMR (400 MHz,
[D6]DMSO): d=8.38 (s, 2H; NH-Ar), 7.22 (s, 4H; Ar), 6.24 (s, 2H; NH-
C), 4.33 (s, 12H; CH2-OAc), 2.05 ppm (s, 18H; OAc); 13C NMR
(100 MHz, [D6]DMSO): d=170.1 (6C; acetates), 154.5 (2C; C=O, urea),
134.0 (2C; C-1, C-4, Ar), 118.6 (4C; Ar), 61.9 (6C; CH2-OAc), 56.2 (2C;
C-NH), 20.6 ppm (6C; acetates); IR (KBr): n˜ =3334 (NH), 1747 (C=O,
À
À
acetates), 1650 (C=O, urea), 1574 (NH, urea), 1511 (Ar), 1219 (C O C),
1048 cmÀ1 (C O); elemental analysis calcd (%) for C28H38N4O14: C 51.37,
À
H 5.85, N 8.56; found: C 51.06, H 5.81, N 8.59.
4,4’-Methylene-N,N’-di(1,4-phenylene)bis
A
G
ACHTREUNG
37 in a yield of 70% yield as a solid that was recrystallized from EtOH;
m.p. 143–1448C; 1H NMR (400 MHz, [D6]DMSO): d=8.46 (s, 2H; NH-
Ar), 7.24 (d, Jo,m =8.4 Hz, 4H; 3-H, 5-H), 7.05 (d, Jo,m =8.2 Hz, 4H; 2-H,
6-H), 6.29 (s, 2H; NH-C), 4.32 (s, 12H; CH2-OAc), 3.76 (s, 2H; CH2
bridge), 2.04 ppm (s, 18H; OAc); 13C NMR (100 MHz, [D6]DMSO): d=
170.2 (6C; acetates), 154.5 (2C; C=O, urea), 137.8 (2C; C-1, Ar), 134.9
(2C; C-4, Ar), 128.9 (4C; C-2, C-6, Ar), 118.1 (4C; C-3, C-5, Ar), 62.6
(6C; CH2-OAc), 56.2 (2C; C-NH), 39.8 (CH2 bridge), 20.7 ppm (6C; ace-
tates); IR (KBr): n˜ =3333 (NH), 1741 (C=O, acetates), 1649 (C=O, urea),
À1
À
À
À
1603 (Ar), 1551 (NH, urea), 1512 (Ar), 1231 (C O C), 1046 cm (C
O); elemental analysis calcd (%) for C35H44N4O14: C 56.45, H 5.95, N
7.52; found: C 56.07, H 5.70, N 7.46.
Acknowledgements
[9] Quantitative structure–gelation relationships for amphiphilic mole-
cules are indeed scarce. For a recent and outstanding study on
amido and ureido derivatives, although no definitive conclusions
could be established, see: N. Mohmeyer, H.-W. Schmidt, Chem. Eur.
J. 2007, 13, 4499–4509.
We thank the financial support from the Ministry of Education and Sci-
ence (Spain, Grants CTQ2005–07676 and CTQ2007–66641) and FEDER.
We also thank Mrs. I. Cruz and Dr. E. M. S. PØrez for recording analyti-
5668
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 5656 – 5669

Hydrogels Based on Ureido-Linked Amphiphiles
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Received: December 1, 2007
Revised: March 24, 2008
Published online: May 6, 2008
Chem. Eur. J. 2008, 14, 5656 – 5669
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5669