Effective gelation of water using a series of bis-urea dicarboxylic acids

Article abstract of DOI:10.1002/1521-3773(20001002)39:19<3447::AID-ANIE3447>3.0.CO;2-X

At concentrations as low as 0. 3 wt % a novel family of bis-urea dicarboxylic acids gel water (see picture). The aggregation state (vesicles, gel, or fibers) depends on the pH, the ionic strength, and the molecular weight of the gelator. In this way, the gelation properties of an aqueous system are controlled by the molecular design.

Full text of DOI:10.1002/1521-3773(20001002)39:19<3447::AID-ANIE3447>3.0.CO;2-X

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Kleij, H. Kleijn, J. T. B. H. Jastrzebski, A. L. Spek, G. van Koten,
Organometallics 1999, 18, 277 ± 285.
[9] J. W. Jenkins, N. L. Lavery, P. R. Guenther, H. W. Post, J. Org. Chem.
1948, 13, 862± 895.
[10] Similar hyperbranched polycarbosilanes: C. Lach, P. Müller, H. Frey,
R. Mülhaupt, Macromol. Rapid Commun. 1997, 18, 253 ± 260.
[11] See Supporting Information for more details about the obtained
hyperbranched polymers.
lyzed reaction. Table 1 shows that 5 is indeed an active
catalyst for this reaction. Although the initial activity of 5
expressed in TOF per Pd site per h is somewhat lower than
that of 6b, the total turnover number (TTN)/Pd site for both
6b and 5 are similar.
In summary, we have established a general route to
nanosize, hyperbranched-polycarbosilane compounds that
are functionalized with aryldiamine metal complexes using a
lithiation/transmetalation procedure. The PdII centers in the
soluble, macromolecular catalyst 5 function as independent
catalytic sites in a standard aldol condensation reaction and
their activity is similar to that of the single-site Pd catalyst 6b.
To our knowledge, this is the first example of the use of
hyperbranched polymers as soluble macromolecular supports
for homogeneous catalysis. Moreover, the catalyst support
properties of hyperbranched polymers are very similar to
those of analogous dendrimers; thus, structural perfection is
not always required. Purification of the polymers 3 and 4 by
means of dialysis shows that 5 is suitable for continuous
membrane applications.
[12] The theoretical mass of the repeat unit of the HCS polymer 4 is 934.96
and contains two NCN-PdCl groups. However, the undesired double
bond isomerization process (see main text) lowers the average
molecular weight of a repeat unit to 875.4 gmolÀ1
.
[13] See for instance: a) R. Kuwano, H. Miyazaki, Y. Ito, Chem. Commun.
1998, 71 ± 72; b) M. A. Stark, C. Richards, Tetrahedron Lett. 1997, 38,
5881 ± 5884; c) F. Gorla, A. Togni, L. M. Venanzi, A. Albinati, F.
Lianza, Organometallics 1994, 13, 1607 ± 1616.
Experimental Section
Effective Gelation of Water Using a Series of
Bis-urea Dicarboxylic Acids**
Standard protocol for the catalytic aldol condensation reaction: 1 mol% of
Pd catalyst was added to a mixture of benzaldehyde (2.4 mmol), methyl
isocyanoacetate (1.6 mmol), mesitylene (1.6 mmol, internal standard), and
EtN(iPr)2 (10 mol%) in CH2Cl2 (10 mL). Samples were taken from the
reaction mixture at regular time intervals, after careful removal of the
solvent 1H NMR spectra of these samples were recorded.
Lara A. Estroff and Andrew D. Hamilton*
A wide range of small organic molecules has been found,
either through design or serendipity, to gel a variety of organic
solvents.[1] The property of gelation is thought to arise from
the self-assembly of these small molecules into fibers, which,
like polymer gels, become entangled and trap solvent.[2] The
formation of fibers requires a stabilizing intermolecular
interaction and represents a balance between the tendency
of the molecules to dissolve or to aggregate in a given solvent.
Organogelators often have hydrogen-bond donors and
acceptors that promote aggregation and subsequent fiber
formation. The attachment of long alkyl chains onto the
hydrogen-bonded core enhances its solubility in organic
solvents but also promotes association among the fibers,
through van der Waals forces, and eventual gel formation.
One effective class of organogelators exploits bis-urea deriv-
atives to form a central, hydrogen-bonded stack to which long
chain alkyl groups are attached. We[3] and others have shown
that bis-ureas such as 1 are able to gel a variety of nonpolar
organic solvents (including supercritical carbon dioxide)[3d] at
concentrations less than 4 wt%. Recent crystal structures of
these derivatives[3b,c] have confirmed the importance of
Received: April 17, 2000 [Z15003]
[1] Reviews of dendrimers: a) A. W. Bosman, H. M. Janssen, E. W.
Meijer, Chem. Rev. 1999, 99, 1665 ± 1688; b) G. Newkome, E. He,
C. N. Moorefield, Chem. Rev. 1999, 99, 1689 ± 1746; c) M. Fischer, F.
Vögtle, Angew. Chem. 1999, 111, 934 ± 955; Angew. Chem. Int. Ed.
Â
1999, 38, 884 ± 905; d) J. M. J. Frechet, C. J. Hawker, I. Gitsov, J. W.
Leon, J. Macromol. Sci. Pure Appl. Chem. A 1996, 33, 1399 ± 1425;
e) D. A. Tomalia, H. D. Durst, Top. Curr. Chem. 1993, 165, 193 ± 313.
[2] For example: a) A. W. Kleij, R. A. Gossage, J. T. B. H. Jastrzebski, J.
Boersma, G. van Koten, Angew. Chem. 2000, 112, 179 ± 182; Angew.
Chem. Int. Ed. 2000, 39, 176 ± 178; b) M. T. Reetz, G. Lohmer, R.
Schwickardi, Angew. Chem. 1997, 109, 1559 ± 1562; Angew. Chem. Int.
Ed. Engl. 1997, 36, 1526 ± 1529; c) J. W. J. Knapen, A. W. van der
Made, J. C. De Wilde, P. W. M. N. van Leeuwen, P. Wijkens, D. M.
Grove, G. van Koten, Nature 1994, 372, 659 ± 663.
[3] C. Schlenk, H. Frey, Top. Curr. Chem. 2000, 210, 69 ± 129.
[4] a) N. J. Hovestad, E. B. Eggeling, H. J. Heidbüchel, J. T. B. H. Jastr-
zebski, U. Kragl, W. Keim, D. Vogt, G. van Koten, Angew. Chem. 1999,
111, 1763 ± 1765; Angew. Chem. Int. Ed. 1999, 38, 1655 ± 1658; b) N.
Brinkmann, D. Giebel, G. Lohmer, M. T. Reetz, U. Kragl, J. Catal.
1999, 183, 163 ± 168; c) G. Giffels, J. Beliczey, M. Felder, U. Kragl,
Tetrahedron: Asymmetry 1998, 9, 691 ± 696.
[5] a) Y. H. Kim, J. Polym. Sci. Polym. Chem. Ed. 1998, 36, 1685 ± 1698;
b) A. Sunder, R. Hanselmann, H. Frey, R. Mülhaupt, Macromolecules
1999, 32, 4240 ± 4246; c) A. Sunder, J. Heinemann, H. Frey, Chem. Eur.
J. 2000, 6, 2499 ± 2506.
[6] a) M. P. H. Rietveld, D. M. Grove, G. van Koten, New J. Chem. 1997,
21, 751 ± 771; b) G. van Koten, Pure Appl. Chem. 1989, 61, 1681 ± 1693.
[7] L. van de Kuil, J. Luitjes, D. M. Grove, J. W. Zwikker, J. M. G.
van der Linden, A. M. Roelofsen, L. W. Jenneskens, W. Drenth, G.
van Koten, Organometallics 1994, 13, 468 ± 477.
[*] Dr. A. D. Hamilton, L. A. Estroff
Department of Chemistry
Yale University
P.O. Box 208107, New Haven, CT 06520-8107 (USA)
Fax : (‡1)203-432-3221
E-mail: andrew.hamilton@yale.edu
[**] We thank the National Science Foundation (CHE9817240) for
financial support of this work and Dr. James Eckert (Department of
Geology, Yale University) for assistance with the electron microscopy.
[8] a) A. W. Kleij, H. Klein, J. T. B. H. Jastrzebski, W. J. J. Smeets, A. L.
Spek, G. van Koten, Organometallics 1999, 18, 268 ± 276; b) A. W.
Â
We also thank R. E. Melendez for compound 1.
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O
O
O
O
O
H
H
N
N
N
N
H
H
O
1
bidentate hydrogen-bonding interactions between urea
groups in neighboring molecules and an intertwining of alkyl
groups.
As part of an effort to use these aggregates as porous
reaction vessels we were interested in extending the gelation
properties into hydroxylic solvents, such as water. The design
challenge was to modify the character of 1 to cause an already
proven self-aggregating subunit to function in more polar
solvent systems. Fiber formation by amphiphilic organic
molecules in water is well documented,[4] however, these
fibers generally precipitate without forming a gel or display
viscoelastic behavior at concentrations above the critical
micelle concentration.[5] There are only a few examples of
nonpolymeric hydrogels formed by the self-assembly of small
molecules.[6]
Here we report the rational design of a novel family of
hydrogelators (2 ± 15) and the characterization of their
aggregation properties in water. In the design, the self-
assembling bis-urea motif of 1 was retained and free
carboxylic acids were added for both solubility in water and
pH control. We also anticipated that the long alkyl chains
would promote aggregation in an aqueous environment. This
series of compounds shows aggregation in aqueous bases that
displays a strong pH and ionic strength dependence. Of
particular interest is the gelation of water by these molecules
at concentrations less than 0.3 wt% (>17000 molecules of
water per gelator molecule) over a narrow pH range that
varies depending on the total number of carbon atoms (M) in
the spacer and alkyl esters (M ˆ 2n ‡ m ‡ 2; see Table 1).
To test gelation ability, compounds 2 ± 15 were dissolved in
a series of hot phosphate buffers (0.2m; pH 5.2, 5.9, 6.7, 7.9,
and 10.7) with high ionic strength (I ˆ 1 molkgÀ1 from added
NaCl). Upon cooling, one of several types of aggregates (gel,
vesicles, sheets, fibers, or crystallites) was formed depending
on the chemical characteristics of the molecule and the pH of
the solution (Table 1). These aggregates were examined by
both polarizing light microscopy and scanning electron
microscopy (SEM).
Giant vesicles (10 ± 150 mm in diameter) were observed at
pH values below the gelation pH by polarizing light micros-
copy (Figure 1a). Often these vesicles were weakly birefrin-
gent and cracked when gentle pressure was applied. Fibers
Table 1. Aggregation of 0.3 wt% (2mg in 0.75 mL of water) of bis-urea dicarboxylic acids 2 ± 12.[a]
M[b]
Water
pH 5.2[c]
pH 5.9[c]
pH 6.7[c]
pH 7.9[c]
pH 7.9[d]
pH 10.7[c]
2
3
4
5
6
7
8
9
10
16
2
C
F
S
V
S
V
OPG
LG
V
V
V
V
S
AP
C
G
G
LG
G
G
G
V
S
AP
F
S
S
F
F
OPG
S
S
S
S
S
N/A
F
N/A
N/A
S
N/A
N/A
Sh
S/F[e]
Sh
0
Sh
V
20
24
28
28
30
32I
36
38
Sh
I
I
I
I
V
I
BP
N/A
I
S
10
11
12
I
V
V
F
C
F
LG
G
LG
I
I
N/A
N/A
N/A
N/A
OPG
G
V
[a] I: insoluble, AP: precipitate with no definite structure under the microscope, LG: loose gel that forms AP upon mechanical disruption (shaking), BP:
strongly birefringent precipitate, F: fibrous aggregates, weakly birefringent, Sh: sheets, V: giant vesicles (10 ± 150 mm), G: clear gel, S: homogeneous solution,
OPG: opaque gel, C: fibrous crystallites, strongly birefringent. [b] M ˆ 2n ‡ m ‡ 2. [c] 0.2m phosphate buffer, I ˆ 1 molkgÀ1 from NaCl. [d] 0.2m phosphate
buffer, I ˆ 0.4 molkgÀ1. [e] 8 gave a turbid solution at pH 10.7 with no visible precipitate, however, small bundles of fibers were observed at 220X
magnification. The solid line outlines the conditions under which gelation is observed.
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3 and 4, these fibers are entangled and less densely packed,
which is in agreement with their formation of a gel.[7]
The circular dichroism spectra of 4 ± 12 and the water-
soluble derivatives 13 ± 15 have minima at wavelengths similar
to that observed for the corresponding organogelator 1 in
hexanes (Figure 3). The similarity between the CD spectra of
Figure 3. Circular dichroism spectra of 1 in hexanes (‡), 15 in 0.2m (I ˆ
1.0 molkgÀ1) pH 7.9 phosphate buffer (À), and 10 in 0.2m (I ˆ 1.0 molkgÀ1
)
[8]
*
pH 7.9 phosphate buffer ( ). All spectra were recorded at 558C.
Figure 1. Optical micrographs of the precipitate formed by a) 12 in pH 6.7
phosphate buffer, b) 4 in pH 7.9 phosphate buffer and c) 3 in water. Scale
bars: 50 mm.
the alkyl and dicarboxylic acid derivatives suggests a related
mode of aggregation (hydrogen-bonded stacks of bis-ureas)[3c]
for the two families of gelators. Therefore, it appears that the
carboxylic acids do not significantly influence the structure of
the aggregates formed by 2 ± 15.
Potentiometric titrations of water-soluble derivatives 13 ±
15 were performed to further investigate the dependence of
gelation on the pH of the solution.[4b±d, 6c, 9] Bis-ureas 13 ± 15
displayed pKa values in the expected range for free carboxylic
acids (pKa ꢀ 4.3) and the pKa values did not vary significantly
with the linker length. This result suggests that the carboxylic
acids do not play a vital role in the aggregation of this family
of hydrogelators.
were the predominant aggregate at higher pH values, as
observed by both light microscopy (Figure 1b, c) and electron
microscopy. These fibers precipitated above the gelation pH
and were birefringent as observed by polarizing light micros-
copy. The SEM images further revealed that the fibers
themselves were composed of tightly intertwined and thinner
fibers (ca. 500 nm in diameter; Figure 2a). Although the gels
appeared amorphous when viewed by polarizing light micro-
scopy, observation by SEM showed them to be composed of
fibers (Figure 2c, d). In contrast to the fibrous aggregates of
The relationship between the number of methylene units
(molecular weight) and the pH value at which gelation occurs
(Table 1), indicates that a) hydrophobic interactions play an
important role in promoting gelation and b) the primary
function of the carboxylic acids is to modulate the solubility in
water.[6d] By controlling both the degree of ionization of the
carboxylic acids and the hydrophobic surface area (molecular
weight) of the molecule, control over the pH of gelation can
be exercised. At lower pH values, where the carboxylates are
partially protonated, the bolaform molecules assemble into
vesicles.[4c, 6c,d, 10, 11] As the pH is raised the solubility increases
as a result of the increasing negative charge on the molecules.
Aggregation now leads to the formation of fibers that can
become entangled through the hydrophobic alkyl esters, thus
trapping solvent and forming a gel. Above the pH of gelation,
the bis-ureas precipitate from solution as either fibers or
sheets. As the molecular weight decreases, the pH at which
each of the aggregates forms is lowered until the aggregates
Figure 2. Scanning electron micrographs of a) the precipitate formed by 3
in water, b) the precipitate formed by 4 in pH 7.9 phosphate buffer, c) the
dried hydrogel formed by 10 in pH 7.9 phosphate buffer, and d) the dried
hydrogel formed by 7 in pH 6.7 phosphate buffer.
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solutions were then equilibrated at 558C for 30 minutes after which time
wavelength scans from 210 ± 260 nm were recorded on a Model 202 Aviv
CD spectrometer equipped with a temperature control unit.
become too soluble and gelation does not occur at any pH.
This trend can be explained by the reduction in the hydro-
phobic surface area and the accompanying increase in the
solubility of the compounds and their aggregates in aqueous
environments.[6d, 12]
Received: May 5, 2000 [Z15086]
The dependence of aggregation on the ionic strength was
shown to be directly related to the length of the alkyl linker
(Table 1). Bis-ureas 9, 10, and 12 require 0.2m phosphate
buffers with I ˆ 1 molkgÀ1 to form a stable gel or other
aggregate. However, bis-ureas 8 and 11, which have the
longest linkers (12methylene groups), form stable aggregates
in 25 mm phosphate buffer (I ˆ 0.2molkg À1). This result
suggests that the role of the cation is primarily to reduce the
electrostatic repulsion between the carboxylate groups, which
allows the molecule to assume the conformation required to
form gelating fibers. As the linker length increases the
distance between carboxylates increases, which decreases
the concentration of the cation required to shield them from
each other.
In summary, we have developed a novel series of molecules
that can gel water. The presence of carboxylate groups in the
design imparts a pH and ionic-strength dependence on the
gelation process. We are currently investigating the use of
these hydrogels to control reactions and crystal growth within
the matrix.
[1] P. Terech, R. G. Weiss, Chem. Rev. 1997, 97, 3133 ± 3159.
[2] P. J. Flory, Discuss. Faraday Soc. 1974, 57, 7 ± 18.
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1996, 108, 2086 ± 2088; Angew. Chem. Int. Ed. Engl. 1996, 35, 1949 ±
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Science 1999, 286, 1540 ± 1543.
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Approach, Royal Society of Chemistry, Cambridge, 1994.
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1984, pp. 425 ± 454.
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Chem. Soc. Chem. Commun. 1995, 1723 ± 1724; f) G. R. Newkome,
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[7] The large dimensions and high degree of entanglement of these fibers
are in contrast to rodlike micelles that are normally smaller (in terms
of molecular dimensions).[5]
[8] Compounds 10 and 1 (but not 15) exhibit linear dichroism at
temperatures below 408C and 508C, respectively. This effect leads
to a bathochromic shift and an increase in intensity in the circular
dichroism spectra. These changes are presumably the result of further
aggregation of the fibers upon gel formation.
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Experimental Section
Synthesis: The bis-urea dicarboxylic acids (2 ± 15) were accessible by a four
step synthesis (45 ± 70% overall yields). The commercially available N-
tBoc-glutamic acid g-benzyl ester (tBoc ˆ tert-butoxycarbonyl) was first
coupled (3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (EDCI), 4-di-
methylaminopyridine (DMAP)) to the long-chain alcohol. Treatment with
trifluoroacetic acid (TFA) removed the Boc group. The bis-ureas were
synthesized by the reaction of the TFA salts with bisisocyanates in the
presence of triethylamine. Finally, the benzyl ester was cleaved by
hydrogenation (1 atm) using palladium on carbon.
Gelation: A weighed amount (ca. 1 ± 2mgmL À1) of the bis-urea dicarbox-
ylic acid (2 ± 13) was dissolved in hot buffer and cooled to room
temperature in a test tube fitted with a septum. The aggregation state
was observed every ten minutes. The test tube was inverted to check for
gelation. If no flow was observed and the resulting substance was
homogeneous, the compound was said to have successfully gelled the
solution. The solutions were allowed to set and the resulting gels/aggregates
were transferred to glass slides, covered, and observed by a polarizing light
microscope (Olympus SZH12, 7X-225X).
[12] R. Smith, C. Tanford, Proc. Natl. Acad. Sci. US 1973, 70, 289 ± 293.
Electron microscopy: Samples were prepared by evaporation onto glass
slides followed by multiple rinses with water to remove excess salts. The
surfaces of the slides were then coated with carbon and imaged by a JEOL
JXA-8600 electron microprobe with an accelerating voltage of 15 kV and
an emission current of 2± 10 nA.
pH titrations: Aqueous solutions of 13 ± 15 (10 mm) were prepared and
stirred overnight to allow equilibration to occur. They were then titrated
with 0.1m NaOH using a Corning semi-micro combo pH probe. The degree
of ionization (a) was calculated by using Equation (1), where CH
‡
and
, total
‡
CH , free are the total and free molar amounts of protons, respectively, and C
is the molar concentration of bis-urea. The pKa value was determined from
a graph of a versus pH as the pH value at a ˆ 0.5.[6c]
CH
‡
; total À CH
2 C
‡
; free
a
ˆ
1 À
(1)
CD spectroscopy: A hot solution of gelator was prepared as described
above and transferred to a quartz CD cell (0.1-cm path length). The
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