"Click" chemistry in a supramolecular environment: Stabilization of organogels by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition

Article abstract of DOI:10.1021/ja061251w

Organogels are thermoreversible, viscoelastic (soft) materials consisting of low molecular weight compounds which self-assemble into fibers, often of micrometer lengths and nanometer diameters. The installation of terminal azide and alkyne functional grou

Full text of DOI:10.1021/ja061251w

Published on Web 04/15/2006
“
Click” Chemistry in a Supramolecular Environment: Stabilization of
Organogels by Copper(I)-Catalyzed Azide-Alkyne [3 + 2] Cycloaddition
David D. D ´ı az,†,§ Karthikan Rajagopal, Erica Strable, Joel Schneider, and M. G. Finn*
‡
†
‡
,†
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
0550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
1
Received February 21, 2006; E-mail: mgfinn@scripps.edu
Small-molecule organogelators represent remarkable examples
1
of molecular self-assembly. Such compounds make networks of
5
fibers that can immobilize up to 10 liquid molecules per gelator
10
and increase the viscosity of organic media by factors up to 10 ,
2
with the potential to respond to a variety of stimuli. The aggregation
of gelator molecules into fibrous networks is driven by multiple
weak interactions, such as dipole-dipole, van der Waals, and
1
hydrogen bonding, thereby distinguishing organogels from polymer
gels, which have three-dimensional structures created by cross-
3
linked covalent bonds. Recently, several different methods for in
situ enhancement of gel thermostability have been reported,
including post-polymerization of gel fibers, the addition of poly-
mers, the use of host-guest interactions, and the use of metal ion
coordination.4
Figure 1. Left: Organogelators (1-3), cross-linkers (4, 6, 7, 9), and caps
5, 8, 10) used in this work. Right: Proposed hydrogen-bond pattern for
gelation by 1-3 and cross-linking by the CuAAC reaction.
(
“
Click” chemistry represents a modular approach toward syn-
thesis that uses only the most practical chemical transformations
to make molecular connections with excellent fidelity. The 1,3-
5
Table 1. Properties of Organogels Incorporating Azides and
Alkynesa
dipolar cycloaddition of alkynes and azides6 (AAC) to give
substituted 1,2,3-triazoles has emerged as a powerful linking
reaction in both uncatalyzed7 and metal-catalyzed8 forms. The
practical importance of the process derives from the easy introduc-
tion of azides and alkynes into organic compounds and the stability
of these groups toward other reaction conditions. The copper-
catalyzed (CuAAC) version has proven to be popular in applications
ranging from drug discovery to surface science where rapid and
reliable bond formation is required. We describe here the introduc-
tion of azide and alkyne groups into organogelator compounds and
the cross-linking of their noncovalent polyvalent networks by the
CuAAC reaction (Figure 1).
b
104 Pa)c
G′′ (×
104 Pa)c
entry
components
T
gel
G
′
(
×
1
2
3
4
5
6
7
8
9
2 + 4 + CuI
2 + 7 + CuI
86
83
84
91
47
63
65
69
94
93
108
1.9 ( 0.1
14.0 ( 1.3
17.9 ( 1.0
9.3 ( 1.2
nd
30.2 ( 3.5
5.95 ( 0.05
14.9 ( 0.2
12.5 ( 0.5
13.9 ( 0.4
33.8 ( 1.9
0.22 ( 0.01
1.22 ( 0.07
1.40 ( 0.05
0.86 ( 0.02
nd
2.63 ( 0.07
0.36 ( 0.03
0.65 ( 0.04
0.65 ( 0.08
0.74 ( 0.08
2.30 ( 0.15
3 + 6 + CuI
3 + 9 + CuI
2 + 3 + CuI
1 + 2 + 3
1 + 2 + 7
I
1 + 2 + 3 + Cu
1 + 2 + 7 + CuI
I d
10
1 + 2 + 7 + Cu
1 + 2 + 7 + Cu
I e
f
11
a
Each reaction was performed in degassed CH3CN (1.9 mL) and 2,6-
lutidine (0.1 mL), with a gelator concentration of 3 wt % and a gelator:
cross-linker ratio of 10:1. CuI was introduced from a 0.1 M stock solution
We used low molecular weight organogelators based on the
undecylamide of trans-1,2-diaminocyclohexane, 1, first described
9
by Hanabusa and co-workers (Figure 1). Since azides and alkynes
in CH CN; the mixture was heated briefly to dissolve and then was allowed
3
to cool to room temperature. The state of each sample was determined by
visual inspection after allowing the sample to stand overnight at room
are small and nonprotic, their placement at the end of the
hydrophobic chains of the gelator was not expected to severely
disrupt the intermolecular interactions that lead to gelation. The
b
temperature, although gelation in each case occurred within 5 min. Gel-
sol transition temperature (°C) determined by the inverse flow method (see
Supporting Information). c G′ ) average storage modulus; G′′ ) average
loss modulus, both measured by oscillatory rheology as described in the
“
clickable” compounds 2 and 3 were indeed found to make stable
organogels, albeit at a higher concentration (5 wt %) than 1 (3 wt
). For this exploratory study, we used the racemic form of the
d
Supporting Information; “nd” ) not determined. CuI solution was
%
introduced by layering on top of the pre-set gel and allowed to diffuse into
the material for 1 week. The resulting material was then quenched, heated,
chiral gelators; enantiopure materials usually make more stable gels.
The addition of 5% 2,6-lutidine to acetonitrile assists the CuAAC
reaction; in this solvent system, neither 1, 2, nor 3 form gels at
room temperature at concentrations of 3 wt %. In contrast, stable
organogels were obtained when CuI and cross-linkers were
incorporated with 2 or 3 at an optimized10 gelator:cross-linker ratio
of 10:1 (Table 1, entries 1-4). The direct triazole cross-linking of
azide + alkyne gelators 2 + 3 (entry 5) also made a substantial
e
and cooled to re-form the gel. Reaction components heated at 50-60 °C
f
for 8 h prior to analysis. Heterogeneous stable gel, giving rise to a greater
error in Tgel measurement ((3 °C).
difference in that a room-temperature gel was obtained, but it was
weak relative to those produced by the addition of aliphatic R,ω-
cross-linkers. Gels made from 2 or 3 were found to be strengthened
by the incorporation of an equimolar amount of 1 into the mixture
†
I
The Scripps Research Institute.
(entry 6), and introduction of Cu and cross-linkers into these
§
Present address: Departamento de Qu ´ı mica Org a´ nica (C-I), Universidad
samples gave gels with even greater thermostability (entry 6 vs 8,
7 vs 9-11; other examples in Supporting Information).
Aut o´ noma de Madrid, Cantoblanco 28049 Madrid, Spain.
‡
University of Delaware.
6056
9
J. AM. CHEM. SOC. 2006, 128, 6056-6057
10.1021/ja061251w CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
2F), but no other dramatic change. Most interestingly, a transition
to rod-like structures was observed after heating the cross-linking
reaction for 8 h (Figure 2G), obtaining a material of the greatest
T
gel and rigidity (G′) observed in these studies. In all other cases,
such prolonged heating gave rise to phase separation rather than
gelation. This suggests that such heating drives the CuAAC reaction
to greater completion, and that the formation of too high a
concentration of triazoles gives rise to self-aggregation phenomena.
We describe here a method to change the properties of thermo-
reversible gels by the introduction of a chemically innocuous group
(azide or alkyne), with subsequent attachment of cross-linkers by
a versatile catalytic process. Much of the previous work on
polymerizable organogelators uses the gelation process to set a
template for a subsequent polymerization, turning noncovalent
supramolecular assemblies into covalent polymers. These materials
are no longer thermoreversible and tend to lose their well-ordered
arrangements of hydrogen bonds. In the method described here, a
judicious level of click connectivity is used to modify the properties
of organogels while retaining their overall structure and thermo-
reversibility. We plan to continue our exploration of organo- and
hydrogels in this context, incorporating a variety of functional
groups into these versatile materials.
Figure 2. TEM images of gels made with 3 wt % gelator (A) 1 in MeCN;
I
(
2
(
B) 2 in MeCN; (C) 3 in MeCN; (D) 2 + 4 + Cu (Table 1, entry 1); (E)
I
I
+ 7 + Cu (entry 2); (F) 1 + 2 + 7 + Cu , heated for 20-30 s (entry 9);
I
G) 1 + 2 + 7 + Cu , heated for 8 h (entry 11).
The results of click-mediated gel stabilization were very similar
when the reactions were allowed to proceed for only a short time
in solution at higher temperature (followed by incubation in the
gelled state at room temperature) or exclusively in the gelled state
I
at room temperature by layering on Cu after gel formation and
diffusion of the catalyst into the matrix.11 Control experiments
showed that enhancement of gel thermostability upon cross-linking
was dependent upon the simultaneous presence of the metal in the
Acknowledgment. We are grateful to The Skaggs Institute of
Chemical Biology at The Scripps Research Institute for support of
this work. Rheological studies were supported by the NSF
I
active Cu oxidation state and the appropriate bivalent additive (as
(CHE0348323 to JPS). D.D.D. dedicates this paper to Prof. Victor
11
opposed to monovalent capping reagents 5, 8, and 10). Similarly,
S. Mart ´ı n.
I
heating in the absence of Cu does not induce azide-alkyne
Supporting Information Available: Synthetic procedures, com-
cycloaddition. The presence of triazole moieties in cross-linked and
capped materials was confirmed by NMR. The removal of Cu ions
from the gels did not change Tgel significantly, showing that Cu-
triazole interactions are not likely to be important to the stabilization
of these gels.12
plete experimental details and results of control experiments, rheology,
and spectroscopic characterizations. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
Several of the cross-linked gels were found to be stable toward
heating through the boiling point of acetonitrile, despite losing some
solvent between 60 and 90 °C. In appearance, they were signifi-
cantly more turbid than the gels made from 1, 2, or 3 alone, but
did exhibit fully reversible gel-to-sol phase transitions upon repeated
heating and cooling. FTIR spectroscopy showed the same charac-
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of both non-cross-linked and cross-linked materials.11
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found to be an order of magnitude greater than respective loss
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stable over a wide frequency range (0.1 to 100 rad/s), and dynamic
strain sweep (DSS) measurements showed that they break at less
than 1% strain, confirming their brittle nature.11 The material rigidity
(
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as indicated by G′ followed no uniform trend with respect to Tgel
.
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microscopy (TEM). Gels made from the individual gelators in
MeCN (without lutidine) showed differences consistent with the
more efficient gelation properties of 1. Thus, the structure of gelled
(
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(
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2
005, 127, 15998-15999.
1
was characterized by large, rod-like filaments, whereas 2 and 3
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displayed morphologies very similar to 2 and 3 alone (not shown).
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lutidine (Figure 2D,E) were very similar to those of non-cross-
linked analogues, suggesting that their significantly greater stabilities
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of 1 into CuAAC cross-linked samples gave thicker fibers (Figure
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(
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11) See Supporting Information.
(
(
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