Analyte-triggered gelation: Initiating self-assembly via oxidation-induced planarization

Article abstract of DOI:10.1021/ja807651a

An alternative design strategy for inventing new triggered gelations was tested. Single crystal X-ray diffraction confirmed that an oxidation can convert a nonplanar dihydropyridine (1) that exhibits weak 1-D intermolecular interactions into a planar pyri

Full text of DOI:10.1021/ja807651a

Published on Web 11/17/2008
Analyte-Triggered Gelation: Initiating Self-Assembly via Oxidation-Induced
Planarization
Jing Chen and Anne J. McNeil*
Department of Chemistry and Macromolecular Science and Engineering Program, UniVersity of Michigan, 930
North UniVersity AVenue, Ann Arbor, Michigan 48109
Received September 26, 2008; E-mail: ajmcneil@umich.edu
Molecular gels have been studied for over 160 years1 and are
Scheme 1
now used in diverse applications such as regenerative medicine,2
drug delivery,3 biosensing,4 and environmental remediation.5
Despite their utility, many applications rely on a narrow set of
gelator structures because there is no adequate model to guide their
invention. The challenge in designing new gelators is that many
factors can influence their self-assembly, including molecular
structure and medium effects (e.g., pH, ionic strength, temperature,
and solvent identity6). Creating a stimulus-induced gelation is even
more challenging because of the additional need to design a
precursor molecule that does not form a gel.
Because gelation occurs when molecules self-assemble, design
strategies have traditionally focused on promoting this process by
changing the solubility or solvent-molecule interactions;7 for
example, Xu8 and Ulijn9 have used enzymes to cleave a solubilizing
group or add an insoluble moiety, and others have used pH to
protonate or deprotonate a precursor.10 Although successful, this
approach has been limited. An alternative and underutilized
approach is to promote self-assembly by triggering changes in the
intermolecular or molecule-molecule interactions; for example,
light-induced isomerizations11 and employing additives12 have been
used to influence molecular packing. Although it may be difficult
to predict whether the molecular change will more strongly effect
the solubility or intermolecular interactions, we believe the second
approach will prove more useful for designing new triggered
gelations. As evidence, we describe the successful design of a new
analyte-induced gelation using this strategy. Specifically, an oxida-
tion-induced planarization is used to trigger self-assembly and
gelation through donor-acceptor π-stacking interactions.
Dihydropyridine 1 was designed as the precursor for the
following reasons: (1) Nonplanar 1 should not form a gel due to
an absence of obvious 1-D intermolecular interactions. (2) The
molecular framework becomes planar upon oxidation to 2 (due to
a change in hybridization) which should promote π-stacking.13 (3)
The electron-rich aryl ethynylene should interact with the electron-
poor pyridine in 2 through intermolecular donor-acceptor interac-
tions. As a result, it was predicted that 2 would form a gel under
conditions where 1 either precipitated or remained in solution.
Indeed, pyridine 2 forms a gel in mixtures of water with DMSO,
alcohols, acetone, and DMF, whereas 1 either precipitates or
remains in solution at the same concentrations.14,15 The critical gel
concentration of 2 is 16 mM (0.6 wt %) at 2/1 DMSO/H2O and 25
°C. Scanning electron microscopy revealed that the gel consists of
high-aspect-ratio fibers under all conditions examined (Figure 1
and Supporting Information, SI). Single crystal X-ray diffraction
confirmed that the solid-state packing for 1 and 2 are remarkably
different, with oxidized 2 showing predominantly 1-D π-stacking
with donor-acceptor interactions (Scheme 116); powder X-ray
diffraction on the cryo-dried gel confirms that the packing motif in
the gel fibers is similar. Raman spectroscopy on single fibers
revealed that the π-stacking direction is coincident with the fiber
axis (see SI).
To test the proposed oxidation-induced gelation a strong oxidant
was first used: cerium(IV) ammonium nitrate (CAN).17 In situ IR
spectroscopy indicated that the oxidation is quantitative within 15 s
in DMSO/H2O. As anticipated, a gel formed after slow18 addition
of an aqueous solution of CAN to 1 in DMSO/H2O at room
temperature (Figure 2). Note that this gelation is not due to a change
in solvent-molecule interactions because 1 and 2 exhibit similar
solubilities under the final reaction conditions.19
Given this successful result an oxidation-induced gelation was
attempted with a weaker oxidant, nitric oxide (NO). NO is an
appealing analyte because elevated concentrations in exhaled breath
is a biomarker for many diseases.20 NO has been shown to
catalytically oxidize related dihydropyridines under an aerobic
atmosphere.21 Using NO as an oxidant presented a challenge
because it is insoluble in DMSO22 and reacts with alcohols and
water in the presence of oxygen. Therefore the NO-induced
oxidation was performed in CH3CN. Syringe injection of NO (1
equiv) oxidizes 1 in 75 min. Table 1 depicts the reaction times to
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16496 J. AM. CHEM. SOC. 2008, 130, 16496–16497
10.1021/ja807651a CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
noncovalent interactions such as H-bonding, solvophobic, and
electrostatic attraction. We believe that by employing signal
amplification these analyte-triggered gelations can be used in
chemical sensing. Our current efforts are focused on developing
methods for amplification using functionalized polymers.
Acknowledgment. We thank Dr. Jeff W. Kampf for performing
X-ray crystallography, Ms. Anna Merkle for assistance with NO,
and the University of Michigan for funding.
Supporting Information Available: Experimental details, spectro-
scopic data; X-ray crystallographic data in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
Figure 1. Scanning electron micrograph of the gel formed by 2 (26 mM)
in 1/1.25/3.75 of CH3CN/DMSO/H2O.
References
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Figure 2. Adding an aqueous solution of CAN to 1 (26 mM, 4/1 DMSO/
H2O, left) produces 2 and gelation (2/1 DMSO/H2O, right).
(2) For a recent example, see: Tysseling-Mattiace, V. M.; Sahni, V.; Niece,
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Figure 3. Adding NO to a mixture of 1 in CH3CN (43 mM, upper left)
results in oxidation to 2 (upper right). Adding an aliquot of DMSO/H2O
results in a solution for 1 (lower left) and a gel for 2 (lower right).
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90% conversion for various equivalents of NO. Comparing entries
1 and 4 reveal that although the reaction is catalytic in NO, the
reaction time is substantially slower at lower NO concentrations.
After oxidation a gel formed at room temperature when DMSO/
H2O was added. Control studies showed that the NO-induced
oxidation is essential to gel formation since an unexposed solution
of 1 does not form a gel upon identical treatment of DMSO/H2O
(Figure 3).
(8) For a recent review, see: Yang, Z.; Liang, G.; Xu, B. Acc. Chem. Res.
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In summary, we invented a new analyte-triggered gelation by
employing a molecular design strategy based on a change in
intermolecular interactions. Specifically, an oxidation-induced pla-
narization with concomitant donor-acceptor interactions was shown
to trigger gel formation. Though the present case exploits π-stack-
ing, the general strategy of using an analyte to introduce gel-
promoting intermolecular interactions can be applied using other
(13) For related examples, see: (a) Zang, L.; Che, Y.; Moore, J. S. Acc. Chem.
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Meijer, E. W.; Schenning, A. P. H. J. Chem. ReV. 2005, 105, 1491–1546.
(14) For rheological measurements on these gels, see Supporting Information.
(15) For the role of the 2,6-dimethyl substituents in a related gelator, see:
Baddeley, C.; Yan, Z.; King, G.; Woodward, P. M.; Badjic´, J. D. J. Org.
Chem. 2007, 72, 7270–7278.
(16) X-ray crystal structure images were generated using ORTEP-3. H-atoms
were omitted for clarity.
(17) Pfister, J. R. Synthesis 1990, 689–690. See also: Nair, V.; Deepthi, A. Chem.
ReV. 2007, 107, 1862-1891.
Table 1. Time to 90% Conversion in the NO-Induced Oxidation of
1a
(18) Note that rapidly adding CAN in one aliquot lead to a precipitate.
(19) The equilibrium solubilities were measured by UV-vis spectroscopy in
2/1 DMSO/H2O at room temperature: 1 (0.29 ( 0.04 mg/mL) and 2 (0.61
( 0.07 mg/mL).
entry
equiv of NO
timeb (min)
1
2
3
4
0.25
0.50
1.0
2900
140
75
(20) Lim, K. G.; Mottram, C. Chest 2008, 133, 1232–1242.
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8163. (b) Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A. J.
Org. Chem. 1997, 62, 3582–3585.
10
<1
(22) (a) Shaw, A. W.; Vosper, A. J. J. Chem. Soc., Faraday Trans. 1 1977, 73,
1239–1244. (b) Dimethyl sulfoxide (DMSO) Solubility Data; Bulletin #102B;
Gaylord Chemical Company, L.L.C.: Slidell, LA, 2007.
a Reaction conditions: 13 mmol of 1 in 0.3 mL of CH3CN, 1 atm of
O2, rt. b Conversion was determined by HPLC analysis using an internal
standard.
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