Flipping the switch on chloride concentrations with a light-active foldamer

Article abstract of DOI:10.1021/ja105793c

Here we demonstrate a bioinspired system where light stimulus is used to trigger the wavelength-dependent release and then reuptake of chloride ions in nonaqueous solutions. A chiral aryl-triazole foldamer with two azobenzene end groups has been synthesized to define a folded binding pocket for chloride ions that unfolds with UV light to liberate the chloride. The trans-dominated helical foldamer becomes less stable upon photoisomerization to the cis forms. Simultaneously, the observed binding affinity shows an ～10-fold reduction from K = 3000 M^-1 (MeCN, 298 K). Control of chloride levels using light is demonstrated by switching the conductivity of an electrolyte solution up and down.

Full text of DOI:10.1021/ja105793c

Published on Web 08/27/2010
Flipping the Switch on Chloride Concentrations with a Light-Active Foldamer
Yuran Hua and Amar H. Flood*
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue, Bloomington, Indiana 47405
Received June 30, 2010; E-mail: aflood@indiana.edu
Abstract: Here we demonstrate a bioinspired system where light
stimulus is used to trigger the wavelength-dependent release and
then reuptake of chloride ions in nonaqueous solutions. A chiral
aryl-triazole foldamer with two azobenzene end groups has been
synthesized to define a folded binding pocket for chloride ions
that unfolds with UV light to liberate the chloride. The trans-
dominated helical foldamer becomes less stable upon photoi-
somerization to the cis forms. Simultaneously, the observed
binding affinity shows an ∼10-fold reduction from K ) 3000 M-1
(MeCN, 298 K). Control of chloride levels using light is demon-
strated by switching the conductivity of an electrolyte solution up
and down.
Figure 1. Proposed cycle of photodriven binding and release of chloride
(structures from modeling;17 see text for binding constant determination).
Regulating the availability of bioactive compounds is a funda-
mental feature of biology that is being studied1 and emulated2 with
the aid of designer molecules. Pioneering work3 on photocaged
advantage of the known chain-length dependence in the helical
Ca2+, which involves the photolysis of a covalent bond as a means
to release the cation into solution, has led to a plethora of caged
compounds1 for studying biochemical pathways. In the hopes of
achieving true biological emulation, supramolecular systems are
being investigated as candidates for the reversible and stimuli-
responsive control over local chemical concentrations. An early
example is the photogated binding4 and transport5 of alkali metal
cations using an azobenzene-modified bis-crown ether. These
concepts, while honed in the manipulation of cations (including
transition metals),6 have yet to be fully realized with anions where
understanding and controlling their concentrations is important for
investigating diseases like cystic fibrosis7 and for affecting envi-
ronmental remediation.8 At present, there are only a few isolated
examples of photocontrolled binding9,10 using anion receptors for
which the mechanisms of action are not always obvious.10 In order
to address the fundamental ideas and explore novel designs for the
photocontrol of anions, we report on a switchable foldamer-based
receptor (1, Scheme 1) that can reversibly and predictably modulate
(Figure 1) the concentration of chloride in nonaqueous solvents.
Receptor 1 employs the cis/trans photoisomerization of azoben-
zene11 and the ability of aryl-triazole foldamers12,13 to bind anions
using CH hydrogen bonds.14 The light-switchable receptor takes
stability of solvophobic foldamers.15 Azobenzene has been used
previously to change the stability of foldamers;16 however, those
designs place the azobenzene in the center of the oligomer, which
can prevent the isomerization from occurring.16a,b
Here we propose a new mechanism for controlling the helical-
to-random coil equilibrium: The thermodynamically favored trans
form of azobenzene is coplanar with the aryl-triazole backbone,17
while the cis form breaks coplanarity. This modulation alters the
number of π-π contacts (Figures 1 and 2a) involved in stabilizing
the helical form of the foldameric receptor. Thus, there can exist
three isomers: 1trans-trans, 1cis-trans, and 1cis-cis. Each isomer is expected
to have different helical stabilities arising from three, two and one
π-π overlapping residues, respectively. Consistently, molecular
modeling shows17 isomer 1trans-trans prefers the helical form and is
more organized than 1cis-cis, which is dominated by random coil
conformations. By accessing the cis and trans forms of azobenzene
with 365-nm (UV) and 436-nm (visible) light, it should be possible
to destabilize and stabilize the helix, correspondingly. Therefore,
when the helix-to-random coil equilibrium and subsequently the
preorganization of the receptor are affected,18 the concentrations
of bound and free chloride can be controlled using different colors
of light.
Given the new mode of action, the photocontrolled stability of
both the helical foldamer and the chloride-receptor complex have
to be independently verified. We do this here by taking advantage
of spectroscopic signatures of the cis and trans forms of azoben-
zene,11 the circular dichroism (CD) response provided by the amino
acid derived side chain on 1, and the known chloride binding
behaviors of aryl-triazole receptors.12,14,18 CH3CN is used as a
“poor” solvent to help stabilize the folded state15 while retaining
compound solubility. Lastly, we use the conductivity of a salt
solution to verify the photoregulation of chloride concentrations.
Receptor 1 and control compound 2 (Scheme 1) were prepared17
from alkynyl and azide building blocks by taking advantage of the
Scheme 1. Receptor 1 and Model Compound 2
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12838 J. AM. CHEM. SOC. 2010, 132, 12838–12840
10.1021/ja105793c  2010 American Chemical Society

C O M M U N I C A T I O N S
Figure 2. (a) Representations of the helical-to-random coil equilibria for 1trans-trans and the UV-driven PSS (66% 1cis-trans + 33% 1cis-cis). (b) Variable-
temperature CD spectra of 1trans-trans (black line) and the UV-PSS exposure (red line) (200 µM, CH3CN).
Figure 4. RP-HPLC traces for the PSSs obtained after exposure to UV
(top) and visible (middle) light. Each peak had the same ESI-MS response
for (M + HCOO-) ) 1467.7 m/z. Bottom: 1trans-trans (C18 support, 95%
CH3CN:5% H2O:0.1% HCOOH).
Figure 3. Absorption spectra of 1trans-trans (thick black trace, 100 µM,
MeCN, 298 K) upon addition of TBACl up to 20 equiv. The same data are
On the basis of the proposed mechanism (Figure 1), the stability
shown for the UV-based PSS (thick red trace) upon addition of 200 equiv.
of the helical foldamer is expected to decrease (Figure 2a) upon
Inset: NMR titration17 (10 mM, CD2Cl2, 298 K) with arrows showing
saturation of the triazoles’ peak shifts (protons labeled in Figure 2a).
UV irradiation to the cis-dominated PSS according to the chain-
length dependence of solvophobic foldamers.15 This hypothesis was
modularity of click chemistry.19 Compound identity was confirmed
by electrospray ionization mass spectrometry (ESI-MS) and NMR
spectroscopy.17 Trans- and cis-2 provided NMR signatures evident
in spectra of 1. Broad NMR spectra of 117 (CD3CN) were sharpened
when using CD2Cl2 and upon addition of tetrabutylammonium
chloride (TBACl). 1 was prepared directly as a mixture of the three
isomers. Isomer 1trans-trans can then be separated from the other
isomers utilizing flash column chromatography with C18-function-
alized silica gel.
The photoisomerization of receptor 1 can be unambiguously
identified from both electronic absorption and NMR spectroscopies
(298 K) and using reversed-phase high-performance liquid chro-
matography (RP-HPLC). Upon exposure of the receptor solution
to UV light (∼5 min), the spectrum with a band at 310 nm (Figure
3, thick black trace) transformed into the spectrum with a new band
at 430 nm (Figure 3, thick red trace). Visible light (∼5 min) largely
restores the initial spectrum,17 fully consistent with the photochemi-
cal behavior of azobenzenes.11 The photochemistry of model
compound 2 was investigated using NMR spectroscopy17 to
establish the cis:trans ratios of its photostationary states (PSSs). In
both CD3CN and CD2Cl2, UV irradiation yielded a 20:80 (trans:
cis) ratio, while visible light was able to reverse the composition
to 80:20. It can be inferred, therefore, that the PSSs of receptor 1
will be a linear combination of these. To quantify these PSSs, RP-
HPLC was used to measure (Figure 4) the ratios of isomers on
account of the long half-life of the cis-azobenzene in this molecular
scaffold (t1/2 . 96 h).17 By using the 99% 1trans-trans sample as a
time calibrant for the RP-HPLC, the PSSs for UV and visible light
are 0:33:66% and 67:30:3%, respectively.
verified using variable temperature (VT) CD spectroscopy (Figure
2b). The melting temperature, TM, defined as the temperature when
half of the molecules unfold, was found to be 30 °C. Thus, 1trans-trans
displays good folding in CH3CN, and at 25 °C, 66% of the
molecules are folded. For the solution dominated by the 1cis-cis
isomer (PSS-UV), the melting temperature decreased to 12 °C such
that ∼75% of the receptors are unfolded into random coils. VT-
NMR spectra are consistent with the TM values.17 The helical form
of receptor 1 is more preorganized18 for anion binding with all the
CH groups directed into the cavity’s center. Consequently, the trans
forms are expected to have stronger chloride binding than the cis
isomers.
The chloride affinity of pure isomer 1trans-trans was examined by
a titration (100 µM, CH3CN, 298 K) with TBACl in the dark.
Equilibrium restricted factor analysis20 of the changes in the
electronic absorption spectra (Figure 3, black traces) gave an
association energy of ∆G(1trans-trans) ) -20 kJ mol-1 (Ka ) 3000
M-1). When the same titration was conducted after exposing the
receptor solution to UV light (Figure 3a, red traces), the apparent
chloride affinity was reduced to ∆G(1PSS-UV) ) -15 kJ mol-1 (Ka
) 380 M-1). Exposure to 436-nm light restored the dominance of
the trans-trans isomer in solution and the stronger chloride affinity:
∆G(1PSS-vis) ) -20 kJ mol-1 (Ka ) 3000 M-1).17
At the visible PSS, isomer 1cis-trans is present at 30% and it is
expected to have an intermediate binding strength to the other
isomers. To test this idea, a competitive titration was conducted
by NMR spectroscopy (298 K).17 CD2Cl2 was used to obtain sharp
peaks facilitating interpretation. Fortuitously, equal concentrations
of the three isomers (10 mM total concentration) can be obtained
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C O M M U N I C A T I O N S
In conclusion, we present the first demonstration of regulating
chloride concentrations by photoisomerization of a receptor.
Isomerization alters the effective chain length, and thus the helical
stability of the aryl-triazole foldamer. The trans-dominated isomers
are more preorganized for chloride binding, and an ∼10-fold
reduction in binding affinity was induced by the trans-to-cis
isomerization in CH3CN. A robust chloride binding and release
cycle can be achieved by alternately irradiating the sample with
UV and visible light.
Acknowledgment. This work is supported by the Chemical
Sciences, Geosciences and Biosciences Division, Office of Basic
Energy Sciences, Office of Science, U.S. Department of Energy
and the Camille Dreyfus Teacher-Scholar Award. We thank Mario
Vieweger for assistance with the photoexcitation apparatus.
Figure 5. Light-driven cycles of the solution conductivity obtained upon
exposure to UV (purple) and visible (blue) light. The electrolyte solution
contains equimolar concentrations of TBACl and receptor 1 (1 mM, CH3CN,
298 K). The first point is the addition of 1trans-trans, and the dashed line
corresponds to the conductivity in the absence of receptor.
Supporting Information Available: General methods, compound
syntheses, molecular modeling, NMR data, UV-vis spectra of pho-
toisomerizations and TBACl titrations, NMR titrations, CD spectra,
diffusion NMR, and conductivity analysis. This material is available
free of charge via the Internet at http://pubs.acs.org.
by mixing the PSS-UV and PSS-vis solutions. The signals for the
triazole protons, two each for 1trans-trans and 1cis-cis and four for
1cis-trans, all shift the greatest degree compared to the other protons.
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(1)
∑
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