Synthetic ion channels with rigid-rod π-stack architecture that open in response to charge-transfer complex formation

Article abstract of DOI:10.1021/ja051260p

We describe the design, synthesis, and evaluation of synthetic ion channels with a new rigid-rod π-stack architecture that open in response to guest binding by aromatic electron donor-acceptor interactions. Highly cooperative and highly selective ligand gating is shown to yield anion selective, small ion channels that have the characteristic plum color of the charge-transfer complexes formed between the dialkoxynaphthalene ligands and the stacked naphthalenediimide acceptors of the channel. Copyright

Full text of DOI:10.1021/ja051260p

Published on Web 04/15/2005
Synthetic Ion Channels with Rigid-Rod π-Stack Architecture that Open in
Response to Charge-Transfer Complex Formation
Pinaki Talukdar, Guillaume Bollot, Jiri Mareda, Naomi Sakai, and Stefan Matile*
Department of Organic Chemistry, UniVersity of GeneVa, GeneVa, Switzerland
Received February 28, 2005; E-mail: stefan.matile@chiorg.unige.ch
In this report, we introduce aromatic electron donor-acceptor
interactions to construct synthetic ion channels that open in response
to chemical stimulation. The creation of synthetic ion channels and
pores from scaffolds that are not known to occur in nature is a
topic of increasing scientific concern.1-15 Since some years,
scientific attention is steadily shifting from unifunctional channels8
and pores toward “smart” supramolecular architecture that recog-
nizes nontrivial ions9 or specific characteristics of lipid bilayer
membranes, such as membrane potential,10 surface potential,
membrane composition, and stress.1 Synthetic multifunctional pores2
were introduced11 to combine molecular translocation with molec-
ular recognition11 and transformation12 for practical applications,
such as the detection of chemical reactions.13 Current research on
the use of not only synthetic1,2 but also bioengineered16,17 and
biological18 ion channels and pores as sensors focuses, however,
almost14 exclusively on blockage. Herein, the plum-colored charge-
transfer complexes formed by dialkoxynaphthalene (DAN) donors
and naphthalenediimide (NDI) acceptors, a classical motif in
supramolecular chemistry,19-22 are introduced to create synthetic
ion channels with a novel rigid-rod π-stack architecture that open
rather than close in response to guest binding.
ion channels 1n•2m. Previously established design strategies were
applied in addition to promote cylindrical self-assembly into
supramolecular oligomers rather than linear self-assembly into
supramolecular polymers (nonplanar rigid-rod staves),2 to access
hollow higher oligomers rather than closed dimers (internal
crowding24 and internal charge repulsion;2 Figure 1A, blue), and
to orient π-stacks25 (hydrogen-bonded chains between flanking
amides; Figure 1A and D, red). Geometry-minimized models 1n•2m
were in good agreement with these expectations. The hydrogen-
bonded chains lining the π-stacks (Figure 1D, red arrows), for
example, were not disrupted by ligand intercalation.
Target molecules 1 and 2 were synthesized from commercial
starting materials in overall 13 and 2 steps, respectively (Figures 1
and 2). The NDI hoops were prepared by reacting amines 3 and 4
with dianhydride 5 followed by Z-deprotection of the obtained NDI
6 (Scheme 1). Coupling of the resulting amines 7 with the
carboxylic acids lining the scaffold of the previously reported12
p-octiphenyl 8 followed by hoop deprotection with TFA gave target
molecule 1. Structure and sample homogeneity were confirmed by
NMR spectroscopy, ESI mass spectrometry, and reverse-phase
HPLC.
We felt that this conceptually new approach could provide access
to ligand gating for the following reasons (Figure 1). Self-assembly
of octakis(NDI)-p-octiphenyls 1 was expected to yield π-helices
1nH rather than π-barrels 1n because of the mismatched repeat
distances of stacked NDI hoops and rigid-rod p-octiphenyl staves.
Upon intercalation of DAN ligands 2 into their mismatched NDI
stacks, these closed ion channels 1nH were expected to undergo a
conformational change by a cooperative untwisting23 to give open
Ligand gating was probed in EYPC-LUVs⊃HPTS (i.e., large
unilamellar vesicles composed of egg yolk phosphatidylcholine and
loaded with the pH-sensitive dye, 8-hydroxy-1,3,6-pyrenetrisul-
fonate). In this assay, the ratiometric changes in HPTS emission
are used to follow the collapse of an applied pH gradient by either
H+/M+ or OH-/A- antiport.26,27 As anticipated, neither rod 1 nor
ligand 2 were highly active (Figure 2Ad and Ae). Once mixed
together, however, they were active (Figure 2Aa). Dose response
Figure 1. Ligand-gated opening of notional rigid-rod π-helix 1nH into ion channel 1n•2m by intercalation of DAN ligands 2 (red) into the mismatched NDI
hoops of transient π-barrel 1nH with magnified views of (A) NDI-NDI stack highlighting internal crowding (blue) and H-bonded chains (red), and (B)
DAN-NDI CT complex. (C) Geometry-optimized model of 1n•2m, n ) 4, m ) 12, in side (top) and axial view (bottom); p-octiphenyls (dark green) and
DANs (red) are in ball-and-stick model, NDIs (light green) in wires, 50% amine protonation, 0% sulfate protonation, H omitted. (D) Detail of a minimized
model of 1n•2m with H-bonded chains (red, arrows, C cyan, H gray, N blue, O red, S yellow). All shown suprastructures are, in part, speculative simplifications
that are, however, consistent with experimental data (Figure 2)23,24,28 and molecular models (C and D); stoichiometries of supramolecules are unknown.
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10.1021/ja051260p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
K+, Rb+, or Cs+ did not interfere with OH-/A- exchange. The
appearance of the typical plum color of charge-transfer complexes
completed this consistent experimental evidence for rationally
designed, highly cooperative ligand gating of synthetic anion
channels by aromatic electron donor-acceptor interactions. Taken
together, these findings23,24,28 confirmed the potential of the new
rigid-rod π-stack architecture to expand the practical usefulness of
synthetic multifunctional ion channels and pores13 toward electron-
transfer processes.
Acknowledgment. We thank M. R. Shah for assistance in
synthesis, D. Jeannerat, A. Pinto, and J.-P. Saulnier for NMR
measurements, P. Perrottet and the group of F. Gu¨lac¸ar for MS
measurements, H. Eder for elemental analyses, and the Swiss NSF
for financial support (including National Research Program “Su-
pramolecular Functional Materials” 4047-057496).
Figure 2. Changes in activity of NDI rod 1 (1a: Ad) in response to (D)
DAN ligands 2, 2a (Ac, BO) and 2b (Ab, B×). (A) Fractional HPTS
emission, I (λex ) 450 nm, λem ) 510 nm), as a function of time during
addition of base (∆pH ) 0.9) followed by 2 (a and e, 20 µM), 2a (c, 40
µM), or 2b (b, 15 µM), and then 1 (a-d, 1.6 µM, t ) 0 s) to EYPC-
LUVs⊃HPTS (10 mM HEPES, 100 mM NaCl, pH 7.0). (B) Activity of 1
(1.6 µM) as a function of the concentration of 2 (b), 2a (O), and 2b (×).
Supporting Information Available: Experimental part (8 pages,
print/PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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a (a) TEA, DMF, 48 h, 40 °C, 50%; (b) H2, Pd(OH)2/C, MeOH, 6 h, rt,
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2-
an OH-/A- antiport mechanism with inhibition sequence29,27 SO4
> NO3 ≈ I- > Cl- ≈ Br- > AcO- > F-. Cations such as Na+,
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