A chiral and colorful redox switch: Enhanced π acidity in action

Article abstract of DOI:10.1002/anie.201003722

Deep blue diving: π Acidities up to a new record of -4.74 eV are made possible with simple sulfur redox chemistry (see scheme). This attractive method is able to generate exceptional electron affinities and anion transport efficiencies for applications in optoelectronic devices, medicinal chemistry, and anion-π catalysis.

Full text of DOI:10.1002/anie.201003722

Communications
DOI: 10.1002/anie.201003722
Functional Supramolecular Systems
A Chiral and Colorful Redox Switch: Enhanced p Acidity in Action**
ˇ
ˇ
Jirꢀ Mꢀsek, Andreas Vargas Jentzsch, Shin-ichiro Sakurai, Daniel Emery, Jiri Mareda, and
Stefan Matile*
Herein, we introduce simple sulfur redox chemistry[1,2] to
generate enhanced p acidity,[3–5] demonstrate the functional
relevance of the investigated system through anion transport
experiments,[2,4–7] and create the switchable chiral p-acidic
surfaces that are needed for future applications toward
asymmetric anion–p catalysis. Efforts to expand the number
of noncovalent interactions available to construct new
supramolecular systems with significant functions such as
sensors, optoelectronic devices, and catalysts or drugs are of
paramount importance.[4] To contribute to this adventure, we
have explored the use of potential-macrodipole,[2,7] anion-
macrodipole,[7] aromatic electron donor-acceptor[7] as well as
anion–p interactions[4,5] to build stimuli-responsive transport
systems[4–7] in lipid bilayer membranes. Core-substituted
naphthalenediimides (cNDIs)[8] are ideal to explore the
usefulness of anion–p interactions to create functional
systems because the quadrupole moment of the parent NDI
1 is already QZZ = + 19 B (Figure 1a and b).[3–5] This intrinsic
p acidity is very high, as high as that of the explosive
trinitrotoluene (TNT).[3–5] The introduction of two cyano
p acceptors in the cNDI core doubles the quadrupole moment
to QZZ = + 39 B, which is the highest value known to date.[4]
This increase in p acidity is reflected in decreased LUMO
energy levels from À4.31 eV to À4.62 eV, and increased anion
binding affinity, charge mobility and anion transport activ-
ity.[4,8,9] Synthetic efforts to further lower LUMO energies and
generate enhanced p acidity by adding more cyano p accep-
tors into the cNDI core failed so far despite much interest in
Figure 1. Structures, frontier orbital energies, absorption maxima and
a) favorable and b) unfavorable anion complexes of anion–p redox
academia and industry.[4,8,9]
In the search for synthetic routes to “super-p-acidity”, we
considered that oxidation of sulfide donors[10] in the core of
cNDIs could reversibly yield chiral sulfoxides and powerful
sulfone acceptors (Figure 1). Aromatic sulfur compounds,
particularly thiophenes, are ubiquitous in materials sciences
switches. HOMO (bold) and LUMO (dashed) energies are in eV
against vacuum compared to native NDI 1 (gray), and absorption
maxima in nm (dashed arrows).
because of the high conductivity of their p stacks.[1] Their
reversible oxidation has been much less explored to generate
functional systems, although elegant examples exist for
fluorescent sensors, p- to n-charge mobility inversion (oligo-
thiophene oxidation), switchable secondary peptide struc-
tures, amyloid disease prevention, and voltage-gated syn-
thetic ion channels.[1,2] In the following, we present synthesis,
optoelectronic properties, anion transport activity and com-
putational studies of the cNDIs 2–9 (Figure 1). Tetrasulfone 9
emerges as the most p-acidic cNDI known today, and the
resulting anion transport activity is naturally outstanding.
The cNDI 2 with two sulfide donors in the core and two
diisopropylphenyl (Dip) substituents in the periphery was
prepared as described in the literature (Supporting Informa-
tion, Figure S1).[10,11] To enable anion–p interactions on the
most electron-deficient pyridinedione heterocycles, the
obstructing Dip substituents (Figure 1b) were replaced by
ˇ
[*] Dr. J. Mꢀsek, A. Vargas Jentzsch, Dr. S. Sakurai, D. Emery,
Dr. J. Mareda, Prof. S. Matile
Department of Organic Chemistry, University of Geneva
Geneva (Switzerland)
Fax: (+41)22-379-3215
E-mail: stefan.matile@unige.ch
Homepage: http://www.unige.ch/sciences/chiorg/matile/
[**] We thank D.-H. Tran for contributions to synthesis, D. Jeannerat, A.
Pinto, and S. Grass for NMR measurements, the Sciences Mass
Spectrometry (SMS) platform at the Faculty of Sciences, the
University of Geneva for mass spectrometry services, the Swiss
National Supercomputing Center (CSCS) in Manno for CPU time,
and the University of Geneva and the Swiss NSF for financial
support. J.M. is a fellow of the Roche Research Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003722.
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Chemie
mesityl (Mes) substituents which allow for a practical com-
promise between acceptable anion–p interactions and rea-
sonable solubility (Figure 1a).[4] Reactivity and optoelec-
tronic properties of the Mes- and Dip-cNDIs were roughly the
same. Namely, conversion of the p-donating sulfides 4 into p-
accepting sulfoxides 5 with stoichiometric and sulfones 6 with
an excess of m-chloroperoxybenzoic acid (mCPBA) resulted
in the downfield shift of the signals corresponding to the
protons in positions 3 and 7 of the naphthyl core (d =
for sulfone cNDIs (Figure 1; Supporting Information,
Table S1). HOMO–LUMO gaps were calculated from the
onset of the lowest energy absorptions to approximate the
HOMO energies (Figure 1).
The reversibility of sulfide oxidation was confirmed by
reduction of 5 with triflic anhydride (Tf)2O and KI (Figure 2o
vs 2l). Colorimetric redox switching was readily demonstrated
for repeated reduction and oxidation cycles for 4 and 5
(Figure 2h; Supporting Information, S4). In the presence of
the chiral shift reagent (À)-(R)-1-(9-anthryl)-2,2,2-trifluoroe-
thanol (TFAE, or Pirkleꢀs alcohol),[12] the NMR signals for the
protons in positions 3 and 7 of the naphthyl core in chiral
sulfoxide 5 (but not achiral sulfide 4) splitted into four equal
resonances (Figure 2p vs. 2r). Asymmetric oxidation of 4 with
tert-butylhydroperoxide (TBHP) catalyzed by (R)-(+)-1,1’-
bi(2-naphthol) (R-binol, 20%) and Ti(OiPr)4 (10%) changed
the magnitude of the split signals of 5 (Figure 2q).[11,13] The
upfield signals for the pair of enantiomers integrated for an
enantiomeric excess of 40% ee. Their 1:1 ratio compared to
the meso diastereomer suggested that the second sulfide
oxidation occurs without stereoselectivity (Supporting Infor-
mation, Figure S5). The circular dichroism (CD) spectrum of
enantioenriched 5 showed a weakly negative Cotton effect
(CE) for the CT band at 449 nm and a stronger positive CE at
303 nm (Supporting Information, Figure S6).
1
8.81 ppm to 9.66 ppm in the H NMR spectra; Figure 2l–n).
The absorption maxima suffered a hypsoschromic shift from a
strong, broad charge-transfer (CT) band at 528 nm for sulfide
cNDIs to weakened CT at 448 nm for sulfoxide cNDIs and
complete CT-silencing for sulfone cNDIs (Figure 2e–g;
Supporting Information, Table S1). The p,p* transition
responded to sulfur oxidation with a weak bathochromic
shift from 382 nm for sulfide cNDIs to 398 nm for sulfone
cNDIs. None of the sulfur containing cNDIs was fluorescent.
Cyclic voltammetry (CV) revealed a significant increase
in p acidity in response to the oxidation of the sulfur
substituents in the core (Figure 2a–c). LUMO energies
relative to the vacuum were obtained by subtraction of
À5.1 eV for Fc/Fc+ from the first redox potential at À1.17 V
for sulfide cNDIs, À0.76 V for sulfoxide cNDIs, and À0.64 V
Today, the use of standard intermolecular interactions to
build functional systems that can transport ions across lipid
bilayers is almost routine.[5–8] In a recent inversion of
paradigm, activity to transport anions was considered as a
tool to identify more exotic interactions and to assess their
functional relevance for translocation and catalysis, where
much weaker interactions are of interest than for simple
binding.[4,14] For this purpose, the ability of cNDIs 2–6 to use
anion–p interactions to transport anions across lipid bilayer
membranes was evaluated with the 8-hydroxy-1,3,6-pyrene-
trisulfonate (HPTS) assay. In this assay, EYPC-LUVsꢀHPTS
are exposed to a transmembrane pH gradient. These are large
unilamellar vesicles composed of egg yolk phosphatidylcho-
line and loaded with the pH-sensitive fluorophore HPTS. The
internal pH probes report the ability of externally added
cNDIs to mediate the dissipation of transmembrane pH
gradients (Supporting Information, Figure S8). Dose–
response curves obtained for cNDIs 2–6 were then subjected
to Hill analysis to give the effective monomer concentrations
(EC50) needed to reach 50% activity. For sulfide 4, an
EC50 value of (13.9 Æ 1.2) mm was found (Figure 3a, &;
Supporting Information, Table S2). This value improved
with sulfide oxidation to EC50 = (2.1 Æ 0.2) mm for sulfoxide
~
*
5 and EC50 = (1.8 Æ 0.4) mm for sulfone 6 (Figure 3a, and ).
Increasing activity with increasing p acidity was in support of
operational anion–p interactions in the Mes-cNDI series. In
the Dip-cNDI series, activity decreased with p acidity from
EC50 = (0.9 Æ 0.1) mm for 2 to EC50 = (3.5 Æ 0.4) mm for 3,
probably owing to the decreasing partitioning of more
hydrophilic transporters (Supporting Information, Table S2).
This dichotomic behavior with obstructed anion–p interac-
tions in the Dip series was essential to corroborate the
functional relevance of the operational anion–p interactions
in the Mes-cNDI series 4–6.[7c]
Figure 2. Cyclic voltammograms (a–d), absorption spectra (e–k), and
1H NMR spectra (l–r) of cNDIs 4–9. This covers sulfide 4 (a, e, h, l, o),
sulfoxide 5 (b, f, h, m), and sulfone 6 (c, g, n) compared to tetrasulfide
7 (i), tetrasulfoxide 8 (j), and tetrasulfone 9 (d, k), colorimetric redox
switching with 4 and 5 (h), 4 as product of the reduction of 5 (o), and
racemic 5 (p), enantioenriched 5 (q) and achiral 4 (r) in the presence
of the shift reagent (À)-(R)-TFAE (250 equiv, CDCl3, 508C; Supporting
Information, Figure S5). Fc/Fc+ =ferrocene/ferrocenium.
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The transport activity of tetrasulfone 9 was outstanding:
EC50 = (239 Æ 24) nm is the best value for anion–p trans-
porters known so far (Figure 3a, ).[4] The Hill coefficient n =
*
2.5 Æ 0.7 confirmed that the active structure is an unstable
supramolecule composed of at least three monomers. The
anti-Hofmeister selectivity topology with AcOÀ/FÀ exclusion
and significantly enhanced nitrate recognition found for 8 and
~
).
*
,
9 supported strong anion recognition (Figure 3b,
Compared to disubstituted cNDIs (Figure 2e–g), the absorp-
tion spectra of tetrasubstitued cNDIs were broadened and
showed a stronger, more bathochromic CT band for tetrasulf-
oxide 8 and a stronger hypsochromic effect for the p,p* bands
(Figure 2i–k). The origin of these differences is unknown, but
chromophore twisting resulting from topological crowding
with four substituents in the core is likely to contribute
(Figure 4). The cyclic voltammograms of di- and tetrasubsti-
tuted cNDIs were identical in appearance (Figure 2a–d;
Supporting Information, Figure S7). From the first redox
potential at À0.36 V, a LUMO energy of À4.74 eV was
obtained for 9 (Figure 1). This finding demonstrated that with
tetrasulfone cNDI 9, the so far elusive “super-p-acidity” has
finally been realized.
~
Figure 3. a) Transport activity and b and c) selectivity of 4 (&), 5 ( ), 6
~
&
*
*
( ), 7 ( ), 8 ( ) and 9 ( ). a) Dependence of the fractional activity Y
on cNDI concentration with Hill analysis. b, c) Dependence of Y on the
dehydration energy of external anions (b; 100 mm NaX, inside 100 mm
NaCl) and cations (c; 100 mm XCl, inside 100 mm NaCl), normalized
for Y=1 for Na+ and ClÀ.[11]
The ion selectivity of cNDIs 2–6 was determined by
external ion exchange. The high sensitivity to external anion
exchange and the negligible sensitivity to external cation
exchange (except for Li+) implied selectivity for anions
(Figure 3b, c). The global anti-Hofmeister behavior in the
halide series, preference for oxyanions, occasional nitrate
recognition, and fluoride/acetate rejection with increasing
p acidity were roughly as those described for dicyano cNDIs
and can be interpreted as support for strong, p–p enhanced
anion–p interactions at work (Supporting Information,
Table S2).[4] Anion selectivity sequences were partially
obscured by a lithium anomaly that gained in importance
with increasing sulfide oxidation (Figure 3b,c). This effect
was attributed to the binding of lithium to the pocket formed
by sulfone and diimide oxygens and considered as an
attractive approach to Lewis-acid enhanced p acidity.
Quantum chemical computations suggested that the
p acidity of cNDIs with two sulfones in the core is comparable
to that of previously investigated dicyano cNDIs.[5a,11] Com-
parison of the electrostatic surface potentials (ESP) of
disulfone 6 and dicyano cNDIs revealed only slightly less
electron-deficient surfaces for the former (Supporting Infor-
mation, Figure S21).[11] This suggested that oxidation of the
four sulfides in the core of cNDI 7 should provide access to
the enhanced p acidity that could not be reached with
tetracyano cNDIs (Figure 1).[4] Tetrasulfide 7 was readily
prepared by adapting procedures reported previously in the
literature;[10b] oxidation to tetrasulfoxide 8 with stoichiomet-
ric and tetrasulfone 9 with an excess of mCPBA was
unproblematic.[11] Solutions of the super-p-acid 9 in MeOH
or dimethylsulfoxide (DMSO) turned black within hours, as
did the spots on the thin layer chromatograms.
Figure 4. Electrostatic surface potentials computed for optimized
structures viewed from the top (blue +1.24, green 0, red À1.24 eV,
PBE1PBE/6-311G**) and side views of ball and stick representations
along the N,N’ axes (atom color coding) of tetrasulfide cNDI 7 (left)
and tetrasulfone cNDI 9 (right).
Molecular models confirmed the validity of this interpre-
tation. The exceptional ESP of super-p-acid 9 with a deeply
blue aromatic surface contrasted well with the greenish
surfaces of the less p-acidic tetrasulfide 7 (Figure 4, top).
Increasing peripheral crowding with increasing sulfur oxida-
tion slightly twisted the pyridinedione heterocycles in tetra-
sulfone 9 out of the naphthyl plane. This unprecedented NDI
deplanarization is presumably subject to extensive atropiso-
merism of the ethylsulfonyl side chains (Figure 4, bottom).
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In summary, we have presented a facile access to aromatic
surfaces that unify “super-p-acidity”, operational anion–p
interactions, chirality, and red coloration in a switchable
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Received: June 18, 2010
Published online: September 13, 2010
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Keywords: anion–p interactions · chirality · ion transport ·
molecular switches · p acidity
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