FEATURE ARTICLE

DOI: 10.1002/adfm.200500181

Resorcin[4]arene Cavitand-Based Molecular

Switches**
By Vladimir A. Azov, Andrew Beeby, Martina Cacciarini,
Andrew G. Cheetham, François Diederich,* Markus Frei,
James K. Gimzewski, Volker Gramlich, Bert Hecht, Bernhard Jaun,
Tatiana Latychevskaia, Andreas Lieb, Yoriko Lill, Federica Marotti,
Anna Schlegel, Reto R. Schlittler, Philip J. Skinner, Paul Seiler,
and Yoko Yamakoshi

Resorcin[4]arene cavitands with four quinoxaline bridges are a family of macrocycles that adopt, at elevated tempera-
ture, a contracted, vase-type conformation, capable of guest inclusion, whereas at low temperature they switch to an
expanded, kite-type conformation with a large flat surface. The present investigations lay the foundation for the use of
such dynamic cavitands as miniaturized mechanical grippers for supramolecular construction at the single-molecule
level. New vase–kite switching modes, stimulated by pH changes or stoichiometric metal-ion complexation, have been
discovered and monitored by 1H NMR and optical absorption spectroscopy. The solid-state geometries of the two
states have been revealed by X-ray crystallography, and the kinetics and thermodynamics of the switching processes in
solution as well as their solvent dependency has been investigated in great detail. Monolayers of the cavitand in the
vase form have been studied by scanning tunneling microscopy at molecular resolution; conformational switching is
also observed in Langmuir monolayers at the air/water interface. Synthetic protocols have been developed for prepa-
ration of partially and asymmetrically bridged resorcin[4]arene cavitands, which are also shown to undergo confor-
mational switching. These synthetic advances pave the way to new, dynamic molecular receptors for steroids, tetrathio-
fulvalene-bridged grippers with the potential to undergo electrochemically induced conformational switching, and
systems with greatly extended, rigid cavity walls functionalized at the termini by dipyrrometheneboron difluoride dyes.
The latter cavitands are shown by fluorescence resonance energy transfer to undergo geometrically precisely defined
motions between a contracted (≈ 7 Å linear extension) and a strongly expanded (≈ 7 nm linear extension) state.

– 1. Introduction
[*] Prof. F. Diederich, Dr. V. A. Azov, Dr. M. Cacciarini, A. G. Cheetham,
M. Frei, Prof. B. Jaun, Dr. F. Marotti, A. Schlegel, Dr. P. J. Skinner,
P. Seiler, Dr. Y. Yamakoshi
Laboratorium für Organische Chemie, ETH-Hönggerberg
HCI, CH-8093 Zürich (Switzerland)
E-mail: diederich@org.chem.ethz.ch
Dr. A. Beeby
Department of Chemistry, University of Durham
South Road, Durham DH13LE (UK)
Prof. J. K. Gimzewski, R. R. Schlittler
IBM Research, Zürich Research Laboratory
Säumerstrasse 4, CH-8803 Rüschlikon (Switzerland)
Prof. V. Gramlich
Laboratorium für Kristallographie, ETH-Zentrum
Sonnegstrasse 5, CH-8092 Zürich (Switzerland)
Prof. B. Hecht, Dr. T. Latychevskaia, Dr. A. Lieb, Dr. Y. Lill
Nano-optics group, Institut für Physik, Uni Basel
Klingelbergstrasse 82, CH-4056 Basel (Switzerland)
One of the most fascinating classes of receptors for molecular
recognition studies comprises the resorcin[4]arene cavitands
bridged by four quinoxaline moieties introduced by Cram and
co-workers (Fig. 1).[1] These compounds, for example, 1 (Fig. 1),
are conveniently prepared in two steps by condensation of
resorcinol and an appropriate aldehyde to give an octol,[2] fol-
lowed by fourfold bridging with 2,3-dichloroquinoxaline.
[**] Support by the Swiss National Science Foundation via the NFP 47
Supramolecular Functional Materials and the NCCR Nanoscale
Science is gratefully acknowledged. We thank the Japan Science Tech-
nology Corporation Overseas Fellowship program for a postdoctoral
fellowship to Y.Y.

Adv. Funct. Mater. 2006, 16, 147–156 © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 147
 V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
FEATURE ARTICLE

potential of these systems to act as molecular grippers for

Figure 1. Original quinoxaline-bridged resorcin[4]arene cavitand reported
by Cram and co-workers [1]: top and side views of the vase conformation,
showing approximate dimensions and domain names.
A particularly interesting property of these systems is the re-
versible, temperature-dependent switching between a closed
vase conformation (C4v symmetry), with a hydrophobic cavity
(about 7.5 Å wide and 5.6 Å deep)[3] suitable for guest encap-
sulation,[4,5] and an open kite conformation (C2v symmetry),
with a flat, extended surface approximately 12.5 Å × 18 Å in
size (Fig. 2). The vase conformation is prevalent at room tem-
perature and above, whereas the kite conformer is predomi-
nant at temperatures ≤ –60 °C. According to Cram and co-
workers,[1] the temperature dependence of the vase–kite equi-
librium is caused by solvation effects. At low temperatures, sol-
vation of the larger, solvent-exposed surface favors the kite
conformer, whereas at higher temperature, the entropic term
TDSsolv for solvation of the larger kite surface becomes unfa-
vorable and the vase conformation predominates.
The controllable switching of bridged resorcin[4]arene cavi-
tands resembles the movement of a mechanical gripper, and
this analogy initiated our research program to investigate the
Figure 2. Molecular models of the vase and kite conformers of the qui-
noxaline-bridged resorcin[4]arene cavitand 1. The equilibrium is tempera-
ture- and pH-dependent. H atoms and legs are omitted for clarity.
nanoscale molecular manipulation. The cavitands should be
able to capture a single molecule in the vase form and hold it
during translocation, releasing it upon changing to the kite con-
formation. Applications of this molecular-gripper-type function
could be envisioned in the construction of smart cantilever tips
for atomic force microscopy (AFM), but also in the develop-
ment of dynamic receptors, sensors, and molecular machines.[6]
However, several fundamental issues needed to be addressed
before these objectives can be reached. These include: i) the
invention of more practical switching modes and the applica-
tion of optical spectroscopy in their detection; ii) a detailed
investigation of the kinetics and thermodynamics of the vase–
kite conformational equilibrium and its dependence on envi-
ronmental polarity; iii) the modification of the cavitand legs to
allow monolayer formation as well as surface immobilization;
and iv) the development of new synthetic protocols for altering
and extending the cavitand walls, leading to larger, but still pre-
cisely defined, molecular expansion/contraction motions. Here-
in, we describe the advances made in our laboratory towards
the optimization of the dynamic resorcin[4]arene cavitands for
potential applications in organic nanoscale science.
2. Vase–Kite Switching: Structural and Mechanistic
Studies
Both the vase and kite conformations of bridged resor-
cin[4]arene cavitands have been structurally characterized in the
solid state; their contrasting geometries are depicted in Figure 3.
Although several crystal structures of vase conformations have
been known since the early 1990s,[1b,4,7,8] the solid-state character-
ization of the kite conformation remained elusive until recently.
We observed by 1H NMR spectroscopy (see below) that the oc-
tanitro derivative 2[9] exists exclusively in the kite conformation,
even at room temperature and above, possibly owing to dipolar
repulsion between the eight nitro groups in the vase form:[8]
we confirmed this finding by solving the solid-state structure
(Fig. 3b). Previously, crystal structures of kite conformers had
only been recorded for so-called velcrands.[1c,10,11] In these qui-
noxaline-bridged resorcin[4]arene cavitands, methyl substituents
in the ortho-positions to the two oxygen atoms of each of the four
resorcinol moieties prevent (for steric reasons) the formation of

Born in the Grand Duchy of Luxemburg (1952), François Diederich studied chemistry at the Uni-
versity of Heidelberg (1971–1977). He joined the group of Prof. Heinz A. Staab for his diploma
and doctoral thesis which he completed in 1979 with the synthesis of kekulene. Following postdoc-
toral studies with Prof. Orville L. Chapman at UCLA (1979–1981), investigating arynes in argon
matrices, he returned to Heidelberg for his Habilitation at the Max-Planck-Institut für Medizi-
nische Forschung (1981–1985). Subsequently, he joined the faculty in the Department of Chemistry
and Biochemistry at UCLA where he became Full Professor of Organic and Bioorganic Chemistry
in 1989. In 1992, he returned to Europe, joining the Department of Chemistry and Applied Bio-
sciences at the ETH Zürich. His research interests, documented in more than 440 publications, span
from medicinal chemistry, with a focus on molecular recognition studies, to dendritic mimics of
globular proteins, and to fullerene and acetylene-based advanced materials with novel opto-elec-
tronic properties.

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V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches

FEATURE ARTICLE
in velcrands (≈ 147°)[12] and 2 (≈ 140°) are
quite similar.
Cram and co-workers found that the
vase–kite equilibrium in chloroform solu-
tion can be conveniently monitored by
1
H NMR spectroscopy.[1] In the vase form,
the methine proton Ha appears at
d ≈ 5.5 ppm, whereas upon switching to the
kite form, this resonance shifts upfield to
d ≈ 3.7 ppm (Figs. 4a,b). We later found
that the interconversion can also be moni-
tored by characteristic changes in the UV-
vis absorption spectrum.[7]
In the course of that work, we discovered
another way of inducing vase–kite switch-
ing. Acidifying a solution of 1 and re-
lated cavitands in deuterated chloroform
(CDCl3) or dichloromethane (CD2Cl2)
with TFA (trifluoroacetic acid, CF3COOH,
0.3–0.5 M) at room temperature led to
complete conversion into the kite confor-
mation.[7] This acid-triggered switching pro-
cess is fully reversible: upon addition of
base (potassium carbonate, K2CO3, or ter-
tiary amine), the vase form is quantitatively
Figure 3. Oak Ridge Thermal Ellipsoid Plot (ORTEP) representations of a) a quinoxaline-bridged recovered. The driving force for vase → kite
cavitand similar to 1 but with shorter legs (atomic displacement parameters obtained at 295 K and interconversion at low pH is presumably
drawn at the 50 % probability level) featuring the closed vase conformation and b) octanitro-cavitand
2 (atomic displacement parameters obtained at 253 K and drawn at the 30 % probability level) fea-
the protonation of the mildly basic quinoxa-
turing the extended kite conformation. line N atoms, which leads to repulsive Cou-
lombic interactions in the vase form. Proto-
the vase geometry. Velcrands exclusively adopt the kite form nation of the quinoxaline moieties is clearly indicated by a
and exist as face-to-face dimers (so-called “velcraplexes”),[1c,10] downfield shift of their resonances Hd and He in the 1H NMR
whereas the crystal lattice of 2 shows infinite “head-to-tail” col- spectrum (Fig. 4c). Recently we also showed that the vase → kite
umns with voids filled by Me2CO (Me = CH3) molecules.[8] The transition can be triggered by addition of ZnII ions (see Sec-
angles between the planes of the two opposite aromatic bridges tion 3).[12]

Figure 4. 1H NMR spectra of 1 (concentration c = 1 × 10–2 M, 300 MHz, CD2Cl2) under different conditions: a) Temperature (T) = 295 K; b) T = 193 K;
c) T = 308 K, 0.5 M trifluoroacetic acid (TFA) added; d) T = 243 K, 0.5 M TFA added. Only the aromatic region of the spectra is shown.

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FEATURE ARTICLE
More detailed, variable-temperature Table 1. Thermodynamic and kinetic parameters for different switching modes of cavitands 1 and 2.
(VT)-NMR studies with protonated cavi- (1 kcal = 4.184 J.)
tand 1 in acidic CD2Cl2 later led to
Cavitand Conditions Switching Mode
the discovery of a second, kite 1–kite 2,
switching process (Scheme 1).[13] This
2 (CD3)2CO
equilibrium is fast on the NMR timescale
2 CDCl3
at room temperature; thus, the 1H NMR 1 CD2Cl2
spectrum of the protonated cavitand at 0.75 M TFA
298 K is dynamically averaged and indi- 1 CD2Cl2
cates an apparent fourfold symmetry of 1 CD2Cl2
the kite conformer (Fig. 4c). Upon cool- [a] Degenerate equilibrium.
ing to about 250 K, the number of signals
doubles and the spectrum becomes consis-
tent with the presence of two slowly interconverting kite con-
formers with C2v symmetry (Fig. 4d). The same change in the
number of resonances was also observed by cooling a solution
of neutral cavitand 1 in CD2Cl2 to 193 K, as a result of switch-
ing from the C4v symmetrical vase into two slowly exchanging,
C2v symmetrical kite forms (Fig. 4b). These processes could
also be monitored by 13C NMR spectroscopy, with a doubling
of the resonances seen at low temperature for both neutral and
protonated cavitand 1.
By means of iterative line-shape fitting of the 1H NMR
spectra, the activation parameters for the kite 1–kite 2 equili-
bration of both 1 and 2, and the kinetic and thermodynamic
parameters for the vase → kite transition of 1, were estimated
using the method described by Sandström (Table 1).[14] The
similarity in the activation parameters for the kite 1 → kite 2
switching of 2 to those determined for the kite → vase transi-
tion of neutral 1 led us to assume that both switching processes
proceed through similar, presumably partial-vase-like, transi-
tion states. In addition, we confirmed the prediction of Cram
and co-workers, that vase → kite switching at low temperatures
is an enthalpy-of-solvation-driven process, whereas the entro-
pic term favors the reverse process at elevated temperature.[13]
Scheme 1. Interconversions between vase, kite 1, and kite 2 conformers of resor-
cin[4]arene cavitands with four quinoxaline flaps.
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V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
DH DS DH‡ DS‡
–1 –1 –1 –1 –1 –1
[kcal mol ] [cal mol K ] [kcal mol ] [cal mol K ]
kite 1–kite 2 [a] [a] 10.1 ± 1.5 –12.9 ± 3
kite 1–kite 2 [a] [a] 10.9 ± 1.5 –14.0 ± 3
kite 1–kite 2 [a] [a] 21.2 ± 1.5 –26.6 ± 3
vase–kite –5.8 ± 0.5 –25.2 ± 1.5 3.8 ± 2 –33.2 ± 4
kite–vase –5.8 ± 0.5 –25.2 ± 1.5 9.7 ± 2 ––7.8 ± 4
As the temperature-triggered vase–kite isomerization is a
solvation-driven process, we undertook a solvent scan to inves-
tigate solvation effects on the equilibration.[13] Not unexpect-
edly, a large influence of the solvent was detected. Both tem-
perature- and pH-triggered vase → kite conversions of 1
proceed smoothly only in non-polar, non-aromatic solvents,
such as CDCl3, CD2Cl2, C2D2Cl4, and CCl4; the acid-induced
vase → kite switching is reversible upon addition of base
(K2CO3). In neutral deuterated toluene, the cavitand was fro-
zen in the vase form upon cooling to 193 K. Also, large quanti-
ties of TFA, ten times more then required for complete switch-
ing in CD2Cl2, were necessary to induce the vase → kite
transition in the deuterated aromatic solvents toluene, ben-
zene, and fluorobenzene. The bulkier deuterated mesitylene,
however, was found to be a special case. In contrast to the find-
ings in other aromatic solvents, the vase–kite switching behav-
ior of cavitand 1 in mesitylene is similar to that in CDCl3 or
CD2Cl2. These results imply that the vase–kite equilibrium is
not only dependent on solvent polarity but also on solvent
size.[15] Toluene, benzene, and fluorobenzene can nicely solvate
the inner space of the vase conformation, thereby stabilizing
this structure. On the other hand, mesitylene is too big to fit
into the vase cavity, which remains unsolvated and, in
return, facilitates the vase → kite conversion. These ex-
planations are in agreement with the complexation abil-
ity of self-assembled supramolecular capsules formed by
modified resorcinarene cavitands, as studied by Rebek
and co-workers.[3,5] Thus, the vase–kite equilibrium is
affected by solvent effects in both states involved.
3. Cavitand Monolayers
The visualization of single cavitand molecules and the
construction of practical devices required their immobili-
zation on various types of solid supports. Therefore, a
substantial effort in our research program was aimed at
the synthesis of cavitands suitable for surface immobili-
zation. Previously reported modifications include the in-
troduction of HO–[16] or amino-terminated legs for i) en-
hancing the solubility in aqueous media,[17] ii) covalent
bonding to surfaces,[18] and iii) coordination studies.[11,19]
We selected dialkyl thioether legs owing to their well-
known affinity for gold surfaces under formation of
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V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
stable self-assembled monolayers (SAMs).[20,21] Three cavi-
tands with dialkyl thioether legs of different length were con-
structed, employing slightly different synthetic strategies.[7,22]
SAMs formed by 3 (with the longest legs) on Au(111) were
successfully prepared from solution and imaged by ultrahigh-
vacuum scanning tunneling microscopy (UHV-STM) at the
molecular level, showing a well-ordered monolayer (Fig. 5).
The individual, tightly packed cavitand molecules are fixed in
the vase conformation.[22] Cavitands with shorter legs afforded
only poorly ordered SAMs.
Figure 5. STM image of a SAM of cavitand 3 adsorbed on Au(111) show-
ing the structural model. The ellipses outline individual molecules of 3.
The image was taken using a tungsten tip in constant current mode with
tunneling current It = 4.63 pA and voltage Vt = 1.9 V.
Also, the cavitand with four 3,5-di-(tert-butyl)phenyl legs,
which can be sublimed in ultrahigh vacuum, was prepared for
single-molecule studies on a solid support.[7] It has been pre-
viously shown that these legs provide good adsorption of large
molecules (such as porphyrins) on copper or silver surfaces for
STM imaging.[23,24] STM investigations are currently underway
in collaboration with T. Jung (NCCR Nanoscale Science, Basel).
Cavitand 4, with carboxylic ester legs,[8] was prepared for
Langmuir monolayer formation on an aqueous subphase. We
hypothesized that the macrocycles would arrange themselves
in monolayers in which the ester groups comprise the polar
part of the molecule and the quinoxaline flaps the hydrophobic
head group. Because the molecular area requirements esti-
mated from X-ray crystal structures for the vase (120 Å) and
kite (270 Å) forms differ greatly, we hoped to detect conforma-
tional switching in monolayers at the air–water interface by
evaluating the pressure–area (P–A) isotherms.[12] Upon lower-
ing the pH from 7 to 1 by adding TFA, the area-per-molecule
indeed increased from 125 Å to 225 Å, suggesting formation of
a monolayer of 4 in the kite conformation. The fact that the
theoretical value of 270 Å for the kite form was not reached
can be explained by incomplete protonation of the cavitand.
The monolayer was subsequently investigated upon addition
of Zn(OAc)2 to the water subphase (Fig. 6). The experiments
involved spreading a solution of 4 in CHCl3 and different vol-
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FEATURE ARTICLE
Figure 6. Pressure–area (P–A) isotherms of cavitand 4 on the pure water
subphase (black line) and in the presence of increasing amounts of
Zn(Ac)2 in the water subphase (blue, green, and red lines).
umes of a 7.3 mM solution of Zn(OAc)2 in a mixture of
CHCl3/MeOH (7:1) on the water subphase which was nearly
saturated by Zn(OAc)2. At [4] = 0.0016 mM and [Zn(OAc)2] in
the subphase = 8 mM, upon addition of 0.10 mL of the
Zn(OAc)2 solution, the area-per-molecule became nearly iden-
tical (270 Å; red isotherm in Fig. 6) to the theoretical value cal-
culated for a monolayer of cavitand 4 in the kite conformation.
Further addition of Zn(OAc)2 solution did not change the ob-
served area-per-molecule.
Clear proof for the ZnII-ion-induced vase → kite conforma-
tional change, discovered in the Langmuir studies, was ob-
tained in CDCl3 by 1H NMR spectroscopy, monitoring the
methine proton resonance as described above (see Fig. 4).
Furthermore, a Job plot analysis suggested that the switching
to the kite form results from specific complexation between
the cavitand 4 and ZnII ions, with a 1:2 binding stoichiometry.
This hypothesis was further supported by molecular modeling,
which suggested that the kite form is stabilized by the coordi-
nation of two ZnII ions to the two pairs of neighboring qui-
noxaline N atoms.[25] Such coordination is evidenced experi-
mentally by the substantial downfield shift of the quinoxaline
1
H NMR resonances.
4. Synthesis of Partially and Differentially Bridged
Cavitands
A variety of modifications of the cavity walls to tune the size
and the inner properties of resorcin[4]arene-based cavitands
have been previously reported.[4b,5,9,17,18,26–28] Whereas most of
that work involved the “symmetric” replacement of all four
quinoxaline moieties (Fig. 1) by four new, identical wall com-
ponents, some “asymmetric” systems with one flap differing
from the residual three have also been reported.[4b,26,28] To
reach some of the objectives outlined in the Introduction, such
as the formation of new receptors and sensors, redox-switch-
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 V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
FEATURE ARTICLE
able cavitands, and systems undergoing observable multi-nano-
meter-sized contraction/expansion motions, good access to par-
tially and differentially bridged cavitands is required.
The first goal was to construct cavitands bearing one or
two fluorescent BODIPY (dipyrrometheneboron difluoride)
dyes[29] for mechanistic investigations of the vase–kite switch-
ing process by means of single-molecule confocal fluorescence
microscopy.[30] Octol 5 was obtained by condensation[31] of
resorcinol with heptanal (Scheme 2). Bridging with two
equivalents of 2,3-dichloroquinoxaline yielded a mixture of
products, from which the desired bowls 7 and 8, with the novel
double bridging patterns, could be isolated by column chroma-
tography in 4 % and 20 % yields, respectively, together with
triply bridged cavitand 6 (up to 20 %) and fully bridged 1
(3–5 %).[8,32] Later, a more efficient synthesis of 7 by the con-
trolled removal of two bridges of 1 was described in the litera-
ture.[33] Bridging of 6–8 with the substituted dichlorodia-
zaphthalimide derivative 9, with an appended BODIPY dye
moiety,[29b,c] provided the dye-labeled cavitands 10–12.
The fully bridged cavitands 10–12 all underwent both temper-
ature- and pH-triggered conformational switching,[13] although
in the thermal process, they showed a higher preference for the
kite conformation than the parent structure 1. Cavitands 10–12
Scheme 2. Synthesis of partially and differentially bridged cavitands. a) 2,3-Dichloro-
quinoxaline, K2CO3, Me2SO; ≤20 % (6), 4 % (7), 20 % (8). b) 9, K2CO3, Me2SO; 73 %
(10), 54 % (11), 66 % (12).
152 www.afm-journal.de © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
completely switched to the kite form upon addition of TFA; this
process was reversible upon addition of base (K2CO3). Large
linear expansion/contraction motions occur during the switch-
ing: thus, molecular modeling suggests that the anti-bis-dye-la-
beled cavitand 11 expands from ≈ 7 Å in the vase to ≈ 35 Å (dis-
tance between the two B-atoms) in the kite geometry.
Remarkably, even the partially bridged resorcin[4]arenes
6–8 all underwent switching. For diol 6, low-temperature ex-
periments revealed that the switching was not complete; that is,
both kite and vase conformers were present in about a 1:1 ratio
at 193 K (in CD2Cl2). On the other hand, complete conversion
from vase to kite occurred upon addition of TFA at room tem-
perature. For tetrols 7 and 8, low-temperature scans could not
be performed because they started to precipitate from the solu-
tion below 273 K. Adding TFA at room temperature led to
complete transition from vase to kite.
Preliminary confocal fluorescence microscopy of 10–12 in
spin-coated films in poly(methyl methacrylate) (PMMA), or
neat on glass microscopy cover slides, confirmed the stability
of the BODIPY dye labels and their compatibility with meth-
ods of single-molecule microscopy.[34]
5. Modular Construction of Cavitand
Switches Undergoing Large Expansion/
Contraction Motions
The interest in molecular-scale devices capable of
controlled mechanical movements on the nanoscale,
and mimicking the corresponding natural phenom-
ena such as muscle expansion/contraction, has been
growing steadily over the past decade.[6] A number of
elegant molecular and supramolecular systems pro-
viding large motions between states of profoundly
different geometries, induced by electrochemical or
ionic reactions, have been reported.[35–37] As already
illustrated by the vase–kite equilibration of 11, which
involves expansion/contraction motions with changes
in linear extension from ≈ 7 Å to ≈ 35 Å (see Sec-
tion 4), the resorcin[4]arene cavitand platform is
ideal for the construction of molecular switches un-
dergoing geometrically precisely defined, multi-
nanometer-sized movements between two stable
states. We became interested in further extending
these motions while at the same time introducing at
the termini a BODIPY donor–acceptor dye pair for
monitoring the dynamics by fluorescence resonance
energy transfer (FRET).[38] Theoretical considera-
tions[39] suggested that a large decrease in the intra-
molecular FRET efficiency would be measurable at
distances > 5 nm between donor and acceptor dyes.
To attain this goal, we developed a general proto-
col for the modular construction of cavitands with
one or two greatly extended cavity walls using the io-
dinated and ethynylated cavitands 13–15 (Scheme 3)
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V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
Scheme 3. Iodinated and ethynylated cavitands are key intermediates for the modular
construction of extended molecular switches by Sonogashira cross-coupling.
as key intermediates.[40] Note the two additional ortho-Me-
groups on the phenyl spacers as compared to the related cavi-
tands 10–12 (Scheme 2): these facilitate the synthesis and, in
particular, greatly increase the stability of the imides against
nucleophilic attack. Starting from 13–15, the functionalized
cavity walls can be enlarged to the desired size by Sonogashira
cross-couplings[41] with rigid, terminally ethynylated or iodi-
nated oligo(phenylene ethynylene) oligomers.
The recently accomplished synthesis of the donor–acceptor
BODIPY-dye-labeled cavitand 16[38] nicely illustrates the
highly convergent, modular assembly of extended cavitands
from readily accessible building blocks (Scheme 4). The core
14a was prepared by bridging 7 with imide 17, and the sequen-
tial attachment of the oligo(phenylene acetylene)-appended
donor (18) and acceptor (19) dyes yielded 16. Computer mod-
eling, based on X-ray crystal structures of bridged resor-
Scheme 4. Modular synthesis of the FRET system 16. a) K2CO3, Me2SO, 38 %. b) [Pd(PPh3)4], CuI, Et(i-Pr)2N, THF, 8 % (over two steps).
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FEATURE ARTICLE
cin[4]arene cavitands in both vase and kite confor-
mations,[6,12] suggested a ≈1000 % difference in the
distance between the dye pair in the contracted
(≈ 7 Å) and expanded (≈ 7 nm, distance between the
two B atoms) states (Fig. 7).
The large-scale expansion/contraction movement
of 16 (Fig. 7) was clearly proven by both 1H NMR
and FRET measurements. Reversible vase–kite
switching, induced by changes in temperature or pH,
was undoubtedly evident from the 1H NMR spectra,
which featured the characteristic chemical shifts for
the methine proton resonances of the resorcinarene
macrocycle in the two states (see Fig. 4). Further-
more, upon adding TFA, the fluorescence of the ac-
ceptor dye (kmax = 630 nm) almost completely van-
ished, whereas the emission of the donor dye (kmax = 542 nm)
doubled in intensity. In the expanded kite state, with a spatial
separation of donor and acceptor of ≈ 7 nm, the FRET efficien-
cy was dramatically reduced. This result could only be obtained
with a rigid structure such as 16, with limited available confor-
mational space.
Further modification of 16 offers intriguing potential for the
modular design and construction of dynamic supramolecular
devices of interest for molecular recognition, molecular infor-
mation transfer, and development of molecular grippers for
use in device construction at the single-molecule level. As an
example, additional recognition sites could be attached instead
of the dye labels in 16 for enhancing the selectivity for specific
guest binding or, alternatively, two donor–acceptor moieties
(such as one porphyrin and one fullerene) for creating switch-
able electron-transfer systems.
www.afm-journal.de 153
 V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
FEATURE ARTICLE

we designed cavitands with two tetrathiaful-

valene (TTF) flaps, as illustrated in Fig. 9.
TTF and related derivatives are known to un-
dergo facile reversible oxidation to a stable
dication TTF2+, which can be reduced back to
the neutral form.[46] When the two anti-orient-
ed TTF flaps are in the neutral form, we ex-
pect the vase conformation to be preferred.
Upon oxidation, the two TTF dications
should undergo strong Coulombic repulsion,
leading to a transition to the kite conformer.
The neutral vase form—with its two electron-
rich TTF flaps—should complex in its cavity
suitably sized electron-deficient guests, such
Figure 7. Donor–acceptor dye-labeled cavitand 16 and its extensions in the contracted (vase) as 1,4-dicyanobenzene, quinones, or 7,7,8,8-
and expanded (kite) states. In the models, the alkyl legs of the cavitand are omitted. tetracyano-p-quinodimethane (TCNQ). The
synthesis of a bridged resorcinarene with one
TTF flap has already been accomplished, with
6. Novel Resorcin[4]arene Cavitand-Based the aim of working out the (non-trivial) synthetic protocols for
Receptors introducing the redox-active component.

The access to partially and differentially bridged resor-

cin[4]arene cavitands opens new perspectives in molecular re-
ceptor design that are currently being pursued in our laborato-
ry. It had previously been shown that octols, such as 5, bind
sugars and oxygen-rich steroids by hydrogen bonding in non-
competitive solvents such as chloroform.[42] On the other hand,
resorcin[4]arenes self-assemble with various stoichiometries in
this solvent, with a hexameric capsule, capable of guest encap-
sulation, being the most prominent structure.[43] Such self-as- Figure 8. Partially bridged resorcin[4]arene cavitands are investigated as
sembly should be much less favorable in the case of 6–8 owing molecular receptors featuring hydrophilic (red) and hydrophobic (blue)
domains.
to the presence of the quinoxaline flaps. Rather, these struc-
tures feature an interesting monomeric receptor site, character-
ized by a hydrophilic region, an array of phenolic HO-groups
for hydrogen bonding, and hydrophobic regions, the quinoxa- 7. Conclusions and Future Directions
line flaps (Fig. 8). We anticipated preferential complexation of
extended lipophilic guests with polar residues, in particular by In this research program, ultimately targeting molecular grip-
anti-bridged 7, which could sandwich these lipophilic substrates pers for nanomanipulation, several milestones have been
between its two aromatic flaps. reached: i) synthetic strategies were developed that provide
A preliminary screening of the recognition properties of access to the construction of partially and asymmetrically
cleft-type receptor 7 in CDCl3 by 1H NMR spectroscopy bridged resorcin[4]arene cavitands; ii) the protocols for vase–
showed that sugar derivatives such as octyl pyranosides[44] are kite switching of bridged resorcin[4]arene cavitands were
only weakly bound, whereas stable complexes (association con- greatly expanded by introducing pH changes and metal-ion
stants Ka up to 103 L mol–1 (298 K)) are formed with se-
lected steroids.[45] A comprehensive investigation of ster-
oid recognition by 7, using 1H NMR binding titrations,
has recently been made possible through the gift of a
larger library of structurally related steroids by the com-
pany Schering AG. This ongoing study already shows
that the most stable complexes are formed by steroids
featuring a flat A-ring to sandwich between the quinoxa-
line flaps and two polar, hydrogen bonding functional-
ities in rings A and D. In all binding titrations, the ex-
change rate was fast on the NMR time scale.
In another project, we combined our aim of control-
ling guest recognition by vase–kite switching with the de- Figure 9. Principle of guest complexation of a dynamic resorcin[4]arene cavitand
sire to explore new switching modes. For this purpose, with two TTF flaps.

154 www.afm-journal.de © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Funct. Mater. 2006, 16, 147–156
V. A. Azov et al./Resorcin[4]arene Cavitand-Based Molecular Switches
complexation as triggers; iii) the kinetics and thermodynamics
of the conformational vase–kite switching and its large solvent
dependency were investigated in detail, identifying a hitherto
overlooked kite 1–kite 2 switching mode and demonstrating
that the contraction/expansion mechanism is also operative in
partially bridged cavitands; iv) both vase and kite states are
now fully characterized by X-ray analysis, and the gripper mole-
cules have been visualized in the vase form at the single-mole-
cule level by STM and confocal fluorescence microscopy;
v) amphiphilic cavitands were prepared and vase–kite intercon-
version, induced by pH changes and ZnII ion complexation, was
found to occur in Langmuir monolayers; vi) versatile protocols
for the modular construction of cavitands with greatly extended
cavity walls were developed, and one such system was shown by
1 410. b) Molecular Switches (Ed.: B. L. Feringa), Wiley-VCH, Wein-
H NMR spectroscopy and FRET to undergo multi-nanometer-
sized expansion/contraction motions (from 7 Å to 7 nm) during
conformational switching; and vii) the molecular recognition of
appropriately functionalized steroids by a partially bridged ca-
vitand has been demonstrated, and the detailed analysis of
structure–activity relationships in steroid complexation is under
active investigation. Finally, the synthesis of grippers with TTF
cavity walls for electrochemical switching of both conforma-
tional preferences and guest binding ability is ongoing.
Fascinating perspectives for future work have been opened
up. With efficient FRET systems now in hand, the dynamics of
the switching motions will be investigated in detail in single-
molecule studies using confocal fluorescence microscopy. A
true challenge exists in the introduction of light-induced
switching mechanisms, which would greatly widen the potential
of the molecular grippers for technological applications. With
the arrival of a new, variable-temperature UHV STM instru-
ment at NCCR Nanoscale Science in Basel, imaging of the
grippers in both the vase and kite states will be pursued at the
single-molecule level. Nanomanipulation by the molecular
grippers, immobilized on AFM tips, is now within reach. The
partially bridged receptors will be subjected to further chemi-
cal modification in order to widen their recognition potential
for other classes of substrates. Finally, the geometrically pre-
cisely defined multi-nanometer-sized contraction/expansion
motions available through this work should find numerous ap-
plications. Examples are the opportunity to reversibly change
the spatial orientation of peptide helices attached to the cavi-
tand scaffold, thereby reversibly disrupting helix bundles and
protein dimers, or the realization of switchable photoinduced
energy and electron-transfer devices. The basis for all these
approaches towards practical materials and devices, however,
continues to be the further development of the preparative
chemistry of the resorcin[4]arene cavitands.
Received: April 1, 2005
Final version: May 10, 2005
Published online: September 22, 2005
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