Redox-switchable resorcin[4]arene cavitands: Molecular grippers

Article abstract of DOI:10.1021/ja306473x

Diquinone-based resorcin[4]arene cavitands that open to a kite and close to a vase form upon changing their redox state, thereby releasing and binding guests, have been prepared and studied. The switching mechanism is based on intramolecular H-bonding interactions that stabilize the vase form and are only present in the reduced hydroquinone state. The intramolecular H-bonds were characterized using X-ray, IR, and NMR spectroscopies. Guests were bound in the closed, reduced state and fully released in the open, oxidized state.

Full text of DOI:10.1021/ja306473x

Communication
pubs.acs.org/JACS
Redox-Switchable Resorcin[4]arene Cavitands: Molecular Grippers
Igor Pochorovski,† Marc-Olivier Ebert,† Jean-Paul Gisselbrecht,‡ Corinne Boudon,‡ W. Bernd Schweizer,†
and Francois Diederich*,†
†Laboratorium fur Organische Chemie, ETH Zurich, Honggerberg, HCI, 8093 Zurich, Switzerland
̈
̈
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‡Laboratoire d’Electrochimie et de Chimie Physique du Corps Solide, Institut de Chimie-UMR 7177, C.N.R.S., Universite
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de
Strasbourg, 4, rue Blaise Pascal, 67081 Strasbourg Cedex, France
S
* Supporting Information
ABSTRACT: Diquinone-based resorcin[4]arene cavi-
tands that open to a kite and close to a vase form upon
changing their redox state, thereby releasing and binding
guests, have been prepared and studied. The switching
mechanism is based on intramolecular H-bonding
interactions that stabilize the vase form and are only
present in the reduced hydroquinone state. The intra-
molecular H-bonds were characterized using X-ray, IR, and
NMR spectroscopies. Guests were bound in the closed,
reduced state and fully released in the open, oxidized state.
olecular machines1 that imitate the functions of
Mmacroscopic objects are a fascinating research endeavor
because they stimulate our imagination. While microscopic
analogues of various macroscopic objects, such as rotors,2
shuttles,3 tweezers,4 turnstiles,5 ratchets,6 motors,7 muscles,8
cars,9 and balances10 have been prepared and studied, an
important tool for the microscopic world is undeveloped: a
molecular gripper. Such element could be applied to a wide
range of areas, including nanorobotics, drug delivery, and
fundamental physical organic chemistry studies. The require-
ment for a molecule to act as a gripper is the ability to open and
close upon external stimulation; in doing so, guest molecules
would be released and grabbed (Figure 1, top). A promising
scaffold for the construction of molecular grippers is the
resorcin[4]arene cavitand system11 due to its ability to adopt
two spatially well-defined conformations: an expanded kite and
a contracted vase. While the switching ability of cavitands has
been explored using stimuli such as changes in pH, temper-
ature, metal ion concentration, or light,12 the development of
redox-switchable variants would be desirable in order for
cavitands to be addressable on electroactive metal interfaces.
Here, we describe the synthesis and detailed investigation of
cavitands that can be redox-switched in solution between their
kite and vase forms, thereby releasing and binding guests.
Recently, we reported the synthesis of a family of
resorcin[4]arene cavitands containing quinone moieties as
redox-active wall components.13 However, these systems did
not undergo a conformational change induced by redox
interconversion between their quinone and hydroquinone
states because there was no driving force for the switching
process. We therefore sought to introduce such a driving force
by designing a cavitand that takes advantage of strong
intramolecular H-bonding interactions to specifically stabilize
Figure 1. (Top) Schematic of a redox-switchable molecular gripper.
(Bottom) Redox-switchable cavitand systems 1 and 2 with a vase
conformation in the reduced state, stabilized by H-bonds.
the vase conformation in one redox state. This design was
realized by placing N,N-di(n-butyl)carboxamides as H-bond
accepting groups on the quinoxaline walls of diquinone-
diquinoxaline cavitands ox-1 and ox-2 (Figure 1, bottom).
Cavitands of this type are present in the kite form in
chlorinated solvents, as we established in previous work.13
Reduction would yield hydroquinone cavitands red-1 and red-
2, which would strongly prefer the vase conformation due to
intramolecular H-bonds between the carboxamide and the
hydroquinone moieties. Cavitand red-1 would feature an open
top, whereas the corresponding triptycene-based cavitand, red-
2, would have a fully closed cavity.13 Reoxidation to the
quinone state would remove these interactions, thereby
switching the cavitands back to the kite form.
The syntheses of ox-1 and ox-2 commenced with the
preparation of wall precursor 3, which was accessed from the
commercially available 4,7-dibromobenzo[c][1,2,5]thiadiazole
Received: July 3, 2012
Published: August 20, 2012
© 2012 American Chemical Society
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(4) (Scheme 1). Aminocarbonylation14 of 4 with di(n-
butyl)amine afforded compound 5. Reductive sulfur extru-
Scheme 1. Syntheses of Redox-Switchable Cavitands Ox-1
a
and Ox-2
Figure 2. (Top) Redox interconversion between the quinone and
hydroquinone states of cavitand 1. (a) Na2S2O4, CDCl3/H2O, 60 °C, 3
h, quantitative. (b) Air, quantitative. (Bottom) Sections of the 1H
NMR spectra (298 K) of cavitands ox-1 and red-1 in CDCl3 (300
MHz), THF-d8 (300 MHz), and mesitylene-d12 (500 MHz).
a
(a) n-Bu2NH, CO (balloon), Pd(OAc)2, Xantphos, K3PO4, toluene,
reflux, 20 h, 99%. (b) (1) NaBH4, CoCl2(H2O)6, EtOH, reflux, 2 h;
(2) oxalic acid, EtOH/HCl, reflux, 16 h; (3) SOCl2, DMF, (CH2Cl)2,
reflux, 3 h, 57% over 3 steps. (c) Cs2CO3, THF, reflux, 24 h, 85% (ox-
1); 47% (ox-2). (d) Na2S2O4, CDCl3/H2O, 60 °C, 3 h, quantitative.
DMF = N,N-dimethylformamide, THF = tetrahydrofuran.
NMR spectra of red-1 in various solvents. A rigid vase form was
observed not only in CDCl3 and THF-d8, but also in
mesitylene-d12. Remarkably, only the vase form is present
even at −80 °C in CD2Cl2 and THF-d8. Both cavitands revert
to their oxidized states, ox-1 and ox-2, upon exposing their
solutions to air for 2−4 days.22
sion,15 condensation of the resulting diamine with oxalic acid,16
and chlorination of the resulting diol with thionyl chloride16
yielded wall precursor 3. Reaction with tetrols 6 and 7 provided
cavitands ox-1 and ox-2. We also prepared hydroquinone red-8
from ox-813 as a reference compound.
The H-bonds that hold the cavitands in the vase form were
characterized using X-ray, IR, and NMR spectroscopies. We
obtained a crystal structure of cavitand red-2 with encapsulated
CDCl3 crystallized from mesitylene-d12 (Figure 3, bottom).
Notably, this is the first crystal structure of a hydroquinone
cavitand. The average O···O distances between the amide and
the OH oxygen atoms are 2.73 Å. The OH hydrogen atoms are
rotated out of the aryl plane toward the amide oxygen atoms
with an average dihedral angle of 26.5°.23 Formation of H-
bonds in solution is indicated by a shift and broadening of the
IR peak corresponding to the stretching frequency of the OH
group (in CDCl3 at ca. 1 mM concentration). The peak shifts
from 3555 cm−1 in reference compound red-8 (which lacks H-
bonds to amide units) to 3324 cm−1 in red-1 and 3313 cm−1 in
The conformational properties of the new cavitands in
1
various solvents were characterized by H NMR spectroscopy.
Cavitands ox-1 and ox-2 are present in the kite form in
chlorinated solvents, THF-d8, and mesitylene-d12 (see Figure 2
left for 1H NMR spectra of ox-1), as evidenced by the 1H NMR
resonance of the methine protons between 4.0 and 4.5 ppm.
The NMR spectra are complex due to dynamic behavior on the
NMR time scale, resulting from slow rotation of the amide
moieties around the CNaph−CONBu2 bond17 and slow kite1−
kite2 interconversion.13,18 An averaged C2v symmetry becomes
apparent for ox-1 only above 130 °C.19 Thus, the vase form and
the vase-like transition state for kite1−kite2 interconversion are
strongly destabilized, presumably due to steric repulsion
between the amide and the quinone moieties.
1
red-2. The H NMR signal of the OH group shifts from 5.60
ppm in red-8 to 8.14 ppm in red-1 and 8.54 ppm in red-2,
respectively (in CDCl3). Taken together, these parameters
classify the intramolecular H-bonds as strong, neutral H-
bonds.24
We proceeded to test our switching concept, which is based
on the stabilization of the vase form by H-bonds in the reduced
hydroquinone state. Reduction of ox-1 to red-1 was performed
in a biphasic mixture of CDCl3/H2O using Na2S2O4,20 while
ox-2 was reduced to red-2 using H2, Pd/C in THF.21 To our
delight, both reduced species adopted the vase form in CDCl3,
Having realized conformational switching upon changing the
redox state of the cavitand, we probed the function of the
gripper by assessing its ability to bind and release guests.
Binding studies with cavitands are usually conducted in
mesitylene-d12 due to its large size, which reduces competition
with guest molecules for the binding site. To our surprise, the
hydroquinone cavitand red-2 was insoluble in mesitylene-d12.25
Cavitand 1, on the other hand, was soluble in mesitylene-d12 in
1
as confirmed by characteristic H NMR signals of the methine
protons between 5.7 and 6.0 ppm. Figure 2 (bottom) shows 1H
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Table 1. Association Constants Ka at 298 K for the Binding
a
of Small Molecule Guests to Cavitand Red-1
Figure 3. Crystal structures of cavitands red-1 (guest: cyclooctane)
and red-2 (guest: CDCl3, disordered, not shown) at 100 K, both
crystallized from mesitylene-d12. Mesitylene-d12 solvent molecules
residing outside the cavities, n-hexyl, n-butyl groups, and hydrogen
atoms (except on the OH-group of red-2) are omitted for clarity.
Thermal ellipsoids are shown at the 30% probability level for red-1 and
50% for red-2.
a
Ka values were determined by integration of the 1H NMR resonances
of the relevant species, relative to 1,3,5-trimethoxybenzene as an
internal standard. Errors in Ka values are estimated to be roughly 20%.
both redox states, allowing binding studies to be performed. As
expected, ox-1, which is present in the open kite form, showed
no binding of small molecules. In contrast, the reduced vase
cavitand, red-1, readily bound various guests, as shown by
characteristic upfield shifts of the guest 1H NMR signals.26 Red-
1 complexed a variety of hydrocarbons, including adamantane,
cis-1,2-dimethylcyclohexane, and trans-1,2-dimethylcyclohex-
ane, with slow guest exchange on the NMR time scale. The
highest binding constant measured within the cycloalkane series
was for cyclooctane (Ka = 83 M−1), which is an unusually large
guest for resorcin[4]arene cavitands. Insights into this
selectivity were gained from a crystal structure of red-1 with
encapsulated cyclooctane crystallized from mesitylene-d12
(Figure 3, bottom). The quinoxaline walls have an opening
angle of 7.3°, which results in a rather large cavity among
resorcin[4]arene cavitands.27 This observation explains why
red-1 is present as a rigid vase in mesitylene-d12 (Figure 2,
bottom): red-1 probably also complexes this large solvent
molecule. In contrast, cavitands with smaller cavities that
cannot accommodate mesitylene-d12 show dynamic exchange in
Oxidation of the sample in air allowed the cavitand to revert
to its open kite form (ox-1), resulting in guest release.
In summary, we have successfully developed cavitands that
possess all the necessary features of a redox-switchable
molecular gripper: redox-addressable conformational and
binding properties. This work has broad implications for the
design of switchable molecular systems whose functionality can
be predicted, and moves the field of cavitand chemistry closer
to molecular engineering. Our redox-switchable cavitand
system is now ready to be tested as a molecular gripper by
chemically attaching it to a suitable surface,32 and further
investigating its application in nanorobotics.33
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures, characterization data, kinetic data,
variable-temperature NMR studies, and electrochemistry data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
18,28
1
their H NMR spectra.
Alicyclic guests containing H-bond-accepting carbonyl
groups give, in most cases, even higher association constants,
compared to pure hydrocarbon guests (Table 1). The highest
binding constant measured within the cycloalkanone series was
for cycloheptanone (Ka = 224 M−1), and a binding constant of
similar magnitude was measured for ε-caprolactam. A
remarkably high association constant for the binding of top-
open cavitands to neutral guests was measured for 1,4-
cyclohexanedione (Ka = 1080 M−1). This guest has the ideal
size for fitting into the cavitand.29 The first-order rate constant
for the decomplexation of 1,4-cyclohexanedione from red-1 in
mesitylene-d12 at 298 K was determined using an inversion-
transfer NMR experiment to be k−1 = (10.5 0.2) s−1.30 The
measured rate constant corresponds to an activation free
AUTHOR INFORMATION
Corresponding Author
diederich@org.chem.ethz.ch
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the Swiss National
Science Foundation (SNF). I.P. acknowledges the receipt of a
fellowship from the Fonds der Chemischen Industrie. We thank
Dr. Paolo Mombelli and Boris Tchitchanov for helpful
discussions, Dr. Adam Lacy, Dr. Melanie Chiu, and Dr.
Aaron Finke for reviewing the manuscript, and Dimitry Kotlyar
for the help with the Table of Contents artwork.
enthalpy of ΔG⧧ = (16.1
0.1) kcal mol−1, which is
comparable to other rigid, top-open cavitand systems.31
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(24) Gilli, G.; Gilli, P. The Nature of the Hydrogen BondOutline of a
Comprehensive Hydrogen Bond Theory; Oxford University Press:
Oxford, 2009.
(25) Red-2 was also insoluble in toluene-d8. While the compound
was soluble in CDCl3, no binding was observed with various guests
because of the effective competition of this solvent with the guest
molecules.
(26) Details on binding studies together with a list of guests that
showed no binding, very weak binding, or binding with fast guest
exchange are presented in Section 6 of the Supporting Information.
(27) Pochorovski, I.; Diederich, F. Isr. J. Chem. 2012, 52, 20−29.
(28) (a) Hooley, R. J.; Restorp, P.; Iwasawa, T.; Rebek, J. J. Am.
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(29) See the Supporting Information, Section 6.4, for a binding
model.
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NOTE ADDED AFTER ASAP PUBLICATION
Figure 2 was incorrect in the version published ASAP August
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