Molecular switching in nanospaces

Article abstract of DOI:10.1002/jccs.201000083

Switching devices that operate on the molecular level lie at the heart of nanomachinery. The energies involved range from scores of kcal/mol during cleavage or formation of covalent bonds to a few kcal/mol when the signals are changes in conformation. Her

Full text of DOI:10.1002/jccs.201000083

Journal of the Chinese Chemical Society, 2010, 57, 595-603
595
Invited Paper
Molecular Switching in Nanospaces
Henry Dube,a Fabien Durola,b Dariush Ajamia and Julius Rebek, Jr.a*
aThe Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, USA
bCentre de Recherche Paul Pascal, CNRS - UPR 8641, 115 Avenue Schweitzer, 33600 Pessac, France
Switching devices that operate on the molecular level lie at the heart of nanomachinery. The energies
involved range from scores of kcal/mol during cleavage or formation of covalent bonds to a few kcal/mol
when the signals are changes in conformation. Here we examine three systems that use light, metal/ligand
binding, and acid/base chemistry as switching devices to transfer molecules in and out of the confined en-
vironments of encapsulation complexes or cavitands. The events are reversible and the original states can
be recovered by treatment with brief heating, conventional chelating agents, or changes in protonation
states, respectively. The control over these spaces augurs well for applications in drug delivery and sen-
sors for small molecules.
Keywords: Azobenzene; Signaling; Cavitand; Reversible encapsulation; Photoisomerism.
LIGHT AND THE PHOTOISOMERIZATION OF
AZOBENZENES
rupting hydrogen bonds.15 This facilitates the entry of other
guest species, specifically n-tridecane, which is apparent
1
One of the earliest switching mechanisms applied in
supramolecular chemistry is the cis-trans photoisomeriza-
tion of azobenzenes. This isomerization changes the shape
of the overall structure and atoms attached to the p- and
p¢-positions of the azobenzene move in a predictable way.
This feature makes isomerism useful in many molecular
devices1,2 and azobenzenes have been attached to crown
ethers,3-5 cyclodextrins6,7 and even proteins.8,9 We used
azobenzene photoisomerization in an indirect sense to con-
trol reversible encapsulation.
from its characteristic widely-separated H NMR signals
when encapsulated (Fig. 1b). The NMR signals corre-
sponding to the cis-1 in solution appear at 6.59 ppm and
6.67 ppm. On heating this sample to 160 °C for 2 minutes,
cis-1 reverts to its trans conformation and rapidly replaces
n-tridecane in the capsule. The irradiation/heating cycle
can be repeated many times.
The ready replacement of trans-1 on irradiation sug-
gests that the encapsulation of any other potential guest
can, in principle, be initiated by light. For example, a single
guest often replaces two occupants in an entropy-driven
process.16 We used the photoisomerization to reverse these
preferences. The hydrogen-bonded homodimers of ben-
zoic acid or benzamide are good guests for 2×2 but when 3
equiv. of trans-1 are present, only the azo compound is en-
capsulated. On irradiation the azo compound is quickly re-
placed by the respective dimers. Again, the initial state is
restored after brief heating. This cycle can also be repeated
many times without consequence. The 1H NMR spectra re-
corded for substitution of azobenzene by benzamide are
shown in Fig. 1b.
The cylindrical capsule 2×2 (Fig. 1) can bind several
small guests10 or a single longer guest including benzani-
lides,11 n-alkanes12 and stilbenes.13 The encapsulation com-
plex of 4,4¢-dimethyl-trans-azobenzene (trans-1) with 2×2
involves a nearly ideal fit of the guest in the host.14 Direct
competition experiments in deuterated mesitylene show
that trans-1 is a much better guest than n-tridecane for the
1
capsule: the upfield shift of the methyl singlet in the H
NMR spectrum confirms that only trans-1 is bound and no
n-tridecane is observed inside (Fig. 1b). Irradiation at a
wavelength of 365 nm causes the folding to cis-1 that no
longer fits in the capsule. Accordingly, it “breaks out” of
the capsule by forcing one or more walls outward and dis-
Kinetic studies confirmed that the isomerization of
trans-1 takes place inside of the capsule. The cis geometry
* Corresponding author. Tel: +858-784-2250; Fax: +858-784-287; E-mail: jrebek@scripps.edu

596 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Dube et al.
forces the capsule walls outward, and the “breakout” mech-
anism leads to guest exchange. The vase-to-kite confor-
mational changes of cavitands17 involve related outward
wall motions and the mobility of only 2 walls is enough to
enable guest exchange in these cases.18 The rate of ex-
change of encapsulated azobenzene with n-tridecane as an
incoming guest without irradiation was also determined.
When 30 equiv. of n-tridecane compete with trans-1 as a
guest for the capsule, only 19% of trans-azobenzene is ulti-
mately replaced at equilibrium. This endpoint is reached
only after about 1,600 min, showing that the exchange is
very slow. The slow exchange rates of similar shaped
guests as determined by fluorescence methods are also
fully consistent with these findings.19
The extended capsule 2×34×2 (Fig. 2) was subjected to
parallel experiments. Earlier, we showed that 4 molecules
of highly soluble glycolurils such as dibutylaniline deriva-
tive 3 are incorporated into a new, extended capsule assem-
bly when suitable guests are present.20 We used a longer
azobenzene trans-4-methyl-4¢-hexyl-azobenzene21 (trans-
Fig. 2. (a) Light induced guest exchange of trans-4 by
4-ethylbenzamide in the extended assembly
2×34×2 and light induced guest exchange with
concomitant change of assembly using trans-4
as guest for 2×54×2 and 4,4¢-dibromobenzil as
Fig. 1. (a) Light induced guest exchange of trans-1 by
n-tridecane or benzamide in 2×2. Heating the
sample restores the initial states. (b) Appropri-
1
guest for 2×2. b) Indicative regions of the H
NMR spectra (mesitylene-d12, 20 °C) are
shown before irradiation (trans-4 is the only
guest) and after irradiation at 365 nm wave-
length for 50 min at 20 °C (the homodimer of
4-ethylbenzamide is the only guest in 2×34×2
and 4,4¢-dibromobenzil is the only guest in
2×2). After heating the sample to 160 °C for 2
min, the initial state is completely restored.
1
ate regions of the H NMR spectra (mesity-
lene-d12, 20 °C) are shown before irradiation
(trans-1 is the only guest) and after irradiation
at 365 nm wavelength for 50 min at 20 °C
(n-tridecane or benzamide is the only guest).
After heating the sample to 160 °C for 2 min,
the initial state is completely restored.

Encapsulation Devices
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 597
4) as the light-responsive guest in the extended assembly
2×34×2. Characteristic proton signals in the 1H NMR spec-
trum are shown in Fig. 3b. The assembly is desymmetrized:
the two cavitand ends show separate sets of 1H NMR sig-
nals as do hydrogens on the two edges of the glycolurils. In
a solution containing 10 equiv. of trans-4 and 2 equiv. 4-
ethylbenzamide only the azo compound is encapsulated.
But after irradiation at 365 nm, the encapsulated homo-
dimer of 4-ethylbenzamide has replaced the azo com-
pound. This new assembly is C2 symmetric and its spec-
trum is simplified accordingly. Heating the sample to 160
°C for 2 minutes restores the initial guest and the cycle can
be repeated many times (see Fig. 2).
Finally, we could use photoisomerization as a remote
control to switch between different assemblies 2×2 and
2×54×2. The 4-dodecanephenyl glycoluril 5 has low solubil-
ity in deuterated mesitylene alone but is soluble when it is
incorporated into a capsular assembly. Heating a mixture of
2, glycoluril 5 and 3 equiv. of trans-4 leads to formation of
the extended assembly 2×54×2 with the azo compound as the
only guest. The same assembly is also formed in the pres-
ence of additional 4,4¢-dibromobenzil - a mediocre guest
for 2×2. After irradiation of the mixture for 50 min at 365
nm, only the capsule assembly 2×2 is obtained with 4,4¢-di-
bromobenzil as guest. The precipitation of 5 from solution
is observed and doubtless enhances the disproportionation
process. The original extended assembly 2×54×2 is restored
on heating the turbid solution for 2 min to 160 °C, with
trans-4 reappearing as the only encapsulated species (see
Fig. 2). Again, this cycle can be repeated many times. Ac-
cordingly, the photochemical control can alter the nature of
the capsule assemblies.
A possible application for this system involves using
the photoisomerism of an azo guest to manipulate chemical
reactions not known to be photoresponsive. In order to test
the influence of light on the kinetics of such a reaction, we
chose the dehydration of carboxylic acids by carbodi-
imides. When a mixture of 4-biphenylacetic acid and the
encapsulation complex of trans-1 in 2×2 is treated with 18
equiv. of N,N¢-diisopropylcarbodiimide (DIC) the reaction
is complete after 20 min. If the mixture is irradiated for 50
min at 365 nm prior to addition of DIC the reaction rate de-
creases significantly (23-fold). Irradiation leads to encap-
sulation of the acid and the reaction kinetics are limited by
the slow release of the acid from the capsule as shown in
Fig. 3.
In summary, the cis/trans photoisomerization of azo-
benzenes continues to be a reliable switching mechanism in
supramolecular chemistry. The azo compounds are specta-
tors that indirectly control encapsulation of alkanes, di-
meric amides and an long acid.
Fig. 3. (a) Light induced change of reaction kinetics of
the dehydration of 4-biphenylacetic acid (0.8
mM) by DIC (14.4 mM) in the presence of
trans-1 encapsulated in 2×2 (1.2 mM) in
mesitylene-d12 at 20 °C. (b) Diamonds show
conversion when the sample is not irradiated.
Squares show conversion after the sample was
irradiated with 365 nm light for 50 min prior to
addition of DIC. A 23-fold rate decrease was
observed.
METAL CHELATION AND BIPYRIDYL ROTORS
Molecular devices are notional versions of macro-
scopic objects that reproduce on the nanoscale functions
that are familiar on the macroscale:22 self-assembled cap-
sules act as reaction flasks;23 catenanes and rotaxanes are
shuttle-like machines;24 encapsulation complexes can be
spring-loaded25 and many nanomachines are biaryl ro-
tors.26 On/off switches involving extension/contraction

598 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Dube et al.
motions are among the oldest27 molecular devices28 and
machinery29 and they continually appear in the recent liter-
ature.30 Earlier we introduced bipyridyl rotors as chemical
expressions of the Pauling principle for enzyme catalysis31
– with maximum binding at the transition state – and mod-
els for the allosteric behaviour of proteins: how binding in-
formation at a remote site can alter the behaviour of an ac-
tive site (Fig. 4).32
Ouroboros (“tail-eater” in Greek) is an ancient symbol rep-
resenting a serpent swallowing its own tail. Ouroboros was
Since then, biaryl rotors have become much-admired
as nano devices,33 particularly in the context of forced uni-
directional rotation.34-36 In supramolecular chemistry there
are delightful examples by Lehn involving metal chelation
that result in changes resembling flapping motions,37 and
Lützen38 who controlled the chelation of guests with two
cavitands attached to a bipyridyl. The reliability of the bi-
pyridyl rotor system made it irresistible for us to combine it
with the synthetic receptors currently pursued in the labo-
ratory. We prepared a resorcinarene-based deep cavitand
with one wall functionalized39 as a bipyridyl linked to a
cyclohexyl group.40 When the linker is long enough and
flexible, an intramolecular host/guest complex results (Fig.
5). The appropriate filling of space is one of the key deter-
minants for the binding of guests in these cavitands. Cyclo-
hexane is ordinarily a modest guest but it enjoys an entro-
pic advantage by being covalently bound and it prevents
entry of external guests.
We called this deep cavitand an “Ouroborand” as
Fig. 4. Molecular rotors as allosteric effectors in
chemistry. Top: Binding of transition metals at
the bipyridine restricts the conformation of the
crown ether and alters the ether’s transport se-
lectivity for alkali ions. Bottom: Binding of an
ion at one site fixes the biaryl dihedral angle
and organizes the second site for enhanced
binding.
Fig. 5. Representations of the ouroborand; (a) planar
formula and (b) perspective views with the
bipyridine ligand free or chelating a metal cen-
ter; (c) energy minimized structures.

Encapsulation Devices
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 599
used to describe self-threading molecules41 and it is widely
believed to have inspired Kekule’s formulation of benzene,
nearly 150 years ago.
(Fig. 7c) and some cyclohexyl groups are forced out of the
cavity: a broadened singlet appears for these pyridine-
CH2-O protons, as they are now remote from the asymmet-
ric nanoenvironment. When the very good guest THF-d8 is
used as the solvent more than 80% of the cavitands contain
THF molecules, but some 20% are still cling to the cyclo-
hexyl “tail” (Fig. 7d).
The favored conformation of the free bipyridine of
the cavitand, is anti and allows the cyclohexyl to reach the
cavity (Fig. 6 config. A). When a metal ion is chelated by
the bipyridine, a conformational change is forced that pulls
the guest out the cavity (config. B). Now the cavity is open
to an external guest such as an adamantane derivative
(config. C). When the metal ion is removed, the adaman-
tane is released (config. D) and the initial configuration is
restored. Accordingly, metal coordination-driven switch-
ing opens or closes access of guests to the cavity.
We realized the reversible switching process in 80%
The behavior of this molecule was monitored by 1H
NMR. Integration of the upfield NMR signals in mesity-
lene-d12 revealed that all cyclohexyl hydrogens of the
ouroborand and even a part of the linker chain are located
in the cavity (Fig. 8a). The head-to-tail arrangement of the
secondary amides on the rim the cavitand is directional
(clockwise or counterlockwise) and the cavitand exists as 2
cycloenantiomers. Interconversion of these cycloenantio-
mers (racemization) is slow on the NMR timescale, and the
pattern of signals corresponding to the pyridine-CH2-O
protons shows them to be diastereotopic with a large cou-
pling constant (Fig. 7a). The simplicity of the spectra ex-
cludes dimeric or oligomeric assemblies where a cyclo-
hexyl of one ouroborand is the guest of another. Acetone-d6
is also unable to displace the intramolecular guest (Fig. 7b).
In the smaller dichloromethane-d2 (at a concentration of
~10 M) the solvent molecule competes for the cavitand.
Fig. 7. NMR signals of the pyridine-CH2-O protons
when the ouroborand is solubilized in deute-
rated (a) mesitylene, (b) acetone, (c) dichloro-
methane or (d) THF. Doublets correspond to
the cartoon shown whereas singlets correspond
to solvent-occupied cavitands.
Fig. 8. NMR study of the coordination-triggered switch
and guest-exchange of the ouroborand; (a) pure
ouroborand in mesitylene-d12 (80%) and
CD3CN (20%); (b) 10 eq. AdCN added in the
NMR tube; (c) 10 eq. ZnBr2 added in the NMR
tube; (d) water added to the NMR tube, then ex-
traction and drying on Na2SO4.
Fig. 6. Reversible mechanism of the coordination con-
trolled guest exchange in the ouroborand’s cav-
ity.

600 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Dube et al.
mesitylene-d12 and 20% acetonitrile-d3 (required to dis-
solve the metal complexes). Excess amounts of the free
guest, 1-adamantane-carbonitrile (AdCN) and ZnBr2 as the
metal were necessary for observation of reversible switch-
ing between the two states. Fig. 8 shows the 1H NMR spec-
tra during the steps of the switching cycle: The resting state
with internal cyclohexyl (Fig. 8a); Addition of 10 equiv. of
AdCN to the NMR solution (no changes, Fig. 8b); Addition
of 10 equiv. of ZnBr2, the cyclohexyl tail is now outside the
cavity, replaced in almost half of the molecules by an
adamantane-based guest (Fig. 8c); Extraction of the NMR
sample with water (Fig. 8d), the spectrum returns to the one
after addition of AdCN (Fig. 8b). The zinc ions were washed
out, and allowed the system to revert to the ouroborand
state.
instead it must adopt a compressed one.44 This reduces its
length about 5 Å, just enough to be accommodated and the
compression makes the guest molecule shorter and thicker.
As a result, attractive CH-interactions are enhanced be-
tween hydrogens on the alkane’s surface and the 16 aro-
matic panels that define the lining of the capsule (Fig. 9).
This coiling is not without an energetic penalty because
each gauche interaction (in the liquid phase)45 destabilizes
the structure by some 0.55 kcal/mol. Evidently this price is
paid by the attractive forces and the release of solvent mol-
ACID/BASE CONTROL OF A SPRING-LOADED
DEVICE
We recently engineered an alternative to the rotor us-
ing a system that involves linear motions of expansion and
contraction. Above, we described the cylindrical capsule
2×2 and 2×34×2 (Figs. 1 and 2) and some of their encapsula-
tion complexes in organic solvents. A number of studies
with this capsule have defined its capacity42 but the most
peculiar guests encountered to date have been the normal
alkanes,43 guests that can adopt shapes complementary to
their hosts. We took advantage of this conformational flexi-
bility of normal alkanes and applied their extended and
compressed shapes to create a “spring-loaded” device.
Alkanes as long as tetradecane (n-C14) are encapsu-
lated in 1 but longer alkanes, such as n-C15 are not accom-
modated at all – there is no way they can contort to fit in-
side. But even C14 cannot fit in an extended conformation;
Fig. 10. The reversible compression and expansion of
encapsulated n-tetradecane in the expanded
capsule 2×34×2 (top) and the capsule 2×2. The
coiled and the extended conformations of
tetradecane are evident from the upfield re-
gions of the 1H NMR spectra which are shown
together with the respective host guest com-
plexes. The signals move downfield as tetra-
decane is extended and the methylenes move
away from the capsule’s walls and toward its
center. The chiral nature of the expanded as-
sembly is reflected in the diastereotopic pro-
tons of the methylenes. The glycolurils insert
under basic conditions and allow the guest to
relax in 2×34×2. Acid precipitates the glycouril
and regenerates the capsule 2×2 with coiled
tetradecane inside.
Fig. 9. Dimensions of n-C14 in extended (left) and en-
capsulated (center) conformations. The rele-
vant crosspeaks of the 2D NMR spectra are
color coded on the model of a helically coiled
conformation (right).

Encapsulation Devices
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 601
ecules during the encapsulation of the alkane. The specific
conformation was deduced from two-dimensional NMR
studies that show the close proximity of hydrogens on C1 to
C5, C2 to C6, etc. These indicated a coiled, helical confor-
mation.46
alkane must exert some force on the capsule’s interior as
the alkane tries to extend to the lower energy conformation
of antiperiplanar C-C bonds.
We worked to control the coiling and extension of the
alkane from the outside by addition of acid and bases. A
glycoluril was prepared that had remote basic sites, a di-
butylaniline derivative.48 It showed excellent solubility in
mesitylene-d12, the solvent of choice for these NMR stud-
ies as it is the largest commercially available deuterated
solvent. The coiled alkane in the original capsule is not un-
like a compressed spring and addition of the glycoluril al-
lows the guest to relax and extend in the longer capsule
2×34×2. However, HCl gas bubbled into the NMR solution
protonates the basic sites of the glycoluril and causes it to
precipitate. This treatment regenerates the original capsule
2×2 with the coiled alkane inside. Next, trimethylamine was
introduced into the NMR sample. This base deprotonates
the glycoluril, which re-enters the solution and expands the
capsule to 2×34×2. Then acid is added to regenerate 2×2 (Fig.
10). Some six cycles of acid/base treatment were possible
in a single NMR tube before the buildup of trimethylamine
hydrochloride began to distort the 1H NMR spectra. The
acids and bases control the reversible compression and re-
laxation of n-tetradecane.
The glycolurils that insert into the capsule/tetradec-
ane complex increase the length of the capsule 2×34×2 by
some 7 Å and the volume by nearly 50% and form a new
belt of hydrogen bond donors and acceptors at the center of
the assembly.47 Accordingly, tetradecane relaxes into an
extended conformation in the expanded capsule 2×34×2 and
1
this is evident by changes in the H NMR spectrum. The
methylenes of the alkane in the new capsule move away
from the walls and toward the center of the structure. Their
NMR signals move downfield. The tetradecane in the origi-
nal vs the expanded capsule shows very different NMR
spectra as featured in Fig. 10.
The insertion of four glycolurils constricts the center
of the cavity in 2×34×2 and creates a chiral space. This is re-
flected in the diastereotopic protons seen, for example, at
C2 of the alkane guest. The system reverts to the original
capsule through addition of a guest such as benzanilide,
which is nearly ideal in size for 2×2. These changes take
place on mixing at the millimolar concentrations used for
the NMR studies. But the gauche interactions of the coiled
It came as no surprise that the expanded capsule could
Fig. 11. Energy minimized structures and approximate dimensions of capsules extended by glycolurils. The length refers to
the accessibility of methyl groups in the inner space as determined by semiempirical methods. Peripheral groups
have been removed for viewing clarity.

602 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Dube et al.
Ed. 2007, 46, 2823-2826.
accommodate normal C15, C16, C17, C18 and C19. What was
unexpected was the emergence of yet another capsule in the
presence of C19. A new capsule was formed that involved
two belts of glycolurils: a double expansion had taken
place.49 This new hyperextended capsule 2×38×2 (Fig. 11)
also accommodated some natural products such as capsaicin
and anandamide. The latter is the endogenous ligand for the
cannabanoid receptor of the brain.50
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ACKNOWLEDGEMENTS
We are grateful to the Skaggs Institute and the Na-
tional Institutes of Health (GM 27932) for financial sup-
port. The Alexander von Humboldt Stiftung provided a
Feodor Lynen Fellowship for H. D, who was also sup-
ported by the Swiss National Science Foundation (SNF). A
fellowship for F. D was generously provided by The French
Ministry of Foreign Affairs (Egide, Programme Lavoisier).
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