The ouroborand: A cavitand with a coordination-driven switching device

Article abstract of DOI:10.1002/anie.200906753

(Figure Presented) Molecular switch: The ouroborand coordinates an internal side chain in its cavity, just as it were swallowing its own tail. The presence or absence of zinc(II) in solution switches the cavity between open and closed states to external guests (see scheme: deep blue sphere: Zn).

Full text of DOI:10.1002/anie.200906753

Angewandte
Chemie
DOI: 10.1002/anie.200906753
Self-Hosting Cavitand
The Ouroborand: A Cavitand with a Coordination-Driven Switching
Device**
Fabien Durola and Julius Rebek, Jr.*
Molecular devices reproduce on the nanoscale functions of
macroscopic objects, at least notionally:[1] self-assembled
capsules are reaction flasks;[2] catenanes and rotaxanes are
machines;[3] cylindrical molecular containers can be spring-
loaded;[4] and any number of biaryl nanomachines behave as
rotors.[5] On/off switches involving extension/contraction
motions[6] are among the oldest[7] molecular devices and
here we revisit the conformational changes offered by
bipyridine rotors to regulate access to a deep cavitand.
Intermolecular forces and the appropriate filling of space
usually control the binding of guests inside cavitands. Con-
sider the resorcinarene-based deep cavitand (host) whose
fourth wall is functionalized[8] with a bipyridyl switching
device linked to a cyclohexyl group (guest). With a flexible
linker of appropriate length, this intramolecular guest will
reach and occupy the cavityꢀs space. The entropic advantage
of the tethered cyclohexane is expected prevent entry of
external guests (Scheme 1).
Since such a structure allows this compound to include
itself, the name “ouroborand” seemed appropriate to us:
Ouroboros (“tail-eater” in Greek) is an ancient symbol
representing a serpent swallowing its own tail. It often
represents eternity and cycles, but was also frequently used
in alchemical illustrations. It inspired Kekuleꢀs formulation of
benzene and in the more recent chemical literature, Ouro-
boros was used to describe self-threading molecules.[9] For the
case at hand, the favored conformation of the free bipyridine
is, as usual, anti. This conformation allows the guest fragment
(cyclohexyl) to access the cavity in an intramolecular sense
and prevents another guest from entering (Scheme 2, config.
A). When a suitable metal ion is present the bipyridine ligand
adopts the chelating syn structure. This forces a conforma-
tional change that pulls the guest out the cavity (config. B),
leaving it accessible to an external guest, an adamantane
derivative (config. C). On removal of the metal ion (config.
D), the initial configuration is regenerated when the ada-
mantane is released.
Scheme 1. Representations of the ouroborand; a) planar formula and
b) perspective views with the bipyridine ligand free or chelating a
metal center.
[*] Dr. F. Durola, Prof. Dr. J. Rebek, Jr.
The Skaggs Institute for Chemical Biology and Department of
Chemistry, The Scripps Research Institute
10550 N. Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2876
E-mail: jrebek@scripps.edu
Homepage: http://www.scripps.edu/skaggs/rebek/
Scheme 2. Reversible mechanism of the coordination controlled guest
exchange in the ouroborand’s cavity.
[**] We are grateful to the Skaggs Institute and the National Institutes of
Health (GM 27932) for financial support. A fellowship for F.D. was
generously provided by The French Ministry of Foreign Affairs
(Egide, Programme Lavoisier).
The ouroborand was synthesized in ten steps from
commercially available compounds (Scheme 3) and was
characterized by 1H NMR and mass spectrometry.[10] Diamino
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906753.
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cavity. Integration of the upfield NMR signals in this solvent
reveals that all cyclohexyl hydrogen atoms of the ouroborand
and even a part of the linker chain are located in the cavity,
(see Figure 2a). Another telltale feature of the spectrum is
the AB pattern of signals corresponding to the pyridine-CH2-
O protons. They are diastereotopic and appear as two well-
separated doublets, located between 4 and 5 ppm, with a large
coupling constant (2J = 13 Hz) (Figure 1a). Such a difference
Figure 1. NMR signals of the pyridine-CH2-O protons when the ouro-
borand is solubilized in deuterated a) mesitylene, b) acetone,
c) dichloromethane, or d) THF. Doublets correspond to the cartoon
shown whereas singlets correspond to solvent-occupied cavitands.
Scheme 3. Synthesis of the ouroborand. a) PBr3, 08C 15 min, RT 2 h,
1008C 1.5 h, 100%; b) NaH, THF, RT 2 h, 758C 16 h, 26%; c) BuLi,
toluene, À208C, À788C 2 h, Me3SnCl, À788C 1 h, RT, 55%; d) [Pd-
(PPh3)4], toluene, 1108C 48 h, 75%; e) dioxane, RT 30 min, 1008C
16 h, 67%.
between these seemingly identical protons arises from the
asymmetry of the environment: the head-to-tail arrangement
of the secondary amides on the rim the cavitand is directional
and set by the chain of hydrogen bonds that terminate at the
benzimidazole. The arrangement may be as shown in
Scheme 1 or, through tautomerization of the benzimidazole,
its mirror image and the interconversion of these cyclo-
enantiomers is slow on the NMR timescale of the experi-
ments. Dimeric or oligomeric assemblies of the ouroborand
are excluded by the simplicity of the spectra. Similar results
are observed in [D6]acetone (Figure 1b), despite the smaller
size of the solvent. In [D2]dichloromethane (Figure 1c), the
solvent molecule (at a concentration of ca. 10m) is a good
guest and competes for the cavitand. Some cyclohexyl groups
are regurgitated from the cavity, and a broadened singlet
appears for the pyridine-CH2-O protons, which are now at
some distance from the asymmetric environment. In [D8]THF
(Figure 1d), a solvent that is a very good guest (and again, is
present in multimolar concentration) most of the cavitands
contain THF molecules, but almost 20% still cling to the
cyclohexyl “tail”, a testimony to the advantages of the
intramolecular interaction.
cavitand 8 was obtained in five steps by following an efficient
and well-established procedure.[8] Primary alcohol 1 was first
brominated by using phosphorus tribromide, then the corre-
sponding bromoalkane 2 was used with alcohol 3 in a
Williamson reaction, with sodium hydride as a base to give
the ether 4. The yield of that last step was modest due to the
multiple reactivity of (6-bromopyridin-2-yl)methanol (3), but
fortunately the reaction can be done on a large scale. The
bromopyridine 4 was then converted to the stannylpyridine 5
by forming first an organolithium compound with n-butyl-
lithium, and then by reaction with trimethyltin chloride under
classical conditions. The tin compound 5 so obtained was then
reacted with another bromopyridine 6, following Stille cross-
coupling conditions with [Pd(PPh3)4] as a catalyst, to give the
bipyridine 7 in a typical yield. The aldehyde function of the
bipyridine-incorporating tether was ultimately attached to the
diamino cavitand 8, by formation of an imidazole aromatic
ring, to give the ouroborand 9.
The autophagic behavior of this molecule could be
established in different deuterated solvents by 1H NMR.
Because the cavitandꢀs walls incorporate eight aromatic rings,
any guest molecules in the cavity are exposed to a strong
shielding effect, which shifts the 1H NMR signals upfield,
below d = 0 ppm. [D12]Mesitylene (1,3,5-trimethylbenzene) is
a common NMR solvent for the study of cavitands. Although
its concentration is ca. 10m, its shape is not accommodated
and it does not compete with other molecules for access to the
Some experimentation was required to optimize the
reversible switching process in this system. The primary
solvent was [D12]mesitylene but 20% [D3]acetonitrile (a
somewhat poor guest for the cavitand) was required to
dissolve the metal complexes. Dilute solutions (1 mm,
2 mgmLÀ1) precluded intermolecular interaction between
cavitands. An excess of the free guest, 1-adamantane-carbo-
nitrile (AdCN), which is typically an excellent neutral guest
for cavitands,[11] and an excess of ZnBr2 as the metal source
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were used. These excesses were necessary to drive the
coordination and represented the best conditions for obser-
vation of reversible switching between the two states.
Some dynamic molecular capsules that can change cavity
sizes have been developed[12] but only few examples of
systems combining molecular machines[13] and supramolec-
ular chemistry[14] have been reported in the literature. Here,
we used a bipyridyl rotor in an intramolecular setting to open
or close access to guests through metal coordination-driven
switching. To place these results in an historical perspective,
we note that bipyridyl rotors[15] were among the earliest
chemical models of allosteric behavior of proteins—how
binding at a remote site can alter the behavior of an active
site.[16] More recently, bipyridyls attached to cavitands were
introduced by Lꢁtzen[17] to control chelation of guests. The
most recent applications, involving metal chelation that
results in changes resembling flapping motions[18] indicate
that the predictable consequences of bipyridyl/metal chela-
tion are reliable tools for forging tomorrowꢀs molecular
machinery.
Figure 2 shows the evolution of the 1H NMR spectra
during the steps of the switching cycle. The changes appeared
mainly in two parts of the spectrum: Between d = 3 and
5 ppm, signals integrate for the four pyridine-CH2-O-CH2-
protons; below d = 0 ppm, signals only correspond to protons
located in the cavity. The use of [D3]acetonitrile slightly
broadens the signals but does not interfere with the self-
hosting of the cyclohexyl group (Figure 2a). Addition of
10 equivalents of AdCN to the NMR solution (Figure 2b)
causes no changes; the cavitand is inaccessible to this external
guest. But on addition of 10 equivalents of ZnBr2 (Figure 2c),
the doublets between d = 5 and 3 ppm are converted to
singlets, showing that the coordination-induced switching of
the system is complete. The flexible tail is now outside the
cavity and the chirality of the system is too remote to affect
the geminal CH2 coupling. Integration of the signals below
d = 0 ppm shows that only 45% of the cavitand is occupied
with AdCN molecules. The remaining cavitand is presumably
solvent-filled because the AdCN occupancy decreases when
Received: November 30, 2009
Revised: January 3, 2010
Published online: March 18, 2010
Keywords: bipyridine · cavitands · molecular switches ·
ouroborands · self-hosting
more than 20% of [D ]acetonitrile or less than 10 equivalents
.
3
of AdCN is used. Accordingly, two different singlets appear
around d = 4.6 ppm, integrating for the -pyridine-CH2-O-
protons, with a 55:45 ratio. The ZnII complex is labile but can
be observed by mass spectrometry (MALDI) as [Zn(ouro-
borand)Br]+. Since a bis(ouroborand) complex would be
more stable, this result implies that the zinc(II) cation is
coordinated to only one ouroborand. After addition of water
to the NMR sample, followed by separation of the organic
phase and drying over Na2SO4, the spectrum is very similar to
the one after addition of AdCN to the ouroborand (Fig-
ure 2d). The zinc ions were extracted into the aqueous phase,
and allowed the system to revert to the self-hosting state with
the concomitant release of the AdCN molecules to the bulk
solution.
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Figure 2. NMR study of the coordination-triggered switch and guest
exchange of the ouroborand; 1) 10 equivalents AdCN added in the
NMR tube; 2) 10 equivalents ZnBr2 added in the NMR tube; 3) water
added to the NMR tube, then extraction and drying on Na2SO4.
Integration values are shown in gray.
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