Stereochemistry of molecular figures-of-eight

Article abstract of DOI:10.1002/chem.201202070

A trans isomer of a figure-of-eight (Fo8) compound was prepared from an electron-withdrawing cyclobis(paraquat-p-phenylene) derivative carrying trans-disposed azide functions between its two phenylene rings. Copper(I)-catalyzed azide-alkyne cycloadditions

Full text of DOI:10.1002/chem.201202070

FULL PAPER
DOI: 10.1002/chem.201202070
Stereochemistry of Molecular Figures-of-Eight
Megan M. Boyle,[b] Jeremiah J. Gassensmith,[b] Adam C. Whalley,[b] Ross S. Forgan,[b]
Ronald A. Smaldone,[b] Karel J. Hartlieb,[b] Anthea K. Blackburn,[b]
Jean-Pierre Sauvage,*[a, b] and J. Fraser Stoddart*[b, c]
À
Abstract: A trans isomer of a figure-of-
eight (Fo8) compound was prepared
from an electron-withdrawing cyclo-
bis(paraquat-p-phenylene) derivative
carrying trans-disposed azide functions
between its two phenylene rings. Cop-
per(I)-catalyzed azide–alkyne cycload-
ditions with a bispropargyl derivative
of a polyether chain, interrupted in its
midriff by an electron-donating 1,5-di-
oxynaphthalene unit acting as the tem-
plate to organize the reactants prior to
the onset of two click reactions, afford-
ed the Fo8 compound with Ci symme-
try. Exactly the same chemistry is per-
formed on the cis-bisazide of the tetra-
cationic cyclophane to give a Fo8 com-
pound with C2 symmetry. Both of these
Fo8 compounds exist as major and very
minor conformational isomers in solu-
tion. The major conformation in the
trans series, which has been character-
ized by X-ray crystallography, adopts
a geometry which maximizes its C
H···O interactions, while maintaining
À
its p···p stacking and C H···p interac-
tions. Ab initio calculations at the
M06L level support the conformational
assignments to the major and minor
isomers in the trans series. Dynamic
1H NMR spectroscopy, supported by
2D 1H NMR experiments, indicates
that the major and minor isomers in
both the cis and trans series equilibrate
in solution on the 1H NMR timescale
rapidly above and slowly below room
temperature.
Keywords: click chemistry · donor–
acceptor systems
·
rotaxane
·
AHCTUNGTRENNUNG
Introduction
bond formation in order to tailor the way portions of a mole-
cule orient themselves with respect to each other, allowing
chemists to create both single-station and switchable me-
chanically interlocked molecules (MIMs).[3] These methods
result in single molecules composed of several components
held together through mechanical bonds, for example, cate-
nanes,[4] rotaxanes,[5] and Borromean rings.[6] Self-complex-
ing compounds[7] and pretzelanes[8] are synthesized by
means of intramolecularly template-directed protocols.
Here, we describe the synthesis of isomers of a molecular
figure-of-eight[9] (Fo8) using an intermolecularly templated
protocol.
The field of chemical topology[1] has enabled the design of
molecular representations of mathematical topologies and
aided in the syntheses and analyses of both topologically
trivial and non-trivial chemical motifs. Often, molecular rec-
ognition and self-assembly are used to template[2] the forma-
tion of higher-order architectures by stabilizing inclusion
complexes through interactions such as hydrogen bonding
and p–p stacking. Importantly, this use of templates can be
employed to direct the location and geometry of covalent
The electron-deficient cyclophane,[10] cyclobis(paraquat-p-
[a] Prof. J.-P. Sauvage
phenylene) (CBPQT4+), has been employed as the molecu-
Institut de Science et d’Ingꢀniere Supramolꢀculaires
Universitꢀ de Strasbourg
8 allꢀe Gaspard Monge, F-67000 Strasbourg (France)
E-mail: jpsauvage@unistra.fr
lar host to encircle an electron-rich guest en route to ob
ACHTUNGTRENNUNGtain-
AHCTUNGTRENNUNG
family of cyclophanes is synthesized through a template-di-
rected approach.[12] Introducing various functionalities onto
the xyACTHNURGTENNlUG ylACHTUTGNRENeNUNG ne units of the cyclophane precursors can poten-
[b] Dr. M. M. Boyle, Dr. J. J. Gassensmith, Dr. A. C. Whalley,
Dr. R. S. Forgan, Dr. R. A. Smaldone, Dr. K. J. Hartlieb,
A. K. Blackburn, Prof. J.-P. Sauvage, Prof. J. F. Stoddart
Center for the Chemistry of Integrated Systems
and Department of Chemistry, Northwestern University
2145 Sheridan Road, Evanston, IL 60208-3133 (USA)
Fax : (+1)847-491-1009
tially hinder cyclophane formation, depending on the elec-
tronic and steric nature of the functional group. Modifica-
tion of CBPQT4+ with a single functional handle on one of
the phenylene rings is possible and does not alter signifi-
cantly the binding capabilities of the cyclophane. Although
this approach has been used to synthesize complex mole-
cules, such as pretzelanes,[8,13] polymers,[14] and linked nano-
particles,[15] further modification of CBPQT4+ with multiple
functional handles has remained an elusive target until re-
cently, though it does provide access to new topologies that
have been unattainable thus far. Although a two-armed self-
E-mail: stoddart@northwestern.edu
[c] Prof. J. F. Stoddart
NanoCentury KAIST Institute and Graduate School of EEWS
(WCU)
Korea Advanced Institute of Science and Technology (KAIST)
373-1, Guseong Dong, Yuseong Gu, Daejeon 305-701 (Republic of
Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202070.
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complexing rotaxane[7b] has been synthesized containing
a bisfunctionalized cyclophane formed through an intramo-
lecular template approach, an uncomplexed bisfunctional
cyclophane has not been isolated and characterized until
very recently. A straightforward example of a topology ob-
tainable by incorporating bisfunctionality onto the
CBPQT4+ ring is called a self-complexing [1]rotaxane, or
the molecular figure-of-eight[9,16] (Fo8), in which a guest is
threaded through the cavity and linked covalently to the
host twice. Herein, we report the 1) design, 2) synthesis, and
3) characterization of the molecular Fo8, 1·4PF6 via the cy-
clophane intermediate 2·4PF6, and discuss 4) the resulting
stereochemical implications and consequences. Although
this research has been the subject of a preliminary commu-
nication,[9] the recent advent of a crystal structure of one of
the Fo8 compounds has encouraged us to revise our opinion
on the geometry of the major conformation of the com-
pound present in solution.
ples we considered, a dicationic precursor could be synthe-
sized and characterized, the final ring-closing step could not
be performed in all but one case. The synthetic steps neces-
sary to reach the desired cyclophanes, and the yields (if any)
of the final ring-closing steps in the template-directed for-
mation of the tetracationic cyclophane are shown in
Scheme 1. Initial attempts were based on appending alkynes
to the cyclophane to prepare CBPQT4+ for copper(I)-cata-
lyzed azide-alkyne cycloaddition[18] (CuAAC). In the context
of CuAAC, attachment of azides, rather than alkynes, to the
cyclophane was pursued subsequently. It was found that the
azide-modified aryl dibromide 13 was the only suitable sub-
strate and fortunately it afforded (Scheme 2) the highest
yield of cyclophane in a minimum number of synthetic
steps. All of the alkyne-based modifications disrupted the
mechanism of cyclophane formation so significantly that
negligible quantities of product were formed, even when the
final template-driven ring-closing step was performed under
ultra-high pressure (15 kbar). Because the azide group is,
comparatively speaking, sterically small and electronically
benign,[19] it allows retention of the binding affinity of the
tetracationic cyclophane for electron-rich guests, such that
good yields of the cyclophane can still be obtained. Begin-
ning with the commercially available 2-bromo-1,4-dimethyl-
benzene, an Ullman-type coupling was performed in order
to afford compound 12, which was brominated to give 13.
Reaction of 13 with an excess of 4,4’-bipyridine afforded the
Results and Discussion
In an effort to assemble a self-complexing [1]rotaxane, sev-
eral bisfunctional CBPQT4+ derivatives (Scheme 1) were
considered as lead compounds based on functional groups
that had previously been incorporated[7b,17] into monofunc-
tionalized derivatives of CBPQT4+. While in all the exam-
Scheme 1. A description of the synthetic attempts to form a bisfunctional cyclophane based on the CBPQT4+ ring. Three targets were initially designed
incorporating alkynes for further functionalization. Precursors 6·2PF6, 8·2PF6, and 11·2PF6 were synthesized successfully, but the final ring-closing step
in each case yielded little or no product. This result is most likely because functionalization of the aryl group weakened significantly the ability of a transi-
tion state to recognize a guest and thus a template approach could not be utilized to form the final cyclophanes.
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Molecular Figures-of-Eight
FULL PAPER
dicationic precursor 14·2PF6,
which could be reacted with an-
other equivalent of 13 in the
presence of an electron-rich
template to afford[20] two insep-
arable isomers of 2·4PF6—cis-
2·4PF6, in which both azides
are pointing toward the same
bipyridinium unit, and trans-
2·4PF6, in which the azides are
pointing toward opposite bipyr-
idinium units.
The synthesis of the molecu-
lar Fo8 is templated by the
strong host–guest complex that
is formed between the p-elec-
tron-deficient
cyclophane
2·4PF6 and the p-electron-rich
guest 15. Functionalization of
CBPQT4+ at both xylylene
linkers is expected to alter the
binding properties of the host
towards guests. In order to
probe the ability of 2·4PF6 to
bind with electron-rich sub-
strates, the association con-
stants (Ka values) and other
thermodynamic data for the
complexation of the bisfunc-
tionalized host with electron-
rich guests have been obtained
experimentally using isothermal
titration calorimetry (ITC) and
compared (Table 1) to a similar
monofunctionalized cyclophane
(in which only one xylylene
linker contains the azide func-
tion—CBPQT4+-N3) and the
free unsubstituted CBPQT4+
.
For ITC isotherms, see the Sup-
porting Information. In the case
Scheme 2. Synthetic route to the two separated constitutional isomers of 1·4PF6 detailing the synthesis of the
constitutional isomers of the electron-deficient bisfunctionalized cyclophane 2·4PF6. The conformation ob-
served according to the solid-state structure is shown along with the previously proposed[9] structure trans’-14+
in which the conformations differ in the directionality and location of the polyther loops.
of
a
1,5-dioxynaphthalene
(DNP) unit functionalized with
hexaethylene glycol (HEG)
chains at each phenolic hydrox-
Table 1. Thermodynamic binding data corresponding to the complexation between various CBPQT4+-based hosts and both 1) DNP-HEG-dA guest and
2) TTF-HEG-dA guest in MeCN as determined by isothermal titration microcalorimetry at 298 K.[a]
DNP-HEG-dA Guest
TTF-HEG-dA Guest
[e]
[e]
DH[b]
DS[c]
DG[d]
Ka
DH[b]
DS[c]
DG[d]
Ka
CBPQT4+
À15.34Æ0.03
À14.38Æ0.04
À12.65Æ0.01
À29.3Æ0.1
À28.6Æ0.9
À25.2Æ0.2
À6.61Æ0.04
À5.86Æ0.29
À5.14Æ0.13
67.5Æ1.1
19.3Æ0.3
5.71Æ0.1
À12.50Æ0.06
À12.20Æ0.07
À11.94Æ0.05
À16.7Æ0.5
À16.7Æ0.2
À16.5Æ0.2
À7.52Æ0.16
À7.22Æ0.09
À6.98Æ0.08
333Æ26
195Æ14
141Æ7
CBPQT4+-N3
CBPQT4+-(N3)2
[a] All ITC measurements were performed in dry, degassed MeCN at 298 K. A solution of CBPQT4+, CBPQT4+-N3, or CBPQT4+-(N3)2 (0.5 mm) was
used as the host solution. Solutions of DNP-HEG-dA or TTF-HEG-dA (5 mm unless otherwise stated) were added by successively injecting 10 mL of a ti-
trant solution over 20 s (23 times) with a 300 s interval between each injection. Experiments for each host and guest were repeated three times. [b] [kcal
molÀ1]. [c] [calmolÀ1 KÀ1]. [d] [kcalmolÀ1]. [e]ꢂ103 [mÀ1].
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J.-P. Sauvage, J. F. Stoddart et al.
yl group, and terminated with alkynes (DNP-HEG-dA),
going from the unfunctionalized cyclophane to a monosubsti-
tuted one and subsequently to a difunctionalized one results
in a decrease of the Ka value between the host and guest by
no more than an order of magnitude. Furthermore, in the
case of another electron-rich guest, a bis(methylene)-substi-
tuted tetrathiafulvalene (TTF) similarly extended at both
functional groups with hexaethylene glycol chains and termi-
nated with alkynes (TTF-HEG-dA), the binding affinity is
only decreased ever so slightly. Hence, the binding capabili-
ties of the host 2·4PF6 remain sufficiently strong, encourag-
ing us to proceed with further experiments.
The DNP-based derivatives, possessing a sufficiently high
Ka value when complexed with cyclophane 2·4PF6, yet lack-
ing the isomer complications common to TTF derivatives,[21]
make them ideal guests for the synthesis of a molecular Fo8.
Using a mixture of the CBPQT4+ bisazides and DNP-HEG-
dialkyne derivative 15, CuAAC was employed to link the
complex covalently to produce (Scheme 2) the Fo8 (1·4PF6).
As a result of using a mixture of the two isomers of 2·4PF6,
the product was a mixture of two isomers. Recycling re-
verse-phase high-performance liquid chromatography (RP-
HPLC) was used in order to separate and characterize
fully[9] two very similar compounds—cis-14+, in which both
triazoles are pointing toward the same bipyridinium unit,
and trans-14+, in which the triazoles are pointing toward op-
posite bipyridinium units.
Crystals of trans-1·4TFA (Figure 1a), grown from Me2CO
using slow vapor diffusion of Et2O, possess a solid-state
structure (Figure 1b) which aids the identification of the ge-
ometry of the Fo8—the solid-state structure is found to be
in contrast to trans’-14+, the structure (Scheme 2) previously
proposed,[9] in terms of its constitution and conformation.
Figure 1. The structural formula a) of trans-14+ and a tubular representa-
tion of its b) X-ray crystal structure (non-interacting H atoms and anions
have been omitted for clarity). Note that in the solid-state structure, the
calculated energetically favorable orientation of the dioxynaphthalene
¯
The compound crystallizes in the triclinic space group P1
with one half of a molecule, two CF3COOÀ counterions, and
two MeCN solvent molecules in the asymmetric unit. The
complete molecule was generated by an inversion operation
through the center of the molecule at the origin, in concert
with its proposed Ci point group. The CBPQT4+ portion of
the molecule sits flat along a plane through the corner meth-
ylenes and, as with the majority of solid-state structures[4q,22]
containing CBPQT4+, the pyridinium rings are twisted
slightly from planarity, with an angle of 168 present between
neighboring heterocycles. The 1,2,3-triazole rings bound to
each xylyl moiety are twisted from the plane of the xylene
rings by 478, while the nitrogen atoms of the triazole func-
tionality are directed towards the center of the molecule.
The hexaethylene glycol chains are then directed around the
outside of the CBPQT4+ moiety and connected to the DNP
unit, which sits inside the CBPQT4+ ring. As a result of the
generation of the full structure from the inversion operation,
the glycol chains are located on opposite sides of the mole-
À
core is, in fact, observed. The C H···O interactions which hold the Fo8 in
this orientation are denoted in c). The X-ray crystal packing d) shows
that parallel sheets of trans-14+ are found in the crystal structure.
glycol O closest to the triazole ring), to 2.98 ꢃ in the case of
C H···O (methylene H to glycol O in the middle of the
À
chain). Bifurcated interactions between pyridyl H and the
glycol chain closest to the DNP unit are also present. These
noncovalent bonding interactions are known[23] to impart
significant stability to MIMs, such as 1·4PF6, and are the
most likely driving force behind the arrangement of the
polyether loops such that they connect DNP and triazole
units located on opposite faces of the Fo8 rather than on the
same face. The DNP unit sits inside the CBPQT4+ ring so
À
that C H···p interactions (3.46 ꢃ) are present between the
peri-hydrogen atoms on the DNP unit with both the aromat-
ic xylylene components of CBPQT4+. The packing of the
molecules is such that parallel sheets of the Fo8 are formed
(Figure 1d) through bifurcated hydrogen bonding with
CF3COOÀ counterions.
À
cule. Multiple C H···O interactions (Figure 1c) are present
between CBPQT4+ and the oxygen atoms of the glycol
chains, which act to hold the polyether loops in close prox-
imity around the macrocycle. These interactions range in
The orientation of the polyether loops with respect to the
directionality of the extending triazoles on the xylylene link-
À
distance from 3.40 ꢃ in the case of C H···O (pyridyl H to
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ers may seem, at first glance, to be somewhat unexpected,
since the loops do not simply extend from the triazole link-
age and thread directly through the cavity of the cyclo-
phane, but rather, the polyether loops fold back around the
outside of the cyclophane and enter the cavity from the op-
posite side with respect to the protruding triazole rings. In-
spection of the solid-state structure of trans-1·4TFA demon-
gen atoms of the bipyridinium units, there are four (a1, a2,
a3, a4) heterotopic pairs of homotopic protons. Of the eight
protons b to the same nitrogen atoms, there are four (b1, b2,
b3, b4) heterotopic pairs of homotopic protons. Of the six p-
xylylene protons, there are three (a, b, c) heterotopic pairs
of homotopic protons; the two triazole protons are homo-
topic. Conversely, the trans isomer contains only a center of
inversion, implying that trans-1·4PF6 resides in the Ci point
group (Figure 2b). Thus, of the eight protons a to the bipyri-
dinium nitrogen atoms, there are four (a1, a2, a3, a4,) hetero-
topic pairs of enantiotopic protons, such that we observe
four resonances. Of the eight protons positioned b to these
nitrogen atoms, there are four (b1, b2, b3, b4) heterotopic
pairs of enantiotopic protons. Of the six xylylene protons,
there are three (a, b, c) heterotopic pairs of enantiotopic
protons; the two triazole protons are enantiotopic. The
result is that each isomer is expected to display nine aniso-
tropic aromatic signals, which is, in fact, what is observed
À
strates clearly the structure-directing properties of the C
H···O interactions, and it would seem prudent to assume
that this particular orientation, stabilized by these noncova-
lent bonding contacts, is also favored in solution. This con-
formation maintains the predicted symmetry[9] assignments
and also sheds light on the orientation of the DNP unit
inside the cyclophane in solution, in which the oxygen
atoms of the DNP unit point away from triazole rings to
avoid steric clashes—a point we could not determine with
certainty by using any 1D or 2D NMR spectroscopic tech-
niques.
1
1
In an effort to establish the H NMR spectroscopic assign-
(Figure 2c,d) by H NMR spectroscopy.[9]
ments as fully as possible, a symmetry analysis was conduct-
ed on each isomer. The cis isomer of 1·4PF6 resides (Fig-
ure 2a) in the C2 point group, that is, it contains only a C2
axis of rotation. Hence, of the eight protons a to the nitro-
The resulting Fo8 architecture (Figure 3a) resembles, both
through topological deformation (Figure 3b) and in appear-
ance, the rose topology (or figure-of-eight, Figure 3c). Al-
though a molecular Fo8 is considered topologically trivial,
Figure 2. Constitutional isomers of the molecular Fo8 in which a) cis-14+ is oriented such that both triazoles are pointed toward the same bipyridinium
unit and b) trans-14+ such that the triazoles are pointed toward opposite bipyridinium units. Their corresponding 1H NMR (600 MHz, CD3CN, 298 K)
spectra are fully assigned as c) cis-1·4PF6 and d) trans-1·4PF6.
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J.-P. Sauvage, J. F. Stoddart et al.
It also transpires that each
isomer occupies two non-degen-
erate conformations that are in
dynamic equilibrium with each
other, as evidenced by 2D
1H NMR experiments in an ap-
proximate 9:1 ratio in CD3CN.
In order to study the dynamic
equilibria more closely, solu-
tions of one single pure isomer
were employed: for this discus-
sion, the trans isomer (Figure 4)
the structure of which is known
in the solid-state will be used to
draw conclusions. The same ob-
servations and conclusions (see
Supporting Information) can be
reached in the case of the cis
isomer. We will consider the
major solution species (desig-
Figure 3. The molecular Fo8 (a) can be deformed continuously through the topology graph (b) to the rose top-
ology (c) at which the self-complexing [1]rotaxane is thus considered homeomorphic to the rose topology con-
taining two petals. Furthermore, the Fo8 can be considered to resemble, even through appearance, the rose
topology. In an effort to render the topologically trivial Fo8 onto topologically non-trivial graph, residual top-
ology may be invoked by adding two vertices to a [2]rotaxane in which the thread is considered infinitely long
(d).
a residual topological analysis
can be conducted to render the
Fo8 topologically non-trivial.[24]
Adding vertices to a topological-
ly non-trivial object, instead of
rendering their molecular graph
more complex, will—most of
the time—convert the non-trivi-
al graph to a trivial one, which
is indeed the situation we ob-
served with the Fo8. Let us
start from a [2]rotaxane that
can be considered as non-trivial
and identical to a [2]catenane,
if we assume that the thread is
infinitely
long
(Figure 3d).
Adding a connection between
the ring and the rod leads (Fig-
ure 3e) to a [1]rotaxane. This
structure is now trivial because
it is identical (Figure 3 f) to
a ring bearing a lateral rod.
Going further, and now adding
two vertices (i.e., two connec-
tions between the ring and the
rod) yields the molecular Fo8.
In the same manner as for the
Figure 4. The major conformation Maj-trans-14+ as observed in the solid-state structure is expected to undergo
three dynamic processes in solution: 1) a process by which a) DNP is dislodged from the cavity, followed by b)
a 1808 rotation around its [O···O] axis, and c) its reinsertion inside the cavity; 2) pyridinium ring rotation; and
previous [1]rotaxane, this spe- 3) phenylene ring rotation. The first process involving the rotation of the DNP unit results in a conformation
trans’’-14+ that is predicted to be highly unstable because of multiple steric interactions between the oxygen
atoms of the DNP unit and the extending triazole rings. Pyridinium ring rotation does not result in a different
conformation, but simply exchanges previously heterotopic protons on the bipyridinium ring and results in
cies is trivial. Thus, the conclu-
sion is simple: adding connec-
tions (or vertices) can lead to
simple (trivial) graphs from
non-trivial ones. As a conse-
quence of the way the molecule
is generated, it can be consid-
ered to have residual topolo-
gy.[24]
new homotopic pairs. Phenylene rotation results in a conformation that is wholly asymmetric and is predicted
1
to be the minor species present in the H NMR spectrum, Min-trans-14+. The major conformation is calculated
as the more energetically favorable conformation over Min-trans-14+ by 4.5 kcalmolÀ1 in which one phenylene
ring has rotated to introduce steric strain between one appended triazole and the extending DNP oxygen. The
remaining conformation trans’-14+ is not observed by 1H NMR spectroscopy, but initially was predicted to be
the major conformation. This conformation results as a combination of dynamic processes: phenylene ring ro-
tation and DNP dislodgement/rotation/reinsertion and is expected to be highly unstable because of various
steric clashes between the triazole rings and the oxygen atoms of the DNP unit.
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Molecular Figures-of-Eight
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nated Maj-trans-14+) as the conformation determined by the
solid-state structure and draw conclusions about the uniden-
tified minor conformation (Min-trans-14+) using 1H NMR
spectroscopy.
trans-1·4PF6 at higher temperatures in CD3SOCD3 resulted
in decomposition of the compound.
Finally, we consider phenylene ring rotation, a process
that, in previous examples,[25a] has been observed in systems
of lower symmetry, that is, a modified cyclophane as in our
case. The barrier to rotation is typically not as high as that
for pyridinium ring rotation. However, the barrier of phen-
ylene ring rotation in a cyclophane containing a DNP guest
is higher than that without the guest. In light of this observa-
tion, phenylene ring rotations in the Fo8 are expected to
occur slowly on the 1H NMR timescale at temperatures
above room temperature. By examining all the different
conformations which result from phenylene ring rotation,
we have identified three different isomers that should, in
Typically, donor–acceptor MIMs, that is, catenanes and ro-
taxanes, containing DNP units and CBPQT4+ rings will en-
counter three dynamic processes: 1) a process by which a)
the DNP unit is dislodged from the cavity, followed by b)
a 1808 rotation around its [O···O] axis, and c) its reinsertion
inside the cavity;[25] 2) pyridinium ring rotation; and 3)
phenylene ring rotation. Let us first of all consider the pro-
cess of DNP dislodgement/rotation/reinsertion. The local
C2h symmetry of DNP unit imposes two different environ-
ments on the modified CBPQT4+ ring. One DNP orienta-
tion—the one present in the solid state—is observed as the
1
fact, result in three different H NMR spectra at low tem-
1
major conformation by H NMR spectroscopy. The two ori-
peratures. Two of these conformations reside in the Ci point
group as predicted. Maj-trans-14+ adopts a Ci point group
and is observed (Figure 4) in the solid-state structure. The
other Ci symmetric conformation, in which both phenylene
rings have rotated by 1808, is most likely unstable because
of steric interactions between the oxygen atoms of the DNP
unit and the triazoles. The remaining conformation—the
one in which only one phenylene ring has rotated 1808 such
that both triazoles are pointing in the same direction with
regard to the plane of the cyclophane—contains no symme-
try whereby, for example, each of the protons a to the nitro-
gen atoms are heterotopic to each other, resulting in the ex-
pected eight resonances for this set of protons. This number
of signals is precisely what should be observed for Min-
entations—one in which the oxygen atoms of the DNP
moiety are pointing towards the triazole rings and one in
which they are not—are predicted to be in exchange with
each other through a previously described[25b] DNP dislodge-
ment/rotation/reinsertion process. In all of the previous ex-
amples involving an unmodified symmetrical CBPQT4+
ring, this process is a degenerate one. In the case of the Fo8,
however, steric factors governed by the need for the DNP
oxygen atoms to be located near the triazoles, render one
orientation energetically more favorable than the other one.
Reorganization of the DNP unit results in two conforma-
tions of trans-14+ that differ in the orientation of the DNP
unit inside the cyclophane cavity and are shown in
Figure 4—the observed major conformation (Maj-trans-14+
)
trans-14+ in the H NMR spectrum, suggesting that this con-
1
contains the DNP unit in the cavity, such that its oxygen
atoms are pointing away from the triazole rings. The other
(trans’’-14+) minor conformation (Figure 4) has the oxygen
atoms pointing toward the triazole ring, where significant
steric interactions lessen its stability so that trans’’-14+ is not
observed by 1H NMR spectroscopy. Although the magnitude
of the charge-transfer interaction is likely to be similar for
both conformations, it is believed that unfavorable steric
contacts between the triazole rings and the oxygen atoms of
the DNP units, along with the contorted conformations of
the polyether loops, are the primary contributors to this pro-
posed stability difference.
formation is most likely the one which is observed as the
minor isomer by H NMR spectroscopy at low temperatures.
1
This conformation was minimized at the M06L/6-31G*
level; the M06L functional has previously been shown[26] to
be an accurate method for studying MIMs containing the
CBPQT4+ ring. This Min-trans-14+ conformation is predict-
ed by DFT calculations to be slightly destabilized (4.5 kcal
molÀ1), as the rotation of one phenylene ring will likely dis-
À
rupt only half of the C H···O interactions and create an ad-
ditional steric interaction between one of the oxygen atoms
of DNP and one of the triazoles. As the temperature of the
NMR probe is raised, the resonances for Min-trans-14+ are
observed to coalesce with those for Maj-trans-14+ at approx-
imately room temperature (Figure 5), at which phenylene
ring rotation is sufficiently fast on the NMR timescale to
allow the various site-exchange processes to occur.
Let us next consider pyridinium ring rotation. Previously,
this process has been shown[25a] to be limited by the energy
required to remove the DNP unit from the core of the cy-
clophane. Furthermore, pyridinium rotation of Maj-trans-14+
is expected to be a degenerate process, whereby the pyridi-
nium protons are exchanged with each other in the follow-
ing pairs: Ha2/Ha3, Hb2/Hb3, Ha1/Ha4, and Hb1/Hb4. However,
because this rotational barrier is sufficiently high, and al-
though broadening of the resonances for the pyridinium
protons of trans-1·4PF6 in CD3CN is observed (Figure 5a) at
We also consider here the previously proposed conforma-
tion[9] of trans-14+ in which the polyether loops extend away
from the triazole and connect to the DNP unit on the same
face of the cyclophane. This conformation (trans’-14+) can
be attained when Maj-trans-14+ undergoes a combination of
two phenylene ring rotations and DNP dislodgment/rota-
tion/reinsertion. Gas-phase calculations predict that trans’-
14+ is 20.1 kcalmolÀ1 less stable than the observed major
conformation. We now believe that this isomer is not ob-
1
high temperatures in the H NMR spectra, coalescence was
not achieved. Upon performing variable-temperature ex-
periments in CD3NO2, significant broadening was also ob-
served at high temperatures. Attempts to observe coales-
cence of these resonances for the pyridinium protons of
À
served because of extensive weakening of the C H···O inter-
actions involving both polyether loops.
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J.-P. Sauvage, J. F. Stoddart et al.
for example, between the pyri-
dinium protons a to the nitro-
gen atoms of Min-trans-14+
with Maj-trans-14+ (see Fig-
ure S6 in the Supporting Infor-
mation). These exchange peaks
can be rationalized by invoking
the process of phenylene ring
rotation. We have also used
EXSY to probe pyridinium ring
rotations and observed that, for
example, Ha1 is in exchange
with Ha4 by this particular pro-
cess (Figure S6 in the Support-
ing Information). Furthermore,
in an effort to assign the
1H NMR spectra of Min-trans-
14+, COSY spectra were em-
ployed to identify the protons
labeled H4/8
. This particular
identification of signals at
2.78 ppm verifies that the DNP
unit of Min-trans-14+ does in
fact lie in the cavity of the cy-
clophane (Figure S6 in the Sup-
porting Information) as indicat-
ed by the strong upfield shift of
the H4/8 protons with respect to
the corresponding chemical
shifts of a free DNP unit.
Conclusion
The use of topological concepts
and the application of molecu-
lar symmetry arguments are
crucial when it comes to identi-
fying the structure and dynam-
ics of higher-order topologies,
such as those exemplified by
molecular
figures-of-eight
(Fo8s). Using topological con-
cepts, we have demonstrated
the ability to design and synthe-
size this particular molecular
representation of a mathemati-
cal topology. Beginning with
the synthesis of a bisfunctional,
tetracationic electron-deficient
cyclophane, subsequent inclu-
sion of an electron-rich guest
followed by covalent attach-
1
Figure 5. Variable-temperature H NMR (600 MHz, CD3CN) spectra of a) downfield and b) upfield regions of
trans-1·4PF6 were used to probe the equilibrium processes. The minor species, Min-trans-14+ equilibrates into
Maj-trans-14+ at around room temperature. At approximately 328 K, dislodgement of the DNP unit is fast on
the NMR timescale, such that pyridinium ring rotation causes the observed broadening (coalescence) of the
protons a to the nitrogen atoms of the bipyridiniums.
In an effort to probe the dynamic equilibrium between
the two observed conformations (Maj-trans-14+ and Min-
trans-14+) even further, exchange spectroscopy (EXSY) ex-
periments were employed. Exchange peaks are observed,
ment of the guest to the host resulted in a pair of subtly dif-
ferent cis and trans constitutional isomers of a molecular
Fo8. Not only was the non-trivial separation and full charac-
terization of these isomers achieved, but also the cis and
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Molecular Figures-of-Eight
FULL PAPER
centrated to afford the crude product, which was absorbed on silica gel
trans isomers were observed to adopt two different confor-
mations—a major one (Maj) and a minor one (Min). By uti-
lizing dynamic and 2D 1H NMR spectroscopic techniques,
molecular modeling, and solid-state structural analysis (in
one case), two different conformations of Fo8 have been
identified and investigated in detail by dynamic 1H NMR
spectroscopy. Furthermore, the solid-state structure of the
trans-1·4TFA isomer confirms the sterochemistry of the
major product. Previously,[9] without the knowledge of the
solid-state structure, and despite our reliance on ab initio
calculations, we failed to identify the “correct” conformation
for the Fo8 compound with respect to the stereochemical re-
lationship between the appendages to the tetracationic cy-
clophane and the polyether loops joining them to the includ-
ed 1,5-dioxynaphthalene unit. There is an important lesson
to be learned here: it is that no matter how sophisticated
molecular modeling, it is foolhardy to believe that 1) com-
putational work alone or 2) computational work which ig-
nores[27] the experimental evidence will reveal the “correct”
scientific answer.
and purified by column chromatography (SiO2, hexanes) to afford 3 as
a
pure compound (9.03 g, 31.1 mmol) in a
88% yield. 1H NMR
(500 MHz, CDCl3): d=7.46 (s, 1H), 7.22 (s, 1H), 7.07 (m, 2H), 2.33 (s,
3H), 2.23 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=136.9, 135.2,
135.1, 132.9, 130.0, 129.2, 129.0, 91.3, 21.0, 19.4 ppm; HR-ESI-MS: m/z
calcd for C10H10Br2 [M]+: 287.9149; found: 287.9147.
Synthesis of compound 4: Compound 3 (5.0 g, 17 mmol) was dissolved in
anhydrous THF (150 mL) in a 250 mL flame-dried round bottomed flask.
The reaction mixture was cooled to À788C in a dry-ice/Me2CO bath and
nBuLi (15.2 mL of 2.5m in hexanes, 37.9 mmol) was added dropwise over
30 min. The mixture was stirred for 30 min at À788C before the lithiate
was quenched by the addition of TMSCl (3.28 mL, 25.9 mmol). The mix-
ture was slowly warmed to RT then was left to stir for 16 h before it was
quenched with sat. NH4Cl(aq), extracted with CH2Cl2, dried (MgSO4), fil-
tered, and concentrated to afford the crude product that was absorbed
on silica gel and purified by column chromatography (SiO2, hexanes) to
1
afford 4 as the pure product (2.02 g, 9.98 mmol) in a 58% yield. H NMR
(500 MHz, CDCl3): d=7.09 (s, 1H), 6.89 (d, 3J=7.8 Hz, 1H), 6.84 (d,
3J=7.8 Hz, 1H), 2.22 (s, 3H), 2.10 (s, 3H), 0.09 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=137.4, 134.8, 132.5, 129.3, 129.1, 122.5, 104.2, 97.6,
20.6, 20.0, 0.0 ppm; HR-EI-MS: m/z calcd for C13H18Si [M]+: 202.1178;
found: 202.1177.
Synthesis of compound 5: Compound 4 (200 mg, 0.988 mmol), N-bromo-
succinimide (387 mg, 2.17 mmol), and AIBN (8 mg, 0.05 mmol) were dis-
solved in CCl4 (10 mL) in a 50 mL round-bottomed flask and the mixture
was heated under reflux for 16 h. After cooling to RT, the reaction mix-
ture was washed with H2O, extracted with CH2Cl2, dried (MgSO4), fil-
tered, and concentrated to afford the crude product that was absorbed
on silica gel and purified by column chromatography (SiO2, hexanes) to
Experimental Section
General methods: Dibromide 7,[17] dibromide 9,[28] dibromide 13,[15a] and
1,5-bis(2-{2-[2-(2-{2-[2-(2-hydroxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-
afford the pure intermediate dibromide as
a clear oil (260 mg,
ACHTUNGTRENNUNG
ethoxy)naphthalene[29] (DNP-HEG-OH) were prepared according to lit-
0.721 mmol) in a 73% yield. 1H NMR (500 MHz, CDCl3): d=7.50 (d,
3J=1.8 Hz, 1H), 7.39 (d, 3J=8.0 Hz, 1H), 7.32 (dd, 3J=8.0 Hz, 4J=
1.8 Hz, 1H), 4.64 (s, 2H), 4.42 (s, 2H), 0.29 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=139.9, 138.3, 133.3, 130.3, 129.8, 123.7, 101.6,
101.4, 32.3, 31.4, 0.0 ppm. This dibromide (100 mg, 0.278 mmol) and
K2CO3 (20 mg, 0.139 mmol) were dissolved in a 1:1 THF/MeOH mixture
(10 mL) in a 25 mL round-bottomed flask. The reaction mixture was
stirred at RT for 3 h while being closely monitored by TLC. The reaction
was quenched by the addition of H2O, extracted with CH2Cl2, dried
(MgSO4), filtered, and concentrated to afford the crude product that was
absorbed on silica gel and purified by column chromatography (SiO2,
hexanes) to afford 5 as the pure compound (46 mg, 0.16 mmol) in a 57%
yield. 1H NMR (500 MHz, CDCl3): d=7.56 (d, 3J=1.3 Hz, 1H), 7.44 (d,
3J=8.0 Hz, 1H), 7.38 (dd, 3J=8.0 Hz, 4J=1.3 Hz, 1H), 4.67 (s, 2H), 4.45
(s, 2H), 3.46 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=139.9, 138.2,
133.6, 130.3, 130.0, 122.4, 83.3, 80.1, 31.9, 30.9 ppm; HR-ESI-MS: m/z
calcd for C10H8Br2 [M]+: 285.8993; found: 285.8990.
erature procedures. All reagents were purchased from commercial suppli-
ers (Aldrich or Fisher) and used without further purification with the ex-
ception of N-bromosuccinimide, which was recrystallized from boiling
water. Analytical thin-layer chromatography (TLC) was performed on
aluminum sheets, precoated with silica gel 60-F254 (Merck 5554). Flash
column chromatography was carried out using silica gel 60 (Silicycle) as
the stationary phase. Compound purification was performed on a prepara-
tive RP-HPLC instrument (Shimadzu LC-8 A), using a C18 column (Agi-
lent, 10 mm packing, 30 mmꢂ250 mm). The eluents used were MeCN and
H2O, both mixed with 0.1% (v/v) trifluoroacetic acid (TFA). The detec-
tor was set to l=254 nm. Nuclear magnetic resonance (NMR) spectra
were recorded at the temperatures noted on Bruker Avance III 500 and
600 MHz spectrometers, with working frequencies of 499.373 and
1
600.168 MHz for H, and 125.579 and 150.928 MHz for 13C nuclei, respec-
tively. All 13C NMR spectra were recorded with the simultaneous decou-
1
pling of H nuclei. Chemical shifts are reported in ppm relative to the sig-
nals corresponding to the residual non-deuterated solvents (1.94 ppm for
CD3CN, 7.26 ppm for CHCl3). Electrospray ionization (ESI) mass spectra
were obtained on an Agilent 6210 LC-TOF high-resolution mass spec-
trometer. Electron Impact (EI) mass spectra were obtained on a Waters
GCT Premier mass spectrometer using a Direct Insertion Probe. Crystal-
lographic data were collected at 100 K using a Bruker d8-APEX II CCD
diffractometer (CuKa radiation, l=1.54178 ꢃ). Intensity data were col-
lected using w and f scans spanning at least a hemisphere of reciprocal
space for all structures (data were integrated using SAINT[30]). Absorp-
tion effects were corrected on the basis of multiple equivalent reflections
(Integration). Structure was solved by direct methods (SHELXS[30]) and
refined by full-matrix least-squares against F2 (SHELXL[30]). Hydrogen
atoms were assigned riding isotropic displacement parameters and con-
strained to idealized geometries, including those bound to oxygen, as no
hydrogen atoms could be located in the difference Fourier map.
Synthesis of compound 6·2PF6: Compound 5 (100 mg, 0.35 mmol) and
4,4’-bipyridine (325 mg, 2.1 mmol) were combined in MeCN (50 mL) and
heated under reflux for 12 h. The crude reaction mixture was filtered, the
residue dissolved in H2O (200 mL), and the crude product precipitated
by the addition of NH4PF6. Column chromatography (SiO2, 2m NH4Cl/
MeOH/MeNO2 12:7:1) was employed to obtain 6·2PF6 as a pure white
solid (190 mg, 0.26 mmol) in a 74% yield. 1H NMR (CD3CN, 500 MHz,
3
293 K): d=8.85 (m, 4H), 8.76 (m, 4H), 8.32 (m, 4H), 7.87 (d, J=6.6 Hz,
4H), 7.72 (s, 1H), 7.59 (m, 2H), 5.90 (s, 2H), 5.76 (s, 2H), 3.87 ppm (s,
1H); 13C NMR (CD3CN, 125 MHz, 293 K): d=155.85, 152.11, 149.51,
147.99, 146.30, 146.11, 142.00, 136.77, 136.14, 135.09, 132.43, 131.52,
127.36, 127.04, 124.54, 123.55, 122.86, 87.42, 80.02, 73.12, 63.79,
63.16 ppm; HR-ESI-MS: m/z calcd for [MÀPF6]+: 585.1637; found:
585.1652.
Synthesis of compound 8·2PF6: Dibromide 7[17] (120 mg, 0.35 mmol) and
4,4’-bipyridine (325 mg, 2.1 mmol) were combined in MeCN (50 mL) and
heated under reflux for 12 h. The crude reaction mixture was filtered, the
residue dissolved in H2O (200 mL), and the crude product precipitated
by the addition of NH4PF6. Column chromatography (SiO2, 2m NH4Cl/
MeOH/MeNO2 12:7:1) was employed to obtain the product 8·2PF6 as
Synthesis of compound 3: 2,5-Dimethylbenzaldehyde (5.00 mL,
35.4 mmol), CBr4 (23.5 g, 70.8 mmol), and PPh3 (37.1 g, 142 mmol) were
combined in PhMe (100 mL) in a 250 mL round-bottomed flask. The re-
action mixture was heated under reflux for 6 h, during which time
a white precipitate formed. After cooling, the precipitate was filtered and
washed with CH2Cl2. The filtrate was dried (MgSO4), filtered, and con-
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J.-P. Sauvage, J. F. Stoddart et al.
a white solid (150 mg, 0.19 mmol) in a 54% yield. 1H NMR (CD3CN,
500 MHz, 293 K): d=8.86 (m, 4H), 8.75 (d, 3J=6.7 Hz, 4H), 8.32 (m,
4H), 7.79 (m, 6H), 7.57 (d, 3J=8.0 Hz, 1H), 6.09 (s, 2H), 5.85 (s, 2H),
6.9 Hz, 2H), 7.82 (m, 4H), 7.68 (d, 3J=7.9 Hz, 1H), 7.51 (d, 3J=1.4 Hz,
1H), 7.35 (dd, 3J=7.9 Hz, 4J=1.4 Hz, 1H), 5.78 (s, 2H), 5.67 ppm (s,
2H); 13C NMR (CD3CN, 125 MHz, 293 K): d=154.2, 153.9, 150.2, 150.1,
144.9, 144.7, 141.6, 141.4, 140.7, 136.2, 135.2, 132.7, 126.0, 125.6, 124.3,
121.9, 121.8, 120.1, 62.7, 59.6 ppm; HR-ESI-MS: m/z calcd for [MÀPF6]+:
602.1651; found: 602.1660.
4.9 (d, J=2.5 Hz, 2H), 2.85 ppm (t, J=2.5 Hz, 1H); 13C NMR (CD3CN,
125 MHz, 293 K): d=165.72, 155.86, 155.62, 152.14, 152.11, 150.43,
147.12, 146.15, 142.03, 141.97, 136.27, 135.46, 135.38, 134.41, 133.73,
131.02, 127.33, 126.81, 123.03, 122.84, 78.15, 77.16, 63.75, 62.85,
54.31 ppm; HR-ESI-MS: m/z calcd for [MÀPF6]+: 643.1703; found:
643.1694.
4
4
General procedure for cyclophane formation: Precursor salt (0.14 mmol),
dibromide
(0.14 mmol),
and
the
template—1,5-bisACHTUNGTRENNUNG[ethoxy-
AHCTUNGTREG(NNUN ethoxy)]dioxynaphthalene (DNP-DEG) (238 mg, 0.41 mmol)—were
Synthesis of compound 10: Dibromide 9[28] (2.357 g, 6.03 mmol), proparg-
yl bromide (0.676 g, 12.06 mmol), a catalytic amount of pyridinium p-tol-
uenesulfonate, and a catalytic amount of 4-dimethylaminopyridine were
combined in CH2Cl2 (150 mL) at RT. Dicyclohexyl carbodiimide (2.48 g,
12.06 mmol) was added to the CH2Cl2 solution and the reaction was left
under stirring for 12 h. The crude product was purified by column chro-
matography (SiO2, hexanes/EtOAc) to afford the pure dibromide 10
(2.14 g, 4.99 mmol) in an 82% yield. 1H NMR (CD3CN, 500 MHz,
293 K): d=7.79 (s, 2H), 4.98 (s, 4H), 4.78 (d, 4J=2.6 Hz, 2H), 4.45 (s,
2H), 2.84 ppm (t, 4J=2.6 Hz, 1H); 13C NMR (CD3CN, 125 MHz, 293 K):
d=167.9, 167.5, 138.5, 137.7, 129.5, 78.1, 76.8, 54.0, 39.5, 27.1 ppm; HR-
ESI-MS: m/z calcd for C15H11O4NBr2 [M]+: 426.9055; found: 426.9042.
combined in dry DMF (250 mL) and the solution was stirred at 258C for
5 days before the solvent was removed in vacuo. The crude reaction mix-
ture was stirred in a saturated aqueous solution of NH4Cl until the resi-
due dissolved, after which it was diluted with H2O (ca. 400 mL). Liquid–
liquid extraction using CHCl3 (2 L) was employed to remove the DNP-
DEG template (2 days). The remaining crude product was precipitated
by the addition of NH4PF6 and RP-HPLC was used to attempt to purify
the final product. Precursors 6·2PF6, 8·2PF6, and 11·2PF6 were utilized in
attempts to form tetracationic cyclophanes that failed for the most part.
Synthesis of compound 2·4PF6: Precursor 14·2PF6 (120 mg, 0.15 mmol),
dibromide 13 (50 mg, 0.15 mmol), and the template DNP-DEG (250 mg,
0.75 mmol) were combined in dry DMF (35 mL), and the solution was
stirred at 258C for 5 days before the solvent was removed in vacuo. The
crude reaction mixture was stirred in a saturated aqueous solution of
NH4Cl until the residue dissolved, after which it was diluted with H2O
(ca. 400 mL). Liquid–liquid extraction using CHCl3 (2 L) was employed
to remove the DNP-DEG template (2 days). The remaining crude prod-
uct was precipitated by the addition of NH4PF6 and purified by column
chromatography (SiO2, 2m NH4Cl/MeOH/MeNO2 12:7:1) to yield the
isomeric mixture of bisazides 2·4PF6 as an off-white solid (45.5 mg,
Synthesis of compound 11·2PF6: Dibromide 9 (305 mg, 0.35 mmol) and
4,4’-bipyridine (325 mg, 2.1 mmol) were combined in MeCN (50 mL) and
heated under reflux for 12 h. The crude reaction mixture was filtered, the
residue dissolved in H2O (200 mL), and the crude product precipitated
by the addition of NH4PF6. Column chromatography (SiO2, 2m NH4Cl/
MeOH/MeNO2 12:7:1) was employed to afford 11·2PF6 as a white solid
(190 mg, 0.22 mmol) in
a
75% yield. 1H NMR (CD3CN, 500 MHz,
293 K): d=8.86 (m, 8H), 8.33 (d, 2J=6.4 Hz, 4H), 7.88 (s, 2H), 7.79 (d,
2J=6.4 Hz, 4H), 6.17 (s, 4H), 4.75 (d, 4J=2.4 Hz, 2H), 4.45 (s, 2H),
2.85 ppm (t, 4J=2.4 Hz, 1H); 13C NMR (CD3CN, 125 MHz, 293 K): d=
167.7, 167.5, 156.0, 152.0, 146.6, 141.9, 137.8, 133.2, 131.6, 127.0, 122.8,
78.0, 77.0, 59.8, 54.1, 39.7 ppm; HR-ESI-MS: m/z calcd for [MÀPF6]+:
725.1705; found: 726.1720.
1
0.04 mmol) in a 27% yield. H NMR (CD3CN, 500 MHz, 293 K): d=8.90
(m, 8H) 8.17 (m, 8H), 7.65 (d, 3J=7.81 Hz, 2H), 7.42 (dd, 3J=7.81 Hz,
4J=1.55 Hz, 1H), 7.41 (dd, 3J=7.81 Hz, 4J=1.55 Hz, 1H), 7.32 (d, 3J=
1.55 Hz, 2H), 5.73 (s, 4H), 5.68 ppm (s, 4H); 13C NMR (CD3CN,
125 MHz, 293 K): d=150.57, 150.46, 146.74, 146.68, 146.20, 146.15,
141.61, 141.57, 138.70, 138.62, 133.60, 133.53, 128.33, 128.27, 127.75,
127.69, 127.10, 127.04, 121.04, 120.98, 65.09, 61.25, 61.22 ppm; ESI-MS:
m/z calcd for [MÀPF6]+: 1037.1580; found: 1037.1579.
Synthesis of compound 12: Compound 12 was prepared using a modified
procedure developed by Molander et al.[31] Commercially available 2-
bromo-p-xylene (30.0 g, 162 mmol), NaN3 (10.5 g, 162 mmol), CuBr
(2.4 g, 16.7 mmol), Cs2CO3 (26.4 g, 81 mmol), and N,N’-dimethylethylene-
diamine (2.85 g, 32.3 mmol) were combined in dry DMF (500 mL) and
the solution was heated to 908C with stirring. After 12 h, H2O (500 mL)
was added and the product was extracted with EtOAc (3ꢂ400 mL). Sol-
vent was removed in vacuo and the product was purified by column chro-
matography (SiO2, hexanes). The fractions containing the product were
combined and the solvent was removed in vacuo to yield the azide 12 as
Synthesis of compound 15: NaH (60% in mineral oil, 40 mg, 1 mmol)
was added to a solution of DNP-HEG-OH[29] (185 mg, 0.269 mmol) in
dry DMF (20 mL) and stirred for 15 min. Propargyl bromide (80% w/w
in PhMe, 0.25 mL, 2.3 mmol) was added slowly, and the mixture stirred
for 16 h. MeOH (5 mL) was added carefully to quench remaining NaH,
the solvents were removed in vacuo to yield a brown oil, which was puri-
fied by column chromatography (SiO2, Me2CO/CH2Cl2 5:95) to yield the
product 15 as a light brown oil (137 mg, 0.179 mmol) in a 67% yield.
1H NMR (CDCl3, 500 MHz, 293 K): d=7.85 (d, 3J=8.4 Hz, 2H), 7.34 (t,
3J=7.8 Hz, 2H), 6.84 (d, 3J=7.8 Hz, 2H), 4.29 (t, 3J=5.0 Hz, 4H), 4.19
a
yellow oil (20.5 g, 139 mmol) in a
86% yield. 1H NMR (CDCl3,
500 MHz, 293 K): d=7.04 (d, 3J=7.7 Hz, 1H), 6.93 (s, 1H), 6.85 (d, 3J=
7.7 Hz, 1H), 2.34 (s, 3H), 2.17 ppm (s, 3H). The 1H NMR spectrum of
the product matches that previously reported.[15a]
3
3
(d, J=2.4 Hz, 4H), 3.99 (t, J=5.2 Hz, 4H), 3.80 (m, 4H), 3.62–3.71 (m,
18H), 2.43 ppm (t, 3J=2.3 Hz, 2H); 13C NMR (CDCl3, 125 MHz, 293 K):
d=154.4, 126.9, 125.2, 114.7, 105.7, 79.8, 74.7, 71.1, 70.8, 70.7, 70.7, 70.7,
70.7, 70.7, 70.5, 70.0, 69.2, 68.0, 58.5 ppm; ESI-MS: m/z calcd for [M+
Na]+: 782.4364; found: 782.4340.
Synthesis of compound 13: Compound 12 (294 mg, 2.0 mmol), N-bromo-
succinimide (764 mg, 4.3 mmol), and AIBN (50 mg, 0.37 mmol) were
combined in dry CCl4 (50 mL) and heated under reflux for 12 h. The mix-
ture was cooled and filtered to remove the insoluble solid. The solvent
was then evaporated under reduced pressure and purified by silica gel
column chromatography (SiO2, CH2Cl2/hexanes 1:6) to give 13[15a] as
a white solid (310 mg, 0.9 mmol) in a 47% yield. 1H NMR (500 MHz,
CDCl3, 298 K): d=7.35 (d, 3J=7.8 Hz, 1H), 7.18 (d, 3J=1.4 Hz, 1H),
7.14 (dd, 3J=7.8 Hz, 4J=1.4 Hz, 1H), 4.47 (s, 2H), 4.46 ppm (s, 2H);
13C NMR (125 MHz, CDCl3, 298 K): d=138.9, 138.0, 130.7, 127.9, 124.6,
117.9, 30.9, 26.7 ppm; HR-ESI-MS: m/z calcd for [M]+: 302.9007; found:
302.9001.
Synthesis of figure-of-eight 1·4PF6: The bisazides 2·4PF6 (68.3 mg,
0.06 mmol) and guest 15 (39.7 mg, 0.06 mmol) were degassed in DMF
(25 mL) with argon before addition of CuI (1.1 mg, 0.006 mmol) and the
solution was stirred for 2 days. Solvent was removed in vacuo and the
crude product was precipitated from H2O by the addition of NH4PF6
before being purified further using reverse phase high-performance
liquid chromatography (RP-HPLC) (MeCN/H2O 0–40% in 55 min) to
yield a pink solid 1·4PF6 as a mixture of constitutional isomers of
(13.0 mg, 0.006 mmol) in a 12% yield. 1H NMR (CD3CN, 500 MHz,
293 K): d=9.36 (d, 3J=6.8 Hz, 2H), 9.31 (d, 3J=6.8 Hz, 2H), 8.97 (d,
3J=6.8 Hz, 2H), 8.92 (d, 3J=6.8 Hz, 2H), 8.70 (d, 3J=6.8 Hz, 2H), 8.67
(d, 3J=6.8 Hz, 2H), 8.55 (s, 2H), 8.54 (s, 2H), 8.50 (d, 3J=8.5 Hz, 4H),
8.30 (dd, 3J=8.5 Hz, 4J=2.5 Hz 4H), 8.14 (d, 4J=2.5 Hz, 7.82 (d, 3J=
6.8 Hz, 2H), 4H), 7.80 (d, 3J=6.8 Hz, 2H), 7.45 (dd, 4J=2.4 Hz, 3J=
6.8 Hz, 2H), 7.40 (dd, 4J=2.4 Hz, 3J=6.8 Hz, 2H), 7.38 (dd, 4J=2.4 Hz,
3J=6.8 Hz, 2H), 7.35 (dd, 4J=2.4 Hz, 3J=6.8 Hz, 2H), 7.31 (dd, 4J=
Synthesis of compound 14·2PF6: Dibromide 13[15a] (300 mg, 0.9 mmol)
and 4,4’-bipyridine (922 mg, 5.9 mmol) were combined in MeCN (50 mL)
and heated under reflux for 12 h. The crude reaction mixture was fil-
tered, the residue dissolved in H2O (200 mL), and the crude product pre-
cipitated by the addition of NH4PF6. Column chromatography (SiO2, 2m
NH4Cl/MeOH/MeNO2 12:7:1) was employed to obtain 14·2PF6 as
a white solid (605 mg, 0.81 mmol) in a 94% yield. 1H NMR (CD3CN,
3
3
500 MHz, 293 K): d=8.86 (m, 8H), 8.33 (d, J=6.9 Hz, 2H), 8.29 (d, J=
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Molecular Figures-of-Eight
FULL PAPER
2.4 Hz, 3J=6.8 Hz, 2H), 7.26 (dd, 4J=2.4 Hz, 3J=6.8 Hz, 2H), 7.12 (dd,
4J=2.4 Hz, 3J=6.8 Hz, 2H), 6.52 (dd, 3J=7.8 Hz, 3J=7.8 Hz, 2H), 6.51
(dd, 3J=7.8 Hz, 3J=7.8 Hz, 2H), 6.36 (d, 3J=7.8 Hz, 2H), 6.35 (d, 3J=
249, 203–259; i) C. D. Meyer, C. S. Joiner, J. F. Stoddart, Chem. Soc.
Rev. 2007, 36, 1705–1723; j) J. D. Crowley, S. M. Goldup, A.-L. Lee,
D. A. Leigh, R. T. McBurney, Chem. Soc. Rev. 2009, 38, 1530–1541.
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2
2
7.8 Hz, 2H), 6.05 (d, J=14.7 Hz, 2H), 6.04 (d, J=14.7 Hz, 2H), 5.93 (d,
2J=14.7 Hz, 2H), 5.91 (d, 2J=14.7 Hz, 2H), 5.75 (d, 2J=14.7 Hz, 2H),
2
2
2
5.73 (d, J=14.7 Hz, 2H), 5.59 (d, J=14.7 Hz, 2H), 5.56 (d, J=14.7 Hz,
2H), 4.88 (m, 8H), 4.41 (m, 8H), 3.3–3.8 (m, 80H), 3.16 (m, 8H),
2.85 ppm (d, 3J=7.8 Hz, 4H); ESI-MS: m/z calcd for [MÀ2TFA]2+
:
796.3169; found: 796.3214. By using iterative RP-HPLC techniques (col-
lection and resubmission through an XBridge Prep C18 OBD 19ꢂ
100 mm column: H2O/MeCN 0–60% in 60 min l=254 nm), the cis and
trans isomers were separated in small quantities for NMR spectroscopic
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peaks, fractions collected from the RP-HPLC showed increasing enrich-
ment of one isomer and repetitive collection and resubmission allowed
for approximately 2 mg of each isomer to be collected.
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Crystallographic data for trans-1·4TFA: Formula: [C76H90N10O14·
¯
ACHTUNGTRENNUNG
0.995 mmÀ1, F
which 5934 were unique, with Rint =0.1101. Final R CTHUNGTRENNUNG
ACHTUNGTRENNUNG
The atoms of the glycol chain and of the CBPQT4+ ring showed elongat-
ed displacement parameters. Attempts to model this disorder using
DFIX and global rigid bond restraints (SIMU/DELU) restraints did not
improve the refinement significantly. Hydrogen atoms were refined as
riding models with their isotropic displacement parameters linked to
their parent atoms. In some cases, the parent atom exhibited disorder
with an elongated displacement parameter and therefore the riding hy-
drogen atom was also large. Portions of the glycol chain were disordered;
however, they are bonded to relatively well-ordered parts of the struc-
ture. CCDC-867861 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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Received: June 11, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Molecular Figures-of-Eight
FULL PAPER
The use of topological concepts and
the application of molecular symmetry
arguments are crucial when it comes to
identifying the structure and dynamics
of higher-order topologies, such as
those exemplified by molecular fig-
ures-of-eight. Using topological con-
cepts, the ability to design and synthe-
size this particular molecular represen-
tation of a mathematical topology has
been demonstrated.
Topology
M. M. Boyle, J. J. Gassensmith,
A. C. Whalley, R. S. Forgan,
R. A. Smaldone, K. J. Hartlieb,
A. K. Blackburn, J.-P. Sauvage,*
J. F. Stoddart* ................. &&&& — &&&&
Stereochemistry of Molecular Figures-
of-Eight
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!