Twistophane macrocycles with integrated 6,6′-connected-2,2′-bipyridine units: A new lead class of fluorescence sensors for metal ions

Article abstract of DOI:10.1002/1521-3765(20021115)8:22<5250::AID-CHEM5250>3.0.CO;2-Q

The new twistophane macrocycles 2 and 3 have been synthesised; these compounds are composed of a cyclically conjugated dehydrobenzo-annulene framework that incorporates 6,6′-connected-2,2′-bipyridine moieties for the purpose of coordinating metal ions. The cyclophanes were characterised by spectroscopic techniques, and shown by molecular mechanics calculations to be helically twisted and chiral molecules that may exist in several possible ground state conformations. UV/vis spectroscopic studies revealed that 2, 3 and precursor 9 bind with different selectivities to particular members of the following small group of metal analytes: Cu^II, Ag^I, Hg^II, TI^I and Pd^II. Significantly, 2, 3 and 9 signal the presence of Cu^II ions through fluorescence emission quenching output responses. Furthermore, cyclophane 3 exhibited a particularly sensitive protontriggered chromogenic fluorescence response. With respect to their unique structural features, high analyte selectivity coupled with their enhanced and characteristic fluorescence emission responses, these molecules are among the first examples representing a new lead class of chemosensory materials. Compounds 2, 3 and 9 and derivatives thereof may, therefore, be expected to find many future applications in the detection of metal-based environmental pollutants, biologically important trace elements and monitoring proton fluxes.

Full text of DOI:10.1002/1521-3765(20021115)8:22<5250::AID-CHEM5250>3.0.CO;2-Q

FULL PAPER
Twistophane Macrocycles with Integrated 6,6'-Connected-2,2'-Bipyridine
Units: A New Lead Class of Fluorescence Sensors for Metal Ions
Paul N. W. Baxter*[a]
Abstract: The new twistophane macro-
cycles 2 and 3 have been synthesised;
these compounds are composed of a
cyclically conjugated dehydrobenzo-
annulene framework that incorporates
6,6'-connected-2,2'-bipyridine moieties
for the purpose of coordinating metal
ions. The cyclophanes were character-
ised by spectroscopic techniques, and
shown by molecular mechanics calcula-
tions to be helically twisted and chiral
molecules that may exist in several
possible ground state conformations.
UV/vis spectroscopic studies revealed
that 2, 3 and precursor 9 bind with
different selectivities to particular mem-
bers of the following small group of
metal analytes: CuII, AgI, HgII, TlI and
PdII. Significantly, 2, 3 and 9 signal the
presence of CuII ions through fluores-
cence emission quenching output re-
sponses. Furthermore, cyclophane 3 ex-
hibited a particularly sensitive proton-
triggered chromogenic fluorescence re-
sponse. With respect to their unique
structural features, high analyte selec-
tivity coupled with their enhanced and
characteristic fluorescence emission re-
sponses, these molecules are among the
first examples representing a new lead
class of chemosensory materials. Com-
pounds 2, 3 and 9 and derivatives thereof
may, therefore, be expected to find many
future applications in the detection of
metal-based environmental pollutants,
biologically important trace elements
and monitoring proton fluxes.
Keywords: alkynes
merization
macrocyclic ligands ¥ sensors
¥
cyclooligo-
¥
cyclophanes
¥
medium-sized ring that incorporated an ethyne group as an
integral structural unit.[10] However, interest in ethynyl-
incorporated macrocycles remained dormant for nearly 50
years until the 1960×s when annulenes became the target of
synthetic effort,[11] in order to determine whether molecules
with expanded cyclic conjugation pathways obeyed the
H¸ckel theory of aromaticity.[12a b] Interest in the field waned
again until the early 1990×s, at which point ethynyl macro-
cycles once again became the focus of intense research
activity.[13] The latter resurgence of interest was fuelled
predominantly by the discovery of carbon buckyballs and
nanotubes[14] and the potential for the development of new
classes of carbon allotropes, high carbon-content material-
s[15a g] and nanostructures.[16]
Introduction
Over the past 30 years, macrocyclic chemistry has developed
into a field of major scientific and technological importance.[1]
Owing to their guest inclusion and complexation properties, a
wealth of applications have been discovered for the vast range
of macrocyclic structures thus far prepared. These applica-
tions include diverse areas such as: medical diagnostics and
drug delivery,[2a d] analytical chemistry,[3] metal extraction and
separation,[3, 4a chemical synthesis,[5] polymer chemistry,[6]
c]
food science[7] and, more recently, the domain of nanochem-
istry.[8] They have also played a pivotal role in the synthesis
and study of challenging molecular architecture and to-
pology.[9]
Of historic interest is the fact that one of the earliest
reported macrocycle syntheses concerned the preparation of a
Currently, cyclic ethynyl-containing materials collectively
represent a significant proportion of all known macrocyclic
architectures, encompassing a diverse variety of species such
b, 17]
d]
as annulenes,[11, 12a
dehydroannulenes,[13, 18a expanded
[a] Dr. P. N. W. Baxter
¬
Laboratoire de Chimie Supramoleculaire
b]
b]
radialenes,[19a [n]pericyclynes,[13, 20a [n]rotanes, exploded
¬
Institut Le Bel, Universite Louis Pasteur
[n]rotanes[13, 21a and many types of ethynyl-incorporated
b]
4 rue Blaise Pascal, 67000 Strasbourg (France)
Fax : (‡33)3-9024-1117
cyclophanes.[22a Some of these materials exhibit intriguing
e]
properties such as liquid crystallinity[23] and solid-state nano-
porosity,[24] and also can function as high-energy materials and
as precursors to carbon nanotubules.[13, 25]
E-mail: pbaxter@chimie.u-strasbg.fr
Supporting information for this article is available on the WWW under
http://www.chemeurj.org or from the author: Figures illustrating 1) the
1H NMR spectroscopic variable temperature behaviour of 2;
2) molecular models of the tubular conformation of 3; 3) the UV/vis
titration of 2 with successive amounts of AgI; and 4) the UV/vis
titration of 3 with AgI.
In the light of the aforementioned considerations, a
particularly interesting avenue of investigation would be to
endow conjugated macrocycles of this type with sites for the
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5250 5264
purpose of binding metal ions.[26a c] Awealth of new functional
physicochemical properties would be expected to emerge
from such hybrid organic inorganic materials, such as multi-
ple redox, magnetic, photochemical, optical, catalytic, sub-
strate inclusion, sensing ability and perhaps unusual mechan-
ical behaviour.
In previous work, preliminary investigations of this type
were reported; these described the synthesis of a ortho-
cyclically conjugated twistophane 1.[27a] Cyclophane 1 is
enhanced optical response and thus an amplified ion-sensory
output signal.
Twistophane 2 is an isomeric analogue of 1 in which two
6,6'-disubstituted-2,2'-bipyridine units are incorporated into
the tetrabenzodehydroannulene framework (Scheme 1). Mo-
lecular modelling studies on 2 revealed that it may potentially
function as a mechano-responsive ion sensor that is capable of
binding two metal ions, and in so doing, would be forced to
undergo three consecutive changes in conformation
(Scheme 1); while uncoordinated, 2 would reside in the
conformation of lowest strain, in which the pyridine rings of
each bipyridine unit are arranged in a transoid relationship
(denoted trans-trans in Scheme 1). Upon coordination to the
first metal ion, the twistophane 2 would have to partly unwind
to allow one of the bipyridine units to adopt a cisoid
conformation. The overall geometry would have to switch to
a trans-cis arrangement as shown in Scheme 1. Binding of the
second metal ion would force the remaining transoid bipyr-
idine unit to convert to a cisoid conformation, thereby
completely unwinding the macrocycle to give the geometri-
cally open cis-cis cyclophane. Unlike its predecessor 1, metal-
ion binding to 2 would be accompanied by a dramatic change
in overall geometry of the macrocyclic ring. As a result, the
comparatively greater mechanically induced electronic per-
turbations may translate into an increased ion-sensing re-
N
N
N
N
1
composed of a tetrabenzodehydroannulene-type hydrocarbon
framework that incorporates two 5,5'-disubstituted-2,2'-bipyr-
idine ligand units positioned on opposite sides of the macro-
g]
cyclic ring.[28a It was anticipated that the highly conjugated
e]
sponse for the latter cyclophane.[29a
structure of 1 would undergo significant electron-distribution
perturbations upon coordination to metal ions of comple-
mentary size within the chelating ligand pocket. The elec-
tronic redistribution within 1 would in turn be translated into
visual spectroscopic output signals with energies character-
istic of particular metal ions. This in fact proved to be the case,
and 1 was found to function as a specific chromogenic
fluorescence sensor for ZnII ions.[27a]
For both of the bipyridine subunits of 1 to bind a single
metal ion, the twisted hydrocarbon framework must slightly
unwind, thereby allowing the bipyridine rings to rotate about
their longitudinal axes and orient the four nitrogen lone pair
electrons towards the interior of the macrocyclic cavity. Only
a minimal change in the conformation of 1 is necessary for
complete metal-ion coordination. In this case, the spectro-
scopic response resulting from a metal-ion binding event must
originate principally from electron distribution perturbations
relayed through the bipyridine nitrogen lone pairs.
The following full account describes the successful synthesis
and characterisation of 2 and its trimeric analogue 3, and a
detailed spectroscopic investigation into the metal-ion sensing
propensities of 2, 3 and their precursor 9 (Scheme 2). The
spectroscopic studies revealed that 2, 3 and 9 exhibited
different ion-binding properties, but all afforded character-
istic and specific fluorescence quenching sensory outputs in
f]
the presence of CuII ions.[30a
Results and Discussion
Synthesis of 2 and 3: The macrocycles 2 and 3 were
synthesised by two separate, six-step convergent pathways,
each utilising the key building block 6,6'-dibromo-2,2'-bipyr-
idine (4; Scheme 2; not all steps are shown). Thus the first
synthetic approach started from the commercially available
(2-bromophenylethynyl)trimethylsilane which was converted
to the iodo derivative 8 by a lithiation/iodination protocol
described previously.[27a] The reaction between 8 and 6,6'-
diethynyl-2,2'-bipyridine (7) under classical Sonogashira con-
ditions by employing [PdCl2(PPh3)2] and CuI as catalyst and
cocatalyst, respectively, in a 1:1
However, a much greater perturbation in overall electron
distribution would be expected to occur if the macrocycle was
to additionally experience a significant change in conforma-
tion upon binding to a metal ion. In such a system, the metal-
ion-triggered change in spatial geometry should result in an
mixture of toluene/Et3N result-
ed in the formation of a dis-
appointingly moderate yield
(30%) of bipyridine 9.[31] Rep-
etition of the reaction in a 6:1
mixture of pyridine/Et3N gave
only a slight increase in the
yield of 9 to 35%. However,
changing the reaction solvent to
an 8:1 mixture of toluene/Et3N
N
N
N
+Mn+
-Mn+
+Mn+
-Mn+
N
N
N
Mn+
Mn+
N
N
N
N
N
Mn+
trans-trans
trans-cis
cis-cis
Scheme 1. Expected conformational rearrangement of twistophane 2 upon sequential binding to metal ions.
Chem. Eur. J. 2002, 8, No. 22
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P. N. W. Baxter
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(nBu)3Sn
Me3Si
(i)
N
2 4
2
4
+
N
SiMe3
SiMe3
5
6
(ii)
H
SiMe3
H
SiMe3
N
N
N
N
N
(iii)
(iv)
H
(v)
I
4
2
2
2
+
N
N
N
N
N
8
7
Me3Si
H
9
10
2
(vii)
+
Me
OH
OH
Br
Me
Me
Me
N
N
(vi)
2
4
2
+
N
H
N
N
N
N
Me
Br
HO
Me
N
11
4
12
N
N
3
Scheme 2. Synthesis of macrocycles 2 and 3. i) [Pd(PPh3)4] cat., toluene, 1228C, 36 h (63%); ii) aq. KOH/MeOH/THF, 208C, 20 h; iii) [PdCl2(dppf)] ¥
CH2Cl2 and CuI cat., toluene, Et3N, 20 8C, 8 d (86%); iv) 1m (nBu)4NF, THF, H2O, 20 8C, 18 h (97%); v) Hay procedure: CuCl cat., O2, pyridine, 208C, 25
days, 13% (2); Breslow procedure: CuCl, [Cu2(OAc)4], 608C, 6 h then 208C for 14 days, 9% (2), 5% (3); vi) [PdCl2(PPh3)2], CuI cat., THF, Et3N, 20 8C, 7 d
(51%); vii) KOH, toluene, 1108C, 7 h (79%).
and, most importantly, by using [PdCl2(dppf)] as the catalyst
resulted in a dramatic increase in the yield of 9 to 80 86%.
The enhancement in catalyst activity in the case of
[PdCl2(dppf)] can be correlated with the unusual P-Pd-P bite
angle, which lies at an optimum for facilitating both the
oxidative addition of the aryl halide and reductive elimination
steps in the catalytic cycle.[32] To date, this catalyst has only
rarely been used for effecting the Sonogashira mediated
alkynylations of aryl halides. In the light of the above
observation, a more widespread utility may be discovered
for [PdCl2(dppf)] in cases in which the conventional catalysts
give low yields and in which sensitive substrates are employed.
Having defined the optimal conditions for the preparation
of 9, it was then desilylated with TBAF in THF to give the
macrocycle precursor 10. The yield of this deprotection
appeared to be particularly sensitive to the water content of
the reaction solution. If 9 was deprotected in anhydrous or
normal reagent grade THF, the reaction became dark brown,
and only low yields of 10 were subsequently isolated. If,
however, a few drops of water were added to the THF
reaction solution prior to TBAF addition, the deprotection
then proceeded normally with the formation of 10 in high
yield. The fluoride ion in the commercial 1m TBAF may be
acting as a strong nucleophile to initiate polymerisation-type
reactions as well as the desired desilylation. The presence of
excess water considerably reduces both the nucleophilicity
and basicity of fluoride anions, presumably enabling the
desilylation to occur alone.
c]
Bipyridine 7[33a was prepared in two steps from 4 via 6.
The Sonogashira reaction of 4 with trimethylsilylethyne has
c]
been reported to give 6 in 87% yield.[33b In the course of
experimental investigations aimed at exploring the scope of
the Pd-catalysed alkynylations of heterocycles with alkynyl-
stannanes, it was decided to investigate the possibility of using
a Stille-type alkynylation for the preparation of 6.[34] Thus
heating 4 with an excess of 5, LiCl and [Pd(PPh3)4] in toluene
resulted in the successful generation of 6 in 63% isolated
yield.
In the second synthetic approach to 10, commercial 1,
2-diiodobenzene was converted to the monoprotected dieth-
yne 11,[35] which reacted with 4 under Sonogashira conditions
to provide the diprotected bipyridine 12 in a reasonable
(51%) isolated yield. The yield of this transformation
appeared to be highly dependent on the type of reaction
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Twistophanes
5250 5264
solvent, with much lower yields of 12 resulting if toluene was
used in place of THF. Subsequent base-catalysed elimination
of acetone from 12 afforded diethyne 10 in 79% yield.
With the precursor diethyne 10 in hand, the synthesis of the
target macrocycle 2 could finally be undertaken. Initially, it
was decided to prepare 2 by the oxidative cyclisation of 10
under medium dilution conditions by using the Hay coupling
protocol,[36] as this methodology has been successfully em-
ployed for the generation of 1 as reported previously.[27a]
However, this approach resulted in the isolation of a surpris-
ingly low yield (13%) of the desired cyclophane 2 relative to
that of 1 (34%) under similar conditions. The major reaction
product by mass recovery consisted of a brown solid, totally
insoluble in the common laboratory solvents. This material
may be composed of uncyclised oligomers and polymers and
possibly high molecular mass cyclooligomers.
An effective method of improving the poor yields often
encountered during the copper-catalysed oxidative macro-
cyclisation of terminal alkynes has been reported by Breslow
et al.[37] In this procedure, a mixture of CuCl and [Cu2(OAc)4],
both present in large excess relative to the alkyne substrate,
were found to considerably improve the yield of a macrobi-
cycle compared to the use of each copper reagent alone. Also,
these conditions do not require the reaction to be continually
exposed to oxygen gas. Application of this modification to the
cyclisation of 10 resulted in the formation of 2 in 9% yield,
that is, lower than that of the Hay procedure! However, a
small quantity of the trimer-cyclophane 3 was isolated from
this reaction in 5% yield.
the macrocyclic structures 2 and 3, respectively, plus one
hydrogen in each case.
The infrared spectra of the coupling products of 10 were
also supportive of the macrocyclic structural assignments of 2
À ꢀ
and 3, in that vibrational modes characteristic of the n(H C )
stretch of terminal alkynes were completely absent in each
case. This result establishes that the coupling products are in
fact macrocyclic, and not linear oligomers with unreacted
terminal ethyne groups.
The 13C NMR spectra of the coupling products of 10 each
have fifteen peaks, consistent with the above macrocyclic
structural assignments. The chemical shifts of four peaks
corresponded to the chemically and magnetically inequivalent
carbons of two unsymmetrically substituted alkyne groups,
and the remaining eleven to inequivalent carbons of aromatic
rings. In the case of 2, it was possible to assign the proton-
bearing C3, C4 and C5 pyridine-ring carbon atoms to the
peaks at 120.6, 136.9 and 128.9 ppm respectively by an HMQC
experiment.
The 1H NMR spectra of both coupling products of 10, also
displayed the five sets of peaks (two of which overlapped)
expected for the macrocyclic structures 2 and 3. 1H 1H
COSY measurements also verified that they were each single
compounds and not mixtures of species. Peaks originating
from the protons of terminal ethynes were completely absent
in the spectra of both coupling products, lending further
support for the macrocyclic identities of these compounds.
Spectral assignments were made on the basis of coupling
1
constants, H 1H COSY correlations as well as comparisons
Although the exact factors responsible for the poor yield of
2 are currently unknown, negative ion-templating phenomena
may account for one possible cause. The relatively enhanced
yield of 1 is consistent with a positive ion-templating
mechanism, in which the coordination of two bipyridine
macrocycle precursors to the same CuI/II ion would orient the
four terminal ethynes into the correct position for subsequent
cyclisation to 1. In the case of 2, the above process would
result in the formation of a coordinated macrocyclic structure
that possesses significantly greater ring strain. The avoidance
of ring strain may preferentially direct the reaction pathway
toward the formation of linear oligomers and polymers. The
copper ions may therefore be playing the role of a negative
with the spectra of 9, 10 and 12. Thus the multiplets at 7.44 and
7.41 ppm in 2 and 3, respectively, were each assigned to the
overlapping peaks of the phenyl H4 and H5 protons, and
those at 7.66 and 7.65 ppm in 2 and 3, respectively, were each
assigned to the overlapping peaks of the phenyl H3 and H6
protons. The chemical shifts of the phenyl H3 proton appear
to be quite sensitive to the substituent on the adjacent ethyne.
In the case of 2 and 3 the phenyl H3 multiplet is observed
further downfield relative to those of the precursors 9, 10 and
12, and overlaps with that of the phenyl H6 due to the
similarity in electron-withdrawing ability of the phenylbuta-
diynyl and ethynylpyridyl groups (Figure 1). The character-
istic doublet at approximately 8.1 ppm is the furthest down-
field signal in the spectra of 2 and 3, and corresponds to the
pyridine H3 protons, which are anisotropically deshielded by
the nitrogen lone-pair electrons of the adjacent pyridine ring.
The remaining triplet and doublet at 7.74 and 7.61 ppm in 2
and at 7.35 and 7.47 ppm in 3 were, therefore, assigned to the
pyridine H4 and H5 protons, respectively.
The chemical shifts of the H3 and H4 pyridine ring protons
in 2 and all the pyridine ring protons in 3 are substantially
shifted upfield in comparison to those of 9, 10 and 12
(Figure 1). This evidence further establishes the macrocyclic
identities of 2 and 3, in that such shielding would be ex-
pected of protons pointing toward the interior of a macro-
cyclic cavity and/or lying alongside the face of an adjacent
aromatic ring.
b]
templating agent during the formation of 2.[22a
Characterisation of cyclophanes 2 and 3: The structure of the
products isolated from the copper-mediated Hay and Brelsow
couplings of 10 were established to be that of the macrocyclic
architectures 2 and 3 (Scheme 2) on the basis of MS and IR,
1H and 13C NMR spectroscopic studies.
The FAB mass spectra of the coupling products recorded in
10 20% CF3COOH/CHCl3 each displayed a single isotope
cluster peak at an m/z of 805 and 1208; these correspond
‡
exactly to that calculated for the [M ‡H] isotopic envelopes
of macrocycles 2 and 3, respectively. This structural assign-
ment was further substantiated by high-resolution FAB mass
‡
spectroscopic measurements of the [M ‡H] isotopic enve-
lopes, which confirmed the exact elemental composition of
the products to be C60H29N4 and C90H43N6 in accordance with
Molecular modelling and solution dynamics of 2 and 3:
Information concerning the possible three-dimensional struc-
Chem. Eur. J. 2002, 8, No. 22
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P. N. W. Baxter
FULL PAPER
and bending of the butadiyne bridges. Each conformer is also
helically twisted and chiral, and, therefore, can be represented
as either one of a pair of enantiomers.
An inspection of CPK and wireframe models of 2 revealed
that major distortions of the macrocyclic framework would be
necessary in order to allow direct interconversion between
enantiomers of the same conformer. The most sterically
accessible mechanism for enantiomer interconversion of a
given conformer must therefore proceed indirectly in several
steps, which involve the sequential interconversion between
enantiomers of different conformers. Interconversion between
the three different conformers would require stepwise rota-
tions of the bipyridine moieties about the mean axes through
their ethyne substituents.
1
However, the H NMR spectra of 2 and 9 in CDCl2CDCl2
solution change with variation in temperature in similar ways.
The most pronounced shifts are experienced by the pyridine
H3 protons, which move downfield by Dd ˆ 0.079 ppm in 2
and 0.057 ppm in 9 upon increasing the temperature from 20
1208C. These downfield shifts reflect the increased rotational
motion of the pyridine rings in 9 and indicate that 2 is at least
flexible enough to allow changes in the dihedral angle
between the pyridine subunits of each bipyridine.[39]
In the case of twistophane 3, semiempirical AM1 calcu-
lations showed that this macrocycle was particularly confor-
mationally mobile. The calculations revealed that 3 may
potentially exist in a range of different collapsed and helically
twisted conformations of similar energy, some of which
possess interpyridine van der Waals contacts (Figure 3). An
Figure 1. 500 MHz 1H NMR spectra of 2, 3, 9, 10 and 12 recorded in
CDCl2CDCl2 at 208C.
tures of 2 and 3 was obtained by AM1 semiempirical
theoretical calculations.[38] This study revealed that twist-
ophane 2 could exist in three main conformations of similar
energy (Figure 2). The conformers differ principally in the
Figure 2. Energy-minimised structures of macrocycle 2, showing the three
principle conformations, denoted OO (left), PO (centre) and PP (right):
plan view stick representation. Note that each conformer represents one of
a pair of enantiomers. The minimisations were obtained by AM1 semi-
empirical calculations by using SPARTAN 02 Linux/Unix, Wavefunction,
Irvine, CA (USA).
Figure 3. Energy-minimised structure of 3, showing a collapsed and folded
conformation: space-filling representation (left), stick representation
(right). The minimisation was obtained by AM1 semiempirical calculations
using SPARTAN 02 Linux/Unix.
relative orientation of the two bipyridine subunits within each
macrocyclic ring. Thus for each conformer, the longitudinal
axes of the pair of bipyridines can be arranged both
approximately parallel (denoted PP), both approximately
orthogonal (denoted OO), or one approximately parallel and
one orthogonal (denoted PO) to the axes of the butadiynes
(Figure 2). Interestingly, all three conformers are hinged
structures, as increasing the interpyridine dihedral angles
within each bipyridine unit results in opening of the cyclo-
phane to give a central box-shaped void. Lateral compression
of the conformers, until each pair of bipyridine subunits are
within van der Waals contact, results in a pronounced flexing
inspection of CPK and wireframe models of 3 verified that
conformer interconversion is sterically facile and that it would
involve the sequential rotational motion of the bipyridine
subunits within the interior of the macrocycle. This conclusion
is also consistent with the 1H NMR spectrum of 3 in which all
the pyridine protons are strongly shielded relative to those of
the uncyclised precursors 9, 10 and 12.
A variable temperature study of the 1H NMR spectrum of 3
in CDCl2CDCl2 (Figure 4) revealed that the solution dynam-
ics of this macrocycle is partly different from those of 2 and 9.
Raising the temperature from 0 to 1208C caused the chemical
shifts of all the pyridine protons to progressively move
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Twistophanes
5250 5264
interconversion and opening of macrocycle 3. This suggests
that the pyridine H3 and H4 protons spend comparatively
more time on the NMR timescale pointing towards the
interior of the folded framework of 3 at lower temperatures.[40]
Metal-ion sensing by twistophane 2: To evaluate the metal-ion
sensing capabilities of 2, a detailed spectroscopic investigation
into its cation-binding properties was undertaken.
The UV/visible spectrum of uncomplexed 2 in CHCl3
exhibits five absorbances at 285, 298, 318, 341 and 373 nm,
which are invariant in energy and shape over the concen-
tration range of 2.2 Â 10À6 2.2 Â 10À5 moldmÀ3; this shows
that aggregation does not occur in dilute solution. However,
all bands do undergo a slight hypsochromic shift when the
spectrum of 2 is recorded in 1:2 CHCl3/MeOH (see Exper-
imental Section).
UV/visible spectra were then recorded of 1:1 stoichiometric
mixtures of 2/Mn‡ in 1:2 CHCl3/MeOH, in which [2] ˆ 1.09 Â
10À5 moldmÀ3 and Mn‡ ˆ LiI, NaI, KI, MgII, CaII, CrIII, MnII,
FeII, CoII, NiII, PdII, PtII, ZnII, CdII, HgII, PbII, TlI, AlIII, InIII,
‡ [41]
ScIII, YIII, LaIII, EuIII, TbIII and NH4 . All spectra showed
zero or negligible changes relative to the UV/visible spectrum
of 2; this indicates insignificant binding of the macrocycle to
the above cations in dilute solution. However, the UV/visible
spectra of stoichiometric 1:1 combinations of 2/CuII and 2/AgI
in 1:2 CHCl3/MeOH, in which [2] ˆ 1.09  10À5 moldmÀ3,
were significantly different from the spectrum of pure 2,
demonstrating that coordination of these ions was occurring.
In both cases, the spectral changes involved a drastic
reduction in the intensity of all absorption maxima of 2, and
a shift to lower energy of the 317 nm band of the free ligand.
The strengths and intensities of the coordination-induced
spectral changes of 2 are exemplified by comparison with the
spectra of free 2,2'-bipy and 1:1 mixtures of 2,2'-bipy:CuII and
2,2'-bipy:AgI in 1:2 CHCl3/MeOH, in which [2,2'-bipy] ˆ
1.09 Â 10À5 moldmÀ3 (Figure 5). The latter comparison dem-
onstrates the importance of the extended, cyclic conjugation
of 2 in amplifying the spectroscopic response to metal-ion
Figure 4. Variation in the chemical shifts of the protons of
3 with
temperature. The 1H NMR spectra were recorded at 500 MHz in
CDCl2CDCl2.
downfield. The greatest reduction in shielding was experi-
enced by the pyridine H3 and H4 protons, which moved
downfield by Dd ˆ 0.093 and 0.103 ppm, respectively, on
increasing the temperature from 20 1208C. The magnitude
of these thermally induced downfield shifts are much greater
than those of the pyridine H3 and H4 protons of 2 and 9, and
presumably reflects a greater degree of conformational
Figure 5. UV/Vis absorption spectra of 1:1, 2/Mn‡ in 1:2 CHCl3/MeOH, in
which Mn‡ ˆ AgI and CuII and [2] ˆ 1.09  10À5 moldmÀ3. The spectra of 1:1
mixtures of Mn‡ with 2,2'-bipyridine in 1:2 CHCl3/MeOH at identical
concentrations are also included for comparison.
Chem. Eur. J. 2002, 8, No. 22
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P. N. W. Baxter
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binding events. A 1:1:1 mixture of 2/CuII/AgI in 1:2 CHCl3/
MeOH, where [2] ˆ 1.09  10À5 mol dmÀ3, produced a spec-
trum intermediate in shape between those of the separate 1:1
combinations of 2/CuII and 2/AgI. This competitive binding
experiment therefore showed that the complexation prefer-
ence of 2 for CuII versus AgI is approximately equal.
polymerises. The AgI-ion-induced spectral decay of 2 also
occurs in the dark, ruling out possible photochemical origins.
The precise reason for the metal-ion-induced destruction of 2
is presently unknown, but suggests intriguingly, that 2 may be
able to exist in more strained and energetically enhanced
conformations than those predicted by AM1 calculations. The
low yield of 2 may also be partly attributable to an instability
towards the copper catalyst involved in the oxidative coupling
of 10.
Solutions of 2 in organic solvents emit a blue-purple
fluorescence when irradiated with UV light. The fluorescence
emission of 2 in deoxygenated CHCl3 is composed of two
maxima at 391 and 419 nm when excited at the wavelength of
the absorption envelope at 318 nm. The energies of the
emission maxima remained unchanged over the concentration
range of 1 Â 10À6 1 Â 10À5 moldmÀ3; this shows that aggre-
gation of the excited state does not occur in dilute solution.
Changing the solvent to aerated 1:2 CHCl3/MeOH also had a
negligible effect upon the emission spectrum of 2. Fluores-
cence emission spectra of 1:1 solutions of 2/Mn‡ in 1:2 CHCl3/
MeOH were then recorded, where [2] ˆ 1  10À5 moldmÀ3
and Mn‡ ˆ all cations and metal chlorides investigated in
UV/visible spectroscopic studies described above. Of all
metals examined, only CuII and AgI evoked changes in the
fluorescence emission of 2, and in each case caused quenching
of the fluorescence of the macrocycle. The fluorescence
quenching is illustrated for the 2/AgI system, which shows the
spectra of solutions of 2 with increasing incremental additions
of AgI (Figure 7). From this titration experiment, the detec-
tion limit for silver ions was estimated to be at [AgI] ˆ 1 Â
10À6 moldmÀ3.
A particularly surprising observation was that the UV/
visible spectra of 1:1 mixtures of 2/CuII and 2/AgI in 1:2
CHCl3/MeOH, in which [2] ˆ 1.09  10À5 moldmÀ3, decayed
irreversibly upon standing for several days, finally reaching a
limiting situation in which virtually all spectral absorptions
had disappeared. This slow, time-dependent spectral decay
phenomenon was also displayed by 1:1 mixtures of 2 with
apparently non-coordinating metal ions such as MnII, FeII,
ZnII, CdII, HgII and InIII. To obtain further insight into the
origin of this apparent instability of 2 towards particular metal
ions, the 2/AgI system was selected for study in greater detail.
Thus when solutions of 2/AgI in 1:2 CHCl3/MeOH were
prepared with incrementally increasing proportions of AgI,
the maximal spectral changes occurred up to a ratio of 1:1. A
slow reduction in the absorbance of all titration curves (to
differing degrees) occurred within the first 0.5 h of mixing.
This change was, however, reversible, as addition of excess aq.
KCN completely regenerated the original spectrum of
uncomplexed 2 in every case. These initial spectral changes
must therefore be attributable to the slow kinetics of the
binding mechanism of AgI to 2. After 0.5 h from mixing, the
addition of excess aq. KCN regenerates the spectrum of 2 with
reduced absorbances, showing that irreversible changes have
begun to take place. The spectral decay process is also
catalytic in AgI as a 1:0.1 combination of 2/AgI in 1:2 CHCl3/
MeOH underwent a significant reduction in absorbance upon
standing for seven days (Figure 6). The fact that a catalytic
Figure 7. Fluorescence emission spectra of 2 with successive incremental
additions of AgI with [2] ˆ 1.09  10À5 moldmÀ3 in 1:2 CHCl3/MeOH and
2/AgI ratios of 1:0.2, 1:0.4, 1:0.6, 1:0.8 and 1:1.
Figure 6. Time dependent decay of the UV/Vis absorption spectrum of a
1:0.1 ratio of 2/AgI with [2] ˆ 1.09  10À5 moldmÀ3 in 1:2 CHCl3/MeOH.
amount of AgI causes an almost complete extinction in
absorbance of 2 demonstrates that the process is not due to
the formation and precipitation of a coordination polymer, as
this would require at least a stoichiometric quantity of AgI
ions. The phenomenon is, therefore, most likely to result from
a chemical reaction in which 2 itself either decomposes or
Twistophane 2 is therefore a particularly selective complex-
ant in dilute solution, binding to only two of the twenty-seven
cations and metal chlorides studied. As a result, 2 also
functions as a selective sensor for CuII and AgI ions signalling
their presence through a fluorescence quenching output
response.
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Twistophanes
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Metal-ion sensing by twistophane 3: The metal-ion binding
capabilities of 3 would be expected to be significantly
different from those of 2, due to the greater degree of
conformational freedom available to the former macrocycle.
To determine the effect of increased conformational mobility
on the selectivity of the metal-ion sensing response, a
spectroscopic investigation into the complexation properties
of 3 was undertaken. The UV/visible spectrum of 3 in
deoxygenated CHCl3 is composed of five envelopes at 285,
297, 318, 341 and 365 nm which remained identical in shape
and energy over the concentration range of 2.9 Â 10À6 3.6 Â
10À5 moldmÀ3, showing that aggregation does not occur in
dilute solution. When the spectrum of 3 is recorded in 1:2
CHCl3/MeOH the three highest energy bands undergo a slight
hypsochromic shift (see Experimental Section).
The metal-ion binding experiments were conducted by
using 1:1.5 ratios of 3/Mn‡ in 1:2 CHCl3/MeOH in which [3] ˆ
7.3  10À6 moldmÀ3 and Mn‡ ˆ all cations and metal chlorides
investigated in the spectroscopic studies of 2 above. Of all
analytes investigated, only CuII, AgI, HgII, PdII and TlI
engendered changes in the UV/visible spectrum of 3 (Fig-
ure 8). The first four analytes caused a reduction in the
To reveal the ion-binding selectivity of 3, competitive ion-
complexation studies were conducted using 1:1.5:1.5 mixtures
of 3/M1n‡/M2n‡ in 1:2 CHCl3/MeOH, in which [3] ˆ 7.3 Â
10À6 moldmÀ3. The binding preference of 3 to the five metal
species was thus found to follow the qualitative sequence
CuII ꢁ AgI > PdII > TlI > HgII, arranged in order of decreasing
binding strength. In the case of PdII, the measurements were
hampered by slow binding kinetics. For example, CuII initially
preferentially coordinated to 3 in the presence of PdII, but
after 10 h the degree of binding of the two species to 3 was
approximately equal. Slow binding kinetics was also observed
in the 1:1.5, 3/HgII system, in which gradual changes in the
UV/visible spectrum continued to take place up to 36 h after
mixing.
Interestingly, the irreversible metal-ion-induced spectral
decay phenomenon exhibited by 2 was not observed to occur
with any 1:1.5 3/Mn‡ combinations. This finding supports the
conclusion that the instability of the former macrocycle
towards certain metal ions may originate from a unique
structural feature within 2 such as inherent ring strain.
Similarly to 2, solutions of 3 in organic solvents emit a blue-
purple fluorescence when irradiated with UV light. The
fluorescence emission of 3 in deoxygenated CHCl3 is com-
posed of a single maximum at 400 nm when exited at the
energy of the absorption envelope at 318 nm. The latter
emission maximum remained unchanged in energy at [3]X
2.9 Â 10À6 moldmÀ3, showing that aggregation of the excited
state does not occur in dilute solution. The fluorescence
emission spectrum of 3 recorded in aerated 1:2 CHCl3/MeOH
at [3]X2.9 Â 10À6 moldmÀ3, also consists of a single but much
broader emission envelope, which was shifted to slightly lower
energy.
Fluorescence emission spectra of 1:1 mixtures of 3/Mn‡ in
1:2 CHCl3/MeOH were then recorded, in which [3] ˆ 2.9 Â
10À6 moldmÀ3 and Mn‡ ˆ CuII, AgI, HgII and PdII. The
qualitative changes in the fluorescence emission of 3 were as
follows: CuII caused almost complete quenching, AgI and PdII
caused partial quenching and HgII produced slight quenching.
A titration experiment, in which the spectra of solutions of 3
with incremental additions of CuII were recorded, enabled an
estimation of the sensory detection limit for CuII to be at
[CuII] ˆ 6  10À7 moldmÀ3 (Figure 9). These measurements
were again accompanied by time-dependent changes in the
fluorescence maxima, which involved slow and continually
increased quenching during the first hour after mixing.
The 1:1 3/AgI system in 1:2 CHCl3/MeOH exhibited
particularly curious time-dependent variations in the fluo-
rescence maximum (Figure 10). Initially, a rapid partial
quenching of the fluorescence of 3 ensued directly after
mixing with silver ions. After 5 min however, the fluorescence
began to return, and by 1.5 h had become slightly greater in
intensity than that of the emission maximum of 3 prior to
mixing. This change was also accompanied by the growth of a
lower energy emission envelope at 550 nm. The latter
observation of a nonlinear time-dependent change in emissive
species suggests that they are being generated by a reaction
mechanism between 3 and metal ions that is more complex
than originally anticipated. The expanded range of conforma-
tional states available to 3, coupled with the additional ability
Figure 8. UV/Vis absorption spectra of 1:1.5 ratios of 3/Mn‡ in 1:2 CHCl3/
MeOH in which [3] ˆ 7.3  10À6 moldmÀ3, and Mn‡ ˆ CuII, AgI, HgII, TlI and
PdII.
strongest absorption envelopes of 3, with CuII and AgI
producing the greatest coordination induced changes. In
contrast, TlI caused a simultaneous increase in absorbance
and shift to higher energy of the 316 nm band of 3. A titration
experiment performed on the 3/AgI system, revealed that
addition of further aliquots of AgI caused only minor changes
in the UV/visible spectrum once the 1:1.5 3/AgI ratio was
passed. This result suggests that the main reaction product is
‡
probably a species of stoichiometry [Ag(3)] , in which two of
the bipyridine subunits of 3 are coordinated to a single AgI
ion. Modelling studies supported this conclusion and showed
that binding of two bipyridine subunits to the same AgI ion
causes the third bipyridine to be locked into a transoid
conformation and therefore unavailable for further coordina-
tion.[42]
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P. N. W. Baxter
FULL PAPER
response characteristic to CuII. Macrocycle 3 may therefore be
considered to be a more selective sensor than 2, as the latter
ligand gives identical signal outputs for two different analytes
(i.e., CuII and AgI).
Proton sensing by twistophane 3: Protonation of 2, 3 and 9
also caused changes in the energy and intensity in their
respective fluorescence emission spectra. Macrocycle 3 was
particularly sensitive in this respect, emitting a turquoise or
green fluorescence upon irradiation with UV light when
dissolved in aged batches of CHCl3. This effect was discov-
ered to originate from the presence of HCl, which is a product
from the slow photochemical decomposition of CHCl3. In a
qualitative investigation of this process, excess CF3COOH
was added to a 2.9 Â 10À6 moldmÀ3 solution of 3 in 1:2 CHCl3/
MeOH and the fluorescence emission spectrum monitored
with time (Figure 11). As in the case of silver ion coordination
Figure 9. Fluorescence emission spectra of 3 with successive incremental
additions of CuII with [3] ˆ 2.9  10À6 moldmÀ3 in 1:2 CHCl3/MeOH and
3/CuII ratios of 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1, 1:2 and 1:3.
Figure 11. Time-dependent changes in the fluorescence emission spectrum
of a solution of 3 (2.9 Â 10À6 moldmÀ3) in 1:2 CHCl3/MeOH; 0.1 mol dmÀ3
in CF3COOH. (The spectra were recorded at 1 min intervals between 0 and
8 min; at 5 min intervals between 8 and 43 min; and at 15 min intervals
between 43 and 88 min ageing).
Figure 10. Time-dependent changes in the fluorescence emission spectrum
of a 1:1 ratio of 3/AgI with [3] ˆ 2.9  10À6 moldmÀ3 in 1:2 CHCl3/MeOH.
After 90 min ageing, the 3/AgI ratio was adjusted to 1:3 and the final
spectrum recorded at 280 min from the initial mixing of 3 with AgI. (The
3/AgI ratios are shown on each spectrum).
to 3, the emission maximum of the protonated macrocycle
changed considerably with time. Thus upon addition of
CF3COOH to 3, the absorption maximum underwent a
sudden simultaneous increase in intensity and shift to lower
energy over the first few seconds after mixing. The new
fluorescence maximum then gradually decayed with time,
eventually becoming much less intense than the original
fluorescence envelope of 3. This was also accompanied by the
development of an additional fluorescence envelope at lower
energy. Addition of excess aq. K2CO3 resulted in complete
regeneration of the original emission maximum of 3, un-
ambiguously demonstrating that the fluorescence changes
originated from protonation equilibria and not irreversible
chemical reactions.
of CuII, AgI, HgII and PdII to form interactions of varying
c]
strength with alkynes and in some cases phenyl rings,[18c, 43a
indicates that a large number of ground and excited state
coordination structures may potentially be accessible to 3.
The mechanism of complexation of a given cation by 3 may
therefore involve multiple sequential hopping or riding of ions
over the cyclophane framework as it passes through different
conformations, until the final thermodynamically preferred
species or mixture of entities are formed.
In summary, 3 was found to bind to five out of the twenty-
seven cations and metal chlorides studied. In terms of the
number of different analytes that a ligand is able to bind, 3 is a
less selective complexant than 2 in dilute solution. Twist-
ophane 3 binds most strongly to CuII and AgI, but similarly to
2, cannot discriminate between them. However, of all four
coordinating metal species, CuII produced the most intense
and enduring fluorescence quenching response. With respect
to the signal output, 3 thus gives a single type of output
These time-dependent spectral changes suggest that the
protonation of 3 involves the generation of several emissive
species, the most kinetically stable of which are formed
initially, and which then redistribute over time to the
thermodynamically favoured speciation profile.
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Twistophanes
5250 5264
Metal-ion sensing by precursor 9: Finally, a comparative
spectroscopic investigation into the metal-ion binding proper-
ties of acyclic precursor 9 was undertaken in order to assess
the effect of macrocyclisation on the complexation and
sensory capabilities of 2 and 3. The UV/visible spectra of 9
in CHCl3 and 1:2 CHCl3/MeOH consists of three bands, and
are, therefore, simpler than those of 2 and 3 recorded in the
same solvents. The metal-ion binding experiments were
conducted by using a 1:0.5 ratio of 9/Mn‡ in 1:2, CHCl3/
MeOH in which [9] ˆ 2.2  10À5 moldmÀ3 and Mn‡ ˆ all
cations and metal chlorides investigated in the spectroscopic
studies of 2 and 3 above. Similarly to 3, only CuII, AgI, HgII,
and PdII produced changes in the UV/visible spectrum of 9.
The presence of CuII, AgI and PdII caused reductions in the
absorbances of 9 (Figure 12). However, the 9/HgII system
Having established the metal-ion coordination preferences
of 9, the complexation selectivity was then investigated using
1:0.5:0.5 mixtures of 9/M1n‡/M2n‡ in 1:2 CHCl3/MeOH, in
which [9] ˆ 2.2  10À5 moldmÀ3. These competition studies
showed that the binding selectivity followed the qualitative
sequence CuII > PdII > AgI ꢁ HgII, arranged in order of de-
creasing binding strength. This series was constructed from
measurements taken within the first three minutes of mixing,
as the selectivities of some of the reactions again continued to
change further over time. For example, the spectrum of the 9/
CuII/PdII system evolved over 0.5 h into a new spectrum that
was completely different to both the 1:0.5, 9/CuII and 9/PdII
spectra (Figure 14). In addition, the reaction solution became
Figure 14. UV/Vis absorption spectra of 1:0.5 ratios of 9/CuII and 9/PdII,
and a 1:0.5:0.5 ratio of 9/CuII/PdII in 1:2 CHCl3/MeOH with [9] ˆ 2.2 Â
10À5 moldmÀ3
.
Figure 12. UV/Vis absorption spectra of 1:0.5 ratios of 9/Mn‡ in 1:2 CHCl3/
MeOH, in which Mn‡ ˆ AgI, CuII and PdII, with [9] ˆ 2.2  10À5 moldmÀ3
.
yellow. This finding suggests that the product or products of
the reaction between 9, CuII and PdII are chemically very
different from those generated from 9 and the metal species
separately. The 9/CuII/PdII system may therefore be forming
products of a higher structural complexity such as aggregates
or clusters, composed of multiple ligands simultaneously
coordinated to CuII and PdII.
exhibited slow time-dependent changes in which the absorp-
tions of 9 at 319 and 326 nm decreased over the first 0.5 h, and
by 24 h a new absorption had appeared at 306 nm (Figure 13).
The fluorescence response of 9 to metal ions was also
investigated under identical conditions to those of the UV/
visible spectroscopic metal-ion binding studies of 9 above.
These investigations showed that the coordinating analytes
AgI, HgII and PdII had a zero or negligible effect upon the
fluorescence emission of 9, whereas CuII caused partial
fluorescence quenching.
Thus ligand 9 binds to four out of the twenty-seven cations
and metal chlorides studied and is, therefore, a slightly more
selective complexant than 3, but much less selective than 2.
The binding discrimination of 9 is superior to that of 2 and 3 as
it coordinates most strongly to a single metal species (i.e.,
CuII). Unlike 3, precursor 9 on the other hand cannot
discriminate between AgI and HgII and shows no fluorescence
sensory response for these ions. Ligand 9 affords a single,
fluorescence output response characteristic of CuII, and in this
respect displays a similar sensory selectivity to 3, but greater
sensory selectivity than 2. However, the coordination-induced
Figure 13. Time-dependent changes in the UV/Vis absorption spectrum of
the 1:0.5, 9/HgII system with [9] ˆ 2.2  10À5 moldmÀ3 in 1:2 CHCl3/MeOH.
Chem. Eur. J. 2002, 8, No. 22
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P. N. W. Baxter
FULL PAPER
change in emission intensity, or in other words, the output
signal amplification, was qualitatively lower for 9 compared to
2 and 3, reflecting the greater degree of conjugation in the
macrocyclic structures.
a new lead class of ion sensors that may find a rich variety of
applications in the fields of supramolecular sensorics and
ionics, as well as related areas such as catalysis, materials
science and nanotechnology.[47]
Conclusion
Experimental Section
The above work discloses the successful preparation of
macrocyclic dimer 2 and trimer 3, which are the first reported
examples of 6,6'-connected-2,2'-bipyridyl twistophanes. These
molecules represent a new type of cyclically conjugated
metal-ion binding scaffold capable of existing in a range of
conformational states depending upon the mode and degree
of metal-ion coordination. The characterisation of 2 and 3 as
macrocyclic entities was based upon MS, and IR and NMR
spectroscopic evidence. Variable temperature NMR experi-
ments suggested that 3 was a conformationally mobile entity,
exhibiting shielding effects for particular protons, character-
istic of motions in and out of the macrocyclic rings. Molecular
modelling studies identified the lowest energy conformational
states of 2 and 3 as helically twisted and chiral architectures.
It was anticipated that 2 and 3 would function as partic-
ularly efficient metal-ion sensors due to their enhanced cyclic
conjugation, electronically linked coordination sites and
potential for undergoing complexation-induced mechano-
structural changes. Subsequent spectroscopic investigations
confirmed that 2 and 3 do indeed function as metal-ion
sensors. Cyclophane 2 acts as a fluorescence-quenching sensor
for CuII and AgI, and 3 as a fluorescence-quenching sensor for
CuII. The acyclic precursor 9 was also found to respond to CuII
by fluorescence quenching but to a qualitatively lesser
General: Standard inert atmosphere and Schlenk techniques were em-
ployed for reactions conducted under argon. The catalysts [Pd(PPh3)4],[48]
[PdCl2(PPh3)2],[49] [PdCl2(dppf)] ¥ CH2Cl2,[50] CuI, CuCl and [Cu2(OAc)4]
were purchased from Aldrich and used as received. Precursors 4,[51] 8[27a]
and 11[35] were prepared according to published procedures. The toluene,
THF and triethylamine used in the preparation of 6, 9 and 12 were
deoxygenated by bubbling with argon for 0.5 h directly prior to use. The
alumina used for the chromatographic purification of marocycles 2 and 3
was purchased from Merck (Aluminium Oxide 90, standardised activity II/
III). The silica used for all flash chromatography was also purchased from
Merck (Geduran, Silica gel Si 60, 40 60 mm).
Intramolecular proton connectivities were determined by 1H 1H COSY
and NOESY NMR measurements, and carbon assignments of 2 and 12 by
1H 13C HMQC experiments. All 1H and 13C NMR spectra were referenced
to the solvent peaks (in the former case, to those of the residual
nondeuterated solvent). The fluorescence emission spectra were recorded
at 20 258C on a Aminco, Bowman Series 2 luminescence spectropho-
tometer (SLM Instruments, Inc.). The free ligand fluorescence emission
spectra of 2, 3, 9, 10 and 12 given below were recorded in argon-bubbled
CHCl3 and were corrected for the instrumental response. The fluorescence
emission spectra of the metal-ion binding experiments with 2, 3 and 9 were
conducted in aerated 1:2 CHCl3/MeOH, in order to obtain optical
responses under environmental conditions of most practical utility for
sensory applications. The metal-ion binding emission spectra for 2 and 9
recorded under these conditions were corrected for the instrumental
response. All infrared spectra were recorded as KBr discs. Melting point
measurements were performed on an Electrothermal Digital melting point
apparatus calibrated with standards of known melting points. Elemental
analyses were performed by the Service de Microanalyse, Institut de
c]
degree.[44a The metal-ion binding and sensory properties of
¬
Chimie, Universite Louis Pasteur (France).
2, 3 and 9 were found to be subtly different, being best
compared and summarised using four descriptors as follows:
complexation selectivity, 2 ꢂ 9 > 3; complexation discrimina-
tion, 9 > 2 ꢁ 3; sensory selectivity, 3 ꢁ 9 > 2 and output signal
intensity, 2 ꢁ 3 > 9.[45] The overall ability of structures such as
2, 3 and 9 to function as sensors depends, therefore, on a
complex interplay of steric, structural and electronic factors
such as, for example, the degree of conjugation, the type of
conjugation pathway, the electronic nature and position of
substituents, intramolecular strain, the number of accessible
conformations, the number and accessibility of binding sites
and binding site preorganisation.[46]
Many of the reactions studied exhibited prolonged time-
dependent spectral changes upon complexation, indicative of
slow binding kinetics. This, however, did not adversely affect
the sensory capabilities of 2, 3 and 9 as coordination-induced
fluorescence responses invariably occurred immediately upon
contact with the analyte.
Interestingly, 2, 3 and 9 also function as chromogenic
fluorescence sensors for protons, a finding that suggests that
these and structurally related compounds may have applica-
tions in the field of molecular protonics.
The unique structural features of the conjugated ligands
described above, endow these molecules with the ability to
signal the presence of particular metal ions through character-
istic fluorescence output responses. They therefore constitute
6,6'-Bis(trimethylsilylethynyl)-2,2'-bipyridine (6): Toluene (15 mL), which
had been bubbled with argon, was added by syringe to a mixture of 4
(0.434 g, 1.38 Â 10À3 mol),
5
(1.8 g, 4.65 Â 10À3 mol) and [Pd(PPh3)4]
(0.030 g, 2.6 Â 10À5 mol) under an argon atmosphere. The reaction was
placed in an oil bath, and refluxed and stirred at 1228C for 36 h. During
heating the reaction turned black. All solvent was then removed under
reduced pressure on a water bath, and the residue was purified by flash
chromatography on a column of silica, eluting with CH2Cl2. The product
eluted as a single component, free from accompanying contaminants. The
CH2Cl2 was removed by distillation at atmospheric pressure on a water
bath and the remaining product dried under vacuum (0.01 mm Hg)
1
overnight to yield 6 (0.302 g, 63%) as a cream crystalline solid. H NMR
(CDCl3, 500MHz, 258C): d ˆ 8.428 (dd, 3J(3,4) ˆ 8.0 Hz, 4J(3,5) ˆ 0.9 Hz,
2H; pyridine H3), 7.758 (t, 3J(4,3;4,5) ˆ 7.8 Hz, 2H; pyridine H4), 7.485 (dd,
3J(5,4) ˆ 7.7 Hz, 4J(5,3) ˆ 0.9 Hz, 2H; pyridine H5), 0.294 ppm (s, 18H;
‡
‡
Si(CH3)3); EIMS: m/z (%): 348 (96) [M ], 333 (100) [M À CH3].
6,6'-Bis[(2-trimethylsilylethynylphenyl)ethynyl]-2,2'-bipyridine (9): Tol-
uene (100 mL), which had been bubbled with argon, was added by syringe
to a mixture of 7 (0.789 g, 3.86 Â 10À3 mol), 8 (2.42 g, 8.06 Â 10À3 mol) and
[PdCl2(dppf)] ¥ CH2Cl2 (0.078 g, 9.55 Â 10À5 mol) under an argon atmos-
phere. The suspension was then placed in a bath at 758C and stirred for
0.25 h, that is, until 7 had completely dissolved. A solution of CuI (0.045 g,
2.36 Â 10À4 mol) in Et3N (13 mL) was added by syringe; this initiated the
slow formation of a chocolate-brown suspended solid. Directly after
addition of the CuI solution, the stirred mixture was allowed to cool to
ambient temperature and stirring continued in the dark for 8 d. All solvent
was then removed under reduced pressure on a water bath and the residue
slurried in 25/75 CH2Cl2/hexane and purified by flash chromatography on a
column of silica, eluting with 25/75 CH2Cl2/hexane. Unreacted 8 eluted
initially, and was followed eventually by 9. The product was thus obtained
as a colourless glass after removal of the solvent by distillation on a water
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Twistophanes
5250 5264
1
bath and drying under vacuum. Final purification was achieved upon
recrystallisation from hexane and drying under vacuum (0.01 mmHg for
24 h), to yield 9 (1.824 g, 86%) as colourless crystals. M.p. 142.4 143.08C;
1H NMR (CDCl3, 500 MHz, 258C): d ˆ 8.503 (dd, 3J(3,4) ˆ 7.9 Hz,
4J(3,5) ˆ 0.9 Hz, 2H; pyridine H3), 7.819 (t, 3J(4,3;4,5) ˆ 7.9 Hz, 2H;
pyridine H4), 7.636 (m, 2H; phenyl H6), 7.600 (dd, 3J(5,4) ˆ 7.6 Hz,
4J(5,3) ˆ 0.9 Hz, 2H; pyridine H5), 7.531 (m, 2H; phenyl H3), 7.324 (m,
4H; phenyl H4, H5), 0.272 ppm (s, 18H; Si(CH3)3); 13C NMR (CDCl3,
125.8 MHz, 258C): d ˆ 155.9, 142.8, 136.9, 132.3, 132.2, 128.6, 128.2, 127.8,
give 10 (1.309 g, 97%) as a white powder. M.p. 142.5 143.58C; H NMR
(CDCl3, 500 MHz, 258C): d ˆ 8.498 (dd, 3J(3,4) ˆ 8.0 Hz, 4J(3,5) ˆ 0.7 Hz,
2H; pyridine H3), 7.830 (t, 3J(4,3;4,5) ˆ 7.8 Hz, 2H; pyridine H4), 7.661 (m,
3
4
2H; phenyl H6), 7.618 (dd, J(5,4) ˆ 7.6 Hz, J(5,3) ˆ 0.8 Hz, 2H; pyridine
H5), 7.569 (m, 2H; phenyl H3), 7.358 (m, 4H; phenyl H4/5), 3.420 ppm (s,
2H; H C C); 13C NMR (CDCl3, 125.8 MHz, 258C): d ˆ 155.9, 142.7, 137.0,
À ꢀ
À ꢀ
132.6, 132.3, 128.64, 128.58, 128.0, 125.4, 125.1, 120.9, 92.7 ( C ), 87.3
À ꢀ
À ꢀ
À ꢀ
( C ), 82.0 ( C ), 81.5 ppm ( C ); UV/Vis (CHCl3): lmax (e) ˆ 297
(39575), 320 nm (44596mÀ1 cmÀ1); fluorescence emission ([10] ˆ 1.98 Â
10À6 moldmÀ3 in CHCl3, 320 nm excitation): lmax ˆ 340 nm; IR: nÄ ˆ 3291
À ꢀ
À ꢀ
À ꢀ
À ꢀ
126.2, 125.2, 120.9, 103.2 ( C ), 99.1 ( C ), 92.6 ( C ), 87.7 ( C ),
À ꢀ
ꢀ
0.0 ppm (Si(CH3)3); UV/Vis (CHCl3): lmax (e) ˆ 301 (42145), 319 (48580),
(s) (H C ), 2221 (w) (C C), 1568 (s), 1561 (s) 1478 (s), 1446 (s), 1435 (s),
328 nm (47606 mÀ1 cmÀ1); fluorescence emission ([9]
ˆ
1.46 Â
795 (s), 754 (s), 616 (s); FABMS: m/z (%): 405 (100) [M ‡H].
‡
10À6 moldmÀ3 in CHCl3, 319 nm excitation): lmax ˆ 342 nm; IR: nÄ ˆ 2954
6,6'-Bis[(2-ethynylphenyl)ethynyl]-2,2'-bipyridine (10), (from 12): Toluene
(7 mL), which had been bubbled with argon, was added by syringe to a
mixture of 12 (0.043 g, 8.26 Â 10À5 mol) and powdered KOH (0.011 g,
1.96 Â 10À4 mol) under an atmosphere of argon; the suspended solids were
dispersed by brief ultrasonication. The reaction was then stirred and heated
in a bath at 1108C for 7 h, during which time the reaction solution turned
pale yellow and some brown solid formed on the flask walls. TLC (1%
MeOH/CH2Cl2, silica) performed at this point showed that 12 had been
consumed. The reaction was then poured onto CH2Cl2 (25 mL) and
extracted with distilled water (2 Â 20 mL). The organic layer was dried
(anhydrous MgSO4), filtered and the solvent removed by distillation under
reduced pressure on a waterbath. The residue was then dissolved in CH2Cl2
(10 mL) and the concentrate was purified by flash chromatography on a
column of silica with CH2Cl2 as eluant. The product thus obtained was
finally purified by dissolving in hot hexane (100 mL), adding NORIT A
decolourising charcoal (0.03 g) and briefly boiling followed by gravity
filtration. The filtrate was reduced in volume to about 3 mL by distillation
under reduced pressure on a waterbath and left to cool to ambient
temperature. The mixture was then filtered under vacuum, and the
collected solid washed with ice-cold hexane (2 mL) and air-dried to give 10
(0.026 g, 79%) as a white microcrystalline solid. M.p. 145.6 146.68C; the
1H and 13C NMR spectra of the product were identical to those of 10
prepared from 9 as described above; elemental analysis calcd (%) for
C30H16N2: C 89.09, H 3.99, N 6.93; found: C 89.08, H 3.94, N 6.83.
ꢀ
ꢀ
(s), 2218 (w) (C C), 2160 (s) (C C), 1568 (s), 1560 (s), 1480 (s), 1431 (s),
1249 (s), 846 (s), 802 (s), 757 cmÀ1 (s); EIMS: m/z (%): 548 (57) [M ], 533
‡
‡
‡
(30) [M À CH3], 475 (100) [M À SiMe3]; elemental analysis calcd (%) for
C36H32N2Si2: C 78.78, H 5.88, N 5.10; found: C 78.62, H 5.69, N 5.11.
6,6'-Bis{{2-[4-(2-methyl-2-hydroxy-3-butyne)]phenyl}ethynyl}-2,2'-bipyri-
dine (12): THF (20 mL), which had been bubbled with argon, was added by
syringe to a mixture of 11 (0.286 g, 1.55 Â 10À3 mol), 4 (0.235 g, 7.48 Â
10À4 mol) and [PdCl2(PPh3)2] (0.020 g, 2.85 Â 10À5 mol) under an atmos-
phere of argon. The mixture was stirred for 0.25 h, that is, until 4 had
dissolved, and then a solution of CuI (0.014 g, 7.35 Â 10À5 mol) in Et3N
(2 mL, bubbled with argon) was added by syringe. Directly after addition of
the CuI in Et3N, the suspended [PdCl2(PPh3)2] dissolved to give a yellow
solution from which a another suspended solid slowly began to form. The
reaction was stirred at ambient temperature for 7 d in the absence of light.
All solvent was subsequently removed under reduced pressure on a water
bath to give
a brown glassy residue, which was purified by flash
chromatography on a short column of silica. The column was eluted first
with CH2Cl2 to remove a contaminant that was visualised as a purple-blue
fluorescent band with a fluorescent lamp operating at 365 nm. Gradient
elution with 1% MeOH/CH2Cl2 and finally 2%MeOH/CH2Cl2 resulted in
removal of 12 from the column. The product 12 was also observable on the
column as a strong purple-blue fluorescent band with a fluorescent lamp
operating at 365 nm. The product was thus obtained as a clear pale-brown
glass after removal of solvent and drying under vacuum. The glass was then
dissolved in boiling n-heptane (600 mL), NORIT A decolourising charcoal
(0.06 g) added, and boiling continued for a further 0.1 h. The mixture was
subsequently gravity filtered and left to stand for 24 h. The crystalline solid
that separated was isolated by filtration under vacuum, washed with n-
heptane (4 mL) and air-dried to give 12 (0.200 g, 51%) as a microcrystalline
cream solid. M.p. 175.1 175.78C; 1H NMR (CDCl3, 500 MHz, 258C): d ˆ
8.417 (dd, 3J(3,4) ˆ 7.5 Hz, 4J(3,5) ˆ 0.8 Hz, 2H; pyridine H3), 7.817 (t,
3J(4,3;4,5) ˆ 7.9 Hz, 2H; pyridine H4), 7.612 (m, 4H; pyridine H5/phenyl
H6), 7.448 (m, 2H; phenyl H3), 7.314 (m, 4H; phenyl H4/5), 1.649 ppm (s,
12H; C(CH3)2OH); 13C NMR (CDCl3, 125.8 MHz, 258C): d ˆ 156.1, 142.8,
137.1 (C4 pyridine), 131.9 (C5 pyridine/C6 phenyl), 131.2 (C3 phenyl), 128.7
(C4/5 phenyl), 127.9 (C4/5 phenyl), 127.7 (C5 pyridine/C6 phenyl), 126.1,
Macrocycle 2 (Hay procedure): In a well-ventilated hood, a solution of
CuCl (0.023 g, 2.32 Â 10À4 mol) in pyridine (2 mL) was added to a solution
of 10 (0.167 g, 4.13 Â 10À4 mol) in pyridine (230 mL) contained in a ribbed
500 mL three-necked round-bottomed flask, and the reaction solution
vigorously stirred and bubbled with oxygen for 14 d. During this time, the
volume of the reaction solution evaporated down to about 90 mL. The
reaction was subsequently re-diluted to 230 mL by the addition of pyridine
and further CuCl (0.025 g, 2.53 Â 10À4 mol) added. Oxygen bubbling and
vigorous stirring was then continued for a further 11 d, periodically re-
diluting to 230 mL with pyridine, whenever evaporation down to 100 mL
occurred. During the periods of maximum solvent volume reduction, a
suspended solid formed on the flask walls. All solvent was then removed
under reduced pressure; a concentrated aqueous KCN solution (20 mL)
was then added to the residue and the mixture rapidly stirred for 1 h. The
mixture was filtered under vacuum and, the isolated dark brown solid
washed with excess distilled water and air-dried. The solid was then
suspended in CHCl3 (250 mL), boiled for 0.1 h, and gravity filtered to
remove polymeric by-products; then the solvent was removed by distil-
lation on a water bath at atmospheric pressure. The remaining solid was
finally boiled in toluene (150 mL) and the hot mixture introduced onto a
29 Â 6.5 cm diameter column of alumina and the column eluted with
toluene. The product thus obtained was subject once again to chromatog-
raphy under identical conditions and suspended in MeOH (3 mL), briefly
ultrasonicated, isolated by filtration under vacuum, washed with MeOH
and air-dried to give 2 (0.021 g, 13%) as an amorphous off-white powder.
1H NMR (CDCl2CDCl2, 500 MHz, 208C): d ˆ 8.083 (dd, 3J(3,4) ˆ 7.9 Hz,
4J(3,5) ˆ 0.8 Hz, 4H; pyridine H3), 7.735 (t, 3J(4,3;4,5) ˆ 7.7 Hz, 4H;
pyridine H4), 7.658 (m, 8H; phenyl H3/6), 7.609 (dd, 3J(5,4) ˆ 7.6 Hz,
4J(5,3) ˆ 0.8 Hz, 4H; pyridine H5), 7.444 ppm (m, 8H; phenyl H4/5);
13C NMR (CDCl2CDCl2, 125.8 MHz, 808C): d ˆ 154.9, 142.2, 136.9 (C4
pyridine), 132.2 (C3/6 phenyl), 131.8 (C3/6 phenyl), 129.2 (C4/5 phenyl),
128.9 (C5 pyridine), 128.7 (C4/5 phenyl), 127.2, 125.5, 120.6 (C3 pyridine),
À ꢀ
À ꢀ
À ꢀ
À ꢀ
125.3, 121.3 (C3 pyridine), 99.3 ( C ), 92.6 ( C ), 87.9 ( C ), 80.8 ( C ),
65.6 (C(CH3)2OH), 31.4 ppm (C(CH3)2OH); UV/Vis (CHCl3): lmax (e) ˆ
297 (48204), 319 (53143), 326 nm (53833mÀ1 cmÀ1); fluorescence emission
([12] ˆ 1.54  10À6 moldmÀ3 in CHCl3, 319 nm excitation): lmax ˆ 345 nm;
À
ꢀ
IR: nÄ ˆ 3356 (s) (O H), 2979 (m), 2219 (m) (C C), 1569 (s), 1560 (s), 1445
(s), 1432 (s), 1169 (s), 1155 (s), 964 (s), 798 (s), 759 cmÀ1 (s); FABMS: m/z
‡
‡
(%): 521 (100) [M ‡H], 505 (20) [M À CH3]; elemental analysis calcd (%)
for C36H28N2O2: C 83.05, H 5.42, N 5.38; found: C 83.01, H 5.46, N 5.23.
6,6'-Bis[(2-ethynylphenyl)ethynyl]-2,2'-bipyridine (10), (from 9): TBAF
(7 mL, 1.0m solution in THF) was added to a stirred solution of 9 (1.824 g,
3.32 Â 10À3 mol) in THF (40 mL) and distilled water (0.5 mL). The clear
reaction was then stirred at ambient temperature in the absence of light for
18 h. TLC (CH2Cl2/Silica) of the reaction at this point showed all the 9 to be
consumed. All solvent was removed under reduced pressure on a water
bath and the residue dissolved in CH2Cl2 (50 mL) and extracted with
distilled water (4 Â 60 mL). The organic layer was separated, dried
(anhydrous MgSO4) and filtered, and the solvent volume reduced to
20 mL by distillation at atmospheric pressure on a water bath. The
concentrate was then purified by flash chromatography on a column of
silica with CH2Cl2 as eluant. The product thus obtained was finally purified
by brief ultrasonication in MeOH (4 mL), filtering under vacuum, and
washing the collected solid with MeOH (2 mL) followed by air drying to
À ꢀ
À ꢀ
À ꢀ
À ꢀ
94.7 ( C ), 87.3 ( C ), 81.9 ( C ), 78.6 ppm ( C ); UV/Vis (CHCl3): lmax
(e) ˆ 285 (80637), 298 (sh) (67987), 318 (66496), 341 (sh) (36952), 373 nm
(11040mÀ1 cmÀ1); UV/Vis (1:2 CHCl3/MeOH): lmax (e) ˆ 284 (85636), 296
Chem. Eur. J. 2002, 8, No. 22
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5261

P. N. W. Baxter
FULL PAPER
(74995), 317 (72068), 340 (42104), 370 nm (12342mÀ1 cmÀ1); fluorescence
[3] E. Blasius, K.-P. Janzen, Top. Curr. Chem. 1981, 98, 163.
emission ([2] ˆ 9.94  10À7 moldmÀ3 in CHCl3, 318 nm excitation): lmax
ˆ
[4] a) J. D. Lamb, R. G. Smith in Comprehensive Supramolecular Chem-
istry, Vol. 10 (Eds.: J.-M. Lehn, J. L. Atwood, J. E. D. Davies, D. D.
McNicol, F. Vˆgtle, D. N. Reinhoudt), Pergamon, Oxford, 1996,
Chapter 4, pp. 79 112; b) L. Echegoyen, R. C. Lawson in Compre-
hensive Supramolecular Chemistry, Vol. 10 (Eds.: J.-M. Lehn, J. L.
Atwood, J. E. D. Davies, D. D. McNicol, F. Vˆgtle, D. N. Reinhoudt),
Pergamon, Oxford, 1996, Chapter 6, pp. 151 170; c) Z. Chen, L.
Echegoyen in Crown Compounds: Towards Future Applications (Ed.:
S. R. Cooper), VCH, NY, 1992, pp. 27 39.
[5] C. L. Liotta in Synthetic Multidentate Macrocyclic Compounds (Eds.:
R. M. Izatt, J. J. Christensen), Academic Press, NY, 1978, pp. 111
205.
[6] A. Harada, Y. Ederle, K. S. Naraghi, P. J. Lutz in Materials Science and
Technology: A Comprehensive Treatment, Vol. 18 (Eds.: R. W. Cahn,
P. Haasen, E. J. Kramer, A.-D. Schl¸ter), Wiley-VCH, Weinheim,
Germany, 1999, Chapter 14, pp. 485 512; Chapter 19, pp. 621
647.
[7] H. Hashimoto in Comprehensive Supramolecular Chemistry, Vol. 3
(Eds.: J. L. Atwood, J. E. D. Davies, D. D. McNicol, F. Vˆgtle, J.
Szejtli, T. Osa), Pergamon, Oxford, 1996, pp. 483 502.
[8] E. Mena-Osteritz, P. B‰uerle, Adv. Mater. 2001, 13, 243.
[9] F. Vˆgtle, Cyclophan-Chemie, Synthesen, Strukturen, Reactionen,
Teubner, Stuttgart, 1990.
[10] P. Ruggli, Justus Liebigs Ann. Chem. 1912, 392, 92.
[11] H. Meier, Synthsis 1972, 235.
[12] a) K. G. Untch, D. C. Wysocki, J. Am. Chem. Soc. 1966, 88, 2608;
b) W. H. Okamura, F. Sondheimer, J. Am. Chem. Soc. 1967, 89, 5991.
[13] For an informative series of reviews covering the field up to 1999, see:
Top. Curr. Chem. 1999, 201, whole volume.
ꢀ
391, 419 nm; IR: nÄ ˆ 2920, 2215 (w) (C C), 1569 (s), 1560 (s), 1472 (s), 1453
(s), 1430 (s), 1259 (m), 1082 (m), 796 (s), 753 (s), 735 (s), 637 cmÀ1 (m);
FABMS (recorded in 10 20% CF3COOH/CHCl3): m/z (%): 805 (100)
‡
‡
[M ‡H]; HRMS (FAB, CF3COOH, [M ‡H]) calcd for C60H29N4:
805.2392; found: 805.2394.
Macrocycles 2 and 3 (Breslow procedure): A solution of 10 (0.202 g, 4.99 Â
10À4 mol) in pyridine (35 mL) was added dropwise over 4 h to a rapidly
stirred suspension of CuCl (1.48 g, 1.5 Â 10À2 mol) and [Cu2(OAc)4] (3.63 g,
2.0 Â 10À2 mol) in pyridine (300 mL), heated in a bath at 608C. After the
addition of 10 was complete, the green mixture was stirred at 608C for a
further 2 h, then allowed to cool to ambient temperature and stirring
continued for 14 d. All solvent was then removed under reduced pressure
on a waterbath at 708C and pyridine (15 mL) added to wet the remaining
solid residue. A concentrated aqueous solution of KCN (100 mL) was
added to the reaction product, and the mixture rapidly stirred for 1 h and
filtered under vacuum; then the isolated solid washed with excess distilled
water and air-dried. The dark brown solid was then boiled in toluene
(900 mL) and gravity filtered while still hot; the filtrate reduced in volume
to 200 mL by distillation under reduced pressure on a water bath. The hot
solution was introduced onto a large column of alumina and eluted with
toluene. The progress of the chromatography was monitored with a
fluorescent lamp operating at 365 nm, whereby 2 appeared as the first blue-
purple fluorescent band to elute from the column and 3 the second. Each
macrocyclic component was then separately subjected once again to
chromatography on alumina columns with toluene as eluant. Both macro-
cycles thus isolated were further purified by boiling each in acetone
(10 mL), filtering under vacuum, washing the collected products with
acetone and finally air dried to give 2 (0.019 g, 9%) and 3 (0.011 g, 5%) as
off-white dusty solids. Characterisation data for 3: 1H NMR (CDCl2CDCl2,
500 MHz, 208C): d ˆ 8.126 (d, 3J(3,4) ˆ 8.0 Hz, 6H; pyridine H3), 7.652 (m,
[14] Top. Curr. Chem. 1999, 199, whole volume.
[15] a) K. M. Merz Jr, R. Hoffmann, A. T. Balaban, J. Am. Chem. Soc.
1987, 109, 6742; b) R. H. Baughman, H. Eckhardt, M. Kertesz, J.
Chem. Phys. 1987, 87, 6687; c) F. Diederich, Y. Rubin, Angew. Chem.
1992, 104, 1123; Angew. Chem. Int. Ed. Engl. 1992, 31, 1101; d) F.
Diederich, Nature 1994, 369, 199; e) P. E. Eaton, E. Galoppini, R.
Gilardi, J. Am. Chem. Soc. 1994, 116, 7588; f) K. S. Feldman, C. K.
Weinreb, W. J. Youngs, J. D. Bradshaw, J. Am. Chem. Soc. 1994, 116,
9019; g) T. Lange, J.-D. van Loon, R. R. Tykwinski, M. Schreiber, F.
Diederich, Synthesis 1996, 537.
3
12H; phenyl H3/6), 7.472 (d, J(5,4) ˆ 7.8 Hz, 6H; pyridine H5), 7.406 (m,
12H; phenyl H4/5), 7.346 ppm (t, 3J(4,3;4,5) ˆ 7.8 Hz, 6H; pyridine H4);
13C NMR (CDCl2CDCl2, 125.8 MHz, 1208C): d ˆ 155.8, 142.3, 136.6, 132.8,
À ꢀ
À ꢀ
132.2, 128.9, 128.4, 127.7, 126.8, 125.4, 120.8, 94.6 ( C ), 86.9 ( C ), 81.7
À ꢀ
À ꢀ
( C ), 78.7 ppm ( C ); UV/Vis (CHCl3): lmax (e) ˆ 285 (106193), 297
(101515), 318 (105301), 341 (sh) (62344), 365 nm (sh) (20772mÀ1 cmÀ1);
UV/Vis (1:2 CHCl3/MeOH): lmax (e) ˆ 283 (106907), 294 (103065), 316
(102256), 341 (sh) (57144), 365 nm (sh) (19345mÀ1 cmÀ1); fluorescence
emission ([3] ˆ 2.92  10À6 moldmÀ3 in CHCl3, 318 nm excitation): lmax
ˆ
[16] J. S. Moore, Acc. Chem. Res. 1997, 30, 402.
[17] P. J. Garratt in Comprehensive Organic Chemistry; The Synthesis and
Reactions of Organic Compounds, Vol. 1 (Ed.: J. F. Stoddart),
Pergamon, Oxford, 1979, Chapter 2.6, p. 361.
[18] a) M. M. Haley, Synlett 1998, 557; b) J. J. Pak, T. J. R. Weakley, M. M.
Haley, J. Am. Chem. Soc. 1999, 121, 8182; c) W. J. Youngs, C. A.
Tessier, J. D. Bradshaw, Chem. Rev. 1999, 99, 3153; d) J. M. Kehoe,
J. H. Kiley, J. J. English, C. A. Johnson, R. C. Petersen, M. M. Haley,
Org. Lett. 2000, 2, 969.
ꢀ
400 nm; IR: nÄ ˆ 2922 (m), 2219 (m) (C C), 1567 (s), 1559 (s), 1475 (s), 1450
(s), 1432 (s), 798 (s), 757 (s), 637 (m); FABMS (10% CF3COOH/CHCl3):
‡
m/z (%): 1208 (100) [M ‡H]; HRMS (FAB, 10 20% CF3COOH/CHCl3,
‡
[M ‡H]) calcd for C90H43N6: 1207.3549; found: 1207.3554.
Acknowledgement
[19] a) A. M. Boldi, F. Diederich, Angew. Chem. 1994, 106, 482; Angew.
Chem. Int. Ed. Engl. 1994, 33, 468; b) S. Eisler, R. R. Tykwinski,
Angew. Chem. 1999, 111, 2138; Angew. Chem. Int. Ed. Engl. 1999, 38,
1940.
[20] a) L. T. Scott, G. J. DeCicco, J. L. Hyun, G. Reinhardt, J. Am. Chem.
Soc. 1985, 107, 6546; b) L. T. Scott, M. J. Cooney, C. Otte, C. Puls, T.
Haumann, R. Boese, P. J. Carroll, A. B. Smith III, A. de Meijere, J.
Am. Chem. Soc. 1994, 116, 10275; it may be noted that the name
™pericyclynes∫ used in the last two references has been replaced by the
name ™pericyclines∫ in the review of reference [13].
[21] a) A. de Meijere, S. Kozhushkov, C. Puls, T. Haumann, R. Boese, M. J.
Cooney, L. T. Scott, Angew. Chem. 1994, 106, 934; Angew. Chem. Int.
Ed. Engl. 1994, 33, 869; b) A. de Meijere, S. Kozhushkov, T.
Haumann, R. Boese, C. Puls, M. J. Cooney, L. T. Scott, Chem. Eur.
J. 1995, 1, 124.
[22] For porphyrin-incorporated ethynyl cyclophanes, see: a) S. Anderson,
H. L. Anderson, J. K. M. Sanders, Acc. Chem. Res. 1993, 26, 469;
b) J. K. M. Sanders in Comprehensive Supramolecular Chemistry, Vol.
9 (Eds.: J. L. Atwood, J. E. D. Davies, D. D. McNicol, F. Vˆgtle, J.-P.
Sauvage, M. Wais Hosseini), Pergamon, Oxford, 1996, Chapter 4,
p. 131; para-phenylethynyl belts: c) T. Kawase, N. Ueda, K. Tanaka, Y.
Seirai, M. Oda, Tetrahedron Lett. 2001, 5509; binaphthyl cyclophane
receptors: d) U. Neidlein, F. Diederich, Chem. Commun. 1996, 1493;
¡
The College de France is acknowledged for financial support and Roland
Graff for the 1H NMR COSY, NOESY, ROESY and 1H 13C HMQC
experiments. Dr Bernard Dietrich, Prof. Masakazu Ohkita, Prof. Alex-
andre Varnek and Dr Jonathan Nitschke are also thanked for helpful
discussions.
[1] Comprehensive Supramolecular Chemistry, Vol. 10 (Eds.: J.-M. Lehn,
J. L. Atwood, J. E. D. Davies, D. D. McNicol, F. Vˆgtle, D. N.
Reinhoudt), Pergamon, Oxford, 1996.
[2] a) For reviews on the use of macrocyclic complexes in medical
diagnostics, see for example: Top. Curr. Chem. 2002, 221, whole
volume; b) D. Parker in Comprehensive Supramolecular Chemistry,
Vol. 10 (Eds.: J.-M. Lehn, J. L. Atwood, J. E. D. Davies, D. D.
McNicol, F. Vˆgtle, D. N. Reinhoudt), Pergamon, Oxford, 1996,
Chapter 17, pp. 487 536; c) D. Parker, S. R. Cooper in Crown
Compounds: Towards Future Applications (Ed.: S. R. Cooper),
VCH, NY, 1992, pp. 51 67 and pp. 285 302; d) For the use of
macrocycles in drug delivery, see: K.-H. Frˆmming in Comprehensive
Supramolecular Chemistry, Vol. 10 (Eds.: J.-M. Lehn, J. L. Atwood,
J. E. D. Davies, D. D. McNicol, F. Vˆgtle, D. N. Reinhoudt), Perga-
mon, Oxford, 1996, Chapter 16, pp. 445 485.
5262
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0947-6539/02/0822-5262 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 22

Twistophanes
5250 5264
acetylenosaccharides: e) R. B¸rli, A. Vasella, Angew. Chem. 1997, 109,
1945; Angew. Chem. Int. Ed. Engl. 1997, 36, 1852.
[23] J. Zhang, J. S. Moore, J. Am. Chem. Soc. 1994, 116, 2655.
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[26] For examples of ethynyl macrocycles that externally bind metal ions,
see; a) K. Campbell, R. McDonald, N. R. Branda, R. R. Tykwinski,
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ortho-conjugated, yet helically twisted and, therefore, nonplanar
[38] For an example of the use of semiempirical AM1 calculations for
successfully predicting the conformations of ethynyl macrocycles, see:
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[39] Further studies on, for example, chirally functionalised derivatives
may thus be necessary in order to clarify the solution dynamics of 2.
[40] Interestingly, a somewhat higher energy conformational minimum
accessible to 3 is that of a triangular tube-type structure. In this
conformation, the three bipyridine units are transoid and planar, and
define the walls of a tubular void. Cyclophane 3 may therefore also be
capable of forming inclusion complexes with guests of complementary
size and shape to the triangular cavity.
chiral structures. Such molecules represent
a small but slowly
emergent subclass of conjugated ethynyl macrocycles of which 1, 2
and 3 are the first reported examples with integrated heterocyclic
N-donor sites for metal ion coordination. Examples of this type of
molecule include the following: b) M. J. Marsella, Z.-Q. Wang, R. J.
Reid, K. Yoon, Org. Lett. 2001, 3, 885; c) S. K. Collins, G. P. A. Yap,
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[41] The metal salts and complexes used in the study were CrCl3 ¥ 6H2O,
FeCl2, CoCl2 ¥ 6H2O, NiCl2 ¥ 6H2O, [PdCl2(MeCN)2] and [PtCl2-
(MeCN)2]. All remaining cations investigated were in the form of
their anhydrous triflates. The chromium, iron, cobalt and nickel
chlorides were each dissolved in a drop of distilled water prior to the
preparation of the standard solutions in methanol to ensure complete
solubility. For the same reason, the palladium and platinum complexes
were initially dissolved in warm acetonitrile (1 mL). The CuII, AgI,
HgII and TlI triflates used were ꢂ99.9% purity.
[28] The construction of ethynyl macrocycles that incorporate pyridine and
pyridine-type units has recently attracted a flurry of interest. For
examples of conjugated ethynyl macrocycles incorporating pyridine
units, see a) Y. Tobe, H. Nakanishi, M. Sonoda, T. Wakabayashi, Y.
Achiba, Chem. Commun. 1999, 1625; b) Y. Tobe, A. Nagano, K.
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Sun, A. J. Lees, Organometallics 2001, 20, 2353; d) reference [26a];
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bipyridine units, see e) O. Henze, D. Lentz, A. D. Schl¸ter, Chem. Eur.
J. 2000, 6, 2362; f) reference [26b]; for an example of a conjugated
phenylethynyl macrocycle incorporating phenanthroline units, see
g) M. Schmittel, H. Ammon, Synlett 1999, 750.
[42] The requirement of 1.5 equivalents of AgI for complete coordination
of 3 rather than the expected 1:1 3/AgI ratio, suggests a concentration-
dependent binding process. This indicates that a relatively weak
association between 3 and AgI exists at low [3].
[43] For a study of p cation interactions between benzenoid cyclophanes
and HgII, TlI and AgI, see: a) J. Gross, G. Harder, A. Siepen, J. Harren,
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¬
Chem. 2000, 602, 91. For ethyne PdR2 interactions, see: c) R. Uson, J.
¬
¬
¬
[29] For the employment of analyte-binding-induced mechanical distor-
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example: a) D. H. Charych, J. O. Nagy, W. Spevak, M. D. Bednarski,
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twisted and coplanar forms of 1, 4-bis(phenylethynyl)benzene are
spectroscopically distinct species, see: e) M. Levitus, K. Schmieder, H.
Ricks, K. D. Shimizu, U. H. F. Bunz, M. A. Garcia-Garibay, J. Am.
Chem. Soc. 2001, 123, 4259; the difference originates from the excited
state which can exist as energetically different structures, the all-
planar one of which has a delocalised cumulene-type bonding pattern.
This also supports the expectation that mechanical variations in 2 may
be accompanied by spectroscopic changes.
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[44] CuII is a significant environmental pollutant and an essential trace
element of life. Copper proteins occur in bacteria, plants, higher
organisms and mammals and perform many diverse functions. For
example, superoxide dismutase removes the toxic superoxide radical
anion produced by phagocytes, cytochrome c oxidase mediates the last
phosphorylation in the respiratory chain, the monooxygenases
dopamine b-monooxygenase and tyrosinase perform catalytic oxida-
tive transformations in the adrenal cortex and skin respectively,
plastocyanin and azurin participate in plant and bacterial photosyn-
thesis, and ceruloplasmin mediates copper transport and storage. In
view of the manifold biological roles of copper, the discovery of new
lead sensors for this important element will continue to be of especial
interest. For recent examples of fluorescence chemosensors for CuII
ƒ
[30] Reports on the use of pyridine-type ligands connected to/or within
electronically delocalised organic scaffolds for the sensing of metal
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[45] Within the context of the above work, the qualitative parameters used
to describe the metal-ion binding and sensing properties of ligands 2, 3
and 9, are defined as follows: Complexation selectivity, that is, the
number of different types of metal ions that a given ligand is able to
complex; the greater the number, the lower the selectivity. Complex-
ation discrimination, that is, the number of strongest coordinating
metal ions that equally bind to a given ligand; the higher the number,
the less the discrimination. Sensory selectivity, the number of
coordinating metal ions that produce similar fluorescence responses;
the higher the number, the less the fluorescence selectivity. Output
signal intensity, the estimated fluorescence detection limit for a given
metal ion, which may be signalled both visually and instrumentally.
[46] The fluorescence emission detection limits for AgI by 2 and CuII by 3
were estimated to be at [AgI] ˆ 1  10À6 and [CuII] ˆ 6 Â
10À7 moldmÀ3, respectively, whereas the estimated detection limit
Chem. Eur. J. 2002, 8, No. 22
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5263

P. N. W. Baxter
FULL PAPER
for ZnII by 1 was at [ZnII] ˆ 3  10À6 moldmÀ3 in 1:2 CHCl3/MeOH.
The fluorescence responses of 2 and 3 appear to be generally slightly
more sensitive to the presence of metal ions than that of 1. However, if
complexation-induced mechano-structural changes are occurring in 2
and 3, the resulting influence upon fluorescence signal amplification
must be small. The above results suggest that increasing the
conjugation and electronic delocalisation of the sensors may be a
more effective future approach to optimising the fluorescence
emission sensitivity and thus lowering the sensory detection limit for
particular metal ions.
scaffolds for metal-ion sensory applications. The majority of tradi-
tional ion sensors are constructed from nonaromatic cyclic and acyclic
binding sites connected to or incorporated into classical fluorophores
such as fluorescein. See for example, K. R. Gee, Z.-L. Zhou, W.-J.
Qian, R. Kennedy, J. Am. Chem. Soc. 2002, 124, 776.
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¡
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[47] Molecules 2, 3 and 9 may be regarded as members of a lead class of
metal sensors, as they are structurally significantly different from
systems normally employed for this purpose. In particular, 2 and 3 are
among the first examples of the utilisation of conjugated cyclic ethynyl
53.
Received: May 15, 2002 [F4095]
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