Synthesis and properties of a twistophane ion sensor: A new conjugated macrocyclic ligand for the spectroscopic detection of metal ions

Article abstract of DOI:10.1021/jo001777d

The synthesis of a structurally new type of conjugated macrocyclic ligand (1) is reported that comprises a dehydroannulene framework incorporating two 2,2′-bipyridine units. Modeling studies showed the ligand to possess an unusual chirally twisted and relatively rigid architecture capable of binding metal ions in an enforced tetrahedral coordination geometry. The macrocycle was prepared in seven steps from (2-bromophenylethynyl)-trimethylsilane (2) and characterized by spectroscopic techniques. The pyridine H3 protons in the ¹H NMR spectrum of 1 showed a marked temperature dependencey that may be related to conformational opening and closing motions of the macrocyclic ring. Ligand 1 was found to spectroscopically detect the presence of Co²⁺, Ni²⁺, Cu²⁺, and Zn²⁺ and, in particular, to function as a multiple readout sensor, giving different sequences of signal output depending upon the type of metal ion analyte with which the system was addressed. Macrocycle 1 also gave a highly characteristic and specific visual output response in the presence of Zn²⁺ consisting of a bright turquoise fluorescence and in this respect may find applications in the sensing of this biologically important metal ion.

Full text of DOI:10.1021/jo001777d

4170
J . Org. Chem. 2001, 66, 4170-4179
Syn th esis a n d P r op er ties of a Tw istop h a n e Ion Sen sor : A New
Con ju ga ted Ma cr ocyclic Liga n d for th e Sp ectr oscop ic Detection of
Meta l Ion s
Paul N. W. Baxter
Laboratoire de Chimie Supramole´culair, Institut Le Bel, Universite´ Louis Pasteur, 4 rue Blaise Pascal,
F-67000 Strasbourg, France
pbaxter@chimie.u-strasbg.fr
Received December 22, 2000
The synthesis of a structurally new type of conjugated macrocyclic ligand (1) is reported that
comprises a dehydroannulene framework incorporating two 2,2′-bipyridine units. Modeling studies
showed the ligand to possess an unusual chirally twisted and relatively rigid architecture capable
of binding metal ions in an enforced tetrahedral coordination geometry. The macrocycle was prepared
in seven steps from (2-bromophenylethynyl)-trimethylsilane (2) and characterized by spectroscopic
1
techniques. The pyridine H3 protons in the H NMR spectrum of 1 showed a marked temperature
dependencey that may be related to conformational opening and closing motions of the macrocyclic
ring. Ligand 1 was found to spectroscopically detect the presence of Co2+, Ni2+, Cu2+, and Zn2+
and, in particular, to function as a multiple readout sensor, giving different sequences of signal
output depending upon the type of metal ion analyte with which the system was addressed.
Macrocycle 1 also gave a highly characteristic and specific visual output response in the presence
of Zn2+ consisting of a bright turquoise fluorescence and in this respect may find applications in
the sensing of this biologically important metal ion.
In tr od u ction
carbon network components,8a-e macrocyclic struc-
tures,7c,9a-b hinged molecular cages7c,10a,b and fullerene
precursors.11 Many of these constructs have served as
model systems for the study of fundamental issues such
as electron and energy transfer,12a,b donor-acceptor
conjugation circuitry,13a,b and foldamer dynamics and
molecular helicity.14a-c They have also recently been
demonstrated to exhibit properties such as host-guest
inclusion,14c,15a-c NLO behavior,16 liquid crystallinity,17
sensing,18 and porosity19a-b and may thus play an im-
After a period of quiescence spanning almost 20 years,
acetylene chemistry has again become the focus of intense
activity and interest within the chemical community.1
Many factors have contributed to this era of renaissance,
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availability of a suite of transition metal-catalyzed
carbon-carbon coupling protocols,2a,b (2) the discovery of
naturally occurring enediyne antibiotics,3 (3) the theo-
retical prediction of ethynyl-expanded all-carbon net-
works with novel materials properties,4a-c and perhaps
most importantly, (4) the discovery of fullerenes and
carbon nanotubes.5
In particular, the latter two developments have in-
spired the creation of a wealth of unsaturated hydrocar-
bon architectures incorporating multiple numbers of
ethynyl subunits such as conjugated molecular polymers
and wires,6a,b hyperbranched dendritic structures,7a-c
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31, 1101. (b) Diederich, F. Nature 1994, 369, 199. (c) Feldman, K. S.;
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Science 1997, 277, 1793. (b) Prince, R. B.; Saven, J . G.; Wolynes, P.
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10.1021/jo001777d CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/19/2001

Synthesis and Properties of a Twistophane Ion Sensor
J . Org. Chem., Vol. 66, No. 12, 2001 4171
portant role in the emerging fields of molecular electron-
ics and nanotechnology.
sensor for the detection of specific types of metal ions.28
It was concluded from the latter study that a further
improvement in selectivity toward particular metal ions
may be achieved by designing a macrocyclic analogue
that combines the necessary structural requirements of
enhanced conjugation with a spatially enforced coordina-
tion pocket upon binding to a metal ion of complementary
size. As a first step toward this goal, it was decided to
prepare cyclophane 1 (Scheme 1), which comprises a
dehydroannulene-type hydrocarbon framework incorpo-
rating two 5,5′-disubstituted 2,2′-bipyridine ligand units
positioned on opposite sides of the macrocyclic ring.29a-g
Cyclophane 1 is an ortho-cyclically conjugated structure
and should in principle undergo significant electron
distribution perturbations upon coordination to metal
ions. Macrocycle 1 may, therefore, represent an optimized
scaffold for the optical sensing of metal ions of preferred
tetrahedral coordination geometry.
The following account describes the successful synthe-
sis of 1, its structural characterization by spectroscopic
techniques, its physicochemical properties and a detailed
investigation into its metal ion coordination behavior.
The metal ion-binding studies in particular, amply
demonstrated the validity of the above expectations and
showed 1 to be a specific chromogenic flourescent sensor
for Zn2+ ions.
Syn th esis of 1. Macrocycle 1 was synthesized in
reasonable overall yield via a seven-step reaction se-
quence starting from the commercially available (2-
bromophenylethynyl)trimethylsilane (2) and 2-chloro-5-
iodopyridine (3) (Scheme 1). Initially, 3 was converted
to 2-chloro-5-trimethylsilylethynylpyridine (4) via a So-
nogashira reaction30a,b with trimethylsilylethyne, and 4
subsequently deprotected with aqueous NaOH to give
2-chloro-5-ethynylpyridine (5) as reported previously.28
However, the reaction between 2 and 5 in triethylamine
at 80-100 °C in the presence of CuI and PdCl2(PPh3)2
catalysts resulted in the formation of 2-chloro, 5-[(2-
trimethylsilylethynylphenyl)ethynyl]pyridine (7) in only
low and irreproducible yields. Varying the relative quan-
tities of CuI and PdCl2(PPh3)2 also failed to provide any
yield enhancements. The reason for this may in part
originate from the thermal instability of 4 under the
Sonogashira reaction conditions. It was therefore decided
to proceed using the more reactive (2-iodophenylethynyl)-
trimethylsilane (6) in place of 2.
Interestingly, some of the earliest types of multiethynyl
hydrocarbons to be described in the literature were
macrocycles.1 In recent years, the number of reports on
macrocyclic structures have rapidly increased such that
they currently represent one of the largest classes of
polyethynyl hydrocarbon scaffolds comprising a great
diversity of species such as, for example, annulenes,20
dehydroannulenes,1,21a-c expanded radialenes,22 cyclines,
[n]pericyclines, expanded [n]pericyclines,1,23a,b [n]rotanes,
exploded [n]rotanes,1,24 and many varied types of ethynyl-
incorporated cyclophanes.25a-d As well as addressing basic
questions on aromaticity and cyclic conjugation, a num-
ber of these macrocycles have been shown to function as
high energy materials and as precursors to carbon
nanotubules.1,24,26
To establish new properties and further potential
applications of these fascinating compounds, one avenue
of especial interest would be to create macrocyclic hy-
drocarbon architectures of the types described above,
which additionally incorporate sites for the purpose of
binding metal ions.23a,27 The combined structural features
comprising rigid preorganization, spatially well-defined
shape, extensive conjugation, and electronically linked
metal ions would yield a new class of hybrid organic/
inorganic molecular materials that would be expected to
display a range of physicochemical properties in addition
to those of the parent hydrocarbon. Compounds of this
type may thus exhibit multiple redox, photochemical,
optical, catalytic, substrate inclusion, and sensing ability
as well as bulk properties such as magnetic and unusual
mechanical behavior.
In earlier work, it was demonsrated that the linear
conjugated rigid-rod ligand, 1,4-bis[5-ethynyl-(5′-methyl-
2, 2′-bipyridyl)]benzene was able to function as an optical
(18) McQuade, D. T.; Pullen, A. E.; Swager, T. M. Chem. Rev. 2000,
100, 2537.
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1994, 371, 591. (b) Venkataraman, D.; Gardner, G. B.; Lee, S.; Moore,
J . S. J . Am. Chem. Soc. 1995, 117, 11600.
(20) Garratt, P. J . In Comprehensve Organic Chemistry; The syn-
thesis and Reactions of Organic Compounds; Stoddart, J . F., Ed.;
Pergamon: New York, 1979; Vol. 1, Chapter 2.6, p 361.
(21) For reviews on dehydrobenzoannulenes, see; (a) Haley, M. M.
Synlett 1998, 557. (b) Kehoe, J . M.; Kiley, J . H.; English, J . J .; J ohnson,
C. A.; Petersen, R. C.; Haley, M. M. Org. Lett. 2000, 2, 969. (c) Haley,
M. M.; Wan, W. B. In Advances in Strained and Interesting Organic
Molecules; Halton, B., Ed.; J AI Press: New York, 2000; Vol. 8, pp1-
41.
Thus treatment of 2 in diethyl ether solution at -78
°C with 1 equiv of n-butyllithium resulted in quantitative
(22) Eisler. S.; Tykwinski, R. R. Angew. Chem., Int. Ed. Engl. 1999,
38, 1940 and references therein.
(23) (a) Scott, L. T.; DeCicco, G. J .; Hyun, J . L.; Reinhardt, G. J .
Am. Chem. Soc. 1985, 107, 6546. (b) Scott, L. T.; Cooney, M. J .; Otte,
C.; Puls, C.; Haumann, T.; Boese, R.; Carroll, P. J .; Smith, A. B., III;
de Meijere, A. J . Am. Chem. Soc. 1994, 116, 10275.
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R.; Cooney, M. J .; Scott, L. T. Angew. Chem., Int. Ed. Engl. 1994, 33,
869.
(25) See, for example, porphyrin-incorporated ethynyl cyclophanes;
(a) Sanders, J . K. M. In Comprehensive Supramolecular Chemistry;
Atwood, J . L., Davies, J . E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Vol.
9 (Sauvage, J .-P., Wais Hosseini, M., Vol. Eds.); Pergamon: New York,
1996; Chapter 4, p 131. C60/ethynyl cyclophane conjugates: (b) Isaacs,
L.; Seiler, P.; Diederich, F. Angew. Chem., Int. Ed. Engl. 1995, 34, 1466.
Acetylenosaccharide cyclophanes: (c) Bu¨rli, R.; Vasella, A. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1852. Paraphenylethynyl cyclophane
belts: (d) Kawase, T.; Darabi, H. R.; Oda, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2664.
(28) Baxter, P. N. W. J . Org. Chem. 2000, 65, 1257.
(29) Literature descriptions of pyridine and 2,2′-bipyridine-contain-
ing macrocycles with conjugated bridging units are rare. The synthesis
of such materials has however recently been the focus of revived
interest. For a report on the synthesis of butadiyne-bridged (2,6)-
pyridinophane macrocycles, see: (a) Tobe, Y.; Nagano, A.; Kawabata,
K.; Sonoda, M.; Naemura, K. Org. Lett. 2000, 2, 3265. For a recently
reported planar m-ethynylphenyl-type macrocycle incorporating two
2,2′-bipyridine units, see: (b) Henze, O.; Lentz, D.; Schlu¨ter, A. D.
Chem. Eur. J . 2000, 6, 2362. For a biphenyl-bridged bis-terpyridine
macrocycle, see: (c) Lehmann, U.; Schlu¨ter, A. D. Eur. J . Org. Chem.
2000, 3483. For ethenyl- and phenylethenyl-bridged 2, 2′-bipyridine-
incorporated macrocycles, see: (d) Kocian, O.; Mortimer, R. J .; Beer,
P. D. Tetrahedron Lett. 1990, 31, 5069. (e) Vo¨gtle, F.; Hochberg, R.;
Kochendo¨rfer, F.; Windscheif, P.-M.; Volkmann, M.; J ansen, M. Chem.
Ber. 1990, 123, 2181. For organometallic macrocycles comprising three
2, 2′-bipyridine units with zirconacyclopentadiene bridges, see: (f)
Nitschke, J .; Tilley, T. D. J . Org. Chem. 1998, 63, 3673. (g) Nitschke,
J . R.; Zu¨rcher, S.; Tilley, T. D. J . Am. Chem. Soc. 2000, 122, 10345.
(30) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 50, 4467. (b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627.
(26) Boese, R.; Matzger, A. J .; Vollhardt, K. P. C. J . Am. Chem. Soc.
1997, 119, 2052.
(27) Ethynyl-incorporated cyclophanes that externally bind metal
ions to the macrocyclic framework are rare. See, for example: Solooki,
D.; Bradshaw, J . D.; Tessier, C. A.; Youngs, W. J . Organometallics
1994, 13, 451 and references therein.

4172 J . Org. Chem., Vol. 66, No. 12, 2001
Sch em e 1. Syn th esis of Ma cr ocycle 1a
Baxter
a
Reaction conditions and yields: (i) PdCl2(PPh3)2 and CuI cat., Et3N, TMS(ethyne), 20 °C, 48 h (94%); (ii) aqueous NaOH, THF, MeOH,
20 °C, e24 h (82-95%); (iii) n-BuLi, Et2O, -78 °C, 3 h, then ICH2CH2I quench (95%); (iv) PdCl2(PPh3)2 and CuI cat., Et3N, 20 °C, 48 h
(80%); (v) Sn2Me6, PdCl2(dppf)‚CH2Cl2 cat., toluene, 120 °C, 20 h, (73%); (vi) 1 M (n-Bu)4NF, THF, H2O, 20 °C, 20 h (96%); (vii) CuCl cat.,
O2, pyridine, 20 °C (34%); (viii) as in (ii) (95%); (ix) as in (vii) (86%); (x) as in (v), zero yield.
lithium-halogen exchange to give (2-lithiophenylethyn-
yl)trimethylsilane, which was subsequently quenched
with excess 1,2-diiodoethane to furnish 6 in 95% yield
after workup. This lithiation/iodination protocol was
found to be more efficient than that of the reported
statistical preparation of 6 via a transition metal-
catalyzed reaction between 1,2-diiodobenzene and tri-
methylsilylethyne.31 The latter approach necessitated
the additional laborious chromatographic separation of
the product from unreacted 1,2-diiodobenzene and 1,2-
bis(trimethylsilylethynyl)benzene. The Sonogashira reacion
of 6 with 5 at ambient temperature under conditions
similar to those employed for the reaction with 2 in place
of 6 resulted in the formation of 7 in 80% yield after
chromatography.
Although surprisingly little used, a mild and efficient
method for the palladium-catalyzed homocoupling of aryl
halides has been reported using hexamethylditin as an
in situ stannylating agent.32a-c The documented ability
of 2-chloropyridines to undergo Stille cross-coupling
reactions33a,b therefore suggested that the former meth-
odology may be applicable to the homocoupling of 7.
However, refluxing 7 together with 0.6 equiv of Sn2Me6
and a catalytic amount of Pd(PPh3)4 in toluene solution
resulted only in the isolation of unreacted 7. Subsequent
experimental investigations revealed that a dramatic
effect on the reaction occurred when the Pd(PPh3)4 was
replaced by PdCl2(dppf). Using the latter catalyst, the
desired product 5,5′-bis[(2-trimethylsilylethynylphenyl)-
ethynyl]-2, 2′-bipyridine (8) was isolated in 73% yield
under identical reaction conditions. This effect may be
related to the 96° P-Pd-P bite angle of PdCl2(dppf),
which lies at an optimal value for electronically facilitat-
ing the oxidative addition and reductive elimination steps
of the catalytic cycle, and responsible for the enhanced
activity of this complex.34 The trimethylsilyl protecting
groups of 8 were best removed with an aqueous THF
solution of (n-Bu)4NF to give 5,5′-bis[(2-ethynylphenyl)-
ethynyl]-2,2′-bipyridine (9) in 96% isolated yield as an
air-stable white solid. The alternative procedure using
1-5 equiv of aqueous NaOH per TMS group of 8 required
extended reaction times and resulted in the formation
of a crude product of inferior purity.
Finally, the CuCl-catalyzed oxidative Hay coupling35
of 9 in pyridine solution at ambient temperature fur-
nished the desired cyclophane 1 in 34% yield as an
amorphous white, light-sensitive solid after workup. Prior
to purification, the crude yield of 1 also contained a pale
yellow byproduct that was completely insoluble in the
conventional laboratory organic solvents and probably
comprised uncyclized oligomeric and polymeric deriva-
tives of 9. Interestingly, the column chromatographic
purification of 1 using toluene as the eluant failed to yield
any trace of higher oligomeric cyclized homologues.
(31) Nicolaou, K. C.; Dai, W.-M.; Hong, Y. P.; Tsay, S.-C.; Baldridge,
K. K.; Siegel, J . S. J . Am. Chem. Soc. 1993, 115, 7944.
(32) (a) Ross Kelly, T.; Bowyer, M. C.; Vijaya Bhaskar, K.; Bebbing-
ton, D.; Garcia, A.; Lang, F.; Kim, M. H.; J ette, M. P. J . Am. Chem.
Soc. 1994, 116, 3657. (b) Ross Kelly, T.; Lee, Y.-J .; Mears, R. J . J . Org.
Chem. 1997, 62, 2774. (c) Olivera, R.; Pascual, S.; Herrero, M.;
SanMartin, R.; Dom´ınguez, E. Tetrahedron Lett. 1998, 39, 7155.
(33) For examples of Stille cross-couplings of 2-chloropyridines to
give substituted 2,2′-bipyridines, see, for example: (a) Ghadiri, M. R.;
Soares, C.; Choi, C. J . Am. Chem. Soc. 1992, 114, 825. (b) Zhang, B.;
Breslow, R. J . Am. Chem. Soc. 1997, 119, 1676.
(34) Dierkes, P.; van Leeuwen, P. W. N. M. J . Chem. Soc., Dalton
Trans. 1999, 1519.
(35) Hay, A. S. J . Org. Chem. 1962, 27, 3320.

Synthesis and Properties of a Twistophane Ion Sensor
J . Org. Chem., Vol. 66, No. 12, 2001 4173
1
However, the existence of such cyclic byproducts cannot
be ruled out, as it may be that their solubility in toluene
was also too low to allow isolation by chromatography.
It must be noted that 1 was soluble in only a relatively
restricted number of solvents such as hot 1,1,2,2-tetra-
chloroethane, toluene, pyridine, and very dilute, hot
CHCl3.
basis of H-1H COSY connectivities and spectral com-
parisons with the proton NMRs of 7, 8 and 9 to the
respective H3 and H4 protons of the pyridine rings. The
narrow doublet at 8.71 ppm was also thus assigned to
the characteristically deshielded pyridine H6 proton. The
pair of multiplets centered at 7.70 and 7.44 ppm on the
other hand corresponded to those of the four chemically
and magnetically inequivalent protons of the 1, 2-disub-
stituted phenyl rings. The former group of overlapping
bands of simpler multiplicity were assigned to the H3
and H6 phenyl ring protons ortho to the alkynes. These
would be expected to occur further downfield due to the
electron-withdrawing effect of the pyridine rings trans-
mitted through the intervening ethyne bonds. The latter
higher field and more complex multiplet was therefore
assigned to the overlapping signals of the phenyl ring
H4 and H5 protons in meta and para positions with
respect to the ethyne groups.
In parallel to the above-described synthesis of macro-
cycle 1, an alternative reaction pathway via the inter-
mediate products 10 and 11 was also investigated
(Scheme 1). Thus, aqueous NaOH-promoted deprotection
of the trimethylsilyl group of 7 provided 2-chloro-5-[(2-
ethynylphenyl)ethynyl]pyridine (10) in 95% yield after
chromatography. Subsequent oxidative dimerization of
10 in pyridine solution at ambient temperature with a
catalytic amount of CuCl furnished [1,3-butadiyne-1,4-
diylbis(2,1-phenylene-2,1-ethynediyl)]-bis[5-(2-chloropyr-
idine)] (11) in 86% isolated yield as light-sensitive
crystals. Refluxing 11 together with 1.2 equiv of Sn2Me6
and a catalytic amount of PdCl2(dppf) in toluene solution
under medium dilution conditions resulted in complete
reaction and consumption of the starting 11. However
no trace of 1 was detected in the reaction mixture, a
result that is consistent with the instability of 11 toward
thermally induced polymerizations under Stille coupling
conditions.
Interestingly, the chemical shifts of some of the protons
in the H NMR spectrum of 1 showed a marked temper-
1
ature dependence (Figure 1). In particular, the 2,2′-
bipyridine H3 protons experienced a significant and
continual downfield shift from 7.68 to 7.91 ppm in CDCl2-
CDCl2 solution upon increasing the temperature from
zero to 120 °C. The phenomenon was completely revers-
ible, as re-cooling resulted in regeneration of the original
ambient temperature spectrum and reheating gave spec-
tra identical to those previously obtained at high tem-
perature. Comparison of the ambient temperature (25 °C)
proton NMR spectrum of 1 with those of 8 and 9 revealed
that the pyridine H3 protons of 1 occurred at an abnor-
mally upfield position at 7.71 ppm. In 8 and 9, the
pyridine H3 protons were situated at 8.46 and 8.45 ppm,
respectively, in CHCl3 solution. Heating the solution of
1 therefore causes the surrounding chemical and mag-
netic environment of the pyridine H3 protons to become
more similar to that of the corresponding protons of
uncyclized 8 and 9. Furthermore, heating a CHCl3
solution of 8 from 25 to 60 °C resulted in only a small
change in the chemical shift of the pyridine H3 protons
from 8.46 to 8.47 ppm, showing that the temperature-
dependent effect in 1 originates from the presence of a
specific structural feature within the latter compound.
A possible explanation for the unusually shielded
environment of the pyridine H3 protons of 1 and their
progressive deshielding upon increasing the temperature
may lie in the conformational properties of the macro-
cyclic architecture. Molecular modeling performed upon
the cyclic architectural assignment of 1 (Figure 2) showed
the minimum energy conformation to be highly twisted
with the 2,2′-bipyridine units in very close proximity. The
pyridine H3 protons in particular lie closest of all to each
adjacent 2,2′-bipyridine unit. They must therefore spend
a significant period of time on the NMR time scale lying
against the surface of the partner 2,2′-bipyridine unit and
pointing toward the interior of the cavity of 1 as the two
2,2′-bipyridines rotate alongside each other. As a result,
the pyridine H3 protons would be expected to be shielded
to a greater extent than normal. Furthermore, the
twisted conformation of 1 is chiral and possibly flexible
enough to allow facile enantiomer interconversion via a
flattened and open macrocyclic transition state. Increas-
ing the temperature of the system would induce an
increased degree of enantiomer interconversion and thus
an increased opening of the macrocyclic ring. The pyri-
dine H3 protons would therefore experience a greater
Ch a r a cter iza tion of 1. The structure of the product
isolated from the Hay coupling of 9 was established to
be that of the macrocyclic architecture 1 (Scheme 1) on
the basis of mass spectroscopic, infrared spectroscopic,
1H NMR, and 13C NMR studies.
The FAB mass spectrum of the coupling product
recorded in CF3COOH solution displayed only a single
cluster of isotopic peaks, the most intense of which
occurring at m/z ) 805. The intensity and distribution
pattern of the latter isotope cluster corresponded exactly
to that calculated for the M + 1 isotopic envelope of the
structure depicted for 1. The high-resolution FAB mass
spectrum of the latter M + 1 isotopic cluster also
confirmed the exact elemental composition of the product
to be C60H29N4, i.e., that expected for the macrocyclic
structural assignment for 1 plus a hydrogen atom.
The infrared spectrum of the Hay coupling product of
9 also reinforced the above structural assignment to that
of 1. The IR spectrum was surprisingly simple, displaying
only five strong bands, and indicative of a highly sym-
metric structure such as 1. In addition, the normally very
intense peak originating from the ν(C-H) stretch of a
terminal ethyne was comletely absent in the IR spectrum
of the coupling product of 9. This observation rules out
the possibility of the product being a linear oligomer with
terminal unreacted ethyne groups and establishes that
it is a macrocyclic entity.
The 13C NMR spectrum of the product from the
coupling of 9 was also consistent with that of a macro-
cyclic structural identity and displayed the expected
fifteen peaks, four of which corresponded to the carbons
of two chemically and magnetically inequivalent difunc-
tionalized ethynes at 78.1 to 92.0 ppm. The proton NMR
spectrum of the coupling product of 9, recorded at 100
°C in CDCl2CDCl2 was additionally supportive of the
cyclic structure illustrated for 1 in Scheme 1, displaying
the expected five peaks (two sets overlapping), and with
a complete absence of any bands originating from the
protons of terminal ethynes. The doublet at 7.88 ppm and
the doublet of doublets at 7.80 ppm were assigned on the

4174 J . Org. Chem., Vol. 66, No. 12, 2001
Baxter
F igu r e 2. Energy-minimized structure of macrocycle 1 show-
ing the chirally twisted cyclophane framework: plan view stick
representation (top), CPK representation (center), and side
view through ring (bottom), CPK representation. (The mini-
mization was performed using the MMFF force field with
MacroModel version 5.5 (Columbia University, NY).)
F igu r e 1. Variation in the chemical shifts of the protons of 1
with temperature. Note the maximum relative deshielding
experienced by the pyridine H3 protons upon increasing
1
temperature (the H NMR spectra were recorded at 500 MHz
in CDCl2CDCl2 solution).
be expected to be able to bind metal ions of complemen-
tary size. This possibility coupled with the enhanced
cyclic conjugation resulting from the intervening ethynyl
and butadienyl bridges suggested that 1 may display very
selective binding characteristics toward particular metal
ions and that it would also undergo spectroscopic changes
upon coordination. Subsequent experimental investiga-
tions confirmed that this was indeed the case.
degree of exposure to the surrounding medium at suc-
cessively higher temperatures and thus a progressively
increasing degree of deshielding.
Sp ectr oscop ic Sen sin g of Meta l Ion s by 1. The
relatively rigid and twisted structure of cyclophane 1
comprises a mutually crossed arrangement of two 2,2′-
bipyridine ligands in its lowest energy conformation
(Figure 2), held in position by two bridging diphenyl-1,4-
butadienyl subunits on opposite sides of the macrocycle.
Product 1 may therefore be described as a “twistophane”,
the distinctive and specific stuctural features of which
constitute a rare but slowly expanding class of cyclophane
scaffolds.26,36a-f Molecular modeling studies on 1 also
revealed that when the 2,2′-bipyridine rings are in a
cisoid conformation with all nitrogen lone pairs directed
toward the interior of the cavity of the macrocycle, small
flexures in the ligand framework can open up a small
central void. The cavity possesses an enforced tetrahedral
arrangement of nitrogen lone pair electrons that would
UV/Vis Absor p tion Sp ectr a . To obtain a detailed
picture of the coordination properties of 1, UV/vis spectra
(36) For reports on the preparation of structurally related, twisted
macrocyclic hydrocarbons, see: (a) Baldwin, K. P.; Bradshaw, J . D.;
Tessier, C. A.; Youngs, W. J . Synlett, 1993, 853. (b) Guo, L.; Bradshaw,
J . D.; Tessier, C. A.; Youngs, W. J . J . Chem. Soc., Chem. Commun.
1994, 243.(c) Baldwin, K. P.; Simons, R. S.; Rose, J .; Zimmerman, P.;
Hercules, D. M.; Tessier, C. A.; Youngs, W. J . J . Chem. Soc., Chem.
Commun. 1994, 1257. (d) Haley, M. M.; Bell, M. L.; English, J . J .;
J ohnson, C. A.; Weakley, T. J . R. J . Am. Chem. Soc. 1997, 119, 2956.
(e) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Angew. Chem., Int. Ed.
Engl. 2000, 39, 385. (f) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org.
Lett. 2000, 2, 3189.

Synthesis and Properties of a Twistophane Ion Sensor
J . Org. Chem., Vol. 66, No. 12, 2001 4175
F igu r e 5. UV/vis spectra of the titration of Zn2+ into 1 at a
[1] of 6.56 × 10-6 mol L-1 in 1:2 CHCl3/MeOH and 1/Zn2+ ratios
of, respectively, 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, and 1:2.5.
F igu r e 3. UV/vis absorption spectra of 1:1 stoichiometric
mixtures of 1 with M2+ in 1:2, CHCl3/MeOH, where M2+
)
Co2+, Ni2+, Cu2+ and Zn2+ and at a [1] of 6.56 × 10-6 mol L-1
.
metal ions and were instead replaced by two new bands
at 299 and 332 nm, respectively. The relative magnitudes
of the metal ion-induced perturbations of the absorption
envelopes of 1:1 solutions of 1:Mn+ in 1:2 CHCl3/MeOH
were found to lie in the following order Cu2+ ≈ Co2+
>
Ni2+ > Zn2+ (Figure 3).37
The addition of Co2+ and Cu2+ (Figures 3 and 4)
therefore provokes the greatest and most dramatic
changes in the UV/vis spectrum of 1, and Zn2+ gives the
smallest perturbation within the series (Figures 3 and
5). In addition, Cu2+ causes a further bathochromic shift
in the edge of the lowest energy absorption envelope of 1
(Figure 4). This effect is signaled by the development of
a yellow coloration at 1/Cu2+ ratios of 1:g2. On the other
hand, either negligible or zero changes were observed in
the UV/Visible spectrum of 1 upon 1:1 stoichiometric
combination with Mn+ in 1:2 CHCl3/MeOH at a [1] of
6.56 × 10-6 mol L-1, where Mn+ ) Li+, Na+, K+, Mg2+
,
F igu r e 4. UV/vis spectra of the titration of Cu2+ into 1 at a
[1] of 6.56 × 10-6 mol L-1 in 1:2 CHCl3/MeOH and 1/Cu2+
ratios of, respectively, 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1, 1:1.5, and
1:3.
Ca2+, Sc3+, Cr3+, Mn2+, Fe2+, Ag+, Cd2+, Hg2+, Pb2+, Tl+,
In3+, La3+, Eu3+, and Tb3+ 38
Macrocycle 1 therefore
.
exhibits preferential binding to late first row transition
metals, i.e., metal cations which satisfy the following
criteria: (1) high surface charge density, (2) ionic
radii e 0.96 Å (i.e., the radius of Cu+, which was the
largest cation found to interact with 1),37 (3) adaptable
coordination polyhedra, and (4) an electronic preference
for nitrogen donor ligands.
To evaluate the ability of 1 to discriminate and signal
specific metal ions in the presence of other metal cations,
competitive binding experiments were performed. Thus,
of 1:1 stoichiometric mixtures of 1:Mn+ in 1:2 CHCl3/
MeOH were recorded at a [1] of 6.56 × 10-6 mol L-1. The
UV/vis spectra of free uncoordinated 1 in 1:2 CHCl3/
MeOH and pure CHCl3 display a series of intense
absorption maxima at 316, 356, and 384 nm, character-
istic of conjugated oligophenylethynyl structures. The
energies and shape of these bands remained invarient
over the concentration range of 8.7 × 10-7-1.1 × 10-5
mol L-1 in CHCl3 showing that 1 was not undergoing
aggregation in dilute solution. A slight hypsochromic shift
in the most intense absorption from 356 to 352 nm did,
however, occur upon changing the solvent from pure
CHCl3 to 1:2 CHCl3/MeOH. Stoichiometric 1:1 solutions
of 1 with Co2+, Ni2+, Cu2+, and Zn2+ in 1:2 CHCl3/MeOH
gave spectra that were significantly different from that
of the free ligand and indicative of coordination of these
metal ions to 1 (Figures 3-5). In all four cases, the
presence of the metal ion caused a significant reduction
in the extinction coefficient of the most intensely absorb-
ing band of the free ligand at 352 nm and an accompany-
ing slight shift to higher energy. The maxima at 316 and
384 nm in the spectrum of 1 also completely disappeared
in the presence of gstoichiometric ratios of the above
(37) The metal ion salts used in the study were CoCl2‚6H2O, NiCl2‚
6H2O, ZnCl2, and Cu(CF3SO3)2 and were all g99.9% purity. They were
each dissolved into one drop of distilled water prior to the preparation
of standard solutions in methanol in order to ensure complete solubil-
ity. Copper(I) in the form of [Cu(MeCN)4](CF3SO3), also bound to 1 as
evidenced by coordination induced perturbations in the UV/vis spec-
trum of the ligand. This was not investigated further at this stage as
a greater number of sensory applications are to be found for copper-
(II) which is both more stable and of greater abundance in nature.
(38) Chromium(III) and iron(II) were used as the respective CrCl3‚
6H2O and anhydrous FeCl2 salts, and were also dissolved into a drop
of distilled water prior to solution preparation in MeOH. All remaining
metal ions investigated were in the form of the anhydrous triflate salts.
A 1:1 mixture of NH4(CF3SO3) and 1 in 1:2 CHCl3/MeOH at the same
concentration as that used for the metal ion-binding studies produced
no change in the UV/vis spectrum of the ligand, indicating a weak or
negligible interaction between the latter two species.

4176 J . Org. Chem., Vol. 66, No. 12, 2001
Baxter
UV/vis spectra of 1 at 6.56 × 10-6 mol L-1 with stoichio-
metric mixtures of ions taken from the series Co2+, Ni2+
,
Cu2+, and Zn2+ were recorded in 1:2 CHCl3/MeOH and
compared to those of the corresponding 1:1 1/Mn+ solu-
tions. A 1:1:1 mixture of 1/Zn2+/Cu2+ yielded a spectrum
intermediate in intensity and shape between those of the
1:1 1/Zn2+ and 1/Cu2+ spectra, suggesting that 1 has a
similar binding propensity toward both Zn2+ and Cu2+
.
Mixtures of 1:1:1 1/Zn2+/Co2+ and 1/Zn2+/Ni2+, on the
other hand, gave spectra identical to those of the 1:1
1/Co2+ and 1/Ni2+ spectra, showing that Zn2+ is displaced
from 1 by Co2+ and Ni2+. A 1:1:1 mixture of 1/Co2+/Ni2+
gave a spectrum intermediate between those of the 1:1
1/Co2+ and 1/Ni2+ spectra, indicating that these two metal
ions have similar binding preferences toward 1. These
results therefore demonstrate that the metal ion binding
strengths to 1 follow the qualitative order Co2+ ≈ Ni2+
>Cu2+ ≈ Zn2+. Interestingly, a 1:1:1:1 mixture of 1/Zn2+
/
F igu r e 6. Normalized fluorescence emission spectra (from left
to right) of uncomplexed 1 and mixtures comprising 1/Zn2+
ratios of, respectively, 1:5, 1:10, 1:100, and 1:1000 in 1:2 CHCl3/
Cd2+/Hg2+ was identical to that of the 1:1 1/Zn2+ solution
at the same [1]. This remarkably strong selectivity for
Zn2+ in the presence of Cd2+ and Hg2+ ions must reflect
the importance of complementarity in size between the
Zn2+ ion and the ligating cavity of 1. Cd2+ and Hg2+ are
presumably too large to coordinate both 2,2′-bipyridine
binding sites of 1 in a strain-free conformation.
MeOH and at a [1] of 6.56 × 10-7 mol L-1
.
increasing the 1/Zn2+ ratio from 1:1 to 1:100 caused the
initial disappearance of the higher energy, lower intensity
emission maximum of 1 at 406 nm and a concomitant
broadening and shifting of the remaining higher intensity
emission envelope at 431 nm to lower energy. Further
incremental additions of Zn2+ resulted in only minor
movements of the emission maximum to lower energy.
The emission maximum eventually reached a limiting
value of 466 nm at a 1/Zn2+ ratio of 1:1000 (Figure 6).
This process could be clearly visualized as a progressive
change in color from the purple-blue fluorescence of pure
1 to a bright turquoise fluorescence characteristic of the
Zn2+ complex of 1. The concentration limit for the
detection of Zn2+ ions as indicated by the onset of the
turquoise fluorescence was estimated to be at a 1/Zn2+
ratio of 1:5 corresponding to a [Zn2+] of 3.3 × 10-6 mol
L-1. Significantly, a 6.56 × 10-6 mol L-1 solution of 1 in
CHCl3 was able to extract ZnCl2 from aqueous solution
in the presence of MeOH at 1/Zn2+ ratios of 1:g100. This
latter phenomenon was again signaled by the appearance
of a turquoise fluorescence in the organic layer, and is
particularly noteworthy considering the fact that 1 is
totally insoluble in water. The fact that 1 is able to
extract Zn2+ out of aqueous solution highlights the
potential practical utility of this type of ligand for metal
ion sensing, as further synthetic incorporation of water
solubilizing groups may not be a prerequisite for the
sensory detection of aqueous analytes.
The metal ion-complexation studies thus revealed that
macrocycle 1 functions as a UV/vis spectroscopic sensor
for Co2+, Ni2+, Cu2+, and Zn2+. Of all metal ions investi-
gated, Cu2+ was found to induce the greatest bathochro-
mic shift in the lower energy absorption edge of 1 (Figure
4). The detection limit for Cu2+ was estimated to be at a
[Cu2+] of 2.63 × 10-6 mol L-1 in the latter spectral
window of 390-435 nm. Macrocycle 1 may therefore
potentially function as a chromogenic spectroscopic sen-
sor for Cu2+ providing that the interfering Co2+, Ni2+, and
Zn2+ cations that compete for binding to 1 are absent.39
F lu or escen ce Em ission Sp ectr a . The fluorescence
emission spectrum of free uncoordinated 1 in CHCl3
solution at 6.56 × 10-7 mol L-1 comprised two emission
maxima at 406 and 431 nm when excited at the wave-
length of the absorption peaks at 316, 356 and 384 nm
respectively. Emission spectra of 1 recorded over the
concentration range of 6.56 × 10-8-6.56 × 10-6 mol L-1
showed negligible shifts in the energy of the maxima
indicating that aggregation of the excited state of 1 was
not a dominant process. Emission spectra were then
recorded of 1:1 stoichiometric combinations of 1/Mn+ in
1:2 CHCl3/MeOH at a [1] of 6.56 × 10-7 mol L-1, and
where Mn+ ) Li+, Na+, K+, Mg2+, Ca2+, Sc3+, Cr3+, Mn2+
Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Ag+, Cd2+, Hg2+, Pb2+, Tl+,
In3+, La3+, Eu3+, and Tb3+ 38
Of all metal ions investi-
,
.
Macrocycle 1 therefore functions as a multisubstrate,
multiple readout sensor that is able to generate different
sequences of output responses depending upon the way
the system is externally addressed. For example, the
presence of Co2+ is signaled by both a decrease in the
UV/vis absorption and fluorescence emission intensities
of 1. The output response for Cu2+ consists of a reduction
in the intensity of the fluorescence emission and absorp-
tion maxima of 1, but with an accompanying bathochro-
mic shift of the lower energy absorption edge. However,
in the case of Zn2+ as the input, a reduction in the
intensity of the absorption maxima of 1 occurs, but the
fluorescence emission undergoes a pronounced batho-
chromic shift which is visually signaled by the develop-
ment of a turquoise fluorescence.40a-c
gated, only Co2+, Ni2+, Cu2+, and Zn2+ induced changes
in the fluorescence emission of 1.37 The presence of Ni2+
caused only a minor reduction in the fluorescence inten-
sity of 1, and with no change in emission energy. However
with Co2+ and Cu2+ a significant drop in the fluorescence
intensity of 1 occurred. This latter effect was dramatically
signaled visually by an almost total extinction of the
characteristic strong purple-blue colored emission of free
1 at a 1:1 1/M2+ ratio.
Zinc ions on the other hand produced an entirely
different effect upon the fluorescence emission of 1. Thus
(39) This limitation may potentially be overcome by the selective
precipitation of interfering cations within the sample prior to the
introduction of the sensor.

Synthesis and Properties of a Twistophane Ion Sensor
J . Org. Chem., Vol. 66, No. 12, 2001 4177
Con clu sion
the system is addressed. In this respect, twistophane 1
operates as a multisubstrate, multiple readout sensor for
multiple types of metal ion analyte. The specific fluores-
cence chromogenic sensing of Zn2+ by 1 is especially
interesting in the light of the biological importance of this
metal ion.41 Macrocycle 1 and related structures may
therefore find potential applications in the detection and
monitoring of Zn2+ in biological media.
Many structural modifications of the conjugated frame-
work of 1 may be envisioned in order to further refine
and optimize its sensory properties and selectivity toward
particular metal ions.42a-d The structural and physico-
chemical properties of twistophane 1 therefore suggest
that this fascinating new type of metal ion-binding
cyclophane may potentially discover a rich variety of
future applications in fields such as molecular sensorics,
catalysis and materials science, and for obtaining fun-
damental insights into unusual metal ion-ligand coordi-
nation processes.
In summary, the above work describes the successful
preparation of macrocycle 1, which is the first represen-
tative member of a new class of “bow-tie” shaped,
geometrically twisted metal ion-coordinating cyclophane
or “twistophane” ligands. The synthesis was readily
accomplished using standard organometallic coupling
protocols in a relatively short number of steps starting
from the commercially available (2-bromophenylethynyl)-
trimethylsilane (2) and 2-chloro-5-iodopyridine (3). Thus,
3 was converted to 5 by a reported procedure and the
latter reacted with 6, the lithiation/iodination product of
2, to give intermediate 7. Product 7 was then coupled to
give 8 in the presence of Sn2Me6 via a palladium-
catalyzed Stille reaction. The type of palladium catalyst
used for the homocoupling of 7 was found to be of crucial
importance. Highest yields of the coupled product 8 were
obtained with PdCl2(dppf). Bipyridine 8 was then smoothly
deprotected to give the bis-terminal ethyne 9 and the
latter cyclodimerized to give the final product 1, via the
CuCl-catalyzed oxidative Hay coupling prodedure. The
convenience and economy of the above synthetic pathway
to 1 makes this approach very attractive for the genera-
tion of larger quantities of 1, and as a potentially general
method for the preparation of structurally related twist-
ophane ligands.
The macrocyclic structural assignment of 1 was estab-
lished on the basis of mass spectrometry and IR and
NMR spectroscopy. Interestingly, the 1H NMR of 1
displayed temperature-dependent dynamic phenomena
between zero and 120 °C. In particular, the 2,2′-bipyri-
dine H3 protons moved downfield upon heating and
upfield upon cooling. This may be attributed to temper-
ature-dependent opening and closing motions of the
macrocycle as it interconverts between the two enantio-
meric forms of 1. Molecular modeling of the macrocyclic
structure of 1 confirmed the overall chirally twisted
framework of the lowest energy conformation. The latter
study also revealed the close proximity of the H3 protons
of the two 2,2′-bipyridine units as they reside alongside
each other, lending further support for the explanation
Exp er im en ta l Section
Meth od s a n d Ma ter ia ls. Standard inert atmosphere and
Schlenk techniques were employed for reactions conducted
under argon.The reagents 1,2-diiodoethane, (2-bromophenyl-
ethynyl)trimethylsilane (2),43 trimethylsilylethyne, and cata-
lysts PdCl2(PPh3)2,44a-c PdCl2(dppf)‚CH2Cl2,45a,b CuI, and CuCl
were purchased from Aldrich and used as received. Hexa-
methylditin was prepared according to a published procedure.46
The Et2O was freshly distilled off sodium/benzophenone under
argon and the toluene used in the preparation of 8, was
degassed by bubbling with argon directly before use. Intramo-
lecular proton connectivities were unambiguously determined
(41) More than 200 zinc proteins are currently known and perform
a spectacular range of biological functions. For example synthase,
ligase and polymerase enzymes that catalyse the metabolic conversion
of proteins, nucleic acids, lipids and porphyrin precursors, etc. Zinc
also plays a structural role in the conformational stabilisation of, for
example insulin, hormone receptor complexes and transcription regu-
lating factors for the transfer of genetic information. Zinc is thus
ubiquitous in life, and new methods for the selective detection and
monitoring of this important metal ion will therefore continue to be of
paramount interest. Kaim, W.; Schwederski, B. Bioinorganic Chem-
istry: Inorganic Elements in the Chemistry of Life; J ohn Wiley & Sons
Ltd.: New York, 1998; Chapter 12, p 242.
(42) For example, increasing the degree of conjugation and incor-
poration of organic donor/acceptor dyes to enhance the chromogenic
response, and variations in the geometry, denticity and donor ability
of the binding sites to induce greater metal ion specificity and
discrimination. Furthermore, under particular conditions, it may be
possible to isolate [M1]n+ complexes with metal ions that do not
normally occur with a tetrahedral coordination polyhedron of nitrogen
donor ligands. Compounds such as these would for example enable
the physicochemical properties of entatic state models to be measured
as well as functioning as a new class of redox catalysts. For reports on
the syntheses of ligands which enforce tetrahedral coordination
geometries around metal ions upon binding, and the properties of their
metal complexes, see: (a) Knapp, S.; Keenan, T. P.; Zhang, X.; Fikar,
R.; Potenza, J . A.; Schugar, H. J . J . Am. Chem. Soc. 1987, 109, 1882.
(b) Mu¨ller, E.; Piguet, C.; Bernardinelli, G.; Williams, A. F. Inorg.
Chem. 1988, 27, 849. (c) J udice, J . K.; Keipert, S. J .; Cram, D. J . J .
Chem. Soc., Chem. Commun. 1993, 1323. (d) Frydendahl, H.; Toftlund,
H.; Becher, J .; Dutton, J . C.; Murray, K. S.; Taylor, L. F.; Anderson,
O. P.; Tiekink, E. R. T. Inorg. Chem. 1995, 34, 4467. An additional
possibility for 1 is that of exo-coordination in the case where all the
2,2′-bipyridine nitrogens point outwardly and in an opposite direction
to the centroid of the macrocyclic ring. This latter mode of binding
would give rise to [M21]2n+ complexes from which intriguing types of
metallocyclophane polymer materials could be constructed.
1
of the marked temperature dependence of the H NMR
chemical shift of these protons.
Macrocycle 1 possesses specific structural features such
as (1) a relatively rigid hydrocarbon framework compris-
ing ethynyl and phenyl subunits which is (2) cyclically
conjugated when the 2,2′-bipyridine moieties are in
planar conformations and (3) an enforced tetrahedral
coordination pocket when bound to a metal ion of ap-
propriate size. The summed effect of these characteristics
suggested that 1 might experience electron cloud per-
turbations upon coordination, and may function as a
spectroscopic sensor for specific types of metal ions.
Investigations into the metal ion coordination behavior
of 1 showed that it responded spectroscopically to a
surprisingly narrow range of cations comprising Co2+
,
Ni2+, Cu2+, and Zn2+. Of particular significance is the fact
that 1 displays differing sequences of signal output
depending on the identity of the metal ion with which
(43) Padwa, A.; Austin, D. J .; Gareau, Y.; Kassir, J . M.; Xu, S. L. J .
Am. Chem. Soc. 1993, 115, 2637.
(40) For a detailed review on sensory optodes for metal ions, see;
(a) Bu¨hlmann, P.; Pretsch, E.; Bakker, E. Chem. Rev. 1998, 98, 1593.
For an earlier approach to the fluorescence sensing of zinc(II) using
modified zinc fingers, see; (b) Walkup, G. K.; Imperiali, B. J . Am. Chem.
Soc. 1997, 119, 3443. For a recent review on the fluorescence sensing
of zinc(II) ions with polyamine macrocycles, see: (c) Pina, F.; Bernardo,
M. A.; Garcia-Espan˜a, E. Eur. J . Inorg. Chem. 2000, 2143.
(44) (a) Chatt, J .; Mann, F. G. J . Chem. Soc. 1939, p1631. (b) Tayim,
H. A.; Bouldoukian, A.; Awad, F. J . Inorg. Nucl. Chem. 1970, 32, 3799.
(c) Brumbaugh, J . S.; Sen, A. J . Am. Chem. Soc. 1988, 110, 803.
(45) (a) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi,
T.; Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158. (b) Corain, B.;
Longato, B.; Favero, G.; Ajo`, D.; Pilloni, G.; Russo, U.; Kreissl, F. R.
Inorg. Chim. Acta, 1989, 157, 259.

4178 J . Org. Chem., Vol. 66, No. 12, 2001
Baxter
by 1H-1H COSY measurements. The fluorescence spectra were
recorded at 25 °C on a Aminco, Bowman Series 2 luminescence
spectrophotometer (SLM Instruments, Inc.) and were corrected
for the instrumental responce.47 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 Mi-
croanalyse, Institut de Chimie, Universite´ Louis Pasteur.
(2-Iod op h en yleth yn yl)tr im eth ylsila n e (6). Dry Et2O (55
mL) was added via syringe to 5.173 g (2.04 × 10-2 mol) of 2 in
a dried argon-filled flask equipped with an alcohol thermom-
eter, septum, and argon/vacuum inlet adaptor. The stirred
solution was then cooled to -78 °C, and 13.2 mL (2.11 ×
10-2mol) of 1.6 M n-butyllithium was added dropwise via
syringe. The colorless reaction solution was stirred at -70 to
-78 °C for 0.5 h, allowed to warm to 0 °C over 2.5 h, and finally
recooled to -78 °C with continued stirring. Dry Et2O (23 mL)
was syringed into a separate dried argon-filled Schlenk
containing 6.66 g (2.36 × 10-2mol) of 1,2-diiodoethane, and
this solution was subsequently added dropwise via syringe to
the previously prepared (2-lithiophenylethynyl)trimethylsilane
solution at a rate that maintained the reaction temperature
between -60 and -78 °C. Toward the end of the addition, a
suspended white solid formed. The mixture was stirred at -70
°C for 1 h, allowed to warm to 0 °C with stirring, and quenched
by the addition of 5 mL of water. The solution was extracted
with water (2 × 50 mL), the organic layer dried (MgSO4) and
5), 0.26 (s, 9H; Si(CH3)3). 13C NMR (CDCl3, 125.8 MHz, 25 °C)
δ: ppm: 152.1, 150.6, 140.8, 132.4, 131.8, 128.6, 128.3, 125.8,
124.9, 123.9, 119.4, 103.0 (CtC), 99.2 (CtC), 92.5 (CtC), 88.4
(CtC), 0.0 (Si(CH3)3). EIMS m/z: 309 (M+, 60), 294 ([M -
Me]+, 100), 258 ([M - Me - Cl]+, 20). Anal. Calcd for C18H16
-
ClNSi: C, 69.77; H, 5.20; N, 4.52. Found: C, 69.51; H, 4.98;
N, 4.44.
5,5′-Bis[(2-t r im et h ylsilylet h yn ylp h en yl)et h yn yl)-2,2′-
bip yr id in e (8). Toluene (25 mL) was added via syringe to a
mixture of 1.007 g (3.25 × 10-3 mol) of 7 and 0.069 g (8.45 ×
10-5mol) of PdCl2(dppf)‚CH2Cl2 under an atmosphere of argon.
Hexamethylditin (0.584 g, 1.78 × 10-3 mol) was then added
via microsyringe and the reaction stirred and heated in a bath
at 120 °C for 20 h. The reaction darkened considerably during
reflux. After heating, all solvent was removed under reduced
pressure, CH2Cl2 added, and the solution flash column chro-
matographed on silica eluting with 1% MeOH/CH2Cl2. The
product thus obtained was then recrystallized from boiling
ethanol and dried under vacuum (0.01 mmHg) to give 0.649 g
(73%) of 8 as pale yellow needles (mp 199.0-200.1 °C).
1H NMR (CDCl3, 500 MHz, 24 °C) δ: 8.84 (d, 4J 6,4 ) 1.4 Hz,
3
2H; pyridine H6), 8.46 (d, J 3,4 ) 8.2 Hz, 2H; pyridine H3),
3
4
7.97 (dd, J 4,3 ) 8.2 Hz, J 4,6 ) 2.2 Hz, 2H; pyridine H4), 7.55
(m, 4H; phenyl H3, 6), 7.32 (m, 4H; phenyl H4, 5), 0.29 (s,
18H; Si(CH3)3). 13C NMR (CDCl3, 125.8 MHz, 24 °C) δ: 154.2,
151.7, 139.5, 132.4, 131.9, 128.5, 128.3, 125.8, 125.3, 120.7,
120.5, 103.2 (CtC), 99.1 (CtC), 92.6 (CtC), 90.2 (CtC), 0.0
(Si(CH3)3). UV/vis (CHCl3) λ (nm) (ꢀ, M-1 cm-1): 353 (82300).
Fluor. emission (CHCl3, 350 nm excitation) λ (nm): 388, 410.
IR cm-1: 2958s, 2159s ν(CtC), 1481s, 1249s, 873s, 841s, 755s.
EIMS m/z: 548 (M+, 100), 533 ([M - Me]+, 29). Anal. Calcd
for C36H32N2Si2: C, 78.78; H, 5.88; N, 5.10. Found: C, 78.70;
H, 5.92; N, 5.10.
filtered, and the solvent distilled off on
a waterbath at
atmospheric pressure. The crude product oil was finally
purified by flash chromatography on silica with hexane eluant
followed by drying under vacuum (0.01 mmHg) for 48 h to
remove residual diiodoethane, to yield 5.826 g (95%) 6 as a
pungent smelling oil. The spectral properties of the product 6
48
were as reported.31,
5, 5′-Bis[(2-eth yn ylp h en yl)eth yn yl)-2,2′-bip yr id in e (9).
To a stirred solution of 0.250 g (4.56 × 10-4 mol) of 8 in 15
mL of THF and 0.5 mL of distilled water was added 1.10 mL
(1.10 × 10-3 mol) of a 1.0 M solution of (n-Bu)4NF in THF and
the reaction stirred at ambient temperature for 20 h. All
solvent was then removed under reduced pressure on a
waterbath, and 20 mL of distilled water was added to the
residue. The mixture was briefly ultrasonicated and the
suspended solid isolated by filtration under vacuum, washed
with excess distilled water, and air dried. The crude product
was purified by flash chromatography on silica eluting with
1% MeOH/CH2Cl2 and then washed with Et2O and air dried
to give 0.177 g (96%) of 9 as white flakes (mp 201.0-201.5 °C
dec).
2-Ch lor o-5-[(2-tr im eth ylsilyleth yn ylp h en yl)eth yn yl]-
p yr id in e (7). Triethylamine (15 mL) was added via syringe
to a mixture of 0.829 g (6.03 × 10-3 mol) of 5,28 1.824 g
(6.08 × 10-3 mol) of 6, and 0.086 g (1.23 × 10-4 mol) of PdCl2-
(PPh3)2 under an atmosphere of argon and the suspension
stirred for 0.2 h. A solution of 0.084 g (4.41 × 10-4 mol) of CuI
in 5 mL of triethylamine was then added via syringe, and
stirring was continued for 48 h at ambient temperature.
During this time, the initially formed khaki precipitate became
dark brown in color. After 48 h, all solvent was removed under
reduced pressure and the residue extracted with boiling
hexane (4 × 20 mL). The combined hexane extracts were
filtered, the solvent distilled off under reduced pressure, and
the residue flash chromatographed on silica eluting with 1:1
CH2Cl2/hexane. The product thus obtained was finally boiled
in 50 mL of MeOH with 0.1 g of Norit A decolorizing charcoal,
the mixture filtered, and the solvent removed under reduced
pressure. Further drying under vacuum (0.01 mmHg) yielded
1.492 g (80%) of 7 as a pale yellow oil that slowly crystallized
to a cream solid (mp 47.0-49.6 °C) upon standing for several
days.
1H NMR (CDCl3, 500 MHz, 25 °C) δ: 8.85 (s, 2H; pyridine
3
3
H6), 8.45 (d, J 3,4 ) 8.3 Hz, 2H; pyridine H3), 7.97 (dd, J 4,3
)
4
8.2 Hz, J 4,6 ) 2.1 Hz, 2H; pyridine H4), 7.58 (m, 4H; phenyl
H3, 6), 7.35 (m, 4H; phenyl H4, 5), 3.41 (s, 2H; ethyne H). 13C
NMR (CDCl3, 125.8 MHz, 25 °C) δ: 154.2, 151.9, 139.4, 132.7,
131.9, 128.6, 128.5, 125.6, 124.8, 120.6, 120.4, 92.2 (CtC), 90.4
(CtC), 82.0 (CtC), 81.5 (CtC). UV/vis (CHCl3) λ (nm) (ꢀ, M-1
cm-1): 351 (65870), 373sh (41220). Fluor. emission (CHCl3,
350 nm excitation) λ (nm): 385, 406. IR cm-1: 3294s ν(tC-
H), 3285s ν(tC-H), 1480s, 846s, 761s, 652s. EIMS m/z: 404
(M+, 100). Anal. Calcd for C30H16N2: C, 89.09; H, 3.99; N, 6.93.
Found: C, 89.26; H, 3.90; N, 7.13.
1H NMR (CDCl3, 500 MHz, 25 °C) δ: 8.56 (d, 4J 6,4 ) 1.7 Hz,
3
4
1H; pyridine H6), 7.77 (dd, J 4,3 ) 8.3 Hz, J 4,6 ) 2.4 Hz, 1H;
3
pyridine H4), 7.52 (m, 2H; phenyl H3, 6), 7.34 (dd, J 3,4 ) 8.2
Hz, J 3, 6 ) 0.6 Hz, 1H; pyridine H3), 7.31 (m, 2H; phenyl H4,
5
Ma cr ocycle (1). A solution of 0.022 g of CuCl (2.22 × 10-4
mol) in 3 mL of pyridine was added to 0.135 g (3.34 × 10-4
mol) of 9 dissolved in 230 mL of pyridine and the olive green
reaction solution bubbled with oxygen and vigorously stirred
for 120 h. After 5 days, the solvent had evaporated to about
150 mL and was rediluted to 230 mL. During this time, the
solution also became cloudy due to the formation of a small
amount of a suspended insoluble solid. The solvent was then
distilled off under reduced pressure on a waterbath until about
4 mL remained, then 20 mL of saturated aqueous KCN was
added and the suspension stirred for 24 h at ambient temper-
ature. The solid was then isolated by filtration under vacuum,
washed with excess distilled water, and air dried. After this,
the crude yield was suspended in 200 mL of CHCl3, the
mixture boiled and filtered to remove the insoluble byproducts,
and the solvent distilled off under reduced pressure on a water
(46) Kraus, C. A.; Sessions, W. V. J . Am. Chem. Soc. 1925, 47, 2361.
After evaporation of the ammonia, the product was best worked up by
addition of pentane and extraction with water. The pentane extract
was dried (MgSO4) and filtered, the solvent removed under reduced
pressure at ambient temperature, and the colorless Sn2Me6 product
oil stored under argon.
(47) The fluorescence emission spectra of 1, 8, and 9 recorded,
respectively, in deoxygenated (argon bubbled) and undegassed CHCl3
were found to be identical, demonstrating that the excited states were
insensitive to quenching by oxygen. The fluorescence emission spectra
of the metal ion complexes with macrocycle 1, on the other hand, were
recorded in solvents which had not been previously deoxygenated, to
reveal the optical responses of this system under the normal environ-
mental and atmospheric conditions encountered in sensory applica-
tions.
(48) Lavastre, O.; Cabioch, S.; Dixneuf, P. H.; Vohlidal, J . Tetrahe-
dron 1997, 53, 7595.

Synthesis and Properties of a Twistophane Ion Sensor
J . Org. Chem., Vol. 66, No. 12, 2001 4179
bath. The remaining solid was dissolved in 10-15 mL of
boiling toluene and chromatographed on a column of alumina
(Basic, activity III) with toluene as the eluant. The product
thus obtained was finally purified by extraction with boiling
acetone (2 × 150 mL) and air-dried to give 0.045 g (34%) of 1
as a light-sensitive amorphous white solid (mp >340 °C with
a gradual color change over 200-300 °C to dark brown).49
1H NMR (CDCl3, 500 MHz, 25 °C) δ: 8.56 (d, 4J 6,4 ) 2.0 Hz,
3
4
1H; pyridine H6), 7.78 (dd, J 4,3 ) 8.2 Hz, J 4,6 ) 2.4 Hz, 1H;
pyridine H4), 7.55 (m, 2H; phenyl H3, 6), 7.35 (m, 2H; phenyl
3
H4, 5), 7.33 (d, J 3,4 ) 8.0 Hz, 1H; pyridine H3), 3.37 (s, 1H;
ethyne H). 13C NMR (CDCl3, 125.8 MHz, 25 °C) δ: 152.2, 150.7,
141.0, 132.7, 131.8, 128.70, 128.67, 125.2, 124.8, 123.9, 119.2,
92.1 (CtC), 88.6 (CtC), 81.8 (CtC), 81.5 (CtC). IR cm-1
:
1H NMR (CDCl2CDCl2, 500 MHz, 100 °C) δ: 8.71 (d, 4J 6,4
)
3216s ν(≡C-H), 2098m ν(CtC), 1547s, 1479s, 1454s, 1106s,
834s, 760s. EIMS m/z: 237 (M+, 100), 201 ([M - Cl]+, 48).
Anal. Calcd for C15H8ClN: C, 75.80; H, 3.39; N, 5.89. Found:
C, 76.03; H, 3.28; N, 5.99.
3
1.4 Hz, 4H; pyridine H6), 7.88 (d, J 3,4 ) 8.3 Hz, 4H; pyridine
3
4
H3), 7.80 (dd, J 4,3 ) 8.2 Hz, J 4,6 ) 2.2 Hz, 4H; pyridine H4),
7.70 (m, 8H; phenyl H3, 6), 7.44 (m, 8H; phenyl H4, 5). 13C
NMR (CDCl2CDCl2, 125.8 MHz, 60 °C) δ: 153.5, 151.4, 139.0,
133.3, 132.2, 129.2, 128.7, 126.3, 124.5, 120.3, 119.7, 92.0
(CtC), 91.6 (CtC), 81.5 (CtC), 78.1 (CtC). UV/vis (CHCl3) λ
(nm) (ꢀ, M-1 cm-1): 316 (88670), 356 (127930), 384 (54680).
Fluor. emission (CHCl3, 350 nm excitation) λ (nm): 406, 431.
[1,3-Bu ta d iyn e-1,4-d iylbis(2,1-p h en ylen e-2,1-eth yn ed i-
yl)]-bis[5-(2-ch lor op yr id in e)] (11). A solution of 0.010 g
(1.01 × 10-4 mol) of CuCl in 2 mL of pyridine was added to
0.116 g (4.88 × 10-4 mol) of 10 dissolved in 15 mL of pyridine
and the reaction bubbled with oxygen and vigorously stirred
for 1 h. After this, the reaction was stirred under an oxygen
atmosphere for 24 h. All solvent was then removed under
reduced pressure on a waterbath and the residue flash column
chromatographed on silica eluting with CH2Cl2. The product
thus obtained was further purified by brief ultrasonication in
2 mL of cold MeOH, filtering under vacuum, washing the
collected solid with 1 mL of cold MeOH and air-drying to
furnish 0.099 g (86%) of 11 as a light sensitive white solid (mp
157.0-159.5 °C).
IR cm-1
: 2208w ν(CtC), 1487s, 1480s, 1463s, 840s, 754s.
FABMS (CF3COOH) m/z: 805 ([M + 1]+, 100). HRMS (FAB,
CF3COOH, [M + 1]+): calcd for C60H29N4 805.2392, found
805.2389. Anal. Calcd for C60H28N4: C, 89.53; H, 3.51; N, 6.96.
Found: C, 89.72; H, 3.81; N, 6.91.
2-Ch lor o-5-[(2-eth yn ylp h en yl)eth yn yl)]p yr id in e (10). A
solution of 0.045 g (1.13 × 10-3 mol) of NaOH in 0.5 mL of
water and 1 mL of MeOH was added to a stirred solution of
0.160 g (5.16 × 10-4 mol) of 7 in 8 mL of THF and stirring
maintained for 5 h at ambient temperature. By this time, all
the starting 7 had disappeared as judged by TLC (1:1 CH2-
Cl2/hexane, silica). The reaction solution was poured onto brine
and extracted with 40 mL of Et2O. The organic layer was re-
extracted with distilled water (2 × 20 mL), dried (MgSO4), and
filtered and the solvent evaporated off at ambient temperature
under reduced pressure. The remaining oil crystallized upon
drying under vacuum to give 0.116 g (95%) of 10 of sufficient
purity for the subsequent preparation of 11. Further purifica-
tion could however be achieved upon flash column chroma-
tography on silica with 1:3 hexane/CH2Cl2 as eluant, followed
by washing the product with a small portion of hexane and
drying under vacuum at 0.01 mmHg. The melting point of the
chromatographed 10 was 76.8-77.5 °C. Compound 10 under-
went partial decomposition upon attempted purification by
sublimation.
4
1H NMR (CDCl3, 500 MHz, 25 °C) δ: 8.545 (d, J 6,4 ) 1.9
3
4
Hz, 2H; pyridine H6), 7.77 (dd, J 4,3 ) 8.2 Hz, J 4,6 ) 2.3 Hz,
2H; pyridine H4), 7.58 (m, 4H; phenyl H3, 6), 7.38 (m, 4H;
phenyl H4, 5), 7.25 (d, J 3,4 ) 8.5 Hz, 2H; pyridine H3). 13C
3
NMR (CDCl3, 125.8 MHz, 25 °C) δ: 152.1, 150.6, 141.0, 132.9,
131.8, 129.2, 128.8, 126.1, 124.5, 123.9, 119.0, 92.0 (CtC), 89.4
(CtC), 81.3 (CtC), 77.9 (CtC). IR cm-1
: 3057m, 2219w
ν(CtC), 1475s, 1106s, 1020s, 829s, 750s. EIMS m/z: 472 (M+,
100), 437 ([M - Cl]+, 90). Anal. Calcd for C30H14Cl2N2: C,
76.12; H, 2.98; N, 5.92. Found: C, 75.99; H, 2.69; N, 5.81.
Ack n ow led gm en t is made to the Colle`ge de France
1
for financial support, to Roland Graff for the H NMR
COSY measurements, and to Dr. Alex Varnek for the
molecular modeling of 1.
Su p p or tin g In for m a tion Ava ila ble: Complete 1H and
13C NMR spectra of macrocycle 1. This material is available
free of charge via the Internet at http://pubs/acs/org.
(49) It must be noted that the oxidative macrocyclisation is not
optimised and that further variation in concentration, solvent type, 9:
CuCl ratio, copper catalyst, and temperature my result in the formation
of higher yields of 1 as well as higher molecular mass cyclic oligomers
and possibly catenated structures.
J O001777D