Shape-persistent macrocycle with a self-complementary recognition pattern based on diacetylene-linked alternating hexylbenzene and perfluorobenzene rings

Article abstract of DOI:10.1039/b609004d

The synthesis and characterization of a shape-persistent macrocycle, consisting of alternating electron rich and electron poor sub-units as a self-complementary recognition pattern, is reported, and its increased tendency to form dimer complexes in soluti

Full text of DOI:10.1039/b609004d

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Shape-persistent macrocycle with a self-complementary recognition
pattern based on diacetylene-linked alternating hexylbenzene and
perfluorobenzene rings{
Lijin Shua and Marcel Mayor*ab
Received (in Cambridge, UK) 26th June 2006, Accepted 1st August 2006
First published as an Advance Article on the web 22nd August 2006
DOI: 10.1039/b609004d
The synthesis and characterization of a shape-persistent
macrocycle, consisting of alternating electron rich and electron
poor sub-units as a self-complementary recognition pattern, is
reported, and its increased tendency to form dimer complexes
in solution is demonstrated and discussed.
Shape-persistent macrocycles (SPMs) have attracted considerable
attention due to their unique properties.1 Their ability to control
the spatial arrangement of functional groups, together with their
aggregation behavior, make them promising building blocks for
tailor-made nanoscale objects and materials. Since Moore and co-
workers reported the aggregation of SPMs due to p-stacking,2 the
Fig. 1 Macrocycle 1, providing an alternating sequence of electron rich
phenomenon has been investigated in detail with further
and electron poor aromatic units as self-complementary recognition
functionalized SPMs. In particular, electron donating3 and
pattern, and its aggregation to a dimer.
electron withdrawing4 substituents,2,5 hydrogen bonding units,6
chiral building blocks7 and even coordination sites for metal ions8
been chosen. As displayed in Scheme 1, the tetrafluorobenzene unit
4 was functionalized with bromoacetylenes, and the hexylbenzene
unit was synthesized as mono-protected and unprotected diacety-
lenes 8 and 9, respectively, as modular precursors of the
macrocycle 1.
have been incorporated into SPMs, and their aggregation proper-
ties have been studied in detail.
To further increase the intramolecular aggregation, we designed
macrocycle 1, consisting of diacetylene-linked alternating electron
rich alkylbenzene and electron deficient tetrafluorobenzene units in
a self-complementary recognition pattern (Fig. 1). The p–p
stacking interaction between benzene and hexafluorobenzene was
reported in 1960 by Patrick and Prosser.9 The supramolecular
synthon has meanwhile been investigated in detail and has been
applied successfully in crystal engineering,10 surface patterning,11
topochemistry12 and even to pre-organize reactants.13
Furthermore, the synthon allowed the tuning of the material
properties of liquid crystals,14 polymers,14 hydrogels15 and even
biomolecules such as DNA duplexes.16
Reduction of commercial tetrafluoroisophthalonitrile provided
tetrafluoroisophthaloaldehyde 2 in 45% yield.17c In a Corey–Fuchs
reaction sequence,19 the dialdehyde 2 was converted into the
doubly dibromoethenyl-functionalized precursor 3, which was
isolated in 92% yield after column chromatography (CC) as a
white solid. Treatment of 3 with a strong base provided the doubly
bromoethynyl-substituted tetrafluorobenzene 4 as a white solid
after CC in 94% yield as the first building block for the assembly of
macrocycle 1.
Bromination of 4-hexylaniline with N-bromosuccinimide in
DMF afforded 2,6-dibromo-4-hexylaniline (5) in 85% yield after
CC as a red crystalline solid. Deamination of 5 with sodium nitrite
in sulfuric acid and ethanol provided 1,3-dibromo-5-hexylbenzene
(6) in 67% yield as a colorless oil. Both bromines of 6 were
substituted by tris-iso-proylsilyl (TIPS) acetylenes in a Sonogashira
coupling reaction20 to yield the TIPS-protected diacetylene 7 in
85% as a colorless oil. Careful deprotection of 7 with TBAF in wet
THF provided (besides unreacted starting material) the mono-
protected diacetylene 8 in 27% yield and the diacetylene 9 in
18% yield, both as colorless oils as the unfluorinated building
blocks of 1.
Several macrocyclic oligomers consisting of diacetylene-linked
aromatic units have been synthesized by oxidative acetylene
coupling protocols, often in combination with protection group
strategies.4,5,17 However, for the assembly of the macrocyclic target
structure with two different aromatic units, a Cadiot–Chodkiewicz
coupling,18 allowing the formation of asymmetric diacetylenes, has
aForschungszentrum Karlsruhe GmbH, Institute for Nanotechnology,
Postfach 3640, D-76021 Karlsruhe, Germany.
E-mail: marcel.mayor@int.fzk.de; Fax: +49 7247 82-5685;
Tel: +49 7247 82-6392
bUniversity of Basel, Department of Chemistry, St. Johannsring 19,
CH-4056 Basel, Switzerland. E-mail: marcel.mayor@unibas.ch;
Fax: +41 61 267 1016; Tel: +41 61 267 1006
For the formation of macrocycle 1, several strategies, varying in
the number of assembled molecules and formed bonds, were
envisaged and have been investigated. Already, a 1 : 1 mixture of
diacetylene 9 and di(bromoacetylene) 4 may result in the desired
macrocycle 1 by the assembling of 6 molecules. However, only
{ Electronic supplementary information (ESI) available: Synthetic proto-
cols and analytical data for compounds 1–15, table of the temperature and
concentration dependent 1H NMR investigation, and van’t Hoff analysis
of the dimerization of 1. See DOI: 10.1039/b609004d
4134 | Chem. Commun., 2006, 4134–4136
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assembled in reasonable yields by applying the above described
Pd/Cu-catalyzed Cadiot–Chodkiewicz protocol. Treatment of
di(bromoacetylene) 4 with two equivalents of mono-protected
diacetylene 8 provided the semicircle 12, comprising terminally
TIPS-protected acetylenes, in 67% yield. Subsequent deprotection
with TBAF/THF yielded the acetylene-functionalized semicircle 13
in 79% yield. To assemble the semicircle with terminal bromoa-
cetylenes, the coupling conditions were applied to a mixture of
diacetylene 9 and an excess of di(bromoacetylene) 4. The desired
building block 14 was isolated in 36% yield after CC. Again,
applying the Pd/Cu-catalyzed coupling conditions to a 1 : 1
mixture of 13 and 14 afforded the desired macrocycle in 4% yield
as a brown solid after laborious CC, including size exclusion
chromatography (SEC).
In an alternative strategy, the semicircle 13 was extended to the
terminally bromoacetylene-functionalized pentamer 15 by treating
13 with a seven fold excess of 4. Pentamer 15 was isolated in 54%
yield as beige-brown solid after CC. Subsequently, the macrocycle
was closed by introducing diacetylene 9 into pentamer 15. The
target structure 1 was isolated in 7% yield after SEC. Inspite of the
slightly lower yield over both steps, the considerably simpler and
more efficient isolation procedure for the macrocycle 1 synthesized
via the pentamer 15 route favors this synthetic strategy.
The structure of macrocycle 1 and its precursors were
1
characterized by H and 13C NMR spectroscopy, mass spectrum
analysis and elemental analysis. The rather simple NMR spectra of
1 points to its high structural symmetry. While the 1H NMR is not
particularly rich in structural information, characteristic features of
the 13C NMR spectrum of 1 are the typically large C–F couplings,
in the order of 250 Hz, of the fluorine-substituted benzene carbons
and the four acetylene carbons at 66.1, 74.6, 81.4 and 84.5 ppm,
respectively. An intense signal for the molecular ion was observed
by electron spray ionization mass analysis. Interestingly, MALDI-
TOF MS failed to detect the molecular ion. Instead, intense signals
have been observed for approximately two, three and even higher
multiples of its weight (Fig. 2). As larger oligomers formed during
the macrocyclization were removed by SEC, these signals, most
likely arising from aggregates,22 already point to a pronounced
Scheme 1 Synthesis of the macrocycle 1 and its precursors 2–15.{ (a)
Toluene, DIBAL-H, rt, 45%; (b) CBr4, Zn, PPh3, CH2Cl2, rt, 92%; (c) aq.
KOH, BTEAC, THF, rt, 94%; (d) NBS, DMF, 0 uC, 85%; (e) H2SO4,
NaNO2, EtOH, 75 uC, 68%; (f) Pd(PPh3)4, Et3N, CuI, TIPS-CCH, 80 uC,
85%; (g) TBAF, wet THF, rt, 27% for 8, 18% for 9; (h) Pd2(dba)3?CHCl3,
(i-Pr)2EtN, CuI, toluene, rt; (i) TBAF, wet THF, AcOH until pH 7.5, rt,
5%; (j) TBAF, wet THF, rt, 79%.
traces of the desired macrocycle were formed, together with a rich
variety of side products. To assemble the macrocycle in a stepwise
approach and to optimize the Cadiot–Chodkiewicz coupling
conditions, di(bromoacetylene)
4 was coupled with mono-
protected diacetylene 8 to provide the promising precursor, 11,
of the macrocycle. In a Pd/Cu-catalyzed variation of the Cadiot–
Chodkiewicz coupling,21 the mono-protected diacetylene 8 was
treated with a two-fold excess of 4 in THF using di-iso-
propylethylamine ((i-Pr)2NEt) as a base, and Pd2(dba)3 and CuI
as catalysts at room temperature to provide the TIPS-protected
molecular rod 10 in 64% yield after CC.
However, the deprotection of 10 turned out to be very delicate
due to the limited stability of the bromoacetylene of 10 in basic
TBAF/THF conditions and the limited stability of the perfluori-
nated benzene ring under AcOH-buffered TBAF/THF conditions.
The low yield of 5% of the isolated precursor 11 considerably
reduced the attractiveness of this synthetic route. Macrocycle 1
may also be assembled from two semicircles. However, due to the
three-fold symmetry of 1, two different building blocks, 13 and 14,
are required. As displayed in Scheme 1, both semicircles are
Fig. 2 Oligomeric signals of macrocycle 1 in the MALDI-TOF MS.
Chem. Commun., 2006, 4134–4136 | 4135
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further allowed the determination of thermodynamic data of the
self-assembly system by applying van’t Hoff analysis.{ The
negative signs of the obtained DS = 2156 ¡ 9 J mol21 K21
and DH = 264 ¡ 3 kJ mol21 show that the dimerization of 1 is
enthalpy driven.
The authors acknowledge the support, by a postdoctoral
position for L. S., of the Center for Functional Nanostructures
(CFN) of the Deutsche Forschungsgemeinschaft (DFG) within
´
project C3. We are thankful to Ekaterina Rakhmatullina, Marcel
Mu¨ri and Sergio Grunder for their support in the analytical
investigations.
Notes and references
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Fig. 3 Chemical shift changes with concentration of the exo-annular (&)
and endo-annular ($) protons of 1 in CDCl3 at 20 uC. The solid lines are
the simulated chemical shifts with KDim = 1875 M21
.
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solubility of macrocycle 1 is limited to aprotic organic solvents, e.g.
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chloroform or dichloromethane. However, even in chloroform, the
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1 in solution, which were investigated by concentration dependent
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The signal of the exo-annular protons shifts 0.4 ppm, more
pronounced than the 0.3 ppm for the endo-annular protons in the
investigated concentration range at 20 uC. While the intended
strong intramolecular p–p stacking interaction was confirmed by
the NMR titration experiments, it remained uncertain whether
dimers or larger oligomeric stacks were formed in solution.
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the VPO equipment on the one hand and by the solubility of 1 on
the other, remained open for VPO investigations. Thus, in the
concentration range between 15 and 25 mmol L21, in which,
according to the NMR titration experiments, mainly stacked
objects are present, an average molecular weight of 2000 ¡ 500
was determined by VPO in CHCl3 at room temperature. The
measured molecular weight supports the formation of dimers in
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1
solution, as sketched in Fig. 1. The H NMR titration data were
thus fitted assuming a monomer–dimer equilibrium,23 in similarity
with the already reported investigations of SPM model com-
pounds.2–6 The obtained dimerization constant (KDim) for 1 was
1875 ¡ 605 M21 in CDCl3 at 20 uC, more than one order of
magnitude larger than those reported for SPMs consisting of
uniform aromatic sub-units. The temperature dependence of KDim
23 I. Horman and B. Dreux, Helv. Chim. Acta, 1984, 67, 754.
4136 | Chem. Commun., 2006, 4134–4136
This journal is ß The Royal Society of Chemistry 2006