Molecular daisy chains: Synthesis and aggregation studies of an amphiphilic molecular rod

Article abstract of DOI:10.1002/chem.201202498

A water-soluble cyclophane as the loop subunit, monofunctionalized with a molecular rod, has been synthesized to introduce a new binding motif for mechanically interlinked oligomers. It has been demonstrated that this hermaphroditic compound forms [c2]dai

Full text of DOI:10.1002/chem.201202498

FULL PAPER
DOI: 10.1002/chem.201202498
Molecular Daisy Chains: Synthesis and Aggregation Studies of an
Amphiphilic Molecular Rod
Jꢀrgen Rotzler,[a] Sylvie Drayss,[a] Oliver Hampe,[b] Daniel Hꢁussinger,[a] and
Marcel Mayor*[a, b]
Dedicated to Professor FranÅois Diedrich on the occasion of his 60th birthday
Abstract: A water-soluble cyclophane as the loop subunit, monofunctionalized
with a molecular rod, has been synthesized to introduce a new binding motif for
Keywords: amphiphiles
phanes · daisy chains · host–guest
chemistry · self-assembly
·
cyclo-
mechanically interlinked oligomers. It has been demonstrated that this hermaphro-
ditic compound forms [c2]daisy chains in polar solvent over a wide range of con-
centrations. Furthermore, evidence for the formation of higher mechanically inter-
linked oligomers above the critical aggregation concentration has been obtained.
Introduction
tions (hydrogen bonding, hydrophobic effects, p–p stacking,
or van der Waalsꢀ interactions) to assemble oligomeric or
polymeric structures, covalent irreversible bonding in mac-
romolecules is replaced by mechanical bonding, which gives
rise to several advantages.[26,27] One is the reversibility of
these dynamic aggregates, which makes them thermodynam-
ically controlled regimes. This in turn can lead to self-heal-
ing as incorrect chain extensions can be reversed as the
system strives for energy minimization.[28] Furthermore, the
thermodynamic control of chain propagation allows precise
chemical engineering on a supramolecular scale by changing
the external conditions used for the propagation reac-
tion.[20,27,28] As a positive side effect, only monomers have to
be synthesized. Studying and understanding the aggregation
behavior allows appropriate reaction conditions to be devel-
oped to enable the formation of various architectural devi-
ces.[29,30] Moreover, such systems are extremely sensitive to
the external environment (e.g., mechanical stress or heat)
because of possible internal movement that not only affects
the degree of polymerization but also alters the bulk proper-
ties of these macromolecular assemblies, such as the viscosi-
ty, dimensions, and rheology.[27,31] This approach makes de-
signed architectures of mechanically interlocked molecules
(MIM) possible, leading to new solid-state electronic devi-
ces, mechanized nanoparticles, nanoelectromechanical sys-
tems, switches, molecular motors and machines, as well as
nanovalves and molecular actuators.[27] Various recognition
motifs were introduced to achieve such daisy-chain-like pol-
ymers.[26] Dibenzo[24]crown-8 and dibenzylammonium
salts,[20,28,32,33] viologen,[20] or 1,2-bis(pyridinium)ethane[29]
binding have been widely used, as well as cyclobis(paraquat-
p-phenylene)–naphthyl or TTF[27] and cyclodextrin–naph-
thyl.[34,35] Nevertheless, the assembly of the synthetically
challenging monomers often yielded only [c2]daisy chains or
required a multistep assembly to achieve the desired macro-
molecules of higher order. In some cases the dimeric
[c2]daisy chain was the synthetic target of the studies, but to
One of the main targets of materials science is the conver-
sion of macroscopic physical phenomena into altered and
tailored phenomena with a specific physical output. There-
fore the macroscopic input has to induce a change in the in-
vestigated material on the microscopic level, which then
provides the desired physical output. Such changes in the
molecular dimension can be of a structural,[1] conformation-
al,[2–7] electrochemical,[8] or photochemical[9,10] nature or in
the intermolecular arrangement of the molecules.[11–13] Cur-
rent research in surface and polymer science is thus focused
on the development of new potential structures that are
able to fulfill the desired needs of providing, for example,
more scratch-resistant lacquers and plastics,[14] conducting
plastics,[15,16] or self-cleaning surfaces,[17] to name just a few.
One of the major drawbacks in polymer science is that for
each different purpose a completely new macromolecule has
to be synthesized starting from increasingly complex mono-
mers. To overcome this time-consuming and challenging
problem, a new concept for generating tailored polymers
has been put forward over the last two decades[18–20] by using
the tremendous findings in supramolecular chemistry[21–24]
starting with the demonstration by Pedersen in 1967 that
host–guest complexation is not limited to natural systems
with synthetic crown ethers.[25] By using secondary interac-
[a] Dr. J. Rotzler, S. Drayss, Dr. D. Hꢁussinger, Prof. Dr. M. Mayor
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-10-16
E-mail: marcel.mayor@unibas.ch
[b] Dr. O. Hampe, Prof. Dr. M. Mayor
Institute of Nanotechnology, Karlsruhe Institute of Technology (KIT)
P.O. Box 3640, 76021 Karlsruhe (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202498.
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make them sufficiently stable they had to be stoppered after
assembly.[26] Furthermore, in all cases a photo- or electro-
chemical input was used to generate internal motion. None
of the examples in the literature feature a structural motif
that allows altering of the physical output by internal
motion. Therefore we report herein an inversed recognition
motif for which the complexation behavior of neutral aro-
matic compounds with Diederich-type cyclophanes was
used.[36,37] In this case the driving force for assembly is the
nonclassical hydrophobic effect, which allows complexation
in polar solvents like water or alcohols. In this project it was
of interest to discover how such oligophenylene-ethynylene
molecules (OPE) comprising a terminal loop aggregate in
water and if different daisy chains can be observed by just
varying the concentration. If a defined assembly could be
obtained, it would then be of interest to functionalize the
monomers such that by a simple reaction higher oligomers
can be synthesized resulting in a higher control of the mo-
lecular architecture. Moreover, the inversed binding motif in
principle allows alteration of physical outputs by applying
mechanical stress, in stark contrast to the systems known to
date for which altering the internal motion was the initial
aim.
In this paper we report the synthesis and self-aggregation
studies of monomer 1 (Figure 1) to provide a platform for
future investigations on mechanically bonded oligomers or
even polymers. The design of target compound 1 profits to a
large extent from the outstanding work of Diederich and co-
workers.[36–40] Similarly to this proceeding work, two di
ylmethane units function as rigid spacers and cavity walls.
ACHTUNGTNERpNUNG hen-
ACHTUNGTRENNUNG
Water solubility of the cyclophane is achieved by the intro-
duction of quaternary amines; by varying the counter ions
the solubility can be fine-tuned. Furthermore, these positive-
ly charged moieties support, together with steric repulsion,
the opening and flattening of the cavity loop by electrostatic
repulsion. From solid-state structures it is known that the
quaternary amines are located at a distance from the cavity
and that the oxygen atoms face outwards, away from the
cavity, making it hydrophobic, a necessity for the final su-
pramolecular assembly.[36] The size of the cavity is defined
by the length of the interlinking alkane chains between the
two diphenylmethane units. In accord with the studies of
Diederich et al., a propane chain was chosen, which gives a
cavity large enough to complex benzene cores.[36] Molecular
complexation of neutral substituted benzene guests in aque-
ous solution is driven by a strong nonclassical hydrophobic
Figure 1. A) Hermaphroditic monomer 1 with inversed recognition motif.
B) Structure–property relationship of the target amphiphile 1. C) Possible
aggregates formed in polar solvents.
ꢀ ꢀ
ꢀ
benzylic bonds of the Ar O CH2 OPE motif allows the
guest to find an ideal spatial arrangement with respect to
the mean plane of the host, which is crucial for the forma-
tion of various daisy-chain-like aggregates. A 908 angle be-
tween host and guest, which is only accessible because of
the benzylic linkage, would maybe be an ideal arrangement
to obtain perfect inclusion of the host. Furthermore, this
flexibility allows for conformations in which, for example,
the host is placed in front of the cavity like a cap (even self-
threading cannot be excluded) and therefore potentially
“blocks” one side of the cavity leading to linear acyclic
rather than cyclic daisy chains.
effect.[37] Therefore, a hydrophobic oligophenylene-ethyn
ene rod is linked to the monofunctionalized cyclophane
ACHTUNGERTNyNUNG l-
ACHTUNGTRENNUNG
through a benzyl group, which gives the host system further
flexibility and hence allows for a perfect, thermodynamic-
driven binding of the guest.
Results and Discussion
In addition, it is well known that the nature of the pivot
heteroatom can dramatically influence the aggregation be-
havior of the hermaphroditic daisy-chain monomer, thus al-
lowing for further tuning of the system by changing the
bonding angle of the OPE with respect to the normal of the
mean plane.[41] The free rotation around the phenolic and
Synthesis: The assembly of the loop subunit profits to a
large extent from the cyclophane chemistry developed by
Diederich and co-workers,[38–40] whereas the formation of the
rigid molecular rod is based on classical Sonogashira cou-
pling chemistry.[42] The oligophenylene-ethynylene unit is
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Molecular Daisy Chains
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considered to be coupled to the cyclophane at a late stage in
the synthesis, which allows alteration of the length and sub-
stitution pattern of the molecular rod to be altered and thus
optimization of the extent of intermolecular stacking.
As already mentioned, the amphiphilic monomer 1 was
synthesized inspired by the numerous synthetic routes to-
wards monofunctionalized Diederich-type water-soluble cy-
clophanes reported in literature.[36–40] Molecules 2 and 3
were synthesized according to the literature[40] by Grignard
reaction of 4-bromoanisole and N-acetylpiperidin-4-one fol-
lowed by elimination of the resulting tertiary alcohol 2 and
deprotection of the methoxy group in one step using strong
Lewis acidic boron tribromide (Scheme 1). Because for the
purification of the resulting phenol only washing of the
crude with water and diethyl ether was required, the reac-
tion protocol could be applied to a larger-scale synthesis
(25 g starting material) from which an overall yield of 63%
was obtained. In the following step, the free phenolic hy-
droxy group was protected with a photocleavable 2-nitro-
benzyl group in a yield of 79%, a reaction that was necessa-
ry because a stepwise cycliza-
Scheme 1. Synthesis of the functionalized cyclophane component 5. Re-
agents and conditions: a) Mg, THF, reflux, 1.5 h, then N-acetylpiperidin-
4-one, THF, RT, 4 h; b) BBr3, CH2Cl2, reflux, 3 h; c) 2-nitrobenzyl chlo-
AHCTUNGTERNNGrUN ide, K2CO3, MeCN, reflux, 6.5 h; d) 2-methoxyphenol, BF3·OEt2,
CH2Cl2, RT, 9 d.
tion protocol was chosen for
the cyclophane assembly.[39]
Then the cavity wall bearing
the monofunctionalization was
introduced by addition of 2-
meth
N
ACHTUNGTRENNUNGphenol (guaiacol) to
the styACHTUNGTRENNUNG
strong Lewis acidic media using
a large excess of boron trifluor-
ide (Scheme 1).[40] The addition
of guaiacol seems to be reversi-
ble leading to the electronically
Scheme 2. Synthesis of the unfunctionalized cyclophane component 8. Reagents and conditions: a) 1,3-di-
AHCTUNGTRENNUNG
and thermodynamically favored coupled product para to the
hydroxy group after stirring for 9 days at room temperature
(99%). Shorter reaction times led to the formation of re-
gioisomers.
better leaving group in nucleophilic substitution reactions,
reacted. Before performing the intramolecular macrocycliza-
tion the protecting group was removed by photolytic deben-
zylation. Therefore the nitrobenzyl-protected alcohol 9 was
irradiated for 5 h at room temperature with alternating 300
and 366 nm UV lamps in a Rayonet photochemical reactor
(Scheme 3). To suppress the enrichment of various decom-
position products of 2-nitrosobenzaldehyde, which is formed
by photolytic cleavage of 2-nitrobenzyl groups, radical inhib-
itor BHT was added to the reaction mixture as reported by
Mattei and Diederich.[39] After flash column chromatogra-
phy (SiO2; CH2Cl2/MeOH, 20:1), alcohol 10 was isolated in
a yield of 97% (Scheme 3). The chloroalkylated phenol 10
underwent intramolecular macrocyclization to afford cyclo-
phane 11 in an excellent yield of 72% (Scheme 3). To pre-
vent oligomerization, the concentration of 10 in solution
was kept low by adding the starting material slowly (30 h) to
a suspension of cesium carbonate in acetonitrile at reflux.[39]
Even though the synthesis of cyclophane 11 was success-
fully accomplished, the initial goal of this synthesis was the
development of a protocol for synthesizing large quantities
in an easy and modular synthesis. Furthermore, the trouble-
some coupling of the two subunits 5 and 8 led to an overall
moderate yield of 34% for the cyclization procedure, which
The symmetrical unit 8 of the cyclophane was synthesized
starting from phenol 3 by the introduction of 1,3-dichloro-
propane through an SN2 reaction, followed by the addition
of phenol to the obtained alkene to give a yield of 99%
after column chromatography and recrystallization from
acetonitrile. To avoid homocoupling of the symmetrical di-
phenylpiperidine moiety 8, the second alkyl spacer of cyclo-
phane 11 was installed at the remaining free hydroxy group
of 7. Therefore phenol 7 was treated with 1,3-diiodopropane
in the presence of radical inhibitor 3,5-di-tert-butyl-4-hy-
droxytoluene (BHT) and potassium carbonate as base and
thus the symmetrical unit 8 equipped with two different
leaving groups was obtained as a colorless oil in a yield of
67% (Scheme 2).
Reaction of the two cyclophane units 5 and 8 by nucleo-
philic substitution afforded dimer 9 in a moderate yield of
48% (Scheme 3). Because both alkyl spacers were previous-
ly coupled to only one part of the cyclophane, homodimeri-
zation was excluded. By carefully adjusting the reaction con-
ditions (Cs2CO3, acetone, 408C, 16 h) only the iodide, as the
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M. Mayor et al.
coupled to bis(hydroxyphenyl)-
piperidine 15 by nucleophilic
substitution under high dilution
reaction conditions, which was
synthesized following a litera-
ture protocol in a single step
from
N-acetylpiperidin-4-one
and phenol in acidic media.[36]
Cyclophane 11 was thus ob-
tained as a white powder in a
yield of 31% after column
chromatography and precipita-
tion with ethanol (Scheme 5),
which is comparable to the
overall yield of the stepwise
cyclization procedure. Analyses
of the side-products by ESI-MS
documented the formation of
trace amounts of the tetrameric
product as well as the forma-
tion of higher oligomers. Fur-
thermore, results of the analysis
suggest that over a long reac-
Scheme 3. Stepwise cyclization procedure towards monofunctionalized cyclophane 11. Reagents and condi-
tions: a) Cs2CO3, acetone, 408C, 16 h; b) BHT, THF, hn, RT, 5 h; c) Cs2CO3, MeCN, reflux, 36 h.
is in the range reported for intermolecular macrocyclizations
but far from an optimal procedure.[38] Therefore it was de-
cided to shorten the synthetic route mainly by using an in-
termolecular cyclization procedure.
Thus, to introduce one of the alkyl linkers, phenol 3 was
substituted with 1,3-dibromopropane to give 12 in a yield of
71%. Addition of guaiacol to the alkene moiety of 12 led to
13 in a yield of 94% after column chromatography. Final
nucleophilic substitution of the remaining phenol with 1,3-
dibromopropane gave the desired monofunctionalized com-
ponent 14 of cyclophane 11 in a yield of 91% as a colorless
oil (Scheme 4).
For the intermolecular cyclization it turned out to be cru-
cial to have two leaving groups with the same reactivity to
avoid oligomerization. The monofunctionalized unit 14 was
Scheme 5. Assembly of cyclophane 11 by an intermolecular approach.
Reagents and conditions: a) Cs2CO3, acetonitrile, reflux, 20 h.
tion time (24 h) the amide was cleaved to a certain extent.
Nevertheless, the simple purification procedure and the pos-
sibility of synthesizing the cyclophane precursors 14 and 15
in bulk made this strategy towards monofunctionalized cy-
clophane 11 the method of choice.
Having the desired monofunctionalized cyclophane 11 in
hand, it was of interest to transform the masked functionali-
ty into a suitable reaction center for Sonogashira cross-cou-
pling reactions. Therefore the methoxy group had to be
cleaved without cleavage of the cyclophane alkoxy groups.
The use of nucleophilic demethylation conditions turned out
to be the method of choice. Therefore the cyclophane was
treated with sodium thiomethoxide in dry DMF at 1608C
for 6 h.[43] After quenching with a 0.1m aqueous HCl solu-
Scheme 4. Synthesis of the monofunctionalized cyclophane component
14. Reagents and conditions: a) 1,3-dibromopropane, K2CO3, MeCN,
reflux, 5 h; b) guaiacol, BF3·OEt2, CH2Cl2, RT, 9 d; c) 1,3-dibromopro-
pane, K2CO3, acetone, reflux, 20 h.
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Molecular Daisy Chains
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tion and recrystallization from methanol, the desired phenol
16, which is insoluble in most common solvents, was ob-
tained in an excellent yield of 98% (Scheme 6). Because
thesis of monomer 1 because at room temperature not only
the amides were reduced but also the iodobenzyl ether was
cleaved to a certain extent (around 50%). Unfortunately,
however, the reaction did not show full conversion at 08C
and small amounts of inseparable mono-reduced byproduct
were observed by ESI-MS. Therefore the chosen reaction
conditions are a compromise, and amine 18 was obtained in
a yield of 74% (Scheme 6). The use of other reducing re-
agents like BH3·THF led to partial defunctionalization of
the iodide functionality and were therefore neglected.
The molecular wire 22 was synthesized starting from 1,4-
diiodobenzene. In the first step, acetylenes with orthogonal
protecting groups, namely trimethylsilylacetylene and dime-
thylpropargyl alcohol (HOP) were statistically cross-cou-
pled. Product 19, obtained in a yield of 45%, was then selec-
tively deprotected on the HOP side with sodium hydroxide
in toluene at reflux (Scheme 7).[44] The free acetylene 20 was
Scheme 6. Introduction of a benzyl linker bearing a suitable halide for
Sonogashira cross-coupling reactions and activation of the piperidine ni-
trogen atom for subsequent alkylation. Reagents and conditions:
a) sodium thiomethoxide, DMF, 1608C, 6 h; b) 4-iodobenzyl bromide,
Cs2CO3, DMF, 858C, 20 h; c) DIBAL-H, CH2Cl2, 08C then RT, 4 h.
Scheme 7. Synthesis of the oligophenylene-ethynylene building block 22.
Reagents and conditions: a) [PdCl
1) TMS-acetylene, 4 h, 2) 2-methyl-3-butyn-2-ol, RT, 16 h; b) NaOH, tol-
uene, 808C, 1 h; c) 4-iodobenzene, [PdCl2A(PPh3)2], CuI, DIPA, THF, RT,
2ACHTUGNTREN(UNGN PPh3)2], CuI, DIPA, THF, RT,
CTHUNGTRENNUNG
4 h; d) TBAF, Ac2O, AcOH, THF, 08C then RT, 2 h.
rather harsh reaction conditions had to be used to ensure
full conversion, in some cases, nucleophilic aromatic substi-
tution of thiomethoxide at one of the phenylene groups was
observed. Demethylation with thiophenol or boron tribro-
mide led to no conversion, as indicated by TLC. In the next
step it was decided to introduce a 4-iodobenzyl group
mainly to assist supramolecular aggregation by increasing
the flexibility; directly linking the molecular rod to the cy-
clophane, which would require transformation of the free
phenol 16 into a triflate, would potentially prevent the ag-
gregation because of the resulting stiffness. The benzyl
linker was installed by SN2 reaction of 4-iodobenzyl bromide
with phenol in the presence of cesium carbonate in DMF at
858C. By using these reaction conditions, compound 17 was
isolated after column chromatography in a yield of 98%
(Scheme 6). The use of a weaker base like potassium carbo-
nate did not lead to full conversion after 48 h. Before cross-
coupling with the oligophenylene-ethynylene 22, the acetyl
protecting groups of the piperidinyl moiety were reduced to
the corresponding alkyls to avoid the formation of possible
byproducts. The reduction was performed by slowly adding
DIBAL-H to a dilute solution of diamide 17 in dichloro-
then cross-coupled by means of a Sonogashira protocol with
iodobenzene (Scheme 7). In the final step, the TMS protect-
ing group was removed by tetrabutylammonium fluoride
(TBAF) to yield the desired OPE 22 in a total yield of 33%
over four steps, including one statistical Sonogashira cross-
coupling reaction.
The OPE rod 22 was then cross-coupled with the cyclo-
phane by using [Pd
isopropylamine (DIPA) in THF at room temperature. In the
presence of catalysts such as [Pd(PPh3)4] or [PdCl2A(PPh3)2]
ACHTUNGRTENN(UNG dba)2], triphenylphosphine, CuI, and di-
AHCTUNGTRENNUNG
A
CHTUNGTRENNUNG
or without a large excess of base, no conversion was ob-
served. The crude was purified by extraction and column
chromatography to yield the desired scaffold 23 in a yield of
92% as a white solid (Scheme 8). The tertiary amines were
finally alkylated in dichloroACTHNUGTRENNUGmethACHTUNTGRENaNUGN ne by using freshly distil-
led iodoethane. After stirring for 5 days at room tempera-
ture, monomer 1 was isolated by column chromatography
on silica that had been preconditioned with a 12% (w/v)
methanolic solution of sodium bromide,[45] eluting with a
mixture of dichloromethane and 5% methanol. Ion-ex-
change chromatography (DOWEX 1X8, 200–400 mesh, Clꢀ)
gave the desired product 1 comprising a hydrophobic molec-
ular rod and a terminal hydrophilic loop as the chloride salt
ACHTUNGTRENNUNGmethACHTUNGTRENNUNGane at 08C. After addition of the reducing agent, the
reaction was allowed to warm to room temperature. This re-
action turned out to be one of the crucial steps in the syn-
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M. Mayor et al.
Scheme 8. Final assembly of the amphiphilic monomer 1. Reagents and conditions: a) OPE 22, [PdACTHNUGTRNEUNG(dba)2], PPh3, CuI, DIPA, THF, RT, 3 h; b) iodo-
ethane, CH2Cl2, RT, 5 d, then ion exchange (DOWEX 1X8, 200–400 mesh Clꢀ).
in a yield of 59% as an off-
white
hygroscopic
solid
(Scheme 8).
According to the procedure
described herein, product 1,
comprising a hydrophobic oli-
gophenylene-ethynylene
rod
and terminal hydrophilic
a
loop, was synthesized in 21
steps by an intramolecular step-
wise cyclophane assembly or in
17 steps by intermolecular mac-
rocyclization. It has been shown
that cyclophane 11 can be syn-
thesized in large quantities (2 g)
Figure 2. Possible aggregates formed by amphiphile 1 in polar solvents.[26,28]
and interlinking of the hydro-
phobic and hydrophilic compo-
nents 18 and 22 is possible in good yields. The hermaphro-
ditic monomer 1 was characterized by low-resolution ESI-
MS and H NMR spectroscopy (see the Supporting Informa-
cause of the reversible aggregation, no interruption of oligo-
merization.
1
The formation of an acyclic head-to-tail dimer ([a2]HT)
can be seen as the first propagation step towards polymeri-
zation. Nevertheless, each possible n-mer of the propagating
chain has the possibility of forming, because of the expected
reversible binding, the cyclic version of the oligomer. The
hypothetical formation of this variety of aggregates makes a
tion).
NMR aggregation studies: With the desired hermaphroditic
monomer 1 in hand it was of interest to study its aggrega-
tion behavior in polar solvents by NMR spectroscopy. To
make use of the strong nonclassical hydrophobic effect, the
aggregation studies were solely focused on the chloride salt
of monomer 1, for which the best water-solubility was ex-
pected, as reported by Diederich et al.[36] As outlined in the
introduction, such amphiphilic molecules can potentially
form various aggregates (Figure 2).[28] Monomer 1 may, as
shown in Figure 2, form three different dimer structures ex-
cluding aggregation of the organic ions as well as assemblies
in which the OPE rod comes into close proximity with the
spiro-piperidinyl moieties. The formation of [c2]daisy chains
([c2]HH) is well known in the literature and these confor-
mations are often thermodynamically stable aggregates that
prevent the formation of longer oligomers.[27] Also, the ag-
gregation of two hydrophobic OPE rods ([a2]TT) is possi-
ble, but it is expected that such a binding is weaker than the
inclusion of the rod in host cavities and therefore causes, be-
1
detailed analysis difficult. H NMR titrations, DOSY NMR
spectroscopy, HRMS, and fluorescence measurements were
performed for this purpose.
Previous publications have shown that concentration-
1
dependent H NMR spectroscopy can be used to determine
the aggregation number n and the association constant
1
Ka.[34,46,47] Thus, H NMR spectra were recorded at constant
temperature at different concentrations of monomer 1 in a
3:2 mixture of D2O/[D4]methanol (Figure 3).
The NMR spectra show that the protons are under fast
exchange on the NMR timescale. Therefore the observed
chemical shifts (dobs) can be expressed as the sum of the
chemical shifts of the monomer (dmon) and of the individual
aggregates (dagg), each one as a weighted average of its
molar fraction [Equation (1)].[48]
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Molecular Daisy Chains
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Figure 3. Stacked 1H NMR spectra recorded with a 500 MHz spectrome-
ter showing the aromatic region of monomer 1. 1) 7.96, 2) 3.98, 3) 2.99,
4) 1.99, 5) 1.49, 6) 1.12, 7) 0.32, 8) 0.22, 9) 0.091, 10) 0.055, 11) 0.026,
12) 0.014 mm.
dobs ¼dmonðCmon=CtotÞ þ dagg1ðCagg1=CtotÞþ
ð1Þ
dagg2ðCagg2=CtotÞ þ etc
When assuming that the concentration (C) of an aggre-
gate that is predominant in a certain concentration range re-
mains constant above a certain concentration, a plot of dobs
versus the inverse concentration (1/C) should give a straight
line after each individual change in aggregation. The inter-
section of these lines then gives directly the critical aggrega-
tion concentration (CAC) for each individual aggregate.[46]
For simplification, only one equilibrium was considered for
each aggregate and concentration range, and cooperative ef-
fects were excluded, which means that for all equilibria the
same association constant was assumed (Ka1 =Ka2 =Ka3 etc.).
Thus, Equation (1) simplifies to a linear function. A repre-
sentative plot of dobs for one proton of the amphiphile 1 (as-
signed to the OPE unit by 2D NMR spectra) against the in-
verse total concentration (1/Ctot) is illustrated in Figure 4,
which indicates two critical aggregation concentrations at
0.941 (1/Ctot =1062.7mꢀ1) and 3.03 mm (1/Ctot=330.0mꢀ1).
Below 1 mm, the observed chemical shift remains constant,
which indicates that only one aggregate or monomer is dom-
inant. No further conclusions can be drawn above 3 mm be-
Figure 4. Top: Plot of the observed chemical shift (dobs) against the in-
verse of the concentration (1/C) of monomer 1. Straight lines represent
linear regression analyses; from the intersection, the critical aggregation
concentration (CAC) was calculated. Bottom: The second CAC at higher
concentrations.
1
As mentioned above, the H NMR data can also be em-
ployed to obtain the aggregation number n and the associa-
tion constant Ka from Equation (2), which describes an equi-
librium in which n monomers form a single aggregate.[34,46–48]
ln ½CtotðjdobsꢀdmonjÞꢁ ¼ nln ½CtotðjdaggꢀdobsjÞꢁþ
ln Ka þ ln nꢀðnꢀ1Þln ðjdaggꢀdmonjÞ
ð2Þ
1
Plots of ln[Ctot(jdobsꢀdmon j)] versus ln[Ctot(jdaggꢀdobs j)]
(Figure 5) give a straight line from which the slope and the
intercept can be calculated to yield n and Ka, respectively.
By plotting dobs against the total concentration and extrapo-
lating to zero amphiphile, the chemical shift of the monomer
(dmon) can be approximated.[47] Extrapolation of the concen-
tration to infinity yielded the chemical shift of the aggregate
(dagg; see the Supporting Information).[47]
The variation of the slopes in Figure 5 clearly demonstrate
that the data obtained by NMR titration can be divided into
three different concentration ranges, as has already been
shown by the plot of the observed chemical shifts against
the inverse concentration (Figure 4). An aggregation
cause the H NMR signals broaden and therefore further as-
signment of individual protons is impossible (Figure 3).
Large upfield shifts of the aromatic signals assigned to the
OPE unit were observed above the CAC of 1 mm in contrast
to the proton chemical shifts below 7.00 ppm for which only
weak shifts were observed (Figure 3). By threading the OPE
rod into the cavity of the cyclophane, the phenyl protons of
the rod experience a ring current from the electron-rich aro-
matic systems in the cavity wall, which leads to an induced
chemical-shift change. Thus, the large upfield shift can be
seen as the first evidence for threading of the OPE rod into
the cavity of the cyclophane.
Chem. Eur. J. 2013, 19, 2089 – 2101
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2095

M. Mayor et al.
tion). According to the calculations, the measured substan-
ces are 1.48 times larger than the monomer, which strongly
supports the self-aggregation observed previously in the
NMR titration experiments. The fact that this value is less
than 2, which is the value expected for acyclic dimers,
strongly indicates the formation of [c2]daisy chains. Thus, it
has been shown that the dimer is the predominant species
over a broad concentration range, which allows scope for
functionalization to enable subsequent polymerization.
Fluorescence aggregation studies: To gain further insight
into the dimerization of the hermaphroditic compound 1, a
fluorescence titration in the concentration range of 0.028 to
6.6ꢃ10ꢀ6 mm was performed. Compound 1 in a mixture of
H2O/methanol (3:2) was excited at the absorption wave-
Figure 5. Plot of ln[Ctot(jdobsꢀdmon j)] against ln[Ctot(jdaggꢀdobs j)]. Straight
lines represent linear regression analyses from which the aggregation
number n and Ka were calculated.
length of the p–p* transition of the hydrophobic oligo
ACHTUNGTRENNUNGphen-
AHCTUNGTREGyNNUN lene–ethynylene moiety (321 nm). Emission at 355 and
369 nm with a shoulder at around 380 nm was observed,
which decreases with decreasing concentration, as illustrated
in Figure 6.
Comparison of the emission spectra of amphiphile 1 in
water/methanol (3:2) and dichloromethane, in which only
the monomer should be present, clearly demonstrates that
the intensity of emission of 1 in polar solvent is lower at the
same concentration (see the Supporting Information). Even
though a decrease in intensity is expected due to solvent ef-
number of n=2 was obtained by analysis of the concentra-
tion range between 0.014–1 mm. Different aromatic signals
as well as the shifting signals in the aliphatic region lead to
relative narrow aggregation values between 1.97–2.10, which
strongly suggests the formation of dimeric structures. Fur-
thermore, by analysis of just the concentration range in
which dimer formation is observed, an association constant
of Ka =9.8ꢃ106 mꢀ1 was obtained when the chemical shift of
the aggregate was replaced by the shift of the dimer. Inter-
pretation of the association constant has to be taken with
caution because it was assumed that in each concentration
range only one aggregate is dominant. The concentration
range in which the transition from monomer to dimer can
be observed was unfortunately not reached in this NMR ti-
tration due to instrumentation limits. By closer inspection of
the titration curve obtained by plotting dobs against the con-
centration, it became clear that only the first part of the ex-
pected dimer plateau was reached, which makes a precise
prediction of the monomer chemical shift (dmon) impossible.
In the concentration range between the two CACs, aggre-
gation numbers of between 4.5 and 6 were obtained. Above
3 mm, a precise estimation of the aggregation number was
not possible due to the strong broadening of the proton
peaks, but data suggest n>6 (or even n>10). Even though
the protons are in fast exchange on the NMR timescale, the
wide concentration range in which dimerization can be ob-
served provides evidence for a strong hydrophobic effect. It
is, however, safe to conclude that higher oligomers at con-
centrations above 1 mm are formed, as indicated by the
plots in Figure 5. Furthermore, the strong broadening of the
proton signals, which is typical of polymer formation due to
increased viscosity, strongly supports this finding. DOSY
measurements were performed on amphiphile 1 and a non-
self-aggregating compound as reference to determine the
size of the main aggregate in polar solvent at a concentra-
tion at which NMR titration studies indicate mainly dimer
existence (200 mm). Therefore the hydrodynamic radii of the
aggregates as well as their relative volumes compared with
monomer 1 were calculated (see the Supporting Informa-
Figure 6. Top: Emission spectra of compound 1 in H2O/methanol (3:2) in
a concentration range of 0.028 to 6.6ꢃ10ꢀ6 mm. Bottom: The emission of
1 at the lowest concentrations.
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Molecular Daisy Chains
FULL PAPER
fects, the dramatic decrease is indicative of the inclusion of
the OPE rod in the cavity and is a result of the insulating
nature of the macrocycles. Furthermore, because the emis-
sion spectra of the monomer and dimer show the same
bands, excimer formation can be excluded. Hence, possible
dimeric structures in which the hydrophobic rods aggregate
outside the cavity ([a2]TT) is unlikely.[34] Because it is ex-
pected that a dimer such as the [c2]daisy chain should allow
for excimer formation, this finding suggests an unfavorable
arrangement of the two hydrophobic rods with respect to
each other in the cavity or a structure in which only one rod
is embedded in the cavity of another, as in the [a2]daisy
chain.
The total amphiphile concentration is therefore given by
Equation (4).
Ctot ¼ Cmon þ 2Cdim
ð4Þ
Substitution for the dimer concentration gives Equa-
tion (5).
Ctot ¼ Cmon þ 2KaCm2 on
ð5Þ
Because it has been shown that the fluorescence of the
monomer is significantly higher than that of the dimer, a
good approximation to estimate Ka is to assume that the flu-
orescence of the monomer is directly proportional to its
concentration. Hence, Equation (5) can be written as dem-
onstrated by Margalit et al.[49,50] as Equation (6) in which k
is an experimental coefficient. From the slope and the inter-
cept of a plot of Ctot/Icorr against Icorr, the association constant
was calculated to be 1.33ꢃ106 mꢀ1 (Figure 8).
A plot of the inner filter effect corrected relative intensi-
ties against concentration shows dimer formation down to a
CAC of 1.83ꢃ10ꢀ6 m. Below this CAC, the intensities de-
crease linearly with a decreased slope (Figure 7).
Ctot=Icorr ¼ k þ 2k2KaIcorr
ð6Þ
Figure 8. Plot of Ctot/Icorr against Icorr for estimation of the association con-
stant Ka.
The rather high association constant is in good agreement
with the observation of a strong hydrophobic effect as well
as with the association constants reported by Anderson
et al. for the threading of Diederich-type cyclophanes with
dicationic oligophenylene-ethynylenes.[51] Despite the fact
that direct evidence for the formation of daisy-chain aggre-
gates in solution was not obtained, mainly due to the com-
Figure 7. Top: Plot of the relative intensities (Icorr) at 355 nm against the
concentration (Ctot). Bottom: Graphical extrapolation to estimate the
CAC is shown.
1
plicated H NMR spectra, the high association constant, the
significant upfield shifts of aromatic signals with increasing
concentration, the observation of dimers over a broad con-
centration range and at very low concentrations, and the
strongly reduced emission in water/methanol mixtures are
strong indicators that it was possible to design and synthe-
size an amphiphilic monomer that can form daisy chains.
Furthermore, it has been shown that the nature of these
daisy chains can be varied just by changing the concentra-
tion. Attempts to grow single crystals suitable for X-ray
The NMR titrations demonstrated that at the concentra-
tions used to record the fluorescence spectra, dimerization is
the dominant process. The association constant Ka can thus
be expressed by Equation (3).
Ka ¼ Cdim=C2mon
ð3Þ
Chem. Eur. J. 2013, 19, 2089 – 2101
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2097

M. Mayor et al.
analysis to gain direct proof for aggregation were unfortu-
nately not successful with the chloride salt of monomer 1.
cyclophane 11 by two different pathways and the hydropho-
bic OPE 22 was synthesized by classical Sonogashira cross-
coupling reactions. NMR titration experiments showed the
formation of dimers up to a concentration of 1 mm. Above
this concentration, evidence for aggregation to form larger
oligomers was found by graphic determination of the aggre-
gation number. Fluorescence studies indicate that dimeriza-
tion occurs at concentrations as low as 10ꢀ7 mm. The re-
duced fluorescence intensity observed for the amphiphile 1
in the protic solvent mixture methanol/water compared with
in dichloromethane suggests the inclusion of two rods in
cavities forming a thermodynamically stable [c2]daisy chain,
which is further supported by a high association constant Ka.
It has been demonstrated that such aggregation behavior as
a result of hydrophobic effects can play a major role in the
controlled assembly of mechanically interlinked polymers. It
is now of interest to study the effect of functionalization of
the hydrophobic rod on the generation of well-defined me-
chanically interlinked macromolecules. The influence of
counterions on the aggregation behavior is currently under
investigation.
High-resolution ESI-MS aggregation studies: Direct proof
for the formation and stability of aggregates in the gas
phase was obtained by HRMS (Figure 9). Analysis of a
Figure 9. High-resolution ESI-MS spectrum of compound 1 showing the
formation of dimers to pentamers. Inset: Comparison of the measured
and calculated isotope patterns for [MCl]+.
Experimental Section
General remarks: All chemicals were directly used in the syntheses with-
out purification unless otherwise noted. Dry solvents were purchased
from Fluka. Solvents for chromatography and extractions were distilled
before use. When the Schlenk technique was used, the solvents were de-
gassed with argon for several minutes. Silica gel 60 (40–63 mm) from
Fluka or SilicaFlash P60 (40–63 mm) from Silicycle were used for column
chromatography. TLC was performed on silica gel 60 F254 glass plates
with a thickness of 0.25 mm from Merck. Characterizations were per-
10ꢀ5 m solution of 1 in H2O/methanol (3:2) by employing a
nanospray source revealed oligomers of general composition
MxClyz+, in which M is the dicationic form of the monomer.
Accordingly, these oligomers carry a positive charge of z=
2xꢀy. Mass/charge ratios corresponding to dimers, trimers,
tetramers, and pentamers were observed at this rather low
concentration. Note that due to ion exchange of the chloride
anions with other ions in aqueous solution, peak broadening
was observed for the oligomers.
The peak with the highest intensity in this mass spectrum
is the monomer peak, which is not surprising because the
ions become isolated from the solvent in the spray process
thereby reducing the driving force for aggregation. Despite
the fact that the aggregation behavior of hermaphroditic
daisy-chain monomer 1 in solution and in the gas phase
cannot be directly compared, especially because of the miss-
ing hydrophobic effect on the one hand and the prevailing
electrostatic interaction on the other, the observation of
oligomers in the gas phase together with the results of
1H NMR and emission spectroscopic analyses in solution,
demonstrates the high potential of this new binding concept
for the formation of long oligomeric daisy chains.
1
formed with the following instruments: H and 13C NMR spectra were re-
corded with a Bruker DPX-NMR (400 MHz) or DRX-500 (500 MHz)
spectrometer; the J values are given in Hz. Solvents were obtained from
Cambridge Isotope Laboratories. All spectra were recorded at 298 K.
Mass spectra were recorded with a Finnigan MAT 95Q spectrometer
(EI) and an Bruker esquire 3000 plus spectrometer (ESI). Elemental
analyses were carried out on
a varioMICROcube from elementar.
HRMS were recorded by the group of Schꢄrch at the university of Bern
on a LTQ Orbitrap XL from Thermo Fisher Scientific using a nanoelec-
trospray ion source, except for monomer 1, which was measured at the
Karlsruhe Institute of Technology (see below for details).
NMR titrations: A stock solution of monomer 1 (8.84 mg) in D2O/
[D4]methanol (3:2, 0.8 mL) was prepared. Other concentrations of mono-
mer 1 were obtained by dilution of this solution. NMR spectra of the cor-
responding samples were recorded with a Bruker DRX-500 (500 MHz)
spectrometer at 295 K. Solvents were obtained from Cambridge Isotope
Laboratories. The samples were locked on [D4]methanol. To assign the
peaks in the individual spectra, COESY spectra were recorded for each
individual sample.
NMR diffusion experiments: Self-diffusion measurements were per-
formed on samples of amphiphile 1 and a reference compound lacking
the OPE moiety with the bipolar gradient pulse sequence of Wu et al.[52]
Conclusion
by using
a Bruker Avance III NMR spectrometer operating at
600.13 MHz. The instrument was equipped with a 5 mm BBFO smart
probe with a shielded z-gradient coil and a GAB gradient amplifier
(10 A, maximum gradient strength 52.5 Gcmꢀ1).
Daisy-chain monomer 1 comprising an OPE and a cyclo-
phane loop has successfully been synthesized in excellent
yields, and cyclophane 11 can be synthesized on a large
scale. Owing to the inspirational work of Diederich and co-
workers, it was possible to synthesize monofunctionalized
All samples were dissolved in a mixture of D2O and [D4]methanol (3/2,
v/v). The diffusion experiments were performed at 298 K and the temper-
ature was calibrated by using a methanol standard to an accuracy of
ꢂ0.2 K. The gradient strength was calibrated by using a Shigemi tube
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Chem. Eur. J. 2013, 19, 2089 – 2101

Molecular Daisy Chains
FULL PAPER
filled with H2O to a height of 4.0 mm and imaging this water cylinder.[53]
The resulting gradient calibration was validated by determining the diffu-
sion coefficient of water at 298 K, which reproduced the literature value
within 5%.
(brs, 1H; OH), 4.14–4.07 (m, 2H; phenol-O-CH2), 4.06–3.98 (m, 6H; Ar-
O-CH2), 3.72–3.57 (m, 4H), 3.55–3.44 (m, 4H), 2.47–2.28 (m, 8H), 2.25–
2.12 (m, 4H), 2.07ACHTNUTRGNE(UNG s, 3H; (CO)CH3), 2.06 ppm (s, 3H; (CO)CH3);
13C NMR (101 MHz, CDCl3, 258C, TMS): d=168.9 (Cq, 2C, C=O), 157.1
(Cq, 1C), 157.1 (Cq, 1C), 156.8 (Cq, 1C), 145.7 (Cq, 1C), 144.2 (Cq, 1C),
140.3 (Cq, 1C), 139.1 (Cq, 1C), 138.5 (Cq, 1C), 138.4 (Cq, 1C), 127.0 (Ct,
4C), 126.9 (Ct, 2C), 116.9 (Ct, 1C), 114.8 (Ct, 2C), 114.7 (Ct, 2C), 114.6
(Ct, 2C), 112.9 (Ct, 1C), 111.6 (Ct, 1C), 65.1 (Cs, 1C), 63.9 (Cs, 1C), 63.3
(Cs, 1C), 63.3 (Cs, 1C), 63.3 (Cs, 1C), 43.6 (Cs, 1C), 43.6 (Cs, 1C), 43.2
(Cq, 1C), 43.1 (Cq, 1C), 38.6 (Cs, 1C), 35.8 (Cs, 1C), 35.8 (Cs, 1C), 34.8
(Cs, 1C), 34.8 (Cs, 1C), 29.6 (Cs, 1C), 29.4 (Cs, 1C), 21.6 ppm (Cp, 2C;
(CO)CH3); MS (ESI, positive ion mode, MeCN): m/z (%): 757 [M+K]+,
741 [M+Na]+, 719 [M+H]+; HRMS (ESI): m/z calcd for
[C44H50N2O7+H]+: 719.3691; found: 719.3691.
Twelve single diffusion experiments with constant diffusion times (40 ms)
and gradient lengths (2.5 ms) were performed, and the gradient strength
was varied between 5 and 95% of the maximum strength. The decrease
in the intensity of the signal of interest was determined and fitted with
the Bruker t1/t2 software package suitable for DOSY experiments, which
is included in the instrument software.[54]
Fluorescence measurements: A stock solution of monomer 1 (0.48 mg) in
MilliQ water/methanol (3:2, 3 mL) was prepared. Other concentrations
were obtained by dilution of this solution. Emission spectra were record-
ed with a Shimadzu RF-5301 PC spectrofluorophotometer using 1 cm
115F-QS Hellma cuvettes at room temperature in the presence of air.
The excitation wavelength was 321 nm, which was determined by UV/Vis
spectroscopy. The following instrument parameters were used: Excitation
slit width 1.5 nm, emission slit width 3 nm, response time 2.0 s, and sam-
pling interval 1.0 nm.
1,1’’-Diactyl-5’-(4-iodobenzyloxy)dispiro[piperidine-4,2’-(7,11,21,25-tet-
raoxacyclopenta[24.2.2.23,6.212,15.217,20]hexatriaconta-3,5,12,14,17,19,26,28,
29,31,33,35-dodecaene)-16,4’’-piperidine] (17): Alcohol 16 (150 mg,
1.00 equiv, 0.209 mmol), 4-iodobenzyl bromide (98.0 mg, 1.50 equiv,
0.314 mmol), and cesium carbonate (138 mg, 2.00 equiv, 0.418 mmol)
were suspended in dry DMF (12 mL) under an argon atmosphere. The
reaction mixture was heated at 858C for 20 h. Afterwards, the solvent
was evaporated and the residue taken up in dichloromethane and water.
The layers were separated and the aqueous layer extracted three times
with dichloromethane. The combined organic layers were washed with
water and brine, dried with sodium sulfate, filtered, and concentrated.
ESI mass spectrometry: Mass spectrometric characterization was per-
formed on a hybrid quadrupole/ion mobility/time-of-flight mass spec-
trometer (SYNAPT G2-S HDMS, Waters Inc. Milford, MA, USA). The
instrument was equipped with a nanospray source with gold-coated tips
and a spray voltage of 1200 V. Solutions of monomer 1 in MilliQ water/
methanol (3/2, v/v) at a concentration of ~10ꢀ5 m were freshly prepared
before spraying. The time-of-flight mass spectra were analyzed by using
Watersꢀ MassLynx 4.1 software package.
The crude was purified by column chromatography (SiO2; dichloro
ane then dichloromethane, 2.5% MeOH). The desired product 17 was
obtained as a white powder (98%).
Rf =0.39 (CH2Cl2, 5% MeOH); m.p. 1378C; H NMR (400 MHz, CDCl3,
258C, TMS): d=7.64 (d, 3J
(H,H)=8 Hz, 2H; iodobenzene-H2), 7.12–
7.06 (m, 4H; Ar-H), 6.98 (d, 3J(H,H)=8 Hz, 2H; Ar-H), 6.94 (d, 3J-
(H,H)=8 Hz, 2H; Ar-H), 6.75–6.67 (m, 8H; Ar-H), 6.46 (d, 4J
(H,H)=
ACHTUNGTRENNUNGmeth-
AHCTUNGTRENNUNG
Synthesis of 1,1’’-diactyl-5’-methoxydispiro[piperidine-4,2’-(7,11,21,25-tet-
raoxacyclopenta[24.2.2.23,6.212,15.217,20]hexatriaconta-3,5,12,14,17,19,26,28,
29,31,33,35-dodecaene)-16,4’’-piperidine] (11) by the intermolecular
route: Cesium carbonate (5.64 g, 10.0 equiv, 17.1 mmol), bis-phenol 15
(534 mg, 1.00 equiv, 1.72 mmol), and dialkyl dibromide 14 (1.00 g,
1.00 equiv, 1.72 mmol) were suspended in acetonitrile (0.6 L) and heated
at reflux for 20 h. After cooling to room temperature, the precipitate was
filtered off and the filtrate was concentrated. The residue was taken up
in dichloromethane and the insoluble white solid was again filtered off.
The filtrate was again concentrated and the remaining crude purified by
column chromatography (SiO2; dichloromethane, 5% MeOH). The white
solid product was precipitated with EtOH, filtered, and washed with
EtOH and a small amount of diethyl ether (31%).
1
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
2 Hz, 1H; Ar-H), 4.73 (s, 2H; iodobenzene-CH2O), 4.09–3.99 (m, 8H;
Ar-OCH2), 3.72–3.61 (m, 3H), 3.53–3.36 (m, 5H), 2.42–2.33 (m, 4H),
2.30–2.12 (m, 8H), 2.06 ppm (s, 6H; 2ꢃ(CO)CH3); 13C NMR (101 MHz,
CDCl3, 258C, TMS): d=168.4 (Cq, 2C; C=O), 157.1 (Cq, 1C), 157.1 (Cq,
1C), 157.0 (Cq, 1C), 147.7 (Cq, 1C), 147.5 (Cq, 1C), 139.8 (Cq, 1C), 138.7
(Cq, 1C), 138.6 (Cq, 1C), 137.7 (Cq, 1C), 137.5 (Ct, 2C), 137.3 (Cq, 1C),
129.4 (Ct, 2C), 126.9 (Ct, 2C), 126.8 (Ct, 4C), 118.7 (Ct, 1C), 114.7 (Ct,
4C), 114.6 (Ct, 2C), 114.3 (Ct, 1C), 113.7 (Ct, 1C), 93.0 (Cq, 1C; C-I),
70.4 (Cs, 1C; iodobenzene-CH2O), 64.6 (Cs, 1C), 63.3 (Cs, 1C), 63.2 (Cs,
1C), 63.2 (Cs, 1C), 53.5 (Cs, 1C), 43.5 (Cs, 1C), 43.4 (Cs, 1C), 43.3 (Cq,
1C), 42.9 (Cq, 1C), 38.5 (Cs, 1C), 35.8 (Cs, 1C), 34.8 (Cs, 1C), 29.6 (Cs,
1C), 29.5 (Cs, 1C), 21.5 (Cp, 1C; (CO)CH3), 21.5 ppm (Cp, 1C;
(CO)CH3); MS (ESI, positive ion mode, MeCN): m/z (%): 973 [M+K]+,
957 [M+Na]+.
1
Rf =0.36 (CH2Cl2, 5% MeOH); m.p. 2668C; H NMR (400 MHz, CDCl3,
258C, TMS): d=7.16–7.07 (m, 6H; Ar-H), 6.76–6.67 (m, 8H; Ar-H),
6.63–6.59 (m, 1H; Ar-H), 4.08–3.98 (m, 8H), 3.85–3.74 (m, 1H), 3.68–
3.58 (m, 5H, including s at 3.62 (OCH3)), 3.58–3.40 (m, 5H), 2.46–2.27
(m, 8H), 2.24–2.11 (m, 4H), 2.07 ppm (s, 6H; 2ꢃ(CO)CH3); 13C NMR
(101 MHz, CDCl3, 258C, TMS): d=168.9 (Cq, 2C; C=O), 157.3 (Cq, 1C),
157.2 (Cq, 1C), 157.2 (Cq, 1C), 149.4 (Cq, 1C), 147.0 (Cq, 1C), 140.0 (Cq,
1C), 138.9 (Cq, 1C), 138.6 (Cq, 1C), 138.0 (Cq, 1C), 127.2 (Ct, 2C), 126.9
(Ct, 4C), 118.0 (Ct, 1C), 114.8 (Ct, 2C), 114.8 (Ct, 2C), 114.7 (Ct, 2C),
113.1 (Ct, 1C), 110.4 (Ct, 1C), 64.7 (Cs, 1C), 63.6 (Cs, 1C), 63.4 (Cs, 1C),
63.3 (Cs, 1C), 55.9 (Cp, 1C, OCH3), 43.7 (Cq, 1C), 43.6 (Cs, 2C), 43.1 (Cq,
1C), 38.6 (Cs, 1C), 38.6 (Cs, 1C), 36.0 (Cs, 1C), 35.8 (Cs, 1C), 35.1 (Cs,
1C), 34.8 (Cs, 1C), 29.7 (Cs, 1C), 29.6 (Cs, 1C), 21.6 ppm (Cp, 2C,
(CO)CH3); MS (ESI, positive ion mode, MeCN): m/z (%): 771 [M+K]+,
755 [M+Na]+, 733 [M+H]+; elemental analysis calcd (%) for
C45H52N2O7: C 73.75, H 7.15, N 3.82; found: C 73.73, H 6.96, N 3.82.
1,1’’-Diethyl-5’-(4-iodobenzyloxy)dispiro[piperidine-4,2’-(7,11,21,25-tet
AHCTUNGTRENNUNG
oxacyclopenta[24.2.2.23,6.212,15.217,20]hexatriaconta-3,5,12,14,17,19,26,28,
ACHTUNGTRENNUNGra-
29,31,33,35-dodecaene)-16,4’’-piperidine] (18): In an oven-dried Schlenk
tube, amide 17 (169 mg, 1.00 equiv, 0.181 mmol) was dissolved in di-
chloromethane (35 mL). After cooling to 08C (ice bath), DIBAL-H
(3.62 mL (1m in hexane), 2.82 g, 20.0 equiv, 3.62 mmol) was added drop-
wise over a period of 2.5 h. After stirring for a further 1 h at room tem-
perature, the excess DIBAL-H was quenched with NaHCO3 (saturated
aqueous solution). The solution was mixed with basic Celite and filtered.
The phases were separated and the aqueous layer extracted with di-
chloromethane. The combined organic layers were washed once with
brine, dried with sodium sulfate, filtered, and concentrated. The crude
was purified by column chromatography (SiO2; EtOAc, 5% MeOH, 5%
NEt3) to give diamine 18 as a colorless oil (74%).
1,1’’-Diactyl-5’-hydroxydispiro[piperidine-4,2’-(7,11,21,25-tetraoxacyclo-
penta[24.2.2.23,6.212,15.217,20]hexatriaconta-3,5,12,14,17,19,26,28,29,31,33,35-
dodecaene)-16,4’’-piperidine] (16): Cyclophane 11 (664 mg, 1.00 equiv,
0.906 mmol) and sodium thiomethoxide (317 mg, 5.00 equiv, 4.53 mmol)
were dissolved in DMF (70 mL) and heated at 1608C under an argon at-
mosphere for 6 h. Then 0.1m aq. HCl (46 mL) was added and the sol-
vents removed under vacuum. The residue was taken up in water and the
suspension was filtered. The remaining pale-beige solid was washed once
with diethyl ether (10 mL). The white powder was recrystallized from
methanol (98%).
Rf =0.34 (EtOAc, 5% MeOH, 5% NEt3); 1H NMR (400 MHz, CDCl3,
258C, TMS): d=7.63 (d, 3J
ACHTUNGTRENNUNG
Ar-H), 6.97 (d, 3J
N
ACHTUNGTRENNUNG
Ar-H), 6.74–6.65 (m, 8H; Ar-H), 6.49 (s, 1H; Ar-H), 4.73 (s, 2H; iodo-
benzene-CH2O), 4.10–4.00 (m, 8H; ArOCH2), 2.65–2.25 (m, 16H), 2.23–
2.10 (m, 8H), 1.08–0.99 ppm (m, 6H; CH2CH3); 13C NMR (101 MHz,
CDCl3, 258C, TMS): d=156.9 (Cq, 1C), 156.8 (Cq, 1C), 156.6 (Cq, 1C),
145.7 (Cq, 1C), 144.2 (Cq, 1C), 139.8 (Cq, 1C), 138.7 (Cq, 1C), 138.6 (Cq,
1
Rf =0.35 (CH2Cl2, 5% MeOH); m.p. 2328C; H NMR (400 MHz, CDCl3,
258C, TMS): d=7.16–7.05 (m, 6H; Ar-H), 6.79–6.60 (m, 9H; Ar-H), 5.64
Chem. Eur. J. 2013, 19, 2089 – 2101
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2099

M. Mayor et al.
1C), 137.7 (Cq, 1C), 137.4 (Ct, 2C), 137.3 (Cq, 1C), 129.1 (Ct, 2C), 127.2
(Ct, 2C), 127.1 (Ct, 4C), 118.7 (Ct, 1C), 114.5 (Ct, 4C), 114.4 (Ct, 2C),
114.3 (Ct, 1C), 113.4 (Ct, 1C), 93.0 (Cq, 1C; C-I), 70.4 (Cs, 1C; iodoben-
zene-CH2O), 64.9 (Cs, 1C), 63.7 (Cs, 1C), 63.3 (Cs, 1C), 63.2 (Cs, 1C),
52.3 (Cs, 1C), 49.9 (Cs, 2C), 42.8 (Cs, 1C), 42.7 (Cs, 1C), 42.1 (Cq, 1C),
42.0 (Cq, 1C), 38.5 (Cs, 1C), 29.8 (Cs, 1C), 29.7 (Cs, 1C), 29.6 (Cs, 1C),
29.4 (Cs, 1C), 11.8 ppm (Cp, 2C; CH2CH3); MS (ESI, positive ion mode,
MeCN): m/z (%): 929 [M+Na]+, 907 [M+H]+; HRMS (ESI): m/z calcd
for [C51H59IN2O5+H]+: 907.3541; found: 907.3541.
2.23–2.05 (m, 4H), 1.32–1.14 ppm (m, 12H; CH2CH3); MS (ESI, positive
ion mode, MeCN): m/z (%): 519 [Mꢀ2Clꢀ]2+, 512 [MꢀMeꢀ2Clꢀ]2+, 505
[MꢀEtꢀ2Clꢀ]2+
.
Acknowledgements
The authors acknowledge financial support from the Swiss National Sci-
ence Foundation and the National Center of Competence in Research
ꢅNanoscale Scienceꢀ. We also thank Gino Gꢄnzburger, Silas Gçtz, and
Gregor Meier for their synthetic support during their laboratory course.
Part of this work was supported by the Karlsruhe Nano Micro Facility
(KNMF), Helmholtz Research Infrastructure at the Karlsruhe Institute
of Technology (KIT). Michel Rickhaus is acknowledged for his beautiful
artwork.
1,1’’-Diethyl-5’-{4-[4-(phenylethynyl)phenylethynyl]benzyloxy}dispiro[pi-
peridine-4,2’-(7,11,21,25-tetraoxacyclopenta[24.2.2.23,6.212,15.217,20]hexatria-
ACHTUNGTRENNUNGconta-3,5,12,14,17,19,26,28,29,31,33,35-dodecaene)-16,4’’-piperidine] (23):
Bis(dibenzylideneacetone)palladium (3.81 mg, 10 mol%, 6.62 mmol), tri-
phenylphosphine (13.0 mg, 0.750 equiv, 49.6 mmol), and CuI (2.52 mg,
20 mol%, 13.2 mmol) were placed in a preheated 25 mL Schlenk tube.
The tube was evacuated and backfilled with argon once. Then a solution
of cyclophane 18 (60.0 mg, 1.00 equiv, 66.2 mmol) in THF (crown-cap;
2 mL) and diisopropylamine (DIPA; 2 mL) was added. The resulting sus-
pension was degassed with argon for 10 min. Afterwards, OPE 22
(20.1 mg, 1.50 equiv, 99.3 mmol) was added in one portion and the result-
ing reaction mixture was stirred at room temperature for 3 h. The reac-
tion mixture was poured into water and extracted three times with
EtOAc (30 mL each). The combined organic layers were washed with
water and brine, dried with sodium sulfate, filtered, and concentrated.
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(d, 3J
(H,H)=8 Hz, 2H; Ar-H), 7.38–7.33 (m, 3H; Ar-H(OPE)), 7.16–
7.06 (m, 6H; Ar-H), 6.91 (d, 3J
(H,H)=8 Hz, 2H; Ar-H), 6.77–6.63 (m,
ACHTUNGTNERmNUNG eth-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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8H; Ar-H), 6.47 (s, 1H; Ar-H), 4.85 (s, 2H; ArCH2OAr), 4.13–3.97 (m,
8H; ArOCH2), 2.57–2.25 (m, 16H), 2.24–2.03 (m, 8H), 1.07–1.00 ppm
(m, 6H; CH2CH3); 13C NMR (101 MHz, CDCl3, 258C, TMS): d=156.8
(Cq, 1C), 156.7 (Cq, 1C), 156.7 (Cq, 1C), 147.3 (Cq, 1C), 147.1 (Cq, 1C),
138.2 (Cq, 2C), 131.7 (Ct, 1C), 131.6 (Ct, 2C), 131.6 (Ct, 2C), 131.6 (Ct,
2C), 128.5 (Cq, 2C), 128.4 (Ct, 2C), 127.0 (Ct, 4C), 123.2 (Cq, 2C), 123.0
ꢃ
(Cq, 2C), 122.1 (Cq, 1C), 114.4 (Ct, 2C), 114.3 (Ct, 1C), 91.4 (Cq, 1C; C
ꢃ
ꢃ
ꢃ
C), 91.3 (Cq, 1C; C C), 89.4 (Cq, 1C; C C), 89.1 (Cq, 1C; C C), 70.6
(Cs, 1C; ArCH2O), 63.4 (Cs, 1C), 63.2 (Cs, 1C), 63.0 (Cs, 1C), 53.0 (Cq,
1C), 52.4 (Cs, 2C), 50.0 (Cs, 1C), 50.0 (Cs, 1C), 46.2 (Cs, 4C), 43.0 (Cq,
1C), 42.7 (Cs, 1C), 35.1 (Cs, 1C), 35.0 (Cs, 1C), 29.6 (Cs, 1C), 29.5 (Cs,
1C), 12.1 (Cp, 1C; CH2CH3), 12.0 ppm (Cp, 1C; CH2CH3); MS (ESI, pos-
itive ion mode, MeCN): m/z (%): 1003 [M+Na]+, 981 [M+H]+; elemen-
tal analysis calcd (%) for C67H68N2O5: C 82.01, H 6.98, N 2.85; found: C
81.58, H 7.34, N 2.87.
1,1,1’’1’’-Tetraethyl-5’-{4-[4-(phenylethynyl)phenylethynyl]benzyloxy}di-
ACHTUNGTRENNUNG
spiro[piperidine-4,2’-(7,11,21,25-tetraoxacyclopenta[24.2.2.23,6.212,15.217,20]-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
was added to dissolve all of the starting material. The mixture was stirred
at room temperature in the dark for 18 h. Then, further dichloromethane
(2 mL) was added to suspend the precipitate. After stirring for 5 d at
room temperature, the solvent was removed and the crude purified by
column chromatography (SiO2 saturated with 12% methanolic NaBr, di-
chloromethane, 5% MeOH, then 10% MeOH). The pale-yellow solid
obtained was taken up with water and eluted through an ion-exchange
column (DOWEX 1X8, 200–400 mesh, Clꢀ, packed with water, washed
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pale-yellow solid was recrystallized from MeOH/Et2O (1:1) to obtain the
desired amphiphile 1 as a grey solid (59%).
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2H; Ar-H), 7.57–7.49 (m, 4H; Ar-H), 7.41–7.35 (m, 5H; Ar-H), 7.23–7.13
(m, 4H; Ar-H), 7.05–6.94 (m, 5H; Ar-H), 6.92–6.82 (m, 3H; Ar-H),
6.81–6.73 (m, 4H; Ar-H), 6.35 (s, 1H; Ar-H), 4.70 (s, 2H; ArCH2OAr),
4.19–4.03 (m, 8H; ArOCH2), 3.44–3.15 (m, 16H), 2.79–2.48 (m, 8H),
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Received: July 13, 2012
Revised: October 9, 2012
Published online: January 7, 2013
Chem. Eur. J. 2013, 19, 2089 – 2101
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2101