Direct Synthesis of an Oligomeric Series of Interlocked, Cyclodextrin-Based [c2]Daisy Chains

Article abstract of DOI:10.1002/ejoc.201900136

Despite their anticipated utility and aesthetic appeal, attempts to prepare extended molecular daisy chains have been thwarted by preferential formation of cyclic dimers ([c2]-rotaxanes). Previously, to circumvent this limitation, an alternative type of m

Full text of DOI:10.1002/ejoc.201900136

A Journal of
Accepted Article
Title: Direct Synthesis of an Oligomeric Series of Interlocked,
Cyclodextrin-Based [c2]Daisy Chains
Authors: Lisa Randone, Hideki Onagi, Stephen F. Lincoln, and
Christopher J. Easton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900136
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900136
Supported by

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
Direct Synthesis of an Oligomeric Series of Interlocked,
Cyclodextrin-Based [c2]Daisy Chains
Lisa Randone,[a] Hideki Onagi,[a] Stephen F. Lincoln,[b] and Christopher J. Easton*[a]
Abstract: Despite their anticipated utility and aesthetic appeal,
attempts to prepare extended molecular daisy chains have been
thwarted by preferential formation of cyclic dimers ([c2]-rotaxanes).
Previously, circumventing this limitation, an alternative type of
molecular chain has been synthesized by linking pre-prepared
[c2]rotaxanes already interlocked with bulky capping groups. Instead
of this step-wise approach, here we describe the direct self-
assembly of dimeric complexes and their in situ oligomerization,
which simultaneously interlocks the dimers so that no prior capping
of the complexes is required. Eight individual supramolecular
species, including a tetramer, hexamer, octamer and decamer series,
have been isolated and characterized. The decamer is derived from
sixteen molecular components, through ten highly selective
reactions of six equivalents of bifunctional linking reagent with five
self-assembled dimeric cyclodextrin inclusion complexes, all in one
pot.
Introduction
Mechanically-interlocked, molecular daisy chains have attracted
considerable attention as challenging targets for synthesis, due
Figure 1. Conceptual formation of linear and cyclic, molecular daisy chains,
to their aesthetic appeal and potential utility as components of
functional materials.[1-5] Conceptually, they are comprised of
hermaphroditic monomer units having both host and guest
recognition sites, assembled into linear and cyclic chains, and
physically blocked to prevent dissociation of the components
(Figure 1). Although these arrangements are simple to imagine,
in practice and with very few exceptions,[5-7] related syntheses
generally produce only [c2]-species.[8-11] This occurs because
the corresponding cyclic-dimeric complexes are formed in
preference to those that would lead to [cn]- (n > 2) and acyclic
(an) chains. This bias results from the greater thermodynamic
stability of complexes having the least number of monomer units
that still allow every guest component to be included in a host
and every host moiety to have an included guest.
and related species.
Figure 2. Representation of the production of molecular chains from pre-
prepared, capped [c2]rotaxanes.
An alternative type of molecular chain may be prepared
without this limitation, by linking [c2]rotaxanes that are already
mechanically interlocked with covalently-attached, bulky capping
groups (Figure 2).[4,12-21] In various cases that have been
reported, oligomerization of dimers of this type has been
accomplished through covalent modification of the blocking
groups,[4,12-14] while dynamic metal chelation[15,16] and hydrogen-
bonding[17,18,19,20] have been used for their polymerization. As an
example of the former of these methods, Kaneda et al.,[12]
produced the tetrameric, hexameric, octameric and decameric
cyclodextrin derivatives 2a-d (n = 1-4) in the ratio 33:14:4:2 from
the dimer 1 (Scheme 1). In a similar way, Grubbs and Stoddart
et al.,[4,13,14] employed acyclic-diene metathesis and double-Cu-
catalyzed-Huisgen 1,3-dipolar cycloaddition (Click chemistry), to
give mixtures of oligomerized [c2]rotaxanes. Molecular chains of
this configuration retain the inherently-flexible rotaxane units, in
some cases with switchable behavior.[12-19]
[a]
[b]
L. Randone, Dr. H. Onagi, Prof. C. J. Easton
Research School of Chemistry
The Australian National University
Canberra ACT 2601 (Australia)
E-mail: Chris.Easton@anu.edu.au
Homepage: https://chemistry.anu.edu.au
Prof. S. F. Lincoln
Department of Chemistry
The University of Adelaide
Adelaide SA 5005 (Australia)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
Scheme 1. Preparation of oligomeric chains of [c2]rotaxanes reported by Kaneda et al.[12]
In a recent, seminal paper, Harada et al.,[22] reported the
incorporation of a dimeric cyclodextrin complex into a polymer
gel network, and demonstrated photochemically-induced
expansion and contraction of the gel in accord with the
corresponding realignment of the incorporated complex. More
recently, Guiseppone and Buhler et al.,[23] used Click chemistry
to prepare chemical gels incorporating cyclodextrin dimers. Their
gels expanded and contracted in response to pH changes. Here,
we describe a related strategy for the direct synthesis of a
homologous series of interlocked, cyclodextrin-based [c2]daisy-
chains. It involves self-assembly of dimeric complexes and their
in situ oligomerization, which simultaneously interlocks the
dimers to produce the [c2]rotaxane moieties (Figure 3). Unlike
previous reports,[4,12-20] it does not require prior synthesis of a
capped [c2]rotaxane. It produces discrete molecular entities,
Figure 3. Representation of the direct synthesis of molecular chains of
[c2]rotaxanes, by linking and simultaneously interlocking self-assembled
dimeric complexes.
they highlight the challenges faced. An aqueous medium is
normally required to accomplish cyclodextrin host-guest
complexation, and therefore the linking reagents had to be
compatible with this solvent. This had not been necessary in the
indirect synthesis reported previously by Kaneda et al.,[12] where
the complexation and linking were performed separately, so the
synthesis of their [c2]rotaxane was performed in aqueous
methanol and their subsequent oligomerization employed NaH
in DMF. Earlier, we had prepared the cyclodextrin [c2]rotaxanes
4a,b through reaction of the hermaphroditic monomers 3a,b with
2-chloro-4,6-dimethoxy-1,3,5-triazine in water (Scheme 2),[10,24]
so our initial attempts involved the monomer 3a and bifunctional
triazine variants such as 2,4-dichloro-6-methoxy-1,3,5-triazine
as potential linkers. However, these reactions were all ineffective
due to competing hydrolysis of the triazines and their side
reactions with cyclodextrin hydroxyl groups.
including
a cyclodextrin tetramer, hexamer, octamer and
decamer, which have been separated and individually
characterized. In the case of the decamer, its formation
constitutes the condensation of sixteen molecular components,
through self-assembly of ten cyclodextrin derivatives into five
dimeric complexes, and their interlocking through ten covalent
bond forming reactions with six bifunctional linking reagents.
Results and Discussion
In developing this direct synthesis of daisy-chain oligomers,
we first tried a variety of alternatives that were unsuccessful, but
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
Scheme 2. Synthesis of the [c2]rotaxanes 4a,b.[10,24]
Takata et al.,[25,26] used 2-bromo- and 3,5-dimethyl-
phenylisocyanate as capping reagents to produce the
[3]rotaxanes 5a and 5b, respectively (Figure 4). While we
reproduced the synthesis of 5b without difficulty, attempts to
adapt that method using 4-bromo-2,6-dimethylphenylisocyanate
gave only very small amounts of the analogue 5c, as determined
by HPLC and MALDI-TOF mass spectrometry, even after
extended reaction times and with large excesses of the
isocyanate. Likewise, treatment of the monomer 3a with 4-
bromo-2,6-dimethylphenylisocyanate afforded only a trace of the
[c2]rotaxane 6. In principal, this material could have been
elaborated to chains of [c2]rotaxanes, but its synthesis on any
useful scale proved to be impractical. Instead, we next focused
on reaction of the cyclodextrin derivative 3a with 1,4-
phenyldiisocyanate. This afforded small amounts of species that
were isolated by HPLC and tentatively identified, on the basis of
their MALDI-TOF mass spectra, as a linear tetramer, cyclic
dimer and cyclic tetramer having structures analogous to those
representing 9a, 11 and 12 in Figure 5. Other water-soluble
products were monomeric and trimeric. In addition, a relatively
large amount of precipitate formed in the reaction mixture, which
appeared to be derived from the production of carbamates
through reaction of cyclodextrin hydroxyl groups with the
diisocyanate. In an attempt to avoid this, we prepared the
permethylated cyclodextrin analogue of the monomer 3a, but the
MALDI-TOF mass spectrum of the product of its reaction with
the diisocyanate again showed only traces of dimer, trimer and
tetramer, but no evidence of higher oligomers. Experimental
details are provided in the Supporting Information.
Figure 4. Structures of the [c2]rotaxanes 5a,[25,26] 5b,[25,26] 5c and 6.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
Scheme 3. Synthesis of interlocked [c2]daisy chains through reaction of the cyclodextrin 3a with the suberic acid derivative 7.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
We also investigated several bis-activated dicarboxylic
acids as possible linking reagents. Generally, these also
afforded complex product mixtures, complicated by reagent
hydrolysis and side reactions with the cyclodextrin 3a, until we
tried the suberic acid derivative 7 (Sigma-Aldrich Chem. Co.). It
is water-soluble and known to react selectively with primary
amines, under mild conditions, in aqueous media.[27,28]
Consequently, it has been used extensively in biological
chemistry, as a cross-linking agent to prepare protein-protein,
receptor-ligand and hapten-carrier molecule conjugates. With
the cyclodextrin 3a, it finally afforded a series of oligomers of
interlocked [c2]daisy-chains (Scheme 3, Figure 5).
Figure 6. HPLC analysis of the mixture of products obtained from reaction
of the cyclodextrin 3a with the suberic acid derivative 7 after 3 days.
After 24 h, fractionation of the reaction mixture using HPLC
afforded pure samples of each of the major components; the
tetrameric species 9a and 9b, as well as the starting monomer
3a and its suberic acid derivative 8 (See Supporting Information
for details). Further reaction occurred with extended reaction
times until, after 3 days, only a trace of the unreacted monomer
3a remained and the tetramer 9a was no longer detected using
the same reverse-phase analytical method. Instead, normal-
phase HPLC analysis (Figure 6), suitable for larger and more
polar species, showed that the major components of the product
mixture after this time were the derivatized monomer 8, some of
the tetramer 9b, and an oligomeric series of linearly-linked
[c2]daisy chains, of which the tetramer 10a, hexamer 10b,
octamer 10c and decamer 10d were each separated by HPLC.
Samples of the cyclic dimer 11 and of a species that was
tentatively identified as the cyclic tetramer 12 were also isolated.
Each of the separated compounds 8, 9a,b, 10a-d and 11
was characterized using HPLC, mass spectrometry and NMR
spectroscopy (See Supporting Information for details). HPLC
analysis with a photodiode array detector showed a single
component in every case, with a max at 332 nm for compound 8,
but near 340-345 nm for the others. These wavelengths are
typical of trans-azobenzene moieties, with the shift to higher
wavelength for 9a,b, 10a-d and 11 being characteristic of
inclusion in a cyclodextrin.[29,30] The mass spectra all displayed
diagnostic [M+Na]+ ions. More detailed information was provided
by the NMR spectra. In particular, the relative integrals for the
azobenzene (7.6-8.6 ppm), propyl CONHCH2CH2CH2NHCO-
(~1.85-2.00 ppm) and -CONHCH2CH2CH2NH2 (~2.10 ppm),
and octyl -CH2CH2CH2CO- (~1.30-1.45 ppm), -CH2CH2CH2CO-
(~1.55-1.75 ppm), -CH2CH2CH2CONH- (~2.25-2.35 ppm) and
-CH2CH2CH2CO2H (~2.40-2.45 ppm) proton resonances
uniquely define each structure, including the extent of
substitution of the terminal groups with suberic acid. Each of the
compounds 8, 9a,b, 10a-d and 11 showed a very similar, single
set of aromatic proton resonances, indicating that all the
azobenzenes are in the same type of environment. Cross-peaks
in ROESY NMR spectra established that this is when the
azobenzene moieties are included in cyclodextrin cavities. In the
case of the monomer 8, the inclusion is consistent with formation
of a dimeric complex under the conditions used to record the
NMR spectra in D2O. This inclusion is not reflected in the HPLC
data because very little complexation occurs in the much more
dilute aqueous acetonitrile solution eluting from the HPLC
column. For 9a,b, 10a-d and 11, the simplicity of their NMR
Figure 5. Representation of the production of interlocked [c2]daisy chains
shown in Scheme 3.
A
representative reaction was carried out with the
cyclodextrin 3a (120 mM) and the linking reagent 7 (0.6 equiv.),
at room temperature in pH 9.5 carbonate buffer. This pH was
chosen so as to maintain the amino group of the cyclodextrin 3a
as the nucleophilic free-base, while minimizing deprotonation
and therefore reactivity of the cyclodextrin hydroxyl groups. At 1
mM concentration and higher, aqueous solutions of the
cyclodextrin 3a show concentration-independent 1H NMR
spectra with cross-correlations in the ROESY NMR spectra
between cyclodextrin and azobenzene proton resonances,
indicating effectively complete formation of a symmetric host-
guest complex. A 20 mM concentration of the cyclodextrin 3a
was used in the synthesis of 4a.[10,24] Therefore, the
concentration of 3a used here greatly exceeds that required to
expect full self-assembly into
a
dimeric complex and
[c2]rotaxane formation.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
spectra only matches oligomers of [c2]rotaxanes and there was
no evidence of the formation of other [cn]- or [an]-species. It was
only practical to isolate a small sample of compound 12 but its
max at 345 nm and MALDI-TOF mass spectrum (m/z 5420,
[M+Na]+) are diagnostic of the assigned structure. The HPLC
retention times of the cyclic dimer 11 and tetramer 12 are
strikingly dissimilar (Figure 6). Under the normal-phase
conditions of this analysis, the dimer 11 has a much longer
retention time and therefore appears to be significantly more
polar. A possible reason for this is that geometric constraints in
this small ring system force the cyclodextrin units out of
alignment and expose more of their hydroxyl groups to solvent.
The production of compounds 9a,b, 10a-d, 11 and 12
involves an intricate balance of competing processes.
Formation of 9a occurs through a dimeric inclusion complex of
the cyclodextrin 3a reacting with a second complex formed
between 3a and the product of reaction of 3a with the
bifunctional linking reagent 7. A competing cyclization of this
asymmetric complex leads to 11. The symmetric and
asymmetric complexes are in dynamic equilibrium and 3a may
be either free or included when it reacts with 7. One possible
route to 9b and 10a is through sequential reactions of 9a with 7,
followed by hydrolysis of the end-groups, but there are various
other pathways. Indeed, some hydrolysis of 7 is likely to occur
even before its attachment to a cyclodextrin. Consequently, 9b
and 10a are likely to be formed in multiple ways, from 3a, 8 and
the hydroxysuccinimide ester of 8, and the range of their
inclusion complexes. The situation with 10b-d is even more
complex. With 10d, for example, it could be produced either
through coupling of various dimeric and octameric cyclodextrin
species, or from tetramers reacting with hexamers. Formation of
12 results from cyclization of the hydroxysuccinimide ester of 9b,
which would be in competition with oligomerization of this ester
and its hydrolysis to give 9b. An obvious consequence of this
competition is that the relative proportion of 12 in the product
cis- to trans-azobenzene conversion occurring spontaneously in
the dark at room temperature.
Conclusions
In summary, therefore, compounds 9a,b, 10a-d, 11 and 12
are produced through self-assembly of dimeric cyclodextrin
complexes and their in situ oligomerization, in competition with
cyclization and hydrolysis. The oligomerization (or cyclization in
the case of 11) also serves to mechanically interlock the dimers,
so that no prior capping of the complexes is required. Instead,
the direct syntheses of these chains of [c2]rotaxanes rely on the
high thermodynamic stability of the complexes in water, used as
the reaction solvent, and the marked selectivity of reaction of
hydroxysuccinimide esters with amines in preference to both the
cyclodextrin hydroxyl groups and the water. Considering the
decamer 10d, as an example, it is formed by self-assembly of
ten modules of cyclodextrin derivative into five dimeric
complexes, and their interlocking with six modules of bifunctional
linking reagent. This one-pot condensation of sixteen molecular
components involves ten reactions between hydroxysuccinimide
ester and amino moieties, during which there are only two
competing ester hydrolysis reactions that produce the carboxylic
acid end groups. Initial photochemical experiments illustrate the
potential utility of this class of compounds in functional
supramolecular assemblies and materials.
Experimental Section
(E)-4-((4-((6A-Deoxy--cyclodextrin-6A-yl)carbamoyl)phenyl)diazenyl)
benzoic acid
A solution of 6A-amino-6A-deoxy-α-cyclodextrin[32] (1.60 g, 1.65 mmol)
and Et3N (0.2 mL, 1.4 mmol) in anhydrous DMF (20 mL) was added
drop-wise over 0.5 h to a solution of azobenzene-4,4’-dicarboxylic acid
(1.78 g, 6.6 mmol), BOP (1.06 g, 2.4 mmol) and Et3N (3.2 mL, 23 mmol)
in anhydrous DMF (24 mL), under nitrogen. The resultant mixture was
stirred overnight at room temperature, before it was added drop-wise into
ice-cooled acetone (0.5 L), with stirring. The orange precipitate that
formed was separated by centrifugation, washed with acetone (6 × 50
mL) then Et2O (2 × 50 mL), and dried under vacuum, before it was
dissolved in water (0.5 L). The solution was acidified to pH ~2 with HCl
before it was applied to a Diaion HP-20 column (185 x 45 mm). The
column was then eluted with water that had been acidified with HCl to pH
~2 (3 L), until the eluate was free of the starting aminocyclodextrin, as
determined by TLC. A gradient of methanol-acidified water was then
applied, and the title compound eluted with 30-40% methanol (~ 10 L).
Fractions containing this material were combined and lyophilized to give
an orange powder (1.11 g, 55%). Rf = 0.55 (n-butanol/ethanol/water
5:4:3); m.p. 228-231 °C (dec.); 1H NMR (400 MHz, D2O): δ = 8.51 (d, J =
8.2 Hz, 2H), 8.40 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.70 (d, J =
8.2 Hz, 2H), 5.16–4.96 (m, 6H), 4.32–3.25 (m, 36H); HRMS (ESI): m/z
calcd for C50H69N3O32Na [M+Na]+ 1246.3762, found 1246.3738; HPLC: tR
9.7 min (column: YMC ODS-AQ, 250 × 20 mm, eluent MeCN/H2O (0.1%
TFA) 1:4, flow rate 15 mL min-1).
mixture increases by
a factor of around 10 when the
concentration of the cyclodextrin 3a used in the reaction is
reduced from 120 mM to 30 mM.
The interlocked species 9a,b, 10a-d and 11 exhibit
switchable behavior characteristic of cis-trans isomerization of
azobenzenes.[22,24,31] In preliminary photochemical experiments
(see Supporting Information for details), irradiation at 350 nm of
methanol solutions of all-trans 10a, 10d and 11 resulted in 50,
55 and 60% trans to cis conversion at the photostationary state,
which was reached after around 15, 2 and 60 minutes,
respectively. Species 10a and 10d fully reverted to their trans-
forms on irradiation at 420 nm for 10 min. At the same
wavelength, the cyclic dimer 11 only reverted from 60% cis to
50% even after longer periods of irradiation, but when the
methanol was removed and replaced with water, the trans-form
was quantitatively restored. Aqueous solutions of 10a, 10d and
11 irradiated at 350 nm showed lower degrees of isomerization
at the photostationary state, with respective trans to cis
conversions of 40, 30 and 20%. In this solvent, all three species
showed full reversion to the trans-isomers after irradiation for 10
min at 420 nm. It was impractical to study the conformational
changes associated with interconversions such as these, due to
(E)-tert-Butyl (3-(4-((4-((6A-deoxy--cyclodextrin-6A-yl)carbamoyl)
phenyl)diazenyl)benzamido)propyl)carbamate
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
A solution of (E)-4-((4-((6A-deoxy--cyclodextrin-6A-yl)carbamoyl)phenyl)
diazenyl)benzoic acid (1.11 g, 0.91 mmol), tert-butyl (3-aminopropyl)
carbamate (0.25 g, 1.4 mmol), BOP (0.49 g, 1.1 mmol) and Et3N (0.1 mL,
0.72 mmol) in anhydrous DMF (15 mL) was stirred overnight at room
temperature, before it was added drop-wise into ice-cooled acetone (0.5
L), with stirring. The orange precipitate that formed was separated by
centrifugation, washed with acetone (5 × 200 mL), and dried under
vacuum, before it was dissolved in water (0.5 L). The solution was
applied to a Diaion HP-20 column (185 x 45 mm). The column was then
eluted with water (1 L), followed by a gradient of methanol-water. The
starting material eluted with 5-40% methanol, while the title compound
eluted with 45-80% methanol. Fractions containing this material were
combined and lyophilized to give an orange powder (1.02 g, 81%). Rf =
0.74 (n-butanol/ethanol/water 5:4:3); 1H NMR (400 MHz, D2O): δ = 8.52
(d, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.69
(d, J = 8.2 Hz, 2H), 5.16–4.87 (m, 6H), 4.31–3.14 (m, 40H), 1.88 (m, 2H),
1.47 (s, 9H); HRMS (ESI): m/z calcd for C58H86N5O33 [M+H]+ 1380.5205,
found 1380.5212.
Cyclodextrin monomer 8. HPLC: tR 8.0 min, max 332 nm; 1H NMR (400
MHz, D2O): δ = 8.52 (d, J = 8.1 Hz, 2H), 8.19 (d, J = 8.1 Hz, 2H), 7.74 (d,
J = 8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 5.20–4.90 (m, 6H), 4.40–2.90
(m, 40H), 2.41 (t, J = 7.3 Hz, 2H, -CH2CH2CH2CO2H), 2.30 (t, J = 7.3 Hz,
2H, -CH2CH2CH2CONH-), 1.95–1.85 (m, 2H, -CONHCH2CH2CH2NHCO-),
1.71–1.58 (m, 4H, -CH2CH2CH2CO-), 1.40–1.33 (m, 4H,
-
CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for C61H89N5O34Na
[M+Na]+ 1459, found 1460; HRMS (ESI): m/z calcd for C61H88N5O34 [M-
H]- 1434.5316, found 1434.5312.
1
Linear tetrameric daisy chain 9a. HPLC: tR 16.2 min, max 342 nm; H
NMR (600 MHz, D2O): δ = 8.55 (d, J = 8.2 Hz, 8H), 8.23 (d, J = 8.2 Hz,
8H), 7.77 (d, J = 8.2 Hz, 8H), 7.72 (d, J = 8.2 Hz, 8H), 5.21–4.87 (m,
24H), 4.34–2.99 (m, 160H), 2.34 (t, J = 7.4 Hz, 4H, -CH2CH2CH2CONH-),
2.13–2.08 (m, 4H, -CONHCH2CH2CH2NH2), 1.97–1.91 (m, 4H,
-
CONHCH2CH2CH2NHCO-), 1.72–1.65 (m, 4H, -CH2CH2CH2CO-), 1.42–
1.38 (m, 4H, -CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for
C220H318N20O126Na [M+Na]+ 5282, found 5286; HRMS (ESI): m/z calcd
for C220H319N20O126 [M+H]+ 5259.9264, found 5259.9455.
(E)-N-(3-Aminopropyl)-4-((4-((6A-deoxy--cyclodextrin-6A-
yl)carbamoyl)phenyl)diazenyl)benzamide (3a)
1
Linear tetrameric daisy chain 9b. HPLC: tR 16.9 min, max 340 nm; H
NMR (600 MHz, D2O): δ = 8.55 (d, J = 8.0 Hz, 8H), 8.23 (d, J = 8.0 Hz,
8H), 7.77 (d, J = 8.0 Hz, 8H), 7.72 (d, J = 8.0 Hz, 8H), 5.20–4.88 (m,
24H), 4.40–3.00 (m, 160H), 2.44 (t, J = 7.4 Hz, 2H, -CH2CH2CH2CO2H),
2.34 (t, J = 7.4 Hz, 6H, -CH2CH2CH2CONH-), 2.13–2.08 (m, 2H, -
CONHCH2CH2CH2NH2), 1.97–1.91 (m, 6H, -CONHCH2CH2CH2NHCO-),
A
solution of (E)-tert-butyl (3-(4-((4-((6A-deoxy--cyclodextrin-6A-
yl)carbamoyl)phenyl)diazenyl)benzamido)-propyl)carbamate (0.20 g,
0.15 mmol) in TFA (10 mL) cooled to 5 °C was stirred for 1.5 h, before it
was concentrated under vacuum to dryness, to give a red film. The film
was washed with diethyl ether (3 x 5 mL) to obtain a fine precipitate,
which was dried under vacuum overnight, to give the trifluoroacetate salt
of the title compound as an orange powder (170 mg, 81%). Rf = 0.14 (i-
propanol/ethanol/water/acetic acid 5:4:3:2); m.p. 219-223 °C (dec.); 1H
NMR (400 MHz, D2O): δ = 8.53 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.0 Hz,
2H), 7.74 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 5.16–4.86 (m, 6H),
4.32–2.81 (m, 40H), 2.12–2.00 (m, 2H); HRMS (ESI): m/z calcd for
C53H78N5O31 [M+H]+ 1280.4681, found 1280.4688; HPLC: tR 18.1 min
(column: Agilent Zorbax SB C18 3.5 μm, 150 x 4.6 mm, eluent gradient
MeCN/H2O (0.1% TFA) – MeCN 5% 0-3 min, 5-47% 3-20 min, 47% 20-
30 min, flow rate 1 mL min-1); HPLC: tR 4.2 min (column: Grace Prevail
Carbohydrate ES 9 µm, 300 x 20 mm, eluent gradient MeCN/H2O (0.1%
TFA) – MeCN 70-60% 0-40 min, 60-30% 40-45 min, 30% 45-60 min, flow
rate 10 mL min-1).
1.72–1.65 (m, 8H, -CH2CH2CH2CO-), 1.42–1.38 (m, 8H,
-
CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for C228H330N20O129Na
[M+Na]+ 5438, found 5437; HRMS (ESI): m/z calcd for C228H331N20O129
[M+H]+ 5416.0051, found 5416.0273.
Linear tetrameric daisy chain 10a. HPLC: tR 15.7 min, max 343 nm; 1H
NMR (400 MHz, D2O): δ = 8.52 (d, J = 8.0 Hz, 8H), 8.20 (d, J = 8.0 Hz,
8H), 7.74 (d, J = 8.0 Hz, 8H), 7.68 (d, J = 8.0 Hz, 8H), 5.20–4.88 (m,
24H), 4.36–2.97 (m, 160H), 2.40 (t, J = 7.4 Hz, 4H, -CH2CH2CH2CO2H),
2.30 (t, J = 7.4 Hz, 8H, -CH2CH2CH2CONH-), 1.95–1.86 (m, 8H, -
CONHCH2CH2CH2NHCO-), 1.70–1.58 (m, 12H, -CH2CH2CH2CO-), 1.42–
1.31 (m, 12H, -CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for
C236H342N20O132Na [M+Na]+ 5594, found 5591; HRMS (ESI): m/z calcd
for C236H343N20O132 [M+H]+ 5572.0830, found 5572.0961.
Reaction of (E)-N-(3-aminopropyl)-4-((4-((6A-deoxy--cyclodextrin-
6A-yl)carbamoyl)phenyl)diazenyl)-benzamide (3a) with suberic acid
bis(3-sulfonato-N-hydroxysuccinimide ester) disodium salt (7)
Linear hexameric daisy chain 10b. HPLC: tR 21.7 min, max 342 nm; 1H
NMR (400 MHz, D2O): δ = 8.52 (d, J = 8.0 Hz, 12H), 8.19 (d, J = 8.0 Hz,
12H), 7.73 (d, J = 8.0 Hz, 12H), 7.68 (d, J = 8.0 Hz, 12H), 5.20–4.88 (m,
36H), 4.33–2.95 (m, 240H), 2.40 (t, J = 7.4 Hz, 4H, -CH2CH2CH2CO2H),
2.31 (t, J = 7.4 Hz, 12H, -CH2CH2CH2CONH-), 1.95–1.87 (m, 12H, -
CONHCH2CH2CH2NHCO-), 1.70–1.58 (m, 16H, -CH2CH2CH2CO-), 1.41–
1.32 (m, 16H, -CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for
C350H506N30O196Na [M+Na]+ 8293, found 8290; HRMS (ESI): m/z calcd
for C350H507N30O196 [M+H]+ 8270.0746, found 8270.0883.
In a representative reaction, the trifluoroacetate salt of the cyclodextrin
3a (80 mg, 62 μmol, 120 mM) was added to pH 9.5 carbonate buffer (0.5
mL, 100 mM), and the mixture was stirred at room temperature for 15
min. The suberic acid derivative 7 (22 mg, 38 μmol, 0.6 equiv.) was then
added, and stirring was continued at room temperature for 3 days. HPLC
analysis of the product mixture (Figure 6) after that time showed the
presence of the unreacted starting material 3a, its suberic acid derivative
8, the cyclodextrin tetramers 9b and 10a, the oligomers 10b, 10c and
10d, the cyclic dimer 11 and a tetrameric species 12. Samples of 8, 9b,
10a-10d, 11 and 12 were isolated using preparative HPLC. When the
reaction product was analyzed after 1 day instead of 3, HPLC analysis
showed the presence of 3a, 8, and the cyclodextrin tetramers 9a and 9b.
A sample of 9a was also isolated using preparative HPLC. HPLC was
carried out using a Grace Prevail Carbohydrate ES 9 µm (300 x 20 mm)
column, with a gradient eluent of MeCN/H2O (0.1% TFA) – MeCN 70-
60% 0-40 min, 60-30% 40-45 min, 30% 45-60 min, at a flow rate of 10
mL min-1, monitoring at 352 nm.
Linear octameric daisy chain 10c. HPLC: tR 26.7 min, max 342 nm; 1H
NMR (400 MHz, D2O): δ = 8.52 (d, J = 8.0 Hz, 16H), 8.19 (d, J = 8.0 Hz,
16H), 7.73 (d, J = 8.0 Hz, 16H), 7.68 (d, J = 8.0 Hz, 16H), 5.16–4.93 (m,
48H), 4.33–2.95 (m, 320H), 2.40 (t, J = 7.4 Hz, 4H, -CH2CH2CH2CO2H),
2.30 (t, J = 7.4 Hz, 16H, -CH2CH2CH2CONH-), 1.95–1.86 (m, 16H, -
CONHCH2CH2CH2NHCO-), 1.70–1.59 (m, 20H, -CH2CH2CH2CO-), 1.42–
1.33 (m, 20H, -CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for
C464H670N40O260Na [M+Na]+ 10991, found 10986; HRMS (ESI): m/z calcd
for C464H671N40O260 [M+H]+ 10968.0676, found 10968.1170.
Linear decameric daisy chain 10d. HPLC: tR 32.0 min, max 341 nm; 1H
NMR (400 MHz, D2O): δ = 8.51 (d, J = 8.0 Hz, 20H), 8.19 (d, J = 8.0 Hz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
20H), 7.73 (d, J = 8.0 Hz, 20H), 7.68 (d, J = 8.0 Hz, 20H), 5.16–4.93 (m,
60H), 4.33–2.94 (m, 400H), 2.40 (t, J = 7.4 Hz, 4H, -CH2CH2CH2CO2H),
2.30 (t, J = 7.4 Hz, 20H, -CH2CH2CH2CONH-), 1.95–1.85 (m, 20H, -
CONHCH2CH2CH2NHCO-), 1.70–1.58 (m, 24H, -CH2CH2CH2CO-), 1.42–
1.33 (m, 24H, -CH2CH2CH2CO-); MALDI-TOF MS: m/z calcd for
C578H834N50O324Na [M+Na]+ 13690, found 13689.
[9]
H. Onagi, S. F. Lincoln, C. J. Easton, Org. Lett. 2001, 3, 1041-1044.
[10] R. E. Dawson, S. F. Lincoln, C. J. Easton, Chem. Commun. 2008, 3980-
3982.
[11] D. Cao, C. Wang, M. A. Giesener, Z. Liu, J. F. Stoddart, Chem.
Commun. 2012, 48, 6791-6793.
[12] S. Tsuda, Y. Aso, T. Kaneda, Chem. Commun. 2006, 3072-3074.
[13] L. Fang, M. Hmadeh, J. Wu, M. A. Olson, J. M. Spruell, A. Trabolsi, Y.-
W. Yang, M. Elhabiri, A.-M. Albrecht-Gary, J. F. Stoddart, J. Am. Chem.
Soc. 2009, 131, 7126-7134.
Cyclic dimeric daisy chain 11. HPLC: tR 46.7 min, max 342 nm; 1H
NMR (600 MHz, D2O): δ = 8.55 (d, J = 8.0 Hz, 4H), 8.23 (d, J = 8.0 Hz,
4H), 7.77 (d, J = 8.0 Hz, 4H), 7.72 (d, J = 8.0 Hz, 4H), 5.16–4.93 (m,
12H), 4.36–2.98 (m, 80H), 2.34 (t, J = 7.0 Hz, 4H, -CH2CH2CH2CONH-),
1.97–1.91 (m, 4H, -CONHCH2CH2CH2NHCO-), 1.72–1.64 (m, 4H, -
CH2CH2CH2CO-), 1.43–1.37 (m, 4H, -CH2CH2CH2CO-); MALDI-TOF MS:
m/z calcd for C114H164N10O64Na [M+Na]+ 2721, found 2722.
[14] P. G. Clark, M. W. Day, R. H. Grubbs, J. Am. Chem. Soc. 2009, 131,
13631-13633.
[15] G. Du, E. Moulin, N. Jouault, E. Buhler, N. Giuseppone, Angew. Chem.
Int. Ed. 2012, 51, 12504-12508; Angew. Chem. 2012, 124, 12672-
12676.
[16] L. Gao, Z. Zhang, B. Zheng, F. Huang, Polym. Chem. 2014, 5, 5734-
5739.
Cyclic tetrameric daisy chain 12. HPLC: tR 5.8 min, max 345 nm;
MALDI-TOF MS: m/z calcd for C228H328N20O128Na [M+Na]+ 5420, found
5420.
[17] A. Goujon, G. Du, E. Moulin, G. Fuks, M. Maaloum, E. Buhler, N.
Giuseppone, Angew. Chem. Int. Ed. 2016, 55, 703-707; Angew. Chem.
2016, 128, 713-717.
[18] A. Goujon, G. Mariani, T. Lang, E. Moulin, M. Rawiso, E. Buhler, N.
Giuseppone, J. Am. Chem. Soc. 2017, 139, 4923-4926.
[19] G. Mariani, A. Goujon, E. Moulin, M. Rawiso, N. Giuseppone, E. Buhler,
Nanoscale 2017, 9, 18456-18466.
Photochemical Experiments
Solutions of 10a, 10d and 11 in methanol or water in a 1 cm quartz
cuvette, prepared to an absorbance of around 0.5 at 340 nm, were
irradiated at 25 °C in a Luzchem photoreactor fitted with Hitachi FL8BL-B
8 Watt lamps (350 nm) or Luzchem LZC-420 8 Watt lamps (420 nm).
Reactions monitored using UV-visible spectroscopy showed decreases
or increases in the absorbance near 340-345 nm, characteristic of trans-
azobenzenes, and corresponding increases or decreases in the
absorbance near 270 nm, characteristic of cis-azobenzenes, related in
each case through an isosbestic point near 290 nm.[22,24,29] The ratios of
cis- and trans-azobenzenes in mixtures were calculated from the
percentage change in the absorbance at the max of the trans-isomers,
assuming negligible absorbance of the cis-isomers at that wavelength.
[20] X. Fu, R.-R. Gu, Q. Zhang, S.-J. Rao, X.-L. Zheng, D.-H. Qu, H. Tian,
Polym. Chem. 2016, 7, 2166-2170.
[21] X. Yan, B. Zheng, F. Huang, Polym. Chem. 2013, 4, 2395-2399.
[22] K. Iwaso, Y. Takashima, A. Harada, Nature Chem. 2016, 8, 625-632.
[23] A. Goujon, T. Lang, G. Mariani, E. Moulin, G. Fuks, J. Raya, E. Buhler,
N. Giuseppone, J. Am. Chem. Soc. 2017, 139, 14825-14828.
[24] R. E. Dawson, J. Zhang, C. J. Easton, Australian National University,
unpublished results.
[25] Y. Akae, H. Okamura, T. Koyama, T. Arai, T. Takata, Org. Lett. 2012,
14, 2226-2229.
[26] Y. Akae, Y. Koyama, H. Sogawa, Y. Hayashi, S. Kawauchi, S. Kuwata,
T. Takata, Chem. Eur. J. 2016, 22, 5335-5341.
[27] G. Hermanson, Bioconjugate Techniques 3rd ed., Academic Press,
2013.
Acknowledgements
[28] C. Schmidt, C. V. Robinson, Nature Protocols 2014, 9, 2224-2236.
[29] P. Bortolus, S. Monti, J. Phys. Chem. 1987, 91, 5046-5050.
[30] A. Abou-Hamdan, P. Bugnon, C. Saudan, P. G. Lye, A. E. Merbach, J.
Am. Chem. Soc. 2000, 122, 592-602.
The authors gratefully acknowledge financial assistance
provided by the Australian Research Council.
[31] R. E. Dawson, S. Maniam, S. F. Lincoln, C. J. Easton, Org. Biomol.
Chem. 2008, 6, 1814-1821.
Keywords: Cyclodextrins • Rotaxanes • Daisy chains •
Oligomers • Inclusion complexes
[32] S. E. Brown, J. H. Coates, D. R. Coghlan, C. J. Easton, S. J. van Eyk,
W. Janowski, A. Lepore, S. F. Lincoln, Y. Luo, B. L. May, D. S.
Schiesser, P. Wang, M. L. Williams, Aust. J. Chem. 1993, 46, 953-958.
[1]
P. R. Ashton, I. Baxter, S. J. Cantrill, M. C. T. Fyfe, P. T. Glink, J. F.
Stoddart, A. J. P. White, D. J. Williams, Angew. Chem. Int. Ed. 1998, 37,
1294-1297; Angew. Chem. 1998, 110, 1344-1347.
[2]
[3]
[4]
G. Wenz, B.-H. Han, A. Müller, Chem. Rev. 2006, 106, 782-817.
J. Rotzler, M. Mayor, Chem. Soc. Rev. 2013, 42, 44-62.
E. N. Guidry, J. Li, J. F. Stoddart, R. H. Grubbs, J. Am. Chem. Soc.
2007, 129, 8944-8945.
[5]
[6]
[7]
[8]
J.-C. Chang, S.-H. Tseng, C.-C. Lai, Y.-H. Liu, S.-M. Peng, S.-H. Chiu,
Nature Chem. 2017, 9, 128-134.
T. Kaneda, T. Yamada, T. Fujimoto, Y. Sakata, Chem. Lett. 2001, 1264-
1265.
T. Hoshino, M. Miyauchi, Y. Kawaguchi, H. Yamaguchi, A. Harada, J.
Am. Chem. Soc. 2000, 122, 9876-9877.
M. C. Jiménez, C. Dietrich-Buchecker, J.-P. Sauvage, Angew. Chem.
Int. Ed. 2000, 39, 3284-3287; Angew. Chem. 2000, 112, 3422-3425.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900136
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Lisa Randone, Hideki Onagi, Stephen F.
Lincoln, Christopher J. Easton*
Page No. – Page No.
Direct Synthesis of an Oligomeric
Series of Interlocked, Cyclodextrin-
Based [c2]Daisy Chains
A direct approach is reported for the preparation of a linearly linked series of
[c2]rotaxanes and cyclic analogues, including those illustrated, through
oligomerization and simultaneous interlocking of self-assembled, dimeric
cyclodextrin inclusion complexes.
This article is protected by copyright. All rights reserved.