Hydrazone exchange: a viable route for the solid-tethered synthesis of [2]rotaxanes

Article abstract of DOI:10.1039/d1nj00388g

Controlled and complete assembly of supramolecular systems on solid supports is a challenge that would elevate the function of interlocked architectures. Building on the success of other dynamic covalent synthetic methods, we present hydrazone exchange as a strategy to improve the formation of rotaxanes in solution and on solid surfaces. Solution-state analogues containing naphthalenediimide (NDI) or bipyridinium motifs and 1,5-dinaphtho[38]crown-10 were initially prepared to establish ideal conditions for maintaining thermal equilibrium throughout the exchange reaction. Solid-state rotaxanes were synthesised on hydrazide-functionalised TentaGel polymer resins and analysed with HR MAS¹H NMR spectroscopy. Surface rotaxane functionalisation of 80% was achieved for the NDI rotaxane, which is significantly higher than previously reported with either dynamic covalent or traditional irreversible synthetic strategies.

Full text of DOI:10.1039/d1nj00388g

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Hydrazone exchange: a viable route for the
solid-tethered synthesis of [2]rotaxanes†
Cite this: New J. Chem., 2021,
45, 4414
ab
bc
Rafael Da Silva Rodrigues,a Ena T. Luis,
David L. Marshall,
ab
ab
John C. McMurtrie
and Kathleen M. Mullen
*
Controlled and complete assembly of supramolecular systems on solid supports is a challenge that
would elevate the function of interlocked architectures. Building on the success of other dynamic
covalent synthetic methods, we present hydrazone exchange as a strategy to improve the formation of
rotaxanes in solution and on solid surfaces. Solution-state analogues containing naphthalenediimide
(NDI) or bipyridinium motifs and 1,5-dinaphtho[38]crown-10 were initially prepared to establish ideal
conditions for maintaining thermal equilibrium throughout the exchange reaction. Solid-state rotaxanes
were synthesised on hydrazide-functionalised TentaGelt polymer resins and analysed with HR MAS
1H NMR spectroscopy. Surface rotaxane functionalisation of 80% was achieved for the NDI rotaxane,
which is significantly higher than previously reported with either dynamic covalent or traditional
irreversible synthetic strategies.
Received 25th January 2021,
Accepted 12th February 2021
DOI: 10.1039/d1nj00388g
rsc.li/njc
One challenge with incorporating these structures on surfaces
is ensuring the high ratio of interlocked to non-interlocked
Introduction
Interlocked architectures such as rotaxanes and catenanes have components at the solution–surface interface. In the solution
shown great promise as components in molecular machines.1–6 state, dynamic covalent chemistry has proven to be an attractive
In recent years, they have been developed for applications synthetic strategy for the preparation of interlocked architectures
across catalysis,7–12 sensing,13–16 drug delivery,17–19 nano- and molecular machines.52–60 The reversibility of this class of
electronics,20–22 in vivo imaging23–26 and the development of reactions introduces a proofreading step into the reaction
stimuli-responsive materials.27–29 The majority of known inter- mechanism,61,62 which maximises the proportion of interlocked
locked architectures have shown impressive capabilities in components at the expense of non-interlocked by-products that
solution; however, incorporation of these components onto are typically kinetically favoured. Pioneering work by Sanders
solid supports and surfaces opens new possibilities for their and co-workers63–66 demonstrated the successful synthesis of a
functionality.30–38 By organising functional rotaxanes into an number of catenanes using dynamic reactions initially focused
ordered array, their unique properties can be directed towards a on disulfide exchange. Their work demonstrates that control of
controlled macroscopic output.39–41 The generation and char- the library can be easily manipulated through careful design and
acterisation of functionalised solids with little contamination a detailed understanding of constitutional, steric, and electronic
from unwanted by-products has thus been the focus of intense effects to amplify the desired product.67–69 These fundamental
research.42–48 Understanding the role of surface attachment on studies ultimately led to the synthesis of a macromolecular
modulating molecular motion in surface-bound bistable rotaxanes trefoil knot in near quantitative yield.70
and catenanes is of fundamental importance, with some studies
Dynamic covalent chemistry is also an effective strategy for
revealing significant differences in the way supramolecular rotaxane formation in the gel phase. We have recently reported71,72
switches function when embedded in solids or attached to the successful functionalisation of TentaGelt polymer resins
surfaces.49–51
with [2]rotaxanes using a synthetic approach involving dynamic
disulfide exchange. Conventional irreversible synthetic strategies
typically led to a low proportion of the desired rotaxanes (20–
40%)73 compared to non-interlocked components, complicating
the characterisation and rendering the solid supports non-
homogeneous and therefore inherently less useful. The reversibility
offered by the incorporation of disulfide exchange in the resin
functionalisation step led to an improvement in surface homo-
geneity, with up to 60% coverage of the polymer resin with
a School of Chemistry and Physics, Queensland University of Technology, Brisbane,
Australia. E-mail: kathleen.mullen@qut.edu.au
b Centre for Materials Science, Queensland University of Technology, Brisbane,
Australia
c Central Analytical Research Facility, Queensland University of Technology,
Brisbane, Australia
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1nj00388g
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Fig. 1 Target solid-bound [2]rotaxanes synthesised using a hydrazone
exchange methodology from hydrazide-functionalised solid supports.
rotaxane. Given the symmetrical nature of the disulfide reaction
mechanism, however, analysis of the equilibrium was challenging
with eight different homo- and heterodimeric dumbbell and
rotaxane species present in solution. Whilst it can be argued that
rotaxanes could be preformed and then subsequently attached to
surfaces, the added benefit of a dynamic covalent approach is that
the surfaces could be ‘‘reused’’, given the reversibility of this
surface functionalization. Herein we report the use of dynamic
hydrazone exchange74,75 to assemble interlocked architectures on
polymer resins with the same efficiency as observed in solution,
thereby creating functionalised surfaces with limited kinetic by-
products that result from traditional approaches. Fig. 1 shows the
structures of the target functionalised resins that incorporate 1,5-
dinaphtho[38]crown-10 (5) as the macrocycle and a naphthalene
diimide76–78 (1) or bipyridinium79,80 (2) recognition site on the
axle. The asymmetrical nature of the hydrazone exchange reac-
tion simplifies the exchange process compared to the disulfide
mechanism, and the reaction allows for the incorporation of
recognition sites that are unstable under the basic conditions
used in disulfide exchange, namely bipyridinium motifs. The
stronger interaction between the bipyridinium and crown ether
macrocycles,81 compared to the naphthalene diimide, is expected
to further improve the proportion of interlocked architectures
attached to the bead.
Scheme 1 Synthesis of the solution model hydrazone rotaxane 6 and NDI
dumbbell 11. Reagents and conditions: 1,5-dinaphtho[38]crown-10
macrocycle 5 (5 equiv.), TFA (cat.), r.t., CHCl3, 7 days.
Scheme 2 Synthesis of hydrazide stopper 3. Reagents and conditions:
(i) ethyl 5-bromovalerate, K2CO3, Cs2CO3, MeCN, reflux, 3 days, 98%;
(ii) CH2Cl2/MeOH, NaOH, r.t., 1 h, 99%; (iii) SOCl2, toluene, reflux, 12 h,
quant. yield; (iv) NH2NHBoc, CH2Cl2, 2 days, 32%; (v) CH2Cl2/TFA (50%),
45 min, r.t., 90%.
Results and discussion
Synthesis of rotaxanes via hydrazone exchange in solution
Our initial efforts focused on the synthesis of naphthalene
diimide (NDI) [2]rotaxane 6 (Scheme 1). This necessitated the (TFA) to produce the desired hydrazide 3 in 90% yield. The
1
synthesis of the hydrazide stopper 3 (Scheme 2) and the synthesis of the stopper hydrazide was confirmed by H NMR
naphthalene diimide 4 which possesses a terminal aldehyde spectroscopy and supported by mass spectrometry (Fig. S1 and
(Scheme 3). Williamson etherification of phenol stopper 7 with S2, ESI†). Importantly, the hydrazide stopper 3 was found to be
ethyl 5-bromovalerate, followed by hydrolysis of the resulting prone to dimerisation at room temperature over time, forming
ester with sodium hydroxide, produced the acid-functionalised an unreactive dimer S1. Thus, for all future exchange reactions,
stopper 8 in 98% yield (Scheme 2).82 Reaction of 8 with thionyl the stopper 3 was deprotected immediately before use.
chloride produced the acid chloride derivative which was
To obtain aldehyde-functionalised naphthalene diimide
immediately reacted with tert-butyl carbazate to afford the thread 4, NDI tosylate half-dumbbell 1072 was reacted with
desired Boc-protected hydrazide 9 in 32% yield. Deprotection p-hydroxybenzaldehyde, to give the product in 93% yield
of 9 was readily achieved by reaction with trifluoroacetic acid (Scheme 3). Conditions for the reaction of aldehyde 4 with
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4 for four days). The reaction was carried out with different acid
catalyst concentrations and the product distributions were
monitored (Table 1 and Fig. S5, ESI†). Following the addition
of macrocycle 5, a decrease in concentration of dumbbell 11
was observed in conjunction with the appearance of a new
chromatographic peak with a retention time of 11.6 min, with
a mass corresponding to the [2]rotaxane 6 (m/z 2349.2587,
[M + H]+). This concomitant decrease in the proportion of
dumbbell 11 with the appearance of [2]rotaxane 6 demonstrates
that the formation of interlocked structures is only possible due
to the reversibility of the hydrazone exchange.
The addition of 5 equivalents of macrocycle 5 resulted in
conversions of up to 42% of the desired [2]rotaxane 6 (Fig. S6
and Table S5, ESI†). Solutions with higher concentrations of
acid catalyst (0.1% and 0.5%) were able to re-equilibrate more
rapidly to produce rotaxane 6 in reasonable conversion (B28%)
after only three days. In order to balance the time necessary to
reach thermodynamic equilibrium whilst keeping the acid
concentrations as low as possible, the ideal condition chosen
moving forward was 0.1% TFA in chloroform with the concen-
tration of hydrazide and aldehyde at 5 mM.
Using these conditions, the synthesis of dumbbell 11 and
[2]rotaxane 6 were then carried out on a preparative scale. To
this end, 5 equivalents of macrocycle 5 (25 mM) and TFA (0.1%)
were added to a 5 mM solution of hydrazide stopper 3 and NDI
aldehyde 4. After 7 days, the reaction was quenched (by addi-
tion of Na2CO3(aq)) and, following column chromatography, the
desired [2]rotaxane 6 was obtained as a red solid in 35% yield.
The red colouration is a result of charge transfer interactions
between the electron-rich macrocycle and electron-deficient
naphthalene diimide, and is indicative of a mechanically
interlocked topology73 (Fig. S7, ESI†). Dumbbell 11 was also
isolated from the reaction mixture in 52% yield. The partial
1H NMR spectra of dumbbell 11 and [2]rotaxane 6 in CDCl3 are
displayed in Fig. 2. For the rotaxane 6, significant upfield shifts
in signals for the naphthalene diimide protons Hi and Hj (Dd =
0.46 ppm), and macrocycle aromatic protons Ha, Hb and Hg
(Dda = 0.53 ppm, Ddb = 0.76 ppm, and Ddg = 0.98 ppm) were
observed due to p–p stacking interactions between the crown
ether macrocycle and naphthalene diimide thread, indicative of
successful rotaxane formation. Additional proof of the rotaxane
formation is shown by the short distance cross-peaks between
signals Hi and Hj of the NDI centre and signals Hg, Ha, Hb, Hc
and Hd of the macrocycle observed in the 2D-ROESY NMR
spectrum (Fig. S8, ESI†).
Scheme 3 Synthesis of naphthalene diimide dumbbell 11. Reagents and
conditions: (i) K2CO3, Cs2CO3, MeCN, reflux, 3 days, 93%, (ii) 3, 5 mM, TFA
(cat.), CHCl3; yields reported in Table 1.
hydrazide stopper 3 were then screened to better understand
the hydrazone equilibrium and optimise the synthesis of both
the NDI dumbbell 11 and the desired [2]rotaxane 6 (Scheme 1).
To this end, five small-scale reaction conditions were first
trialled probing the effect of the concentration of acid catalyst
on the reaction of hydrazide stopper 3 and NDI aldehyde 4. The
reactions were followed for four weeks83 by HPLC equipped
with dual mass-spectrometry and UV detection, during which
equilibrium was reached and maintained (Table 1 and Fig. S4,
ESI†). The reaction with no TFA showed minimal formation of
the hydrazone dumbbell 11 after four days which remained very
low over two weeks (Table 1). All other reactions showed the
formation of the desired dumbbell in 65–70% conversion.
The reversibility of the hydrazone exchange reaction is central
to the strategy of dynamic rotaxane synthesis. To investigate the
reversibility, one equivalent of 1,5-dinaphtho[38]crown-10 macro-
cycle 5 was added to a pre-equilibrated solution of NDI dumbbell
11 (obtained from reacting hydrazide stopper 3 and NDI aldehyde
Table 1 Monitoring the hydrazone exchange between NDI aldehyde 4
and hydrazide stopper 3, in the absence and presence of macrocycle 5, as
a function of acid catalyst concentration.a
Reaction
without
macrocycle 5 Reaction with 1 equiv. macrocycle 5b
% NDI
aldehyde 4 dumbbell 11 aldehyde 4 dumbbell 11 rotaxane 6
% TFA (4.7 min) (11.1 min) (4.7 min) (11.1 min) (11.6 min)
% NDI
% NDI
% NDI
% NDI
To examine the versatility of hydrazone exchange to other
supramolecular motifs, attention was turned towards the synthesis
of bipyridinium rotaxane 17.2PF6À. The synthesis of aldehyde
0
499
30
31
30
35
o1
70
69
70
65
90
32
38
38
39
10
56
39
31
35
0
12
24
32
26
0.001
0.01
0.1
À
functionalised bipyridinium thread 15.2PF6 was achieved as out-
lined in Scheme 4. Reaction of 4-(3-hydroxypropoxy)benzaldehyde
12 with tosyl chloride in the presence of triethylamine afforded
3-(4-formylphenoxy)propyl toluenesulfonate as a colourless solid in
66% yield. This was then reacted with sodium azide to give 13 in
96% yield. Coupling of the alkyne-functionalised mono-stoppered
0.5
a
Normalised peak areas of aldehyde 4, dumbbell 11 and rotaxane 6
after 7 days as determined by HPLC at l = 380 nm are reported. NDI-
containing products were detected at this wavelength; hydrazide stop-
per 3 was not detected and is excluded from this comparison. The data
compares the proportions of aldehyde, dumbbell and rotaxane after
À
bipyridinium thread 14.2PF6 with azide 13 via a copper(I)
b
each reaction. Numbers may not add to 100% due to rounding.
catalysed alkyne–azide cycloaddition (CuAAC) reaction afforded
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Fig. 3 Partial 1H NMRÀspectrum (CDCl3, 600 MHz) of the bipyridinium
half-dumbbell 15.2PF6 (top), the hydrazone bipyridinium [2]rotaxane
Fig. 2 1H NMR (CDCl3, 600 MHz) comparison of the NDI dumbbell 11 (top),
the corresponding [2]rotaxane 6 (middle) and the 1,5-dinaphtho[38]crown-10
macrocycle 5 (bottom).
À
17.2PF6 (middle) and the hydrazide stopper 3 (bottom).
rotaxane 6 described above, the preparative-scale synthesis
À
afforded the desired [2]rotaxane 17.2PF6 as a red solid in
12% yield. High resolution electrospray ionisation mass spectro-
metry revealed a Àpeak at m/z = 1160.6640 corresponding to the
rotaxane 17.2PF6 ([M À 2PF6]2+, Fig. S30, ESI†). In addition,
large upfield shifts of the signals for the bipyridinium protons
Hj/m and Hk/l (Dd = 0.19, 1.25 ppm respectively) and the macro-
cycle protons Hb and Hg (Dd = 0.10 ppm and 0.80 ppm respec-
tively) were observed in the 1H NMR spectrum (Fig. 3). The
magnitude of these upfield shifts is consistent with comparable
literature reports of bipyridinium based rotaxanes,73 indicating
rotaxane formation.84
Functionalisation of TentaGelt resins with hydrazide
Having established ideal conditions for the synthesis of
[2]rotaxanes using hydrazone exchange in solution, attention
was then turned to the functionalisation of polymer resins
using this approach. Unlike surfaces such as glass and gold,
the use of these resins allows the collection of solution-like
quality 1H NMR spectra when using a high-resolution magic
angle spinning (HR MAS) NMR probe.85,86 This technique thus
enables a detailed investigation into the binding and dynamic
behaviour of these topologically complex materials, which is
particularly important when investigating systems that may not
have photo- or electroactive reporting groups.
Scheme 4 Synthesis of the bipyridinium rotaxane 17.2PF6À. Reagents
and conditions: (i) TsCl, TEA, DMAP, CH2Cl2, 0 1C - r.t., 66%; (ii) NaN3,
DMF, 120 1C, 96%; (iii) [Cu(CN)4]PF6, TBTA, CH2Cl2À, 58%; (iv) 3, 5 equiv.
macrocycle 5, 5 mM, TFA (cat.), CHCl3, 12% 17.2PF6
.
À
the desired bipyridinium half-dumbbell 15.2PF6 in 58% yield
(Fig. S9, ESI†).
The commercially available Boc-Hydrazido protected resins,
TentaGelt-CONHNHBoc 18 were deprotected with 50% TFA/
To investigate the viability of using hydrazone exchange to CHCl3 for 30 minutes (Fig. S10, ESI†). As a proof of concept,
assemble bipyridÀinium rotaxanes, the bipyridinium half- hydrazide 19 was reacted with naphthalene diimide thread 4
dumbbell 15.2PF6 was reacted with the hydrazide stopper 3 (5 equiv.) in the presence of 0.1% TFA in chloroform to produce
and macrocycle 5 in chloroform with TFA (0.1%) to form thÀe dumbbell functionalised resins 20 (Scheme 5). The HR MAS
À
bipyridinium dumbbell 16.2PF6 and rotaxane 17.2PF6
1H NMR spectrum (Fig. 4) shows clear evidence of functiona-
(Scheme 4). Attempts to monitor these reactions via HPLC were lisation of the resin with the naphthalene diimide thread, with
unsuccessful either as a result of broad elution profiles (when peaks for the NDI moiety observed at 8.71 ppm, and the
using water:acetonitrile or isopropanol:acetonitrile mixtures) or tetraphenyl stopper group observed at 7.09 and 6.79 ppm.
due to decomposition of the mixture (when using water and
The reaction was then repeated with five equivalents of
acetonitrile with 0.1% formic acid, commonly used for the macrocycle 5 (relative to 4) to produce the desired rotaxane-
purification of similar bipyridinium-containing molecules). functionalised resins 1. After two weeks, the reaction was
Nevertheless, by using the conditions established for the NDI quenched and the resulting red-coloured resins were washed
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CPMG pulse sequence indicates that the target naphthalene
diimide rotaxane species 1 accounted for approximately 50% of
the total bead tethered population with the remaining surface
covered by the non-interlocked thread, a significant improve-
ment on literature reports using irreversible coupling methods
(typically B20%).73 The surface functionalisation reaction was
then repeated at À18 1C. At lower temperatures, the interaction
between the half-dumbbell and the macrocycle is amplified,88,89
which in turn should favour the formation of interlocked species.
Again, two sets of peaks corresponding to the dumbbell and
rotaxanes are observed in the HR MAS 1H NMR spectrum
(Fig. 4). However, integration of the 1D NMR spectra shows that
the proportion of rotaxane on the resin is B80%, a far higher ratio
than ever previously reported.51,72
Scheme 5 Synthesis and functionalisation of Tentagelt hydrazide resin
19. Reagents and conditions: (i) TFA/CHCl3 (50%), 30 min; (ii) 4 (5 equiv.),
5 mM, 0.1% TFA, CHCl3, 14 days.
The functionalisation of the hydrazide beads with bipyridi-
nium based rotaxanes was then investigated (Schemes S1 and
S2, ESI†). HydrazÀide resin 19 was reacted with bipyridinium
aldehyde 15.2PF6 in the presence of five equivalents of the
macrocycle 5 and 0.1% TFA. The analogous dumbbell functio-
À
nalised resins 21.2PF6 were also prepared as a control. ThÀe
resulting HR MAS 1H NMR spectrum of the dried beads 2.2PF6
can be seen in Fig. S11 (ESI†). The spectrum shows two sets of
signals: Hj, Hk, Hl and Hm for the non-inÃterlocked Ãdumbbell
(d = 8.80, 8.47, 8.35 and 8.10 ppm) and Hj=m and Hk=l for the
rotaxane structures at 8.07 ppm and 6.98 ppm. In addition,
signals for the naphthyl units of the macrocycle were observed
at 6.63, 7.10 and 7.19 ppm, which were comparable with similar
rotaxanes attached to polymer resins.73 Unfortunately, given
the broad and overlapping rotaxane signals with other signals
of the structure, the proportion of rotaxane attached to the
resins was not able to be calculated. Although rotaxane forma-
tion was observed in both cases, unambiguous characterisation of
resin-bound rotaxanes with HR MAS 1H NMR spectroscopy is
more suited to the NDI-functionalised thread compared to the
analogous bipyridinium system.
Fig. 4 Partial HR-MAS 1H NMR (CDCl3, 400 MHz, 32 CPMG loops) spectra
of the resin bound NDI dumbbell 20 (top), rotaxane 1 when the bead
functionalisation is performed at room temperature (middle), and rotaxane
1 when the bead functionalisation is performed at À18 1C (bottom).
Comparison of the signals corresponding to Hi/j (dumbbell) and Hi*/j*
(rotaxane) shows that rotaxane formation is more favoured at lower
temperatures, resulting in 80% functionalisation at À18 1C compared to
50% functionalisation at room temperature.
Conclusions
In this work, we have demonstrated that hydrazone exchange
can be used for the synthesis of rotaxanes in solution and to
pattern polymer resin beads with rotaxanes. This strategy builds
on previous success with a disulfide exchange mechanism,72 and
overcomes its limitation of requiring building blocks resistant to
basic conditions. Initial investigations both demonstrate that the
extensively to remove any unreacted material.87 Successful presence of an acid catalyst is required for dynamic exchange to
rotaxane formation on the polymer surface was supported by take place in any appreciable timeframe, and prove that the
HR MAS 1H NMR data (Fig. 4). Two sets of peaks for the diimide equilibrium is under thermodynamic control.
protons (Hi and Hj) are observed, with those corresponding to
Using this reversible approach, a high proportion of the NDI
the non-interlocked thread observed at 8.62 ppm, while those rotaxane was obtained in solution, with surface functionalisa-
indicative of rotaxane formation appear upfield at 8.24 ppm. tion of up to 80% achieved for this system. This yield is
Likewise, peaks for the crown ether macrocycle protons (Ha, Hb significantly higher than that typically achieved by traditional
and Hg) were observed at 6.77 ppm, 6.40 and 5.95 ppm, synthetic approaches as well as other dynamic exchange methods.
respectively. These chemical shifts are comparable to those As observed in previous studies, the characterisation of resins
observed in the corresponding solution-state rotaxane 6. Inte- functionalised with bipyridinium based rotaxanes is challenging
gration of the 1D HR MAS spectrum before application of the due to broad and poorly defined peaks observed in the HR MAS
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1H NMR spectrum. In this example, the stability of the bipyridi-
nium rotaxane may be a factor given the low yields observed for
solution analogues, however future work optimising the HR MAS
pulse sequences is needed to improve the characterisation of
resins functionalised with charged supramolecular motifs. Never-
theless, this work clearly demonstrates that hydrazone exchange is
an effective strategy for the attachment of interlocked archi-
tectures onto solid supports. These model components now pave
the way for the complete and controlled surface assembly of more
complex molecular machines.
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Acknowledgements
This work was enabled by use of the Central Analytical Research
Facility hosted by the Institute for Future Environments at
QUT. Access to CARF is supported by funding from the Faculty
of Science, QUT. We also thank the Centre for Materials Science
at QUT for funding the postdoctoral fellowship supporting
E. T. Luis.
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