[2]Rotaxane End-Capping Synthesis by Click Michael-Type Addition to the Vinyl Sulfonyl Group

Article abstract of DOI:10.1002/chem.201900156

We report the application of the click Michael-type addition reaction to vinyl sulfone or vinyl sulfonate groups in the synthesis of rotaxanes through the threading-and-capping method. This methodology has proven to be efficient and versatile as it allowed the preparation of rotaxanes using template approaches based on different noncovalent interactions (i.e., donor-acceptor π–π interactions or hydrogen bonding) in yields of generally 60–80 % and up to 91 % aided by the mild conditions required (room temperature or 0 °C and a mild base such as Et₃N or 4-(N,N-dimethylamino)pyridine (DMAP)). Furthermore, the use of vinyl sulfonate moieties, which are suitable motifs for coupling-and-decoupling (CAD) chemistry, implies another advantage because it allows the controlled chemical disassembly of the rotaxanes into their components through nucleophilic substitution of the sulfonates resulting from the capping step with a thiol under mild conditions (Cs₂CO₃ and room temperature).

Full text of DOI:10.1002/chem.201900156

A Journal of
Accepted Article
Title: [2]Rotaxane End-Capping Synthesis by Click Michael-Type
Addition to the Vinyl Sulfonyl Group
Authors: Arthur H. G. David, Pablo García-Cerezo, Araceli G.
Campaña, Francisco Santoyo-González, and Victor Blanco
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To be cited as: Chem. Eur. J. 10.1002/chem.201900156
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[2]Rotaxane End-Capping Synthesis by Click Michael-Type
Addition to the Vinyl Sulfonyl Group
Arthur H. G. David,[a] Pablo García-Cerezo,[a] Araceli G. Campaña,[a] Francisco Santoyo-González*[a]
and Victor Blanco*[a]
Abstract: Here we report the application of the click Michael-type
addition reaction to vinyl sulfone or vinyl sulfonate groups in the
synthesis of rotaxanes through the threading-and-capping method.
This methodology has proven to be efficient and versatile as it
allowed the preparation of rotaxanes using template approaches
based on different non-covalent interactions (i.e. donor-acceptor -
interactions or H bonding) in yields ranging generally 60%−80% and
up to 91% thanks to the mild conditions required (room temperature
or 0 ºC and a mild base such as Et3N or DMAP). Furthermore, the
use of vinyl sulfonate moieties, suitable motifs for coupling-and-
decoupling (CAD) chemistry, implies another advantage as it allows
the controlled chemical disassembly of the rotaxanes into their
components through nucleophilic substitution of the sulfonates
resulting from the capping step with a thiol under mild conditions
(Cs2CO3 and room temperature).
efficient and orthogonal closing reactions that proceed under
mild conditions to covalently lock the intermediate
supramolecular complexes, i. e. attach the stoppers to both ends
of the linear component or close the macrocycle, without
significantly altering the complexation equilibrium. Thus, among
others, amide[11] and imine bond formation,[12] alkene
metathesis[13] or click reactions[14] soon arose as suitable
methodologies for the efficient synthesis of such interlocked
architectures. Among the latter, the copper(I)-catalyzed azide-
alkyne cycloaddition (CuAAC)[15] became one of the most useful
and extensively exploited synthetic tools in the field when the
capping strategy is followed.[16]
Despite the great success of the CuAAC in the synthesis of
rotaxanes, the availability of other synthetic tools is, as in other
fields of organic synthesis, of key importance to expand the
toolbox of methodologies to choose from to access any potential
rotaxane design. In this fashion, some important pioneering
effort has been done to employ other click reactions,[17] such as
the radical thiol-ene/yne,[18] Diels-Alder reactions,[19] nitrile oxide
cycloadditions[20] or Michael-type additions such as the thiol-
maleimide[21] in the synthesis of rotaxanes.[22] At this point, we
envisioned that the click Michael-type addition reaction of a
nucleophile to the vinyl sulfonyl group,[17e,23] in particular to vinyl
sulfone or vinyl sulfonate derivatives, could become an efficient
and versatile tool in rotaxane synthesis. Click Michael-type
addition reactions of thiols or amines to vinyl sulfone groups
proceed under mild conditions, i.e. at room temperature or lower
in the presence of mild bases, and in a variety of solvents,
including aqueous media. Hence, these reactions have been
exploited by ours and other research groups in a variety of
immobilization and (bio)conjugation applications like protein
Introduction
Rotaxanes are interlocked molecules composed of a linear
component (thread or axle) threaded through a macrocycle with
two bulky stopper groups at both sides of the axle to prevent the
dethreading of the macrocycle.[1] Over the last two decades,
rotaxanes,[2] along with other kinds of interlocked structures such
as catenanes,[1,3] have become more and more relevant due to
their unique structure and, mainly, because of their extensive
application in the development of an increasing number of
molecular devices able to perform different tasks.[4]
The quick progress achieved in the application of rotaxanes
in molecular machines able to perform tasks of increasing
complexity and relevance was only possible due to the
development of efficient synthetic methodologies that allowed
scientists to access such structures in a relatively simple and
convenient manner. In this sense, the classic and most versatile
strategies for the synthesis of rotaxanes, apart from the active
metal template approach,[5] namely threading-and-capping
(including snapping) and clipping, rely on the template effect that
preorganizes the linear and macrocyclic (sub)components due
to the establishment of non-covalent interactions,[6] mainly metal
coordination,[7] hydrogen bonds,[8] - interactions[9] or
hydrophobic forces,[10] to give supramolecular assemblies such
as pseudorotaxanes. Nevertheless, a truly useful synthetic
methodology for rotaxane or catenane synthesis also requires
labelling
and
immobilization,[24]
enzyme
inhibition,[25]
functionalization of carbohydrates,[24d,e] development of carrier
systems[26] or in polymer and materials chemistry.[27]
On the other hand, vinyl sulfonate derivatives[28] exhibit the
same click features than vinyl sulfones as acceptors in Michael-
type additions.[25b,29] However, the use of vinyl sulfonate
derivatives gives the added value of allowing a later cleavage
through nucleophilic substitution of the sulfonate moieties
obtained after the Michael-type addition, as we recently
demonstrated.[28] This behaviour, which enables vinyl sulfonates
as promising reagents for the so-called coupling-and-decoupling
(CAD) chemistry,[30] could be interesting in the development of
cleavable[31] functional rotaxanes, especially relevant for
applications such as controlled delivery or directional
transport,[32] if the decoupling step that leads to the disassembly
of the components takes place in mild conditions.
[a]
A. H. G. David, P. García-Cerezo, Dr. A. G. Campaña, Prof. F.
Santoyo-González, Dr. V. Blanco.
Departamento de Química Orgánica, Universidad de Granada
Facultad de Ciencias, Avda. Fuente Nueva, S/N, 18071 Granada
(Spain)
Therefore, here we report the development of a new efficient
and versatile methodology for the synthesis of rotaxanes based
on the click Michael-type addition reaction[33] of thiols[34] or
amines to vinyl sulfone and vinyl sulfonate moieties as the key
reaction for the capping step. We demonstrate its applicability to
the synthesis of rotaxanes based on a variety of non-covalent
E-mail: fsantoyo@ugr.es; victorblancos@ugr.es
Supporting information for this article is given via a link at the end of
the document.
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interactions (Figure 1). Furthermore, we report the usefulness of
the CAD chemistry features of the vinyl sulfonate group by
presenting the controlled chemical disassembly into its
components of a rotaxane displaying sulfonate moieties.
motif a -acceptor naphthalene diimide unit which has been
shown to interact with crown ether macrocycles with -donor
aromatic moieties. In particular it associates with dinaphto-38-
crown-10 (DNP38C10, 3) with a binding constant Ka ≈ 1 × 102 M-
1
in CHCl3/MeOH 98:2,[35] forming supramolecular entities
exploited in the synthesis of rotaxane architectures.[21b,36] Hence,
we synthesised thread precursors 1a,b displaying the
naphthalene diimide core functionalized with tetraethylenglycol
chains with vinyl sulfonate (1a) or vinyl sulfone groups (1b) on
both ends (see the Supporting Information for synthetic details),
suitable to undergo click Michael-type addition reactions.
At first, we performed the reaction of the different
naphthalene diimide derivatives 1a,b with bulky stoppers
exhibiting a thiol (2a) or an amine group (2b) that can act as
nucleophiles in the Michael-type addition to vinyl sulfonyl
derivatives in the presence of Et3N at room temperature. We
obtained the corresponding free threads in good yields, proving
that this click reaction gives, as expected, good results under
those mild conditions, suggesting its compatibility with rotaxane
synthesis. Therefore, in the search of the target rotaxanes, we
repeated the thia- or aza-Michael addition reactions of 1a,b with
2a,b after mixing the naphthalene diimide vinyl sulfonyl
derivatives with macrocycle 3 to favour the assembly of the
corresponding pseudorotaxanes (Scheme 1). The reaction
afforded the corresponding rotaxanes 4a-d in remarkable 60-
80% isolated yields. Slightly higher yields were obtained when
using thiol stopper 2a, which can be attributed to its higher
nucleophilic character compared to its amine counterpart 2b. In
addition, another factor influencing the yield outcome could be
the relatively easier purification of the corresponding sulfur
rotaxanes, especially 4a, which could be purified by only one
preparative TLC, respect to the isolation of 4c,d, which required
a sequence of column chromatography and successive runs of
gel permeation chromatography.
Rotaxanes 4a-d were characterized by means of 1D and 2D
NMR spectroscopy, showing the expected shifting to lower
frequencies for the signals of the aromatic H atoms of the
macrocycle and the naphthalene diimide core due to the
shielding caused by the establishment of - interactions
between the naphthalene rings of the macrocycle and the
naphthalene diimide unit (H1 = −0.95−0.96 ppm; H2 = −0.53
ppm; H3 = −0.40 ppm and Ha = −0.48 ppm), thus supporting
the formation of the target structures (for 4a, see Figure S1 in
the Supporting Information). Rotaxane 4b was further studied by
DOSY NMR experiments which showed that both thread and
macrocycle diffuse as a whole as both sets of signals show the
same diffusion coefficient, estimated as 7.04 × 10-6 cm2 s-1, also
supporting the presence of an interlocked structure (see Figure
S54 in the Supporting Information). Finally, the identity of the
rotaxanes was confirmed by high resolution mass spectrometry
(HRMS). The ESI-TOF mass spectra show peaks corresponding
to the singly or doubly charged molecular ions with experimental
exact masses and isotopic distributions in good agreement with
the theoretical ones (see Figures S160-S170 in the Supporting
Information).
Figure 1. Proposed synthetic strategy for: a) the synthesis of rotaxanes
through a capping approach based on Michael-type addition reactions to vinyl
sulfone (X = CH2) or vinyl sulfonate (X = O) groups as the key step for the
blocking of the pseudorotaxanes, and b) the disassembly of the rotaxanes
formed from vinyl sulfonates (X = O) by nucleophilic substitution.
Results and Discussion
Synthesis of rotaxanes based on - interactions
Initially, we tested the proposed click Michael-type addition
methodology in the synthesis of rotaxanes based on donor-
acceptor - interactions (Scheme 1). We chose as recognition
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Scheme 1. Synthesis of rotaxanes based on - interactions 4a-d through aza- and thia-Michael addition to the vinyl sulfonyl group.
Synthesis of rotaxanes based on hydrogen bonding
reaction outcome. Therefore, we prepared diketopiperazine
derivatives 5a,b functionalized with vinyl sulfonate or vinyl
sulfone groups as Michael acceptors for thiol stopper 2a,c, but
also axle 5c with thiol groups on both ends that could act as
nucleophiles in the click thia-Michael addition to vinyl sulfonyl-
functionalized stoppers 2d,e. After the very good results attained
in the preparation of the free threads (see the Supporting
Information), we carried out the rotaxane formation following our
methodology by reacting linear compounds 5a,b or 5c with
stoppers 2a,c or 2d,e, respectively, in the presence of
tetralactam macrocycle 6 (Scheme 2). Indeed, the thia-Michael
addition to the vinyl sulfonyl group gave the corresponding
[2]rotaxanes 7a-c in good yields (61%−72%), quite similar to
those observed for the naphthalene diimide rotaxanes.
Again, the structure of rotaxanes of 7a-c was supported by
1D and 2D NMR experiments, which showed in all cases a
downfield shift of the amide H atoms along with H1 due to the
establishment of hydrogen bond interactions with the carbonyl
groups of the diketopiperazine recognition motif on the thread
(H1 = 0.44−0.46 ppm and H2 = 1.02−1.11 ppm). On the
contrary, thread H atoms on or close to the diketopiperazine unit
are shifted to lower frequencies due to the shielding induced by
the aromatic rings on the macrocycle (ΔδHa = −1.29−1.38 ppm)
(for 7a,b see Figures S2-S3 in the Supporting Information). The
structure of 7a,b was also studied by DOSY NMR spectroscopy.
The DOSY experiments show that all signals display the same
diffusion coefficient, with estimated values of 9.29 × 10-6 cm2 s-1
and 7.08 × 10-6 cm2 s-1 for 7a and 7b, respectively, supporting
The good results obtained with this methodology based on
Michael-type additions to the vinyl sulfonyl group in the
synthesis of rotaxanes based on - interactions prompted us to
extend its application to other systems based on different non-
covalent interactions. Therefore, we decided to test this
synthetic strategy in the assembly of rotaxanes based on
hydrogen bonding (Scheme 2). Firstly, we focused on
tetralactam rings as they are macrocyclic components that have
been used in the synthesis of a variety of rotaxanes through the
establishment of hydrogen bonds with a variety of acceptor
templates. In particular, we chose the Hunter/Vögtle-type anilide
macrocycle[37] as most of the usual Leigh-type benzylamide
macrocycles exhibit a very low solubility which makes them
incompatible with the capping approach and they are mostly
used in clipping strategies.[11a,d,f,38] As recognition motif for the
macrocyclic component we selected the diketopiperazine unit
(Scheme 2), which was shown to act as template for tetralactam
macrocycles (binding constant Ka = (1.08 ± 0.09) × 104 M-1 at
233K in CDCl3) in rotaxane synthesis,[39] affording yields among
the highest obtained for organic non-ionic recognition motifs with
this macrocycle.[40]
Based on the results obtained for - rotaxanes, we decided
to focus on the thia-Michael addition as higher yields were
achieved. However, we used this system to investigate whether
the position of the nucleophile or the Michael acceptor group on
the thread or on the stopper would have any influence on the
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2.7 × 104 M-1 at 298 K in CHCl3,[41] has been exploited in the
design of a vast number of rotaxane architectures.[32c,42, 43]
Initially, a series of model studies suggested that the use of
substoichiometric amounts of Et3N and PPh3 could promote the
thia-Michael addition reaction while keeping a high degree of
association between macrocycle and the ammonium unit,
meaning that the latter remained with
a high extent of
protonation. Thus, we prepared dibenzylammonium salts
8a,b•PF6 functionalized with vinyl sulfonate or vinyl sulfone
groups and reacted them with stopper 2c in the presence of
DB24C8 (9) and a catalytic amount of Et3N. However, the 1H
NMR analysis of the crude mixture did not show any evidence of
the formation of the rotaxane but only the presence of free
thread and macrocycle. Therefore, we tried milder conditions
reported in the literature for
consisting on the use of
a
thiol maleimide reaction,
catalytic amount of
a
dimethylaminopyridine (DMAP) as base and performing the
reaction at 0 ºC.[21a] The compatibility of the thia-Michael addition
to the vinyl sulfonyl group with temperatures of 0−4 ºC[24c] is
another of the advantages of this synthetic strategy as it
enhances its scope, enabling its use with temperature-sensitive
substrates (e.g. proteins), to avoid other side or decomposition
reactions or in supramolecular systems to strengthen or not to
disturb the host-guest interactions. The possibility of using
DMAP as base was also confirmed by some model studies.
Under these conditions, reaction of the pseudorotaxane
assembled from 8a•PF6 and 9 with thiol stopper 2c successfully
afforded the target rotaxane 10a•PF6 in a good yield (73%)
(Scheme 3), in line with those observed for previous systems.
Similar results were obtained when using the vinyl sulfone
analogue 8b•PF6, affording the corresponding rotaxane 10b•PF6
in a similar yield (66%) (Scheme 3).
1D and 2D NMR experiments support the rotaxane structure.
Thus, there is a broadening and shift to higher frequencies of the
benzylic CH2 signals, typical of the establishment of hydrogen
bonding between the crown ether and the ammonium unit (Ha
= 0.39 ppm).[18b,42d] On the contrary, the signals of the aromatic
H atoms of the dibenzylammonium motif and the CH2 groups of
the macrocycle are slightly shifted upfield due to the shielding by
the aromatics rings of the macrocycle or the dibenzylammonium
unit, respectively (Hc = −0.11 ppm and H5 = −0.42 ppm) (for
10a see Figure S4 in the Supporting Information). DOSY NMR
experiments also confirmed the interlocked nature of 10a•PF6 as
the same diffusion coefficient (ca. 7.91 × 10-6 cm2 s-1) was
observed for the sets of signals of the macrocycle and the
thread (see Figure S115 in the Supporting Information). Finally,
the identity of rotaxanes 10a,b was also endorsed by the exact
mass and isotopic distributions data obtained by HRMS (Figures
S178-S181 in the Supporting Information).
Scheme 2. Synthesis of hydrogen bonded rotaxanes 7a-c via thia-Michael
addition to vinyl sulfonyl groups placed on the thread precursor or the stopper.
the interlocked nature of the species (see Figures S78 and S86
in the Supporting Information). Finally, rotaxanes 7a-c were also
further characterized by means of HRMS (see Figures S171-
S177 in the Supporting Information).
Prompted by these results, we decided to try the studied
methodology for the synthesis of crown ether-based rotaxanes
using ammonium salts as template. This represents a more
challenging system for the proposed strategy, as the recognition
motif for the macrocycle is a protonated secondary amine that
could undergo deprotonation under the basic conditions required.
We concentrated on the extensively used motif comprising
dibenzo-24-crown-8 (DB24C8, 9) as macrocycle and
a
dibenzylammonium derivative as the secondary ammonium salt
(Scheme 3). This recognition pair, with a binding constant Ka =
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Scheme 3. Synthesis of rotaxanes 10a,b·PF6 from dibenzylammonium derivatives functionalized with vinyl sulfonyl groups 8a,b·PF6 and thiol stopper 2c in the
presence of DB24C8 (9).
Synthesis of pillar[5]arene-based rotaxanes
the 91% isolated yield, the highest found using this methodology,
reached for the synthesis of 13b using the per-methyl
pillar[5]arene 12b.
Finally, we applied the proposed synthetic methodology to the
preparation of rotaxanes with pillar[5]arenes as the macrocyclic
component. Pillar[n]arenes, firstly developed by Ogoshi and co-
workers, are a relatively novel class of macrocycles formed by
hydroquinone rings with two para positions bridged with CH2
groups.[44] These macrocycles are attracting an increasing
interest due to their interesting ability to act as supramolecular
hosts in addition to its easy preparation and functionalization,
which makes them interesting candidates for the development of
supramolecular systems and molecular devices.[45] Hence, we
found it relevant to test the capping strategy of click vinyl
sulfonyl-based Michael-type reactions in the synthesis of
rotaxanes incorporating this type of macrocycles. As templates
we turned our attention to the 1,4-di(1,2,3-triazol-1-yl)butane unit,
previously used in the synthesis of rotaxanes, due to its high
binding constant (Ka = (1.6 ± 0.3) × 104 M-1 at 298 K in CDCl3)
with pillar[5]arene derivatives (Scheme 4).[46]
As in previous examples, we synthesised linear fragments
11a,b with two terminal vinyl sulfone or vinyl sulfonate groups
linked to the recognition core (see the Supporting Information).
Thia-Michael addition of the bulky thiol 2c to the vinyl sulfonyl
moieties afforded the corresponding free threads in the usual
efficient and high-yielding (82% and 94%) manner, which lead
us to undertake the synthesis of the corresponding [2]rotaxanes.
We reached the target structures by reacting a mixture of thread
precursors 11a or 11b and per-ethyl or per-methyl
pillar[5]arenes 12a,b, which assemble into the corresponding
pseudorotaxanes, with stopper 2c under the same mild
conditions employed with previous systems, affording rotaxanes
13a-d in 53%−91% yield (Scheme 4). Especially remarkable is
As previously, exhaustive characterization by means of 1D,
2D and DOSY NMR spectroscopy supported the proposed
interlocked structures, showing the shielding of the H atoms of
the central butylene unit by the macrocycle, which induces a
strong shifting to lower frequencies (Ha = −2.28−2.33 ppm and
Hb = −3.03−3.09 ppm) (for 13a,b, see Figures S5-S6 in the
Supporting Information), and the same diffusion coefficient,
ranging 5.43 × 10-6 − 6.80 × 10-6 cm2 s-1, for all components in
each of the interlocked structures (see Figures S141, S146,
S152 and S157 in the Supporting Information). The identity of
the structures was further confirmed by HRMS (see Figures
S182-S191 in the Supporting Information).
Stability of the rotaxanes
After obtaining the different types of rotaxanes we studied
the stability of representative examples to assess whether the
presence of a sulfonate group or reactions like the retro-Michael
addition could compromise the stability of the systems.[47]
Therefore, the stability of rotaxanes 4a, 7b,c and 13b,d in
solution (CDCl3) at room temperature was monitored over 7 d by
1H NMR spectroscopy. No evidences of decomposition were
observed as the spectra recorded after 3 and 7 days did not
show any significant changes respect to those recorded straight
after the preparation of the samples, thus, confirming the
stability of the systems obtained from both vinyl sulfone or vinyl
sulfonate groups (see Figures S13-S17 in the Supporting
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Scheme 4. Synthesis of pillar[5]arene rotaxanes 13a-d following a capping strategy involving thia-Michael reactions to vinyl sulfonyl-functionalized thread
precursors 11a,b.
Information). Taking a step further, the stability of rotaxanes 4a
and 13d, with a sulfonate or a sulfone group, respectively, was
studied in the presence of an excess of Et3N over 5 days. Again,
the 1H NMR spectra confirmed the stability of both rotaxanes
under those conditions, as the spectra remained unchanged,
except for the presence of Et3N, compared to those in the
absence of base, ruling out the retro Michael addition at room
temperature in the presence of this mild base (see Figures S18-
S19 in the Supporting Information).
and 14. We did not found any evidence of the presence of free
thread or starting rotaxane 4a (see Figures S8-S10 in the
Supporting Information). Moreover, HRMS of the collected
fractions unambiguously confirmed the identity of those species
(see Figures S11-12 in the Supporting Information), supporting
the proposed dethreading mechanism through cleavage or the
stoppers by nucleophilic substitution of the sulfonates with a thiol.
Treatment of 4a with Cs2CO3 and room temperature without the
thiol resulted in the recovery of the starting rotaxane as
confirmed by 1H NMR analysis of the crude mixture after workup,
where only the signals of 4a were observed, without any
evidence of the presence of 14, free 3 or their inclusion complex
(see Figure S20 in the Supporting Information).
These experiments illustrate the chemical disassembly of a
sulfonate rotaxane and the release of its components in a
controlled manner triggered by the reaction with a suitable
nucleophile. This feature exploits the CAD behaviour of the vinyl
sulfonate group as it relies on the presence of a sulfonate which
can undergo nucleophilic substitution but is stable under mild
basic conditions in the absence of a nucleophilic species.
Therefore, these results support our hypothesis of the vinyl
sulfonate moiety as a general versatile group not only for the
efficient synthesis of rotaxanes through click Michael-type
additions, but also for their chemical disassembly and controlled
release of their components.
Chemical disassembly of sulfonate rotaxane 4a
Inspired by our previous research on vinyl sulfonate CAD
chemistry,[28] which showed its compatibility with biological
systems, we decided to explore the possibility of disassembling
into its components the rotaxanes obtained from vinyl sulfonate
groups.
Hence, as proof-of-concept, we studied the disassembly of
naphthalene diimide rotaxane 4a by cleavage of the sulfonate
groups through nucleophilic substitution (Scheme 5). We chose
2-mercaptoethanol as nucleophile as it can displace sulfonate
moieties under mild conditions, i.e. a relatively mild base such
as Cs2CO3 and room temperature in DMF.[48] In this manner, the
reaction of rotaxane 4a with 2-mercaptoethanol afforded a
mixture of compounds which was analysed by HPLC. The main
features of the chromatogram, both the retention time and the
UV traces of the peaks observed, were analysed and compared
to those of the starting rotaxane 4a, its corresponding free
thread, macrocycle 3 and compound 14, the latter synthesised
independently by nucleophilic substitution of the sulfonate
moieties with 2-mercaptoethanol to be used as reference (see
the Supporting Information). Free macrocycle 3 and axle 14
were identified as the major species in the mixture due to the
presence of two peaks whose retention time and UV traces were
in excellent agreement with those of the reference compounds 3
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Scheme 5. Chemical disassembly of rotaxane 4a by nucleophilic attack of 2-mercaptoethanol to the sulfonate groups resulting from the click thia-Michael addition
capping reaction.
chemical disassembly of the rotaxanes obtained via nucleophilic
substitution on the resulting sulfonates. As proof-of-concept to
illustrate this behaviour, we presented the cleavage of a
sulfonate rotaxane with a thiol under mild conditions, i. e. room
Conclusions
temperature and cesium carbonate as base.
As summary, we have demonstrated the application of the click
thia- and aza-Michael addition to vinyl sulfone or vinyl sulfonate
moieties in rotaxane synthesis through the capping strategy. The
main strengths of this approach are its versatility and efficiency
thanks to the mild conditions required. In this fashion, we applied
the described synthetic methodology to the preparation of a
series of rotaxanes based on different templates and recognition
motifs, namely, naphthalene diimide units that establish donor-
Therefore, the click Michael-type addition reaction to the
vinyl sulfonyl group constitutes an interesting capping synthetic
methodology and an alternative to consider when designing and
synthesizing molecular devices based on rotaxane architectures.
Experimental Section
acceptor
diketopiperazine units that interact with tetralactam macrocycles
through H-bonding and 1,4-di(1,2,3-triazol-1-yl)butane
-
interactions
with
dinaphto-38-crown-10,
Synthesis of rotaxane 4a. A solution of 1a (15 mg, 20 μmol) and 3 (25
mg, 40 μmol) in CHCl3 (15 mL) was stirred for 10 minutes at room
temperature. The solvent was removed under reduced pressure. The
crude was redissolved in CHCl3 (1 mL). Under Ar, to this solution were
added a few drops of 2-propanol, 2a (46 mg, 80 μmol) and 2 drops of
Et3N. The mixture was stirred for 18 h at room temperature. The solvent
was evaporated under reduced pressure. The crude material was purified
by a preparative TLC (SiO2, CH2Cl2/MeOH 99:1) to afford 4a (39 mg,
80%) as a red solid. See the Supporting Information for characterization
details.
derivatives as templates for pillar[5]arenes. In all cases the
Michael-type addition reaction to the vinyl sulfonyl group
proceeded under mild conditions, i.e. room temperature or 0 ºC
and with a mild base such as Et3N or DMAP without the need of
a metal catalyst, affording the corresponding rotaxanes in
around 60−90% yield in most cases. These results demonstrate
the efficiency of this methodology and, in most cases, it matches
or improves the yields for similar reported examples based on
the same recognition motifs using alternative capping reactions.
Therefore, the methodology described constitutes an efficient
and convenient synthetic choice in the preparation of rotaxanes.
Moreover, the vinyl sulfonate group carries another
advantage as it not only enables click Michael-type addition
coupling reactions to form rotaxanes but also the controlled
Synthesis of rotaxane 7c. Under inert atmosphere, to a solution of 5c
(5.0 mg, 18 µmol) and 6 (9.0 mg, 8.8 µmol) in CHCl3 (8 mL) were added
2e (45 mg, 71 µmol) and 2 drops of Et3N. The solution was stirred for 20
h at room temperature. The solvent was removed under reduced
pressure. The crude material was purified by gel permeation
chromatography (Bio-Beads® S-X1, CH2Cl2) to afford 7c (16 mg, 71%)
as white solid. See the Supporting Information for characterization details.
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Synthesis of rotaxane 10a·PF6. 8a·PF6 (17 mg, 25 μmol) and 9 (57 mg,
0.13 mmol) were dissolved in CH2Cl2/CH3CN (2:1, 15 mL). The solvent
was removed under reduced pressure and the solid was redissolved in
CH2Cl2 (0.8 mL). Under Ar, the solution was cooled to 0 ºC and was
stirred for 1 h. 2c (42 mg, 0.10 mmol) and a catalytic amount of DMAP
were added. The mixture was stirred for 72 h at 0 ºC. The solvent was
evaporated under vacuum. The crude material was purified by gel
permeation chromatography (Bio-Beads® S-X1, CH2Cl2, and then Bio-
Beads® S-X3, CH2Cl2). The crude was dissolved in CH2Cl2 (20 mL) and
washed with HCl (1%, 3 × 20 mL). The organic phase was dried over
anhydrous Na2SO4 and the solvent was removed under reduced
pressure to yield 10a·PF6 (36 mg, 73%) as a white solid. See the
Supporting Information for characterization details.
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CH2Cl2/MeOH to 49:1; then SiO2, CH2Cl2/MeOH 100:0 to 24:1) to afford
13b (85 mg, 91%) as a colourless syrup. See the Supporting Information
for characterization details.
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Acknowledgements
This work has been funded by the Ministerio de Economía y
Competitividad (MINECO, Spain) (MINECO FEDER CTQ2014-
55474-C2-1-R). We also thank Universidad de Granada (UGR)
(Visiting Scholars PP2016-VS01 and “Intensificación de la
Investigación” PP2017-PRI-I-02 programmes from the “Plan
Propio de Investigación”) for further financial support. A. G. C.
acknowledges MINECO for a “Ramón y Cajal” (RyC-2013-
12943) contract. We also acknowledge the “Unidad de
Excelencia Química Aplicada a Biomedicina y Medioambiente”
(UGR).
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Conflict of interest
There are no conflicts to declare.
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Keywords: Rotaxanes • Michael addition • vinyl sulfonyl •
coupling-and-decoupling chemistry • click chemistry
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Michael-type addition to vinyl sulfonyl
groups emerges as a versatile and
efficient tool for the threading-and-
capping synthesis in mild conditions of
rotaxanes based on different non-
covalent interactions. The
Arthur H. G. David, Pablo García-
Cerezo, Araceli G. Campaña, Francisco
Santoyo-González,* Victor Blanco*
Page No. – Page No.
Title
disassembly of the interlocked
structures is also possible in designs
based on vinyl sulfonate moieties.
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