Generation of Multicomponent Molecular Cages using Simultaneous Dynamic Covalent Reactions

Article abstract of DOI:10.1002/chem.201703868

Cage compounds are very attractive structures for a wide range of applications and there is ongoing interest in finding effective ways to access such kinds of complex structures, particularly those possessing dynamic adaptive features. Here we report the accessible synthesis of new type of organic cage architectures, possessing two different dynamic bonds within one structure: hydrazones and disulfides. Implementation of three distinct functional groups (thiols, aldehydes and hydrazides) in the structure of two simple building blocks resulted in their spontaneous and selective self-assembly into aromatic cage-type architectures. These organic cages contain up to ten components linked together by twelve reversible covalent bonds. The advantage provided by the presented approach is that these cage structures can adaptively self-sort from a complex virtual mixture of polymers or macrocycles and that dynamic covalent chemistry enables their deliberate disassembly through controlled component exchange.

Full text of DOI:10.1002/chem.201703868

A Journal of
Accepted Article
Title: Generation of Multicomponent Molecular Cages using
Simultaneous Dynamic Covalent Reactions.
Authors: Wojciech Drozdz, Camille Bouillon, Clement Kotras,
Sebastien Richeter, Mihail Dumitru Barboiu, Sebastien
Clement, Artur Stefankiewicz, and Sebastien Ulrich
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To be cited as: Chem. Eur. J. 10.1002/chem.201703868
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Generation of Multicomponent Molecular Cages using
Simultaneous Dynamic Covalent Reactions.
Wojciech Drożdż,[a],[b] Camille Bouillon,[c] Clément Kotras,[d] Sébastien Richeter,[d] Mihail Barboiu,[e]
Sébastien Clément,[d] Artur R. Stefankiewicz,*[a],[b] and Sébastien Ulrich*[c]
Abstract: Cage compounds are very attractive structures for a wide
range of applications and there is ongoing interest in finding effective
ways to access this kind of complex structures, particularly those
possessing dynamic adaptive features. Here we report the
accessible synthesis of new type of organic cage architectures,
possessing two different dynamic bonds within one structure:
hydrazones and disulfides. Implementation of three distinct
functional groups (i.e. thiols, aldehydes and hydrazides) in the
structure of two simple building blocks resulted in their spontaneous
and selective self-assembly into aromatic cage-type architectures.
These organic cages contain up to ten components linked together
by twelve reversible covalent bonds. The advantage provided by the
presented approach is that these cage structures can adaptively
self-sort from a complex virtual mixture of polymers or macrocycles
and that dynamic covalent chemistry enables their deliberate
disassembly through controlled component exchange.
and diverse dynamic combinatorial libraries (DCL),[6] in which
some interesting and unexpected constituents may be
expressed, either spontaneously or by medium/templating
effects. The second advantage of DCC is that since it involves
reversible covalent reactions, it produces dynamic systems
which are capable of self-correcting in order to convert
intermediates into thermodynamic products. Finally, the third
advantage provided by DCC is that it enables access to covalent
robust structures which are yet dynamic and capable of adapting
to an environmental pressure such as the presence of a
competitor that operates through component exchange.[7]
The use of multiple reversible covalent reactions and building
blocks of high functionality is of interest to expand the structural
diversity of constituents expressed in a DCL.[6b] However, this
comes at a cost and requires powerful analytical tools to
characterize such constitutionally complex systems. Therefore,
sets of reversible covalent reactions which operate
independently of each other are useful to engineer more focused
and controllable multi-level DCL.[8] Several reports have shown
that condensation reactions (imine, (acyl)hydrazone) and
disulfides can operate orthogonally to each other. For instance,
Otto et al.,[9] Furlan et al.,[10] and Fulton et al.[11] reported
systems where acylhydrazone and disulfide exchange can be
triggered independently at different pH. Typically, acylhydrazone
and disulfide exchange exclusively under acidic and basic
conditions, respectively. The external control of the reactivity
using different reaction conditions can be exploited for instance
for stepwise molecular motions.[12] On the other hand, one may
also wish to conduct both transformations independently (i.e.
with high chemoselectivity, avoiding cross-reactions) but in the
same reaction conditions for moving more effectively up the
Introduction
Cage compounds have attracted considerable interest due to
their potential function as “nano-containers” for (bio)molecular
recognition,
catalysis.[1]
delivery applications,
and supramolecular
Supramolecular chemistry has been particularly successful in
the synthesis of complex supramolecular cages using
coordination chemistry[2] and hydrogen bond interactions.[3] On
the other hand, major advances have been recently made in the
preparation of dynamic covalent cage-type compounds using
dynamic covalent chemistry (DCC).[4],[5] The first advantage
provided by DCC is that it enables the rapid production of large
complexity ladder
–
from small molecules to complex
nanostructures through one-pot multi-steps self-assembly
processes. In this perspective, while Otto and co-workers
showed that using a nucleophilic organocatalyst of hydrazone
exchange can help find reactions conditions where both
reactions operates simultaneously,[9] Alfonso and co-workers
recently demonstrated that the presence of DMSO in DCL can
significantly promote thiol oxidation into disulfides as well as
disulfide exchange, and even at acidic pH,[13] thereby opening a
practical way to carry out both reversible covalent reactions in
the same reaction conditions.
The generation of organic cages through bottom-up self-
assembly represents an interesting challenge. Cage-type
compounds are large multi-component entities which bear
strong interest as functional systems for their host-guest
recognition properties. In this context, imine bonds have been
used for generating organic cages. For instance, Warmuth and
co-workers showed cage formation by reacting pre-organized
cavitands grafted with aldehyde groups with diamines.[14] Cooper
and co-workers reported the one-pot assembly of organic cages
through 12 imine bonds[15] and their corresponding triply-
interlocked assemblies.[16] More recently, Barboiu and co-
[a]
W. Drożdż, Prof. Dr. A. R. Stefankiewicz
Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b,
61-614 Poznań, Poland.
E-mail: ars@amu.edu.pl
W. Drożdż, Prof. Dr. A. R. Stefankiewicz
Centre for Advanced Technologies, Adam Mickiewicz University,
Umultowska 89c, 61-614 Poznań, Poland.
Dr. C. Bouillon, Dr. S. Ulrich
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247,
CNRS, Université de Montpellier, ENSCM, Ecole Nationale
Supérieure de Chimie de Montpellier, 8 rue de l’Ecole Normale,
34296 Montpellier cedex 5, France.
[b]
[c]
E-mail: sebastien.ulrich@enscm.fr
[d]
[e]
C. Kotras, Dr. S. Richeter, Dr. S. Clément
Institut Charles Gerhardt, UMR 5253, CNRS, Université de
Montpellier, ENSCM, Place Eugène Bataillon, 34095 Montpellier
Cedex 05, France.
Dr. M. Barboiu
Institut Européen des Membranes, IEM, UMR-5635, Université de
Montpellier, ENSCM, CNRS, Adaptive Supramolecular
Nanosystems Group, Place Eugène Bataillon, CC 047, F-34095
Montpellier, France.
Supporting information for this article is given via a link at the end of
the document.
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workers reported ligand- and metal-driven selection in imine-
based organic cages.[17] Besides condensation reactions such
as imine and (acyl)hydrazone formation, disulfides represent
another prominent tool in DCC.[18] Of particular interest,
Stefankiewicz and Sanders reported that cage-type compounds
can be expressed in disulfide-based DCL, either spontaneously
or through templating effects.[19] More specifically, cages
featuring rigid aromatics attract great interest for (bio)molecular
recognition. Nitschke et al. have inserted aromatics in metallo-
supramolecular cages,[20] Davis et al. have designed aromatic
cages for sugar recognition,[21] Alfonso et al. have shown the
self-assembly of pseudo-peptidic cages from aromatic
aldehydes,[22] and very recently Stang et al. reported metallo-
supramolecular cages featuring fluorescent aromatics for amino
acid sensing.[23] Yet, the generation of multi-component organic
cages by a one-pot self-assembly process employing a set of
undergo up to three acylhydrazone-forming reactions, the latter
can be involved in both acylhydrazone and disulfide formation.
Therefore, the system can potentially yield a rich DCL made of
many structurally and morphologically distinct products from
linear through cyclic species to larger cage-type products
(Scheme 1). However, based on our previous findings on
disulfide-based system,[19a] we suspected that thanks to weak
supramolecular interactions (e.g. --stacking, hydrogen bonds)
and entropically favoured formation of cage architectures over
polymeric species, the former should significantly emerge from
this DCL. Subsequently, we became interested in inserting
fluorescent aromatic components. Indeed, cages containing a
fluorescent reporter can be useful for sensing applications. We
selected TetraPhenylEthene (TPE) for their fluorescent
properties that display Aggregation-Induced Emission (AIE).[26]
TPE compounds typically exhibit low fluorescent emission in
solution due to the existence of multiple relaxation pathways that
are enabled by the free rotation of the phenyl rings. However, in
an aggregated state, this rotation is restricted, resulting in an
enhanced fluorescence emission. We reasoned that if the
formation of the cage compounds involves -stacking
interactions, it should become visible by an increase in
fluorescence emission. We therefore synthesized TPE-ALD in
two-steps starting from 1,1,2,2-tetraphenylethene (Fig. 1 and
scheme S1). Finally, wishing to expand the scope of our
approach by enabling further chemical modifications, we
synthesized a short heterobifunctional spacer, Cys-Hyd, which
bears a functionalizable amine.
independent
reversible
covalent
reactions
operating
simultaneously remain limited to a few examples combining
imine and olefin metathesis,[24] or imine and boronic ester.[25] To
the best of our knowledge, no investigation into the synthesis of
water soluble, multicomponent cages via two distinct dynamic
covalent bonds has been published. We report herein the one-
pot formation of a new class of multicomponent organic cages
using acylhydrazones and disulfides as independent dynamic
covalent reactions (Scheme 1). These molecular structures
consist of up to ten components connected through up to twelve
dynamic covalent bonds. We show two examples of structurally
distinct cage systems i.e. tripodal and fluorescent tetrapodal
cage architectures. Finally, we demonstrate that self-sorting of
complex DCL takes place, and that component exchange can be
used to deliberately disassemble the cage.
Figure 1. Structure of Benzene-1,3,5-tricarboxAldehyde (BENZ-ALD3),
1,1,2,2-tetraphenylethene (TPE-ALD), thioglycolic hydrazide (1 and 12), and
cysteine hydrazide Cys-Hyd.
Scheme 1. Generation of dynamic combinatorial libraries from aromatic
aldehyde and thioglycolic hydrazide using acylhydrazone and disulfide
reversible covalent reactions, and examples of the various polymeric,
macrocyclic, and cage constituents that can be expressed in the system.
Tripodal cage, Cage 1. We screened mixtures of aqueous
buffers at different pH values, with DMSO as an organic co-
solvent for improving the solubility as well as facilitating disulfide
formation and exchange. At the concentration of 5 mM and
above, we observed precipitate formation upon mixing of BENZ-
ALD3 (1 equiv.) with 1 (3 equiv.), even with different content of
DMSO (10-75%) as a co-solvent. Lowering the concentration of
BENZ-ALD3 to 2 mM, together with three equivalents of 1 in a
mixture of aqueous buffer and DMSO (25/75 v/v) gave us
optimal conditions with homogeneous solution at all pH range.
LC-MS was used to monitor the outcome of the reaction and to
Results and Discussion
We first investigated the potential of our approach using
commercially-available aromatic compound, Benzene-1,3,5-
tricarboxAldehyde (BENZ-ALD3), and the heterobifunctional
compound thioglycolic hydrazide 1 (Fig. 1). While the former can
characterize the constitution of the DCL. Surprisingly,
a
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maximum of two products, out of the many combinations that
are virtually possible, were observed (Fig. 2A). After two days of
incubation at pH=6, the reaction reached completion and led to
the formation of a single product. ESI mass spectrometry
analysis (Fig. 2C) indicated that this product corresponds to the
cage-type structure (Cage 1, Fig. 2D), in which two aromatics
are linked through three spacers – each spacer combining two
thiol components. Longer reaction times, respectively 6 and 7
days, were necessary at pH=5 and pH=7 to reach the same
composition (Fig. S1-S3). Only when carried out at pH=9 the
reaction showed low conversion with multiple products formed,
among which the cage was not detected (Fig. S4).
was found, thereby indicating that the self-assembly yields a
single type of product, even though isomers indiscernible by
DOSY NMR are clearly formed. Secondly, DOSY NMR shows
the size of this self-assembled compound to be significantly
larger than the starting BENZ-ALD3, with solvodynamic radius
and spherical volume being respectively 2.5 and 15 times larger,
which is compatible with the proposed structure of Cage 1
(Table 1 and Fig. 2B, S8-S9). Taken altogether, these data
confirm the self-selection and effective formation of Cage 1 from
the DCL generated by mixing stoichiometric amounts of BENZ-
ALD3 and thioglycolic hydrazide 1.
The formation of Cage 1 requires the one-pot assembly of eight
components through six acylhydrazones and three disulfide
bonds. Its exclusive formation by self-selection within the DCL
indicates a high thermodynamic stability compared to all the
other compounds that can virtually be present in the DCL, which
drives its self-selection and amplification. This is most likely
caused by specific intramolecular non-covalent interactions, as
also previously observed by Alfonso et al. in other systems.[27]
Here, we hypothesize that probable -stacking interactions
between the aromatics and/or hydrogen bonds between the
acylhydrazone groups can stabilize this particular cage. To
probe the origin of the high stability, we first investigated the
importance of medium effect. When the reaction was carried out
in pure acetonitrile, a low conversion into the cage was observed
and much of the starting materials remained unreacted. This
observation shows that the reversible covalent reactions can
proceed in this medium but that, in these conditions, the self-
assembly does not reach completion. Increasing the proportion
of aqueous buffer (100 mM AcONa, pH=5) from 10 to 25%
favours the formation of the cage compound (Fig. S10-S12).
These results show that, in the absence of DMSO as a co-
solvent, the aqueous environment is essential for cage formation,
most probably due to the favoured aggregation of the aromatics
which minimises exposure to water and thereby templates cage-
like structures. In the latter condition, we noticed that the cage
precipitates out (as confirmed by comparative HPLC analyses of
the supernatant solution and isolated solid, see Fig. S13),
thereby enabling its isolation by simple filtration in a remarkable
40% overall yield, which amounts to a 90% isolated yield for
each reaction considering nine equivalent reactions involved in
the formation of Cage 1. We also varied solvent composition in
the presence of DMSO by comparing reactions carried out in
pure DMSO, DMSO/AcONa buffer (100 mM, pH=5) 75/25 (v/v),
and DMSO/acetonitrile 75/25 (v/v). Albeit the kinetic was slightly
affected, we observed cage formation in all three solvents,
thereby indicating that both the acylhydrazone and disulfide
formation can effectively take place when DMSO is present (Fig.
S14-S15).
Figure 2. A) HPLC chromatograms (254 nm) of the reaction between BENZ-
ALD3 (1 equiv.) and thioglycolic hydrazide
1 (3 equiv.) in aqueous
buffer/DMSO 25/75 (v/v), after 2 days at different pH; B) 1H NMR (600 MHz,
d6-DMSO) of Cage 1 with, below, the extracted DOSY NMR spectrum; C) ESI
mass spectrum of Cage 1 (m/z calcd. for [cage+H+K]2+ 443.05, for [cage+H]+
847.00; D) proposed structure of the cage compound Cage 1.
1H NMR spectrum shows the complete disappearance of the
aldehyde peak (10.3 ppm) and the formation of new set of
signals at 11.5 ppm which is typical region for -C(O)NHN=
protons of acylhydrazones (Fig. 2B). We also noticed the
disappearance of the -CH2-S- peak at 3.0 ppm and a new peak
1
formed at 3.4 ppm. By comparing with the H NMR spectrum of
the disulfide compound 12 – which was formed by spontaneous
oxidation in DMSO (Fig. S5-S6) – we found that this new peak
corresponds to the chemical shift of -CH2-S-S-CH2-, thereby
demonstrating that the new compound formed contains both
acylhydrazone and disulfide linkages (Fig. S7). However,
multiple peaks are observed in the 1H NMR spectrum which may
indicate that several isomers are present. Indeed, when taking
into account E/Z imine, cis/trans amide, and disulfide isomers,
we found the maximum number of possible isomers to be 225
(Fig. S25). In support of this hypothesis of coexistence of
multiple conformational isomers, VT 1H-NMR shows partial
coalescence of the 1H NMR signals at high temperature (Fig.
S16). DOSY NMR was then used to further characterize the
system. First of all, we were pleased to see that a single species
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When monitoring the formation of Cage 2 by LC-MS at different
time points (Fig. S24), we could observe the formation of
intermediates, including the TPE-Intermediate compound made
of a single TPE unit in which two intramolecular disulfide bonds
were formed (Fig. 4). While the formation of TPE-Intermediate
occurs within a few hours, its further conversion into Cage 2 is
much slower, which indicates that in these conditions,
acylhydrazone formation is faster and that the rate-limiting step
for forming Cage 2 rests on intra- to inter-molecular disulfide
exchange. In support of this idea, we tested the self-assembly
starting with the pre-formed disulfide compound 12 and found
that Cage 2 was formed much faster – 1 day instead of 3 days.
Similarly, we found that increasing concentration and
temperature (50°C) speed up the conversion of TPE-
Intermediate into Cage 2.
Table 1. Hydrodynamic radii and spherical volumes calculated using Stokes-
Einstein equation from the DOSY NMR data.
Entry
Compounds
BENZ-ALD3
Cage 1
D [m2s-1]
4.8 x 10-10
1.95 x 10-10
rhyd [Å]
2.3
vsph [Å3]
50.0
1
2
5.6
746.3
D: Diffusion coefficient; rhyd: Hydrodynamic radius ; vsph: Spherical volume.
Fluorescent tetrapodal cage, Cage 2. In the next step, the
covalent self-assembly between TPE-ALD (2 mM, 1 equiv.) and
1 (4 equiv.) was investigated. Due to solubility reasons, the
previously employed solvents could not be applied, therefore an
increased amount of DMSO (DMSO/H2O 94/6 v/v) was used.
LC-MS analysis of the resulting DCL showed the complete
conversion, within 3 days, of the starting TPE-ALD into a single
new product (Fig. 3A). The same product was observed when
the reaction was carried out in 100% DMSO. Gratifyingly, this
product was identified by mass spectrometry as the expected
Table 2. Hydrodynamic radii and spherical volumes calculated using Stokes-
cage compound Cage
2 which results from the one-pot
Einstein equation from the DOSY NMR data.
assembly of 10 components through 12 covalent bonds (8
acylhydrazones + 4 disulfides) (Fig. 3C and 3D).
Entry
Compounds
D [m2s-1]
4.77 x 10-10
1.39 x 10-10
rhyd [Å]
vsph [Å3]
1
2
TPE-ALD
Cage 2
2.3
7.9
51.0
2060.5
D: Diffusion coefficient; rhyd: Hydrodynamic radius; vsph: Spherical volume.
Figure 4. Proposed structure of TPE-Intermediate that is transiently formed
during the self-assembly of the cage compound Cage 2.
Monitoring the covalent self-assembly between TPE-ALD and 1
by UV-Vis spectroscopy shows the gradual appearance of a red-
shifted band, which is in line with the formation of aromatic
acylhydrazones that extend the initial conjugation present in
TPE-ALD (Fig 5A). Interestingly, fluorescence spectroscopy
shows an overall 61-fold increase in the fluorescence emission
during the reaction between TPE-ALD and 1 (Fig. 5B). While at
low concentration (0.25 mM) we only observed a fluorescence
Figure 3. A) HPLC chromatograms of TPE-ALD (bottom), and reaction
between TPE-ALD (1 equiv.) and thioglycolic hydrazide 1 (4 equiv.) in
DMSO/H2O 94/6 (v/v) after 6 days (top); B) 1H NMR (600 MHz, d6-DMSO) of
Cage 2 with, below, the extracted DOSY NMR spectrum; C) ESI mass
spectrometry analysis of Cage 2 (m/z calcd for [cage+2H]2+ 793.15, for
[cage+H]+ 1585.29; D) proposed structure of the cage compound Cage 2.
increase (Fig. 5B),
a typical blue shift (12 nm) in the
fluorescence emission was seen when the reaction was carried
out at higher concentration (2 mM) (Fig. 5C). This is explained
by the fact that TPE-Intermediate is the main product when the
reaction is carried out at low concentration (0.25 mM) whereas
Cage 2 becomes the main product when the reaction is carried
out at higher concentration (2 mM), as proved by HPLC
analyses. Therefore, while the increase in the fluorescence
emission of TPE-Intermediate may be due to the rigidification of
the system, the blue shift signal can be attributed to the cage-
hindered arrangement of the TPE units within Cage 2.
Given the possibilities of imine, amide, and disulfide isomers, the
maximum number of isomers of Cage 2 is 400 (Fig. S26), which
most probably explains the multiple peaks observed in the 1H
NMR spectrum (Fig. 3B). DOSY NMR shows the formation of a
single type of product that has a solvodynamic radius and a
spherical volume, respectively, 2.3 and 40 times larger than
TPE-ALD which is compatible with the proposed structure
(Table 2, Fig. 3B and S22-S23).
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Figure 5. Self-assembly between TPE-ALD and thioglycolic hydrazide 1 in DMSO monitored by A) UV-Visible spectroscopy (reaction carried out at 0.25 mM, the
inset shows changes in absorbance at 310 and 390 nm with time), and fluorescence spectroscopy: B) reaction carried out at 0.25 mM (the fluorescence spectrum
of Cage 2 was added for comparison, the inset shows changes in fluorescence emission at 529 nm with time), C) reaction carried out at 2 mM (a typical blue shift
(12 nm) in the fluorescence emission is observed).
Overall, these results show that self-selection also occurs in the
DCL generated from TPE-ALD and thioglycolic hydrazide 1, and
leads to the formation of Cage 2. The observation of AIE effects
during the self-assembly process shows that aggregation of the
TPE units is involved in the formation of Cage 2. Thus, it brings
support to the formation of cage-type products and not
macrocyclic species (see Scheme 1), which may both have
same molecular weights. However, at this stage, we cannot
exclude that disulfides may be arranged in a different way than
the connectivities represented throughout this manuscript in the
structures of cage compounds. For instance, isomers such as
Pacman structures – which can be considered as open-cage
structures – may also exist (Fig. S27).[28] Unfortunately, despite
many attempts, we have not yet been successful in obtaining
single crystals suitable for X-ray crystallography analysis which
would help determining the exact molecular structures.
amino acid Fmoc-Cys(Trt)-OH was engaged in a coupling
reaction with tert-butylcarbazate mediated by EDC/HOBt to
afford Fmoc-Cys(Trt)-Hyd-Boc in 97% yield. Then, the Fmoc
group was removed by reaction with piperidine in DMF to give
the corresponding Cys(Trt)-Hyd-Boc in 56% yield. Finally, the
deprotection of the Boc and Trt protecting groups by
a
TFA/TIS/H2O (95:2.5:2.5) solution yielded the desired Cys-Hyd.
Satisfyingly, LC-MS analyses revealed that the reaction between
TPE-ALD (2 mM, 1 equiv.) and Cys-Hyd (4 equiv.) leads to
complete conversion and formation of a single species which is
identified by mass spectrometry as the desired cage Cage 3 (Fig.
6A-6C). Fluorescence spectroscopy confirms that a strong
fluorescence emission enhancement takes place concomitantly
to the cage formation (Fig. 6D).
This result paves the way toward functionalized self-assembled
cages that can be obtained either by post-functionalization of
Functionalized cages, Cage 3. Hydrazides and thiols can be
readily introduced in peptides. Therefore, as a first step toward
the generation of functionalized cages, we extended our
approach by using the simplest and shortest heterobifunctional
spacer, Cys-Hyd, which contains an amine that can be used as
a reactive site for introducing additional groups.
Cage
cysteine-hydrazide.
3 or through cage formation with N-functionalized
Cys-Hyd was synthesized in three steps using a solution-phase
approach (Scheme 2). The commercially available protected
Scheme 2. Synthesis of Cys-Hyd. Reagents and conditions: i) tert-butylcarbazate, EDC, HOBt, Et3N, CH2Cl2 0°C to rt; ii) DMF/piperidine (8/2), rt iii) TFA/TIS/H2O
(95/2.5/2.5), rt.
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HPLC analyses confirms that upon incubation with
methoxyamine (20 equivalents), Cage 2 is fully converted into
the tetra-oxime compound TPE-Oxime (Fig. 8A-8B).[31] In
addition, fluorescence spectroscopy shows the decrease of
fluorescence emission (Fig. 8C), thereby confirming that Cage 2
dissociates.
Figure 6. A) Structure of Cage 3; B) HPLC chromatograms of TPE-ALD and
reaction between TPE-ALD (1 equiv.) and Cys-Hyd (4 equiv.) in DMSO/H2O
94/6 (v/v) after 2 and 24 hours; C) ESI mass spectrometry analysis (m/z calcd.
for [cage+4H]4+ 455.13, for [cage+2H]2+ 909.25; D) self-assembly of Cage 3
monitored by fluorescence spectroscopy.
Self-sorting of cages. The self-assembly methodology based
on reversible covalent reactions enables complex systems to
correct and adapt their constitution until forming the most stable
structures. Therefore, if allowed by thermodynamics, self-sorting
of DCL can be observed.[29] Here we studied stoichiometric
mixtures of both BENZ-ALD3 and TPE-ALD with either
thioglycolic hydrazide 1 or its corresponding disulfide 12, which
can form a wide range of constituents, including mixed cages.
However, we found by HPLC analysis that the two cages,
tripodal Cage 1 and tetrapodal Cage 2, are the main products
expressed by this complex system (Fig. 7 and S36). We noticed
a new product (retention time 4.2 min, see Fig. 7) – possibly a
mixed compound only present as a minor component of the
system – whose identity could unfortunately not be determined
from the extracted ESI mass spectrum. This narcissistic self-
Figure 7. HPLC monitoring after 1 hour, 1 day, and 3 days of a reaction
between BENZ-ALD3 (1 equiv.), TPE-ALD (1 equiv.) and 1 (7 equiv.), and
comparison with a reference mixture of Cage 1 and Cage 2.
sorting
behaviour,
previously
observed
in
metallo-
supramolecular cages,[20b, 30] can result from an optimization of
spatial distribution of connectivities between the aromatic
platforms and lateral arms within the two cage compounds. Thus,
the observation of self-sorting within this DCL brings further
support to the formation of closed cage-type products. Indeed,
open macrocyclic species are expected to be less constrained
and therefore to accommodate more easily mixed structures
combining BENZ-ALD3 and TPE-ALD, thereby generating
statistical DCL instead of self-sorted DCL.
Figure 8. A) Process of opening of Cage 2 by component exchange with
methoxyamine; B) HPLC monitoring, from bottom to top: Cage 2, after 5 days
of reaction with methoxyamine, TPE-Oxime; C) fluorescence emission during
the reaction of Cage
2 with methoxyamine (inset shows changes in
fluorescence emission at 513 nm with time).
Cage opening by dynamic covalent exchange. Cages self-
assembled through reversible covalent reactions may be
interconverted through dynamic covalent exchange. Here, we
tested the opening of the cages by exchange of the
Conclusions
We reported herein the facile preparation of a new class of
tripodal and tetrapodal aromatic cage-type compounds that are
self-assembled in one-pot using simultaneous dynamic covalent
acylhydrazones with methoxyamine
– a reaction that is
thermodynamically shifted toward the more stable oxime product.
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ESI-MS analyses were carried out at the Laboratoire de Mesures
Physiques, IBMM, Université de Montpellier using Micromass Q-Tof
instruments.
Elemental analyses were performed using an Elementar Vario Micro
Cube instrument.
reactions, namely acylhydrazone and disulfide bonds formation.
This is the first example of multicomponent cage formation in
aqueous media by applying simultaneously two distinct dynamic
covalent bonds. The exclusive formation – self-selection – of
these complex structures from dynamic combinatorial libraries
may be the result of intramolecular interactions and/or
geometric/connectivity fit which would also explain the
narcissistic self-sorting behaviour observed. This methodology
enables the effective access to complex cage-type
nanostructures. We also demonstrated that functional groups
can be easily introduced, thereby allowing future post-synthetic
Synthesis of 1,1,2,2-tetrakis(4-carboxaldehydephenyl)ethene (TPE-
Ald). To a solution of 1,1,2,2-tetrakis(4-bromophenyl)ethene (650 mg, 1
mmol) in dry THF (25 mL) at -78 °C, 2.7 mL (7 mmol, 7 equiv.) of a 2.5M
n-butyllithium solution in hexanes (2.5M) were added dropwise. The
mixture was stirred at this temperature during 2h and then, at 0°C during
1h. After cooling at -78°C, 0.62 mL (8 mmol, 8 equiv.) of dry DMF was
added. The mixture was then warmed at room temperature and stirred
overnight. The reaction was quenched with HCl (2M) (50 mL). The
aqueous layer was extracted with diethyl ether (3 x 50mL). The combined
extracts were then dried over MgSO4, filtered and evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel eluting with a gradient of dichloromethane:diethyl ether (98:2
to 92:8) to give the title compound as a pale yellow solid Yield : 28%
(0.12 g). IR (ATR): CO = 1694 cm-1. 1H NMR (300 MHz, CDCl3): δ = 9.94
(s, 4H, CHO), 7.68 (d, 3JH-H = 8.2 Hz, 8H, CH=CH), 7.18 (d, 3JH-H = 8.2 Hz,
8H, CH=CH). 13C{1H} NMR (75 MHz, CDCl3):  = 191.5 (CHO), 148.0,
142.3, 135.5, 131.9, 129.7 ppm. HR-MS (ESI-TOF+): m/z Calcd C30H21O4
445.1440 (M+H); found 445.1438. Anal. Calcd for C30H20O4 (444.14): %C
81.07, %H 4.54; found %C 81.30, %H 4.92.
functionalization. Interestingly, we successfully identified
a
fluorescent tetrapodal cage which assembly and disassembly
can be monitored by fluorescence spectroscopy. Finally, this
methodology enables controlling the disassembly of the cage by
a deliberate thermodynamically-driven component exchange.
This straightforward bottom-up self-assembly approach is
expected to facilitate the generation of functional cages. Future
studies will focus on assessing the molecular recognition
properties of these cage compounds.
Experimental Section
Synthesis of Fmoc-Cys(Trt)-Hyd-Boc. Tert-butyl carbazate (251 mg,
3.41 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 692 mg, 5.12
mmol) were added to a solution of Fmoc-Cys(Try)-OH (2 g, 3.41 mmol)
and triethylamine (522 L, 3.76 mmol) in dry dichloromethane (190 mM).
Then, the solution was cooled to 0°C and N- (3-dimethylaminopropyl)-N’-
ethylcarbodiimide hydrochloride (EDC, 982 mg, 5.12 mmol) was added.
The reaction mixture was then warmed to room temperature and stirred
overnight. After removal of the solvent, the residue was diluted with
EtOAc (100 mL), washed with a saturated NaHCO3 solution (30 mL) and
brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The resulting crude material was purified by flash chromatography
(cyclohexane/EtOAc gradient 9:1 to 7:3, v/v) to provide Fmoc-Cys(Trt)-
Hyd-Boc with 97 % yield as a white solid. Rf = 0.37 (cyclohexane/EtOAc
Materials and Methods. Solvents and benzene-1,3,5-tricarboxaldehyde
were purchased from commercial suppliers and used without further
purification. Thioglycolic hydrazide 1 was synthesized as previously
described.[32] 1,1,2,2-tetrakis(4-bromophenyl)ethane (TPE-Br) was
prepared according to a literature procedure.[33] Dry DMF and THF were
obtained by a solvent purification system PureSolve MD5 from Innovative
Technology. Preparative purifications were performed by silica gel flash
column chromatography (Merck® 40-60 µM). Solvents used as eluents
are technical grade.
HPLC analyses were performed on a Waters HPLC 2695 (EC Nucleosil
300-5 C18, 125 x 3 mm) column, Macherey – Nagel) equipped with a
Waters 996 DAD detector. The following linear gradients of solvent B
(90% acetonitrile, 9.9% water, and 0.1% TFA) into solvent A (99.9%
water and 0.1% TFA) were used: 0 to 95% of solvent B in 5 min; flow 1
ml/min. Retention time (tR) are given in minutes.
8:2, v/v); tR = 5.54 min (Method A); 1H NMR (400 MHz, DMSO-d6): δ =
3
9.79 (s, 1H, NH-NH-Boc), 8.76 (s, 1H, NH-NH-Boc), 7.88 (d, 2H, JH-H
=
7.6 Hz, CHC(C)CH=CH), 7.77-7.75 (m, 3H, NH-Fmoc + CHCCH=CH),
7.42-738 (m, 2H, CH=CH), 7.35-7.23 (m, 17H, CH=CH), 4.28-4.15 (m,
4H, NHCHCH2 + OCH2CH), 2.46-2.32 (m, 2H, NHCHCH2), 1.36 (s, 9H,
OC(CH3)3); 13C{1H} NMR (100 MHz, DMSO-d6) : δ = 169.5, 155.6, 155.0,
144.3, 143.7, 140.7, 129.1, 128.1, 127.7, 127.1, 126.8, 125.5, 120.1,
79.1, 65.9, 65.8, 52.3, 46.6, 34.1, 28.0; HRMS (ESI): m/z calcd for
[C42H41N3O5S+Na]+ 722.2665, found 722.2661.
LC/MS analyses were performed on a Shimadzu LCMS2020 (Phenomex
Kinetex C18, 2.6 m * 7.5 cm, 100Å) equipped with a SPD-M20A detector
with the following linear gradient of solvent B (99.9% acetonitrile, 0.1%
HCOOH) and solvent A (99.9% water and 0.1% HCOOH): 5 to 95% of
solvent B in 5 min; flow 1 ml/min. Retention times (tR) are given in
minutes.
Fluorescence analyses were carried out on an AF-2500 HITACHI
fluorescence spectrophotometer. UV-Vis absorption experiment was
measured on UV-3100pC UVisco spectrophotometer.
Synthesis of H-Cys(Trt)-Hyd-Boc. Fmoc-Cys(Trt)-Hyd-Boc (2.3 g, 3.31
mmol) was dissolved in a solution of DMF/piperidine (8:2, v/v; 70 mM).
The reaction solution was stirred overnight at room temperature and then
concentrated in vacuo. The resulting crude material was purified by flash
chromatography (CH2Cl2/MeOH gradient 99:1 to 98:2, v/v) and by semi-
preparation HPLC to provide H-Cys(Trt)-Hyd-Boc with 56 % yield as a
white solid. Rf = 0.34 (CH2Cl2/AcOEt 8:2, v/v); tR = 3.17 min (Method A);
1H NMR (400 MHz, MeOD): δ = 7.42-7.39 (m, 6H, CCH=CH), 7.32-7.27
(m, 6H, CCH=CH), 7.25-7.21 (m, 3H, CCH=CH=CH), 3.17-3.14 (m, 1H,
CHCH2), 2.65-2.61 (m, 1H, CHCH2a), 2.42-2.37 (m, 1H, CHCH2b), 1.45
(s, 9H, OC(CH3)3); 13C{1H} NMR (100 MHz, DMSO-d6): δ = 173.1, 154.8,
143.7, 129.1, 128.3, 127.1, 79.7, 66.4, 49.8, 32.3, 28.0; HRMS (ESI): m/z
calcd for [C27H31N3O3S+H]+ 478.2164, found 478.2161.
IR spectra were recorded on
spectrophotometer.
a Perkin Elmer Spectrum 2 FTIR
1H NMR, 13C{1H} NMR, VT and DOSY NMR spectra were recorded at
400 MHz for 1H and 100 MHz for 13C (Bruker Avance 400), or 600 MHz
for 1H and 150 MHz for 13C (Bruker Avance III) in deuterated solvents.
Chemical shifts are reported in ppm relative to the residual solvent peak.
Data are reported as follows: Chemical shift (δ), multiplicity (s for singlet,
d for doublet, t for triplet, m for multiplet), coupling constant (J in Hertz),
and integration. DOSY NMR spectroscopy was carried out at the
Laboratoire de Mesures Physiques, IBMM, Université de Montpellier.
Hydrodynamic radii are calculated using the Stokes-Einstein equation.
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10.1002/chem.201703868
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Synthesis of Cys-Hyd. H-Cys(Trt)-Hyd-Boc was dissolved in
TFA/TIS/H2O (95/2.5/2.5) solution (50 mM) and stirred for overnight at
room temperature. After removal of 90% of the solvent, diethyl ether was
added to the residue. The precipitate was triturated with Et2O and filtered.
The crude material was then lyophilized twice to afford the product H-
Cys-Hyd with 10% yield as a white solid. The number of mole of Cys-
Hyd was calculated by 1H NMR titration method using tert-butyl alcohol
as an internal reference. 1H NMR (400 MHz, MeOD): δ = 3.95 (t, 1H, 3JH-
H = 6.16 Hz, CHCH2), 3.08-2.90 (m, 2H, CHCH2); 13C{1H} NMR (100 MHz,
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Keywords: Cage • Hydrazone • Disulfide • Dynamic covalent
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Entry for the Table of Contents (Please choose one layout)
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Multi-component aromatic cages are
self-assembled, self-sorted, and
reconfigured in aqueous solutions
through two simultaneous dynamic
covalent reactions, hydrazone and
disulfide.
Wojciech Drożdż, Camille Bouillon,
Clément Kotras, Sébastien Richeter,
Mihail Barboiu, Sébastien Clément, Artur
R. Stefankiewicz,* Sébastien Ulrich*
Page No. – Page No.
Generation of Multicomponent
Molecular Cages using Simultaneous
Dynamic Covalent Reactions
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