Dynamic covalent self-sorting and kinetic switching processes in two cyclic orders: Macrocycles and macrobicyclic cages

Article abstract of DOI:10.1021/jacs.0c07131

Dynamic covalent component self-sorting processes have been investigated for constituents of different cyclic orders, macrocycles and macrobicyclic cages based on multiple reversible imine formation. The progressive assembly of the final structures from dialdehyde and polyamine components involved the generation of kinetic products and mixtures of intermediates which underwent component selection and self-correction to generate the final thermodynamic constituents. Importantly, constitutional dynamic networks (CDNs) of macrocycles and macrobicyclic cages were set up either from separately prepared constituents or by in situ assembly from their components. Over time, these CDNs underwent conversion from a kinetically trapped out-of-equilibrium distribution of constituents to the thermodynamically self-sorted one through component exchange in different dimensional orders.

Full text of DOI:10.1021/jacs.0c07131

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Dynamic Covalent Self-Sorting and Kinetic Switching Processes in
Two Cyclic Orders: Macrocycles and Macrobicyclic Cages
Zhaozheng Yang and Jean-Marie Lehn*
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sı Supporting Information
ABSTRACT: Dynamic covalent component self-sorting processes
have been investigated for constituents of different cyclic orders,
macrocycles and macrobicyclic cages based on multiple reversible
imine formation. The progressive assembly of the final structures
from dialdehyde and polyamine components involved the
generation of kinetic products and mixtures of intermediates
which underwent component selection and self-correction to
generate the final thermodynamic constituents. Importantly,
constitutional dynamic networks (CDNs) of macrocycles and
macrobicyclic cages were set up either from separately prepared
constituents or by in situ assembly from their components. Over
time, these CDNs underwent conversion from a kinetically trapped
out-of-equilibrium distribution of constituents to the thermodynamically self-sorted one through component exchange in different
dimensional orders.
1
. INTRODUCTION
namically optimal constitutions, in particular, on the basis of
molecular recognition processes. At the supramolecular or
molecular level, reversible connections, i.e., dynamic non-
covalent interactions or dynamic covalent bonds, allow for
error correction in the formation stage of the self-sorted entity,
thus leading to generation of the thermodynamically favored
constituents from multicomponent libraries.
Adaptation to environmental constraints is one of the types of
collective behavior characterizing living organisms and
represents a major feature of complex matter both animate
and inanimate. Extensive efforts have been devoted to the
development of chemical systems displaying such properties,
leading to an adaptive chemistry involving the construction of
5
6
1
constitutional dynamic libraries (CDLs) and their associated
Generation of multiply dynamic covalent cages as well as
constitutional dynamic networks (CDNs) based on sets of
molecular and supramolecular entities capable of undergoing
constitutional variation through component exchange and
selection. The molecular or supramolecular constituents of
CDLs are dynamically interconnected in CDNs presenting
agonistic and antagonistic relationships between constituents.
As a consequence, if an external perturbation is applied to one
of the constituents, all of the other constituents will be
impacted, inducing a change in constitution by reorganization
and exchange of building blocks. Very significant progress has
been made in multiplicity and diversity of CDLs and CDNs
interlocked covalent structures by means of various reversible
7
8
dynamic covalent connections, in particular, polyimines and
9
their coordination complexes has received great attention in
recent years. Especially attractive are self-sorting processes in
the formation of dynamic covalent polycyclic, cage-like
architectures from a mixture of aldehyde and amine
10,11
components.
Dynamic covalent bonds enable the trans-
formation from nonself-sorted to self-sorted cage structures
(
cage-to-cage transformation) through exchange of compo-
1
0a,b,11
nents in the corresponding DCL
and reversible
structural switching such as, for instance, in the interconversion
2
beyond the simplest [2 × 2] CDLs of four constituents.
A further step toward systems of higher complexity resides in
the design and exploration of dynamic covalent libraries
between macrocycles and polymers under the effect of different
12
agents. Recently, we described the self-sorting of macro-
bicyclic polyimine organic cages generated in situ from a
(
DCLs) presenting time dependence that would autonomously
adapt to their inherent kinetic factors and display self-
recognition processes in the buildup of their constitution
Received: July 2, 2020
2a,3
through component self-sorting processes,
leading to the
emergence of higher states of complex behavior.
1
,4
Self-sorting involves a screening process on the combina-
tions of components and selects the optimal ones for
generating specific organized structures presenting thermody-
©
XXXX American Chemical Society
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A

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library of starting components, aldehydes and amines, via
below in section 2.1.2). All three cases displayed high-fidelity
self-sorting behavior.
11
reversible imine bond formation.
Beyond the separate formation of macrocycles and
1
3
2.1.2. Four-Component Homoself-Sorting Process be-
tween Two Macrocycles and Two Macrobicyclic Cages in
a [2 × 2] Constitutional Dynamic Network. Thereafter, we
investigated four-component self-sorting systems generating
four constituents, two macrocycles and two macrobicycles, and
forming [2 × 2] CDNs (Scheme 2).
8a-d
macrobicyclic cages,
a further step toward systems of
higher complexity resides in component self-sorting between
14
constituents of different cyclic orders, involving the side-by-
side formation of macrocyclic and macrobicyclic constituents.
In the present work, we investigated such self-sorting processes
1
by H NMR spectroscopy and HRMS in CDNs involving both
2
D macrocycles and 3D macrobicyclic cryptand-type cages,
Scheme 2. Four-Component Dynamic Self-Sorting in the
Competitive Generation of Two Macrocyclic and Two
Macrobicyclic Constituents
cogenerated in situ from their components, that display
kinetically vs thermodynamically adaptive features and kinetic
15
switching behavior.
. RESULTS AND DISCUSSION
.1. Self-Sorting Processes between Macrocycles and
2
2
Macrobicyclic Cages. 2.1.1. Three-Component Homoself-
Sorting Processes between Macrocycles and Macrobicyclic
Cages. We first considered self-sorting processes within sets of
three components between macrocycles and macrobicycles
based on reversible imine forming reactions. We proceeded to
investigate the competitive formation of macrocyclic and
macrobicyclic constituents from a mixture of 2,2′-oxybis-
(
ethylamine) (NON) and tris(2-aminoethyl)-amine (T) with
three different dialdehydes (Scheme 1a−c). To ensure
Scheme 1. Three-Component Dynamic Self-Sorting Systems
in Competitive Generation of Macrocyclic and
Macrobicyclic Constituents
The self-sorting within the four-component system (CDN-
1
) was studied for two shape distinct aldehydes (Py/BiPh), T
1
and NON in a 5:5:4:4 ratio (Scheme 2a). The H NMR
spectra revealed formation of four constituents, yielding a
composition of 12%, 47%, 32%, and 5% for BiPh T , Py T ,
3
2
3 2
15
BiPh (NON) , and Py (NON) , respectively, rather than
2
2
2
2
complex heteroleptic mixtures, thus maintaining a high-fidelity
self-sorting (Figures 1). One may consider Py to be more
reactive than BiPh and T more reactive than the less
nucleophilic NON, and its central nitrogen site might also
participate in proton transfer events. As a result, most of the Py
would be expected to selectively react with T to form cage
Py T . In line with the three-component systems above, the
3
2
macrobicyclic cages formed faster than their corresponding
macrocycles sharing the same dialdehyde unit despite the fact
that it requires more condensation reactions, six against four
equivalent formation of macrobicycles and macrocycles, a
1
5
:2:2 ratio of dialdehyde:T:NON was employed. The reactions
for the macrocycles. Furthermore, the H NMR spectra
1
were monitored by H NMR spectroscopy over time. The
spectra revealed the parallel formation of macrocyclic and
macrobicyclic species (Supporting Information Figures S17−
S22).
showed that the consumption of the Py component occurred
much faster than the appearance of the Py T product. This
3
2
behavior indicated the occurrence of an induction period with
multiple condensation reactions generating a number of
unidentified intermediates. Details can be seen in an amplified
Plotting component consumption and product formation
rates showed that in all cases the macrobicyclic cage formed
faster than its corresponding macrocycle sharing the same
dialdehyde unit despite the fact that it requires more
condensation reactions, six against four for the macrocycles.
1
version of the H NMR spectrum of Figure 1a after 5 min, as
well as in the corresponding high-resolution mass spectrum
(see Figures S23−S25 in SI).
Another case of a four-component system CDN-2,
containing pPh, BiPh, T, and NON, was studied in the same
1
H NMR spectra also revealed a fast initial consumption of the
1
Py component indicative of an induction period (see comment
conditions (Scheme 2b, H NMR monitoring, Figures S27 and
B
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1
Figure 1. (a) Evolution of the H NMR spectra (500 MHz, CDCl , 25 °C) of the reaction 5Py + 5BiPh + 4T+ 4NON ([Py] = [BiPh] = 3.6 mM;
3
0
0
[
T] = [NON] = 2.9 mM). Four bottom traces correspond to the isolated cage Py T , macrocycle Py (NON) , cage BiPh T , and macrocycle
0
0
3
2
2
2
3
2
1
BiPh (NON) . (b) H NMR monitoring of the time-dependent evolution of Py, BiPh, cage Py T , cage BiPh T , macrocycle Py (NON) , and
2
2
3
2
3
2
2
2
macrocycle BiPh (NON) in the course of the homoself-sorting process as a function of time over 5770 min. Half-time of consumption of Py and
2
2
F
BiPh is less than 5 and 600 min, respectively; sequence for half-time of formation t1/2 for the cages and macrocycles is Py T (75 min) >
Py (NON) (475 min) > BiPh T (900 min) > BiPh (NON) (1800 min). Percent calculated on the basis of the dialdehyde components (error
in H NMR signal integration 5%).
3
2
15
2
2
3
2
2
2
1
Figure 2. Network switching in CDN-3 (a) and CDN-4 (c) by component recomposition from the starting percent distribution of preformed
constituents (left square) to the final distribution (right square) over 10 days in the presence of 5 mol % (with respect to the dialdehyde
components) dimethylamine hydrochloride (DMA·HCl) as exchange catalyst. (a) CDN-3 starting with macrocycle Py (NON) (1.6 mM) and
2
2
cage BiPh T (1.1 mM). (c) CDN-4 starting with equivalent amounts (0.9 mM each) of preformed BiPh (NON) , Py (NON) , BiPh T , and
3
2
2
2
2
2
3 2
15
1
1
Py T . Percent calculated on the basis of the dialdehyde components (error in H NMR signal integration 5%). (b and d) H NMR monitoring
3
2
of the switching evolution displayed by CDN-3 and CDN-4, respectively, as a function of time over 10 days. Processes were observed up to 300
days where some decomposition of the constituents was taking place.
S28, and HRMS-ESI monitoring, Figures S29 and S30). In
macrobicyclic structures, we first considered a simple macro-
cycle-to-cage mutation reaction using a mixture of preformed
macrocycle BiPh (NON) and T in CDCl (Figures S31 and
comparison to CDN-1, CDN-2 gave about 20% of each
15
homoleptic macrocycle and about 28% of each macrobicycle.
.2. Component Recombination and Constitutional
2
2
3
2
S32). With time, NON in macrocycle BiPh (NON) was
2
2
Dynamic Network (CDN) Switching in the Self-Sorting
of Dynamic Macrocycles and Macrobicycles. To examine
the dynamic cross-talk between entities of macrocyclic and
replaced by T and thus resulted in formation of the
macrobicyclic cage BiPh T . This replacement experiment
3
2
C
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also indicated that the cage BiPh T was thermodynamically
components so as to optimize the self-sorting ability (e.g., one
with respect to two aromatic groups, e.g., Fur and BiPy); (ii)
dialdehydes of suitably different reactivities (e.g., activated by a
neighboring nitrogen site, as in BiPy); (iii) a lower
thermodynamic stability of the kinetically trapped species
formed. For instance in a [2 × 2] CDN consisting of four
constituents AB, AB′, A′B, and A′B′, if the diagonally located
constituents AB and A′B′ are produced initially as kinetic
products from a mixture of the four components A, B, A′, and
B′ then the orthogonal pair AB′ and A′B is expected to form
progressively as thermodynamic products in the course of
3
2
more stable than the macrocycle BiPh (NON) .
2
2
In a similar fashion, the dynamic nature of the imine bonds
provides the capacity to realize a cage-to-cage transformation
10a,b,11
by addition of another building block.
Such trans-
formation may also take place between preformed macrocycles
and macrobicyclic cages. To further explore this behavior in a
four-component self-sorting system, two [2 × 2] macrocycle−
macrobicycle constitutional dynamic networks (CDN-3 and
CDN-4) were designed from mixtures of separately prepared
macrobicycles and macrocycles in the presence of 5 mol %
dimethylamine hydrochloride as exchange catalyst (DMA·
HCl) and self-sorting under component recomposition was
investigated (Figure 2).
3
b,c
time.
Competition between macrobicyclic cages and
macrocycles was chosen because of the differences in cyclic
order of the compounds and in thermodynamic stabilities.
Three sets of self-sorting experiments were carried out
involving (a) a (three components generating two macro-
cycles) system with competition of the two aldehydes BiPy and
Fur (in a 2:2:2 molar ratio) for the diamine NON, (b) a (three
components generating two cages) system with competition of
the two dialdehydes BiPy and Fur (or mPh) for T (in a 3:3:2
molar ratio), and (c) a four constituent [2 × 2] CDN of two
macrocycles and two macrobicycles with competition of four
components, two aldehydes and the two amines NON and T.
2.3.2. Kinetic and Thermodynamic Features of a [2 × 1]
System of Three Components Generating Two Macrocycles.
A competitive self-sorting experiment generating two macro-
cycles was carried out on a DCL containing the aldehydes BiPy
and Fur together with the diamine NON in a 2:2:2 molar ratio
CDN-3, prepared initially from two agonist constituents,
having no common component, 50% of cage BiPh T and 50%
3
2
of macrocycle Py (NON) , acquired after 10 days a
2
2
composition of 6%, 41%, 41%, and 5% for BiPh T , Py T ,
3
2
3 2
BiPh (NON) , and Py (NON) , respectively, where the
2
2
2
2
agonist constituents cage Py T2 and macrocycle
3
BiPh (NON) have become the major products with a
2
2
switching of distribution to the orthogonal diagonal of the [2
2] CDN (Figure 2a). Since no released T or NON was
×
observed during this process, the cage and macrocycle had
broken up and recombined to the preferred structures
concomitantly by component exchange driven by formation
of the most stable cage Py T (Figures S44 and S45).
3
2
Confirmation that the formation of Py T was driving the
3
2
component recombination was obtained from a 3:3:2 mixture
in CDCl at 23 °C (Figure 3). BiPy decreased immediately
3
of BiPh, Py, and T which gave 94% Py T cage together with
3
2
1
% unreacted Py. In addition, 6% BiPh had been consumed,
but no cage BiPh T was detected, and several peaks of
unidentified intermediates were observed in the H NMR
spectrum (Figures S33 and S34).
3
2
1
CDN-4 consisting initially of 25% each of the four
preformed entities BiPh T , Py T , BiPh (NON) , and
3
2
3
2
2
2
Py (NON) (20% of each macrocycle and 30% of each
2
2
1
5
macrobicycle ) was set up to investigate component
redistribution among these four constituents in the same
conditions (Figure 2c). As in the case of CDN-3, CDN-4
underwent an evolution from the initial distribution to the
preferred self-sorted distribution along the same diagonal of
the square network (Figures S46 and S47).
CDN-5 (Figure S48, Scheme S4) was generated by addition
of 4/3 equiv of T into an equilibrium solution of NON (3.6
mM, 2 equiv), Py (3.6 mM, 2 equiv), and BiPh (3.6 mM, 2
equiv). First, Py reacted with NON to give Py (NON) (81%)
2
2
Figure 3. Structure and distribution of macrocycles BiPy (NON)
2 2
as the preferential macrocyclic product. No BiPh (NON) was
2
2
and Fur (NON) generated from a mixture of 2Fur + 2BiPy + 2NON
2 2
15
1
detected. The remainder of NON was contained in
intermediates which were not identified, and the solution
also contained 94% of free BiPh. Then, after addition of 4/3
(percent calculated on the basis of the components; error in H
NMR signal integration 5%).
equiv of T, the macrocycle Py (NON)2 transformed
after mixing, and after about 35 min, the compound
2
progressively into the cage Py T2 and the macrocycle
distribution was as follows: BiPy (10%), Fur (33%),
3
1
5
BiPh (NON) . As for the previous two CDNs, CDN-5
BiPy (NON)2 (40%), and Fur (NON)2 (<1%), the
2
2
2
2
displayed a similar conversion to the preferred self-sorted
distribution along the same diagonal.
remainder being unidentified intermediates. The reaction was
then left for 9 days: the concentration of BiPy (NON)2
2
2
.3. Constitutional Dynamic Network Switching from
decreased accompanied by a steady increase of Fur (NON)2
2
Kinetic to Thermodynamic Distributions of Self-Sorting
Dynamic Macrocycles and Macrobicycles. 2.3.1. Compo-
nent Selection. In order to successfully construct kinetically
switchable dynamic self-sorting systems of constituents, the
following parameters were considered for selecting the
components: (i) the shape difference between the aldehyde
and a release of BiPy, yielding a composition of BiPy (22%),
Fur (7%), BiPy (NON) (17%), and Fur (NON) (19%)
2
2
2
2
15
(Figures S35−S37).
To summarize, for the study of self-sorting between two
macrocycles generated from BiPy and Fur dialdehydes with
NON the most reactive dialdehyde BiPy first reacted with
D
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NON in a rather short time leading to formation of the kinetic
product BiPy (NON) (kinetic self-sorting). Thereafter, the
2
2
latter decreased and the Fur (NON) macrocycle was slowly
2
2
formed, indicating that it was the more stable macrocycle
thermodynamic self-sorting), although the reaction had not
(
yet reached its end. After about 9 days, the time during which
the reaction was followed, BiPy (NON) remained present.
2
2
2
.3.3. Kinetic and Thermodynamic Features of a [2 × 1]
System of Three Components Generating Two Macro-
bicyclic Cages. In order to investigate the selective self-sorting
on formation of macrobicyclic cages in a competitive reaction
environment, a set of experiments was carried out on libraries
containing BiPy together with one of two other aldehydes
(mPh or Fur) competing for T in a 3:3:2 ratio (Figures 4 and
Figure 5. Structure and distribution of macrobicyclic cages mPh T ,
3
2
BiPy T and Int[BiPy T ] generated from a mixture of 3mPh +
3
2
2 2
15
3
BiPy + 2T (percent calculated on the basis of the components;
error in H NMR signal integration 5%).
1
almost undetectable at this moment. The concentration of
BiPy then dropped to 13% after about 1 h. Meanwhile, the
concentration of cage BiPy T increased to its peak value of
3
2
2
2% together with 5% incomplete cage Int[BiPy T ]
2 2
1
(
identified by H NMR and HRMS, see Figures S15 and
S16). In contrast, the concentration of unreacted Fur
decreased smoothly to 26%, and only 1.5% formed cage
Fur T2 (1.5%). Interestingly, on further progress of the
3
reaction, the concentration of BiPy T2 decreased slowly
3
whereas the concentration of Fur T2 and free BiPy
3
progressively increased, indicating a transformation from
BiPy T to Fur T . After about 384 h (around 16 days) the
3
2
3 2
solution contained BiPy (42%), Fur (4%), BiPy T (3%), and
3
2
15
Fur T (48%); thus, Fur T became the major product. This
3
2
3 2
behavior is illustrated for the BiPy−Fur case in Figure 4.
In order to investigate the temperature effects, the same
1
experiments were performed at 40 °C. Integration of the H
NMR signals gave BiPy T2 (19%), Fur T2 (2%), 12%
3
3
unreacted BiPy, and 27% unreacted Fur after 1 h; after 12
days the distribution was 2% BiPy T , 46% Fur T , 38%
3
2
3 2
unreacted BiPy, and 5% unreacted Fur. As expected, a higher
temperature accelerated transformation from cage BiPy T to
3
2
1
Figure 4. Distribution (middle and bottom) H NMR monitoring of
the time-dependent evolution of a mixture of 3BiPy + 3Fur + 2T in
CDCl3 at 23 °C; [BiPy]0 = [Fur]0 = 3.6 mM (middle, percent
cage Fur T but did not increase the amount of BiPy T
3
2
3
2
(Figures S40 and S41).
Starting with a mixture of BiPy and mPh (3 equivalents
each) with T (2 equiv) at room temperature, BiPy was
consumed as soon as T was added into the solution. After 2 h,
the distribution was BiPy (7%), mPh (46%), BiPy T (30%),
15
1
calculated on the basis of the components; error in H NMR signal
integration 5%).
3
2
5
). In all three cases, fast selective formation of cage BiPy T
as well as Int[BiPy T ] species (6%), but no signals
corresponding to mPh T could be detected. After about 14
3 2
3
2
2 2
was observed at the beginning of the reaction; however, T also
exhibited a preference to transform into a thermodynamically
more stable cage containing monoaromatic bridges. For
days, the amounts of BiPy T , Int[BiPy T ], and mPh
3
2
2 2
decreased to 12%, 3%, and 32%, respectively, while those of
1
instance, in the case of BiPy/Fur/T, H NMR tracking (Figure
BiPy and mPh T increased to 27% and 22%, respectively. The
3
2
4
, Figures S38 and S39) revealed that after T was added into a
conversion from BiPy T to mPh T was very slow and was
still continuing even after about 14 days (Figure 5 and Figures
S42 and S43).
3 2 3 2
1
solution of BiPy and Fur mixtures, the H NMR signals of free
T immediately disappeared accompanied by a decrease of BiPy
and Fur signals. Integration of the CHO H NMR signals at
1
In summary, in all cases when BiPy was treated with T in the
presence of Fur or mPh, the reaction mixture contained
predominantly BiPy T at early times, indicating that it was
1
0.19 and 9.86 ppm, respectively, gave 31% of each free BiPy
and Fur, the remainder being in the form of unassigned
intermediates, while the cages BiPy T2 and Fur T2 were
3
2
the kinetic product (kinetic self-sorting), which thereafter
3
3
E
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slowly underwent component exchange toward generation of
the corresponding thermodynamic product (thermodynamic
self-sorting) with release of the dialdehyde component BiPy.
Fur (NON) (9%) together with BiPy T (13%), Fur T
2 2 3 2 3 2
(22%), and BiPy (NON) (20%). At the first two time points,
2
2
the largest fraction of the components was contained in
unidentified intermediates. Finally, after a much longer time,
18 days, a markedly cleaner distribution, probably close to
2
.3.4. Switching from Kinetic to Thermodynamic Dis-
tributions in a [2 × 2] CDN of Two Macrocycles and Two
Macrobicyclic Cages. On the basis of the results above, we
constructed a [2 × 2] CDN of four constituents, two
macrocycles and two macrobicyclic cages, generated from
two aldehydes and two amine components.
equilibrium, was reached containing BiPy
(47%), BiPy (NON) (35%), and Fur (NON)
2
T
(5%), Fur
T
3
2
3 2
(1%). A
2
2
2
minor amount, 12%, of the components was still present as
intermediates, probably on the way to form more of the
1
A CDN-6 containing the components BiPy, Fur, T, and
NON in a 5:5:4:4 molar ratio was first investigated. The
expected antagonist products cage BiPy T and macrocycle
macrobicycles at completion of the reaction (Figure 6, H
NMR monitoring, Figures S49−S51, see also for HRMS-ESI
monitoring, Figures S52 and S53). When 10 mol %
dimethylamine hydrochloride (DMA·HCl) was added as acid
catalyst to CDN-6, the BiPy, Fur, T, and NON (5:5:4:4 molar
ratio) mixture, the reaction was significantly faster, giving after
3
2
BiPy (NON) share the same dialdehyde BiPy, while cage
2
2
Fur T and macrocycle Fur (NON) share the dialdehyde Fur
3
2
2
2
(Figure 6).
5
.5 days a distribution of 4%/42%/34%/1%/7%/1% of
BiPy T /Fur T /BiPy (NON) /Fur (NON) /BiPy/Fur
3
2
3
2
2
2
2
2
with again about 11% unidentified intermediates (Figures S54
and S55).
Altogether, in the course of the process, BiPy T formed
3
2
rapidly and then decreased progressively while Fur T and
3
2
BiPy (NON) increased concomitantly, indicating an evolu-
2
2
tion switching from an initial incomplete kinetic distribution
2g,3c
network
in which the fast formed BiPy T dominates to a
3 2
thermodynamically preferred distribution with amplification of
the agonistic constituents Fur T and BiPy (NON) . The
3
2
2
2
process amounts to an orthogonal switching from one diagonal
to the other of the square network.
This evolution was confirmed by the behavior of CDN-7
starting with a mixture of two agonist constituents having no
common component, the cage BiPy T and the macrocycle
3
2
Fur (NON) . After 10 days, it acquired a composition of 3%,
2
2
4
5%, 47%, and 3% for BiPy T , Fur T , BiPy (NON) , and
3 2 3 2 2 2
Fur (NON) , respectively, where the agonist constituents
2
2
macrobicyclic cage Fur T and macrocycle BiPy (NON) have
3
2
2
2
become the major products with a switch of the distribution to
the orthogonal diagonal of the [2 × 2] CDN (Figure 7 and
Figures S56 and S57).
3. CONCLUSIONS
The evolution of imine-based dynamic covalent libraries and
the corresponding self-sorting processes were monitored for
the side-by-side formation of two representative architectures
Figure 6. (a) Component distribution in CDN-6 showing the
orthogonal switching from a kinetic to a thermodynamic distribution
14
of different cyclic order, macrocycles and macrobicyclic
1
of constituents over 18 days. (b) H NMR monitoring of the time-
cages. The results suggest the initial formation of a range of
intermediates which then evolved toward the final macrocyclic
and macrobicyclic constituents by component exchange.
The study of several constitutional dynamic networks
revealed a kinetic evolution amounting to a switching process
between two distributions in response to the specific kinetic
and thermodynamic features of the network constituents. It
suggested a similar dual-stage process for the different CDNs:
(i) an initial kinetic selectivity leading to an incomplete
network of constituents (containing also dynamic intermedi-
ates); (ii) followed by a thermodynamically driven switching
process from this kinetic distribution to a thermodynamic one.
In general terms, the diverse kinetic and thermodynamic
features of the dynamic system drive a redistribution of all
interconnected constituents by component exchange, thus
illustrating the regulation and self-correction ability of
constitutional dynamic networks. They pave the way toward
extension to DCLs involving more components and to CDNs
of higher order and complexity.
dependent evolution of macrocycle BiPy (NON) and macrobicycle
2
2
Fur T with orthogonal switching of constituents from a mixture of
3
2
5
BiPy + 5Fur + 4T + 4NON in CDCl at 25 °C. (Insert) Spread out
3
of the initial time period. [BiPy]0 = [Fur] = 3.6 mM (percent
calculated on the basis of components; error in H NMR signal
integration 5%).
0
15
1
After 2.5 h, a complex mixture was obtained: the dominant
product BiPy T reached its maximum amount of about 16%
3
2
together with 6% incomplete cage Int[BiPy T ]. There is only
2
2
a very small amount of its agonist Fur (NON)2 (2%)
2
accompanied however by 13% unreacted Fur. Small amounts
of the other two products Fur T and BiPy (NON) were
3
2
2
2
formed, 4% and 9%, respectively, with remaining unreacted
BiPy (2%). After 15 h, free BiPy had disappeared and the
identified compounds were BiPy T (14%), Fur T (14%),
3
2
3 2
BiPy (NON) (17%), and Fur (NON) (8%) as well as some
2
2
2
2
free Fur (2%). After 36 h, the composition of the mixture was
F
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Article
ACKNOWLEDGMENTS
■
The authors thank the ERC (Advanced Research Grant
SUPRADAPT 290585), the ANR Grant DYNAFUN, as well
as the University of Strasbourg Institute for Advanced Study
(
USIAS) for financial support. This work was also supported
by the NSFC (National Natural Science Foundation of China,
1720102007) and the Lehn International Collaboration
2
Center of Functional Materials, the International Science and
Technology Collaboration Center of Guangdong Province
(
2019A050505004). Z.Z.Y. thanks the International Program
for Ph.D. Candidates, Sun Yat-Sen University (02300-
1145400), and the CSC (China Scholarship Council) for
3
doctoral fellowships. Z.Z.Y. also thanks Dr. Jean-Louis Schmitt
and Cyril Antheaume for helpful discussion of NMR and
HRMS data. He also thanks Prof. Jack Harrowfield, Dr. Artem
Osypenko, Dr. Youssef Atoini, Dr. Jean-Francois Ayme, Michał
Kołodziejski, and Meixia He at ISIS in Strasbourg as well as
Prof. Mei Pan and Prof. Ji-Jun Jiang at the Lehn Institute of
Functional Materials, Sun Yat-Sen University, for extensive
helpful discussions.
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Figure 7. (a) Network switching in CDN-7 by component
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50%) and cage BiPy T2 (50%) to (right) the final distribution
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ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c07131.
■
*
Experimental details, synthetic procedures, character-
ization of compounds, NMR spectra, and time-depend-
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AUTHOR INFORMATION
Corresponding Author
Jean-Marie Lehn − Lehn Institute of Functional Materials,
MOE Laboratory of Bioinorganic and Synthetic Chemistry,
School of Chemistry, Sun Yat-Sen University, Guangzhou
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Institut de Science et d’Ingenierie Supramoleculaires (ISIS),
Universite de Strasbourg, Strasbourg 67000, France;
orcid.org/0000-0001-8981-4593; Email: lehn@unistra.fr
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Zhaozheng Yang − Lehn Institute of Functional Materials,
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10275, China; Laboratoire de Chimie Supramolec
Institut de Science et d’Ingenierie Supramoleculaires (ISIS),
Universite de Strasbourg, Strasbourg 67000, France
́
ulaire,
́
́
́
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c07131
Notes
The authors declare no competing financial interest.
G
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15) The present work involves macrocyclic and macrobicyclic
compounds as well as nonnegligible intermediates which incorporate
different numbers of aldehyde components, 2 and 3, respectively, for
the macrocycles and macrobicycles. As a consequence, analysis of the
composition of mixtures in terms of molecular percentage of
constituents would be difficult. Thus, for convenient analysis, in this
paper, all of the compositions are presented on the basis of the
percentages of the dialdehyde components
(component %).
Consequently, the corresponding percent of the actual compounds
themselves is 1/2 and 1/3 of these percent values of components for
the macrocycles and the macrobicycles, respectively. The correspond-
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ease of comparison..
I
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