Metal Ion-Driven Constitutional Adaptation in Dynamic Covalent C=C/C=N Organo-Metathesis

Article abstract of DOI:10.1002/asia.202001001

Knoevenagel barbiturate derivatives and imines are able to undergo efficient component recombination through dynamic covalent C=C/C=N organo-metathesis in absence of a catalyst. A [2×2] dynamic covalent library (DCL) containing two Knoevenagel derivatives Kn1 and Kn2 and two imines A1 and A2 has been established and its adaptive features in response to the addition of metal cations have been investigated. Addition of Cu(I) triflate as an effector, induces fast and remarkable constitutional selection of the DCL towards amplification of the Cu(I)-A2 complex and its agonist Kn1. This adaptation process could be reversed by addition of neocuproine as a competitive Cu(I) ligand. Furthermore, separate addition of five other metal cations as input agents, i. e. Ag(I), Fe(II), Zn(II), Cu(II) and Li(I), led to the generation of cation-specific distribution patterns as outputs, showing the ability of the present DCL to recognize different effectors.

Full text of DOI:10.1002/asia.202001001

DOI: 10.1002/asia.202001001
Full Paper
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Metal Ion-Driven Constitutional Adaptation in Dynamic Covalent
C=C/C=N Organo-Metathesis
Ruirui Gu[a, b] and Jean-Marie Lehn*[a, b]
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Abstract: Knoevenagel barbiturate derivatives and imines are
able to undergo efficient component recombination through
dynamic covalent C=C/C=N organo-metathesis in absence of
a catalyst. A [2×2] dynamic covalent library (DCL) containing
two Knoevenagel derivatives Kn1 and Kn2 and two imines
A1 and A2 has been established and its adaptive features in
response to the addition of metal cations have been
investigated. Addition of Cu(I) triflate as an effector, induces
fast and remarkable constitutional selection of the DCL
towards amplification of the Cu(I)-A2 complex and its agonist
Kn1. This adaptation process could be reversed by addition
of neocuproine as a competitive Cu(I) ligand. Furthermore,
separate addition of five other metal cations as input agents,
i.e. Ag(I), Fe(II), Zn(II), Cu(II) and Li(I), led to the generation of
cation-specific distribution patterns as outputs, showing the
ability of the present DCL to recognize different effectors.
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Introduction
constituents consisting of the starting compounds Kn+A and
the exchange products Kn’+A’ (Scheme 1). We have shown
that the reaction involves an associative mechanism of organo-
metathesis type through the formation and the cleavage of a
four-membered azetidine intermediate I.[30,31] The reaction rate
and the equilibrium position are influenced by several parame-
ters, such as the conjugation within the Knoevenagel com-
pounds, nucleophilicity of the imine nitrogen, steric hindrance
and solvent polarity.[30,31] The equilibrium state of a DCL, namely
of C=C/C=N type, can in principle be perturbed by physical
stimuli, such as the formation of an organized phase.[10]
Herein, we report on the adaptive response of a [2×2] DCL,
based on dynamic covalent C=C/C=N metathesis, and of its
associated CDN to a set of metal ion effectors. The present DCL
involves the four-constituents equilibrium mixture generated
from either Kn1+A1 or Kn2+A2 and undergoes reversible
constitutional selection by adaptation to the modification of
the chemical environment caused by addition of metal cations
leading to the formation of [M-A2] complexes (Scheme 2a).
Constitutional dynamic libraries (CDLs) are dynamic systems
based on dynamic covalent or non-covalent bonds, containing
multiple constituents that may undergo constitutional variation
by the exchange of their components in response to a physical
stimulus or to a chemical effector.[1] Dynamic covalent chemistry
(DCC) has attracted great interest and experienced a rapid
growth.[1–7] The CDLs may be represented in the form of
constitutional dynamic networks (CDNs), where antagonistic
and agonistic relationships between constituents are linked by
edges and diagonals respectively. Numerous CDNs have been
established, from [2×2] squares[8–13] to [2×3] or [3×3] 2D
networks[14] and further to systems displaying even greater
complexity such as a higher order [5×5] network[15] or biphasic
{[2×2]/[2×2]} networks represented as a 3D square prism.[15,16]
Representative reversible covalent reactions involved in the
generation of dynamic covalent libraries (DCLs) include amine/
carbonyl condensations,[13–21] disulfide exchange,[22–24] peptide
exchange,[25]
olefin
metathesis,[26]
and
Diels-Alder
condensation.[27–29]
We have recently described, mechanistically analyzed and Results and Discussion
investigated,[10,30,31] the dynamic covalent C=C/C=N organo-
metathesis between a Knoevenagel derivative and an imine.
The reversible process can be implemented to generate DCLs at
room temperature and investigate the adaptation of the
corresponding CDNs in response to different effectors. Thus,
mixing a Knoevenagel derivative Kn of N,N’-dimethyl barbituric
acid with an imine A produces C=C/C=N DCLs of four
Design of a metal ion responsive Knoevenagel/imine DCL. All the
constituents presented here were separately synthesized using
commercially accessible compounds. The condensation of
aromatic aldehydes with N,N’-dimethyl barbituric acid produced
the Knoevenagel compounds Kn1 and Kn2, while condensation
of aromatic aldehydes and benzylamine gave the aldimines A1
and A2 (see all the synthetic details in SI).
[a] Dr. R. Gu, Prof. Dr. J.-M. Lehn
School of Chemistry, Sun Yat-Sen University
Lehn Institute of Functional Materials
Guangzhou 510275 (P. R. China)
[b] Dr. R. Gu, Prof. Dr. J.-M. Lehn
Université de Strasbourg
Laboratoire de Chimie Supramoléculaire
Institut de Science et d’Ingénierie Supramoléculaires (ISIS)
8 allée Gaspard Monge, 67000 Strasbourg (France)
Scheme 1. Associative mechanism of dynamic covalent C=C/C=N organo-
metathesis between a Knoevenagel derivative and an imine.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202001001
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Figure 1. 1H NMR (500 MHz, 298 K, CD3CN) spectra of: a) equilibrated state
(27% Kn1, 29% A1, 22% Kn2, 22% A2), 4 hours after mixing Kn1 and A1; b)
metal ion selected state (8% Kn1, 9% A1, 42% Kn2, 40% [Cu(A2)2]+), 10
minutes after addition of 0.5 eq. Cu(I); c) re-equilibrated state (27% Kn1,
29% A1, 22% Kn2, 22% A2), 5.5 hours after addition of 1 eq. neocuproine.
See Scheme 2 for the symbols of the compounds.
materials) Cu(I) triflate (CuOTf) in CD3CN, to the previous DCL,
the reaction solution turned immediately dark red (less than
1
10 sec). The H NMR spectrum measured 10 minutes later (see
Figure 1b) demonstrated that the vinyl and methylene protons
of A2 had undergone a change in chemical shifts from 9.80 to
8.81 ppm and from 4.95 to 4.58 ppm, respectively, together
with an increase in intensity, suggesting the formation of a Cu(I)
complex (see Figure S1 for the characterization data of the
separately prepared Cu(I) complex [Cu(A2)2](OTf)). Simultane-
ously, the N-methyl signals of Kn2 were up-regulated. On the
contrary, the peaks of Kn1 and A1 decreased in intensity. The
distribution of the DCL obtained at this moment was 8% Kn1,
9% A1, 42% Kn2 and 40% A2, the latter being present as its
complex [Cu(A2)2]+. The DCL had thus undergone a remarkable
Scheme 2. a) Investigated C=C/C=N metathesis reaction between Knoeve-
nagel compounds and imines. b) Graphical representation of the metallo-
selection response of the square [2×2] CDN to the addition of 0.5 eq. of Cu
(I) triflate. (À ) and (+) indicate respectively an antagonistic and an agonistic
relationship between constituents. c) Columnar charts of the distributions of
the four constituents at different states (from left to right): initial equilibrium
state, 10 min after the addition of 0.5 eq. Cu(I) triflate and 30 min, 150 min,
330 min after the addition of 1 eq. neocuproine. Hydrolysis products <3%.
The % of the constituents have been obtained from the integration of the
signals in the 1H NMR spectra; error of about 1% (see also SI).
shift in equilibrium state with
a reorganization of the
Because of the formation of a stable charge-separated
pyridinium-barbituric acid zwitterion,[32] the Knoevenagel con-
densation product of 2-pyridinecarboxaldehyde could neither
be synthesized nor be produced as an exchange product of the
C=C/C=N metathesis.[33] Therefore, various potential metal ion
binding aldehyde components were explored. It was found that
quinoline-8-carbaldehyde would be suitable for our purposes.
The corresponding Knoevenagel compound Kn1 could be
isolated and was found to be stable in the conditions of the
metathesis reaction, while the corresponding imine A2 has the
ability of binding metal ions.
corresponding CDN. This result was confirmed separately by a
progressive titration of the equilibrated initial library with Cu(I)
triflate, which indicated a 2:1 metal:ligand stoichiometry (see
Figure S3a for the 1H NMR spectra obtained on stepwise
addition of 0.1 eq. of Cu(I) salt). Such stoichiometry of the Cu(I)-
A2 complex was also confirmed by titration of the ligand A2
alone with Cu(I) triflate (Figure S3b).
°
The standard Gibbs free energy difference (ΔG ) of the
present metathesis reaction at equilibrium (T=298 K) was
calculated following equation (1) in SI. The free energy corre-
sponding to the equilibrium before and after the addition of Cu
(I) triflate was respectively 0.3 kcal/mol and À 1.9 kcal/mol, thus
the driving force for the change in equilibrium induced by the
cation complexation amounts to 2.2 kcal/mol.
Equimolar CD3CN solutions of Kn1 and A1 (10 mM each)
were mixed at room temperature. The reaction solution reached
1
equilibrium state after 4 hours. The 500 MHz H NMR spectrum
(Figure 1a) showed a closely statistical mixture of the expected
four constituents Kn1, A1, Kn2 and A2, respectively 27%, 29%,
22%, 22% (see Figure S2 for the spectrum and the comparison
with each separately prepared compound). The slight imbal-
ance of about 5–7%, amounting to a free energy difference of
less than 0.3 kcal/mol (see below) may be attributed to relative
structural factors that are difficult to assign but illustrate the
sensitivity of the system to small perturbations.
Such a metallo-selected state could be reversed on removal
of the Cu(I) cation from the [Cu(A2)2]+ complex by addition into
the reaction mixture of 2 eq. (with respect to Cu(I) ions)
neocuproine, acting as a strong chelator of Cu(I).[34] The
subsequent dark red-to-orange colour variation in twenty
seconds indicated the formation of a Cu(I)-neocuproine com-
plex, as confirmed by comparison of the 1H NMR spectrum with
that of separately prepared [Cu(I)(neocuproine)2] triflate com-
plex (Figure S4, see also Figure 2d for the Cu(I)-neocuproine
complex). Upon the simultaneous release of A2, the reaction
Response of the DCL to perturbation by Cu(I) binding. Upon
addition of 0.5 eq. (with respect to the amount of starting
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mixture started a re-equilibration process at room temperature.
After 5.5 hours, the statistical distribution of 27/29/22/22% for
Kn1/A1/Kn2/A2 was obtained (Figure 1c), indicating a full recall
of the initial equilibrium state presented in Figure 1a (see
spectra of the initial equilibria and the five metal ion-driven
DCLs). The distributions of the constituents and the calculated
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°
standard Gibbs free energy ΔG in the equilibrium states before
and after the addition of the metal ions, are shown in Figure 3
(the yellow columns show the amount of hydrolysis products,
consisting of the two aldehydes quinoline-8-carbaldehyde and
4-methoxybenzaldehyde). Among them, Ag(I) gave a slight shift
of the equilibrium, while Fe(II) and Zn(II) triggered larger shifts,
revealing their stronger ability to bind the dynamic ligand A2.
For Cu(II), the integrals of Cu(II)-A2 complex could not be
precisely obtained due to the strong broadening of all peaks,
however the decrease of the compounds Kn1 and A1, and the
amplification of Kn2 gave evidence for the shift in equilibrium.
The addition of Li(I) led only to a small amount of hydrolysis
indicating that its binding was too weak to be effective.
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Figure S5 for the H NMR spectra of the re-equilibrium process,
recorded every 1 h). To confirm the stronger complexation
ability of neocuproine towards Cu(I) cations in competition with
A2, 0.5 eq. CuOTf was added into a mixture of neocuproine and
A2 (1 eq. each). The resulting 1H NMR spectrum (Figure 2e)
showed a two-constituent mixture of the 1:2 Cu(I)-neocuproine
complex and free A2 (see Figure 2b for the separately prepared
[Cu(A2)2]+ complex and Figure 2a for A2 alone). As expected,
the same mixture was obtained when 1 eq. neocuproine was
added into separately prepared 1 eq. [Cu(A2)2]+ complex (Fig-
ure 2f). These two competition reactions both demonstrate that
neocuproine presents much stronger binding ability towards Cu
(I) than the imine A2. In addition, one notes that whereas on
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To test the effect of increasing the complexity of the system,
0.25 eq. Ag(I) and 0.25 eq. Cu(I) were mixed and injected into
the initially equilibrated DCL. A mixture of 17% Kn1, 18% A1,
33% Kn2 and 32% M-A2 complex was obtained, which is a
distribution intermediate between those of the two DCLs
separately driven by 0.5 eq. Cu(I) (8%, 9%, 42%, 40%) and
1
titration of neocuproine with Cu(I), the H NMR spectra display
the peaks of both the free ligand and the complex (Figure S3c),
in the case of A2 the ligand signals shift progressively from
those of the free ligand to those of the complex (Figure S3b).
These different behaviors indicate that ligand exchange is slow
in the first case and fast in the second one, a further
confirmation that the neocuproine complex is much stronger
than the Cu(I)-A2 complex. Thus, both these thermodynamic
and kinetic features demonstrate that neocuproine is a suitable
reagent for driving the backward process of the Cu(I) driven
constitutional adaptation.
1
0.5 eq. Ag(I) (23%, 22%, 26%, 27%) (see Figure S6b for the H
NMR spectra after separate addition of 0.5 eq. Ag(I), 0.25 eq Ag
(I)+0.25 eq Cu(I) and 0.5 eq. Cu(I)). These results indicate that
Cu(I) is a much better driver of the system than Ag(I) and
dominates the equilibrium shift.
The fingerprint-like outputs caused by the different binding
ability of the metal ions to the ligand A2, have the potential to
discriminate between different effectors, indicating that the
information about the identity of the metal cations operating
Generation of specific dynamic DCL distribution patterns in
response to different metal cations. Besides Cu(I), some other
metal ions were also tested for their effect on the constituent
distributions in the present DCL. To this end, a 2.5 mL CD3CN
solution of the DCL was prepared and, after reaching thermody-
namic equilibrium, was distributed equally into five NMR tubes.
Then to the tubes was added separately 0.5 eq. CD3CN stock
solution of the different triflate salts of Ag(I), Fe(II), Zn(II), Cu(II)
1
and Li(I) tetrafluoroborate. The H NMR spectra were followed
until the equilibrium was reached (see Figure S6a for the
Figure 3. Dynamic constitutional distribution patterns and table of their
normalized integrals (the integral of Cu(II)-A2 was considered as correspond-
ing to that of its agonist Kn2) at the equilibrium state and after the addition
of five different metal ions (from left to right). Every reaction was repeated
Figure 2. 1H NMR (500 MHz, 298 K, CD3CN) spectra of: a) A2; b) [Cu(A2)2]+
complex; c) neocuproine; d) Cu(I)-neocuproine complex; e) reaction mixture
10 min after adding 0.5 eq. Cu(I) triflate into 1 eq. A2 and 1 eq. neocuproine;
f) reaction mixture 10 min after adding 1 eq. neocuproine into 1 eq.
serparately prepared [Cu(A2)2]+ complex.
°
three times. The corresponding standard Gibbs free energies ΔG (T=298 K)
are shown on the bottom. The % of the constituents have been obtained
from the integration of the signals in the 1H NMR spectra; error of about 1%
(see also SI).
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on the DCL and its CDN was expressed in the form of a dynamic
distribution pattern of the four constituents. These results
represent a further demonstration of the adaptive behavior of
constitutional dynamic libraries and networks undergoing
specific changes in constituent distribution in response to
different effectors, here metal cations, as also displayed by
dynamic polymers[35] as well as by two-phase systems.[15]
Compared with earlier studies involving transamination-based
DCLs,[14,17] the present DCL bears the advantages of better metal
ion-responsiveness (42% bias, with respect to 20%[14] and
solutions subjected to the effect of Fe(II), Zn(II) and Cu(II)
(Figure 4d–f), the appearance of the peaks respectively at
328 nm, 326 nm and 325 nm suggested the formation of metal
complexes with A2 as also confirmed by the curves of M-A2
complexes (solid violet) red-shifted from A2 (dash violet) after
adding 0.5 eq. corresponding metal triflates. Moreover, the
absorptions at 266 nm were also reduced due to the decrease
of A1. For the DCL affected by Ag(I) (Figure 4c), only a minor
variation was observed, while addition of Li(I) caused almost no
change of the DCL (Figure S7). All the mentioned UV-vis results,
in line with the NMR data, show different constitutional
adaptation of the present DCL to different metal ion effectors.
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28%[17]), faster kinetics (5 h at r.t., with respect to hours at 60 C)
°
and catalyst-free reaction conditions. While compared with
another C=C/C=N metathesis-based DCL where the driving
force was gel formation,[10] the present DCL not only possesses
better stimuli-responsiveness (42% bias with respect to 28%), Conclusion
but also yields characteristic distributions in response to differ-
ent metal ion effectors.
In conclusion, we have designed and exploited a [2×2] DCL
The constitutional variations of the DCL separately driven by
addition of different metal cations were also investigated by
UV-vis spectroscopy. The absorption spectrum of the equili-
brated DCL (pink dashed lines in Figure 4b–f) showed simple
stacking of the spectra of the four expected constituents
(Figure 4a). After adding 0.5 eq. Cu(I) triflate (Figure 4b), a new
peak at 520 nm showed up due to the formation of the Cu(I)-A2
complex as confirmed by observation of the same peak after
mixing 0.5 eq. CuOTf with A2 alone (solid violet curve in
Figure 4b). Simultaneously, the absorption at 266 nm was
drastically reduced, indicating the decrease of A1. For the DCL
generated by the dynamic covalent C=C/C=N organo-meta-
thesis of Knoevenagel derivatives and imines. Up-regulation of
the two constituents Kn2 and A2 was induced by the addition
of Cu(I) triflate through the formation of [Cu(A2)2]+ complex
and was shown to be reversible on addition of neocuproine as
competitive ligand. On the other hand, different dynamic
distribution patterns of the present DCL were generated by
separate addition of respectively four metal cation effectors, i.e.
Ag(I), Fe(II), Zn(II) and Cu(II) indicating the ability of DCLs to
discriminate between different effectors and provide informa-
tion about the identity of a given effector. Such a feature
stresses the significance of effector-sensitive distribution pat-
terns as another dimension of dynamic chemical systems.
Acknowledgements
We thank Dr. Jean-Louis Schmitt for discussions of the NMR and
Mass spectral data and Dr. Karolina Flidrova for preliminary work.
We also thank the ERC (Advanced Research Grant SUPRADAPT
°
290585), the ANR DYNAFUN grant N ANR-15-CE29-0009-01 and
the University of Strasbourg Institute for Advanced Study (USIAS)
for financial support. RRG gratefully acknowledges a doctoral
scholarship from the China Scholarship Council, a post-doctoral
fellowship from Sun-Yat Sen University as well as financial support
from China Post-doctoral Science Foundation.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: dynamic covalent libraries
· dynamic covalent
reactions · constitutional adaptation · metal ion coordination ·
constitutional dynamic networks
Figure 4. UV-vis spectra of 0.5 mM CH3CN solutions of: a) the four
constituents Kn1, A1, Kn2 and A2 (measured separately); A2 (violet) and the
DCL (pink) before (dash) and after (solid) the addition of b) Cu(I), c) Ag(I), d)
Fe(II), e) Zn(II) and f) Cu(II). All the samples were diluted 20 times from
10 mM solutions and placed in 1 mm quartz cuvettes before UV-vis
measurements.
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Manuscript received: August 24, 2020
Revised manuscript received: October 21, 2020
Version of record online: ■■■, ■■■■
Chem Asian J. 2020, 15, 1–6
www.chemasianj.org
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Full Paper
FULL PAPER
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A specially designed four-member
dynamic covalent library (DCL) based
on C=C/C=N organo-metathesis
responds to the addition of Cu(I)
triflate by constitutional selection,
which could be reversed by addition
of neocuproine. Furthermore, cation-
specific dynamic constitutional distri-
bution patterns of the DCL were
generated on addition of different
metal salts.
Dr. R. Gu, Prof. Dr. J.-M. Lehn*
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Metal Ion-Driven Constitutional
Adaptation in Dynamic Covalent
C=C/C=N Organo-Metathesis
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